Phosphonoacetate esters derived taxane, pharmaceutical composition, methods of inhibiting

 

(57) Abstract:

Proposed phosphonoacetate esters derived taxane General formula

T-[OCH2(OCH2)mOP(O)(OH)2]n,

where T represents taxonomy part that lays on C13the carbon atom substituted 3-amino-2-hydroxypropanoate;

m=0 or 1;

n=1,2,

or its pharmaceutically acceptable salt. Diprosone baccatin formula D

13-OH-txn-[OCH2(OCH2)mSCH3]n,

where txn is taxanomy part; or C13the metal alkoxide. Diprosone taxane formulas IN T1-[OCH2(OCH2)mSCH3]nwhere T1is a T, which periactine hydroxy-group are blocked.

Ester derivatives phosphonoacetate esters derived taxane formula T'-[OCH2(OCH2)mOP(O)(OR7)2]nwhere T1, m, n are defined above;

R7is phosphonothioic group.

Pharmaceutical composition having inhibitory by poolactivate, methods of inhibiting tumor growth in a mammal host. 7 C. and 74 C.p. f-crystals, 6 PL.

This sawka 1993, which is a partial continuation of application reg. N USA 08/108015, filed August 17, 1993, and in turn, which is a partial continuation of the application from the reg. N USA 07/996455, filed December 24, 1992, and now abandonians. Bid with reg. N 08/154840, in its entirety, is introduced into the present description by reference.

The present invention relates to antitumor compounds. In particular, the present invention relates to new derivatives taxane; to pharmaceutical compositions containing these derivatives, and to their use as anticancer agents.

Taxol(paclitaxel) is a natural product extracted from the bark of the Pacific yew tree (Taxus brevifolia). It was found that this product has excellent anti-tumor activity in in vivo models, and in later studies revealed that the compound has a unique mechanism of action that is abnormal polymerization of tubulin and the cessation of mitosis. Recently, this tool has been tested for the treatment of ovarian cancer; and testing for activity against breast cancer, colon and lungs gave promising results is of Antimicrotubule Agents in Cancer Chemotherapentics", Pharmac, Ther., 52: 35-84, 1991.

Recently, it was also discovered that a semisynthetic analogue of paclitaxel, called Taxotereit has good antitumor activity in in vivo models. Currently, Taxoterealso being tested in clinics in Europe and the USA. Below are the structures of paclitaxel and Taxotere, which gives a standard numbering system in the molecule of paclitaxel.

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One of the drawbacks of paclitaxel is its very limited solubility, and therefore for the manufacture of medicines containing paclitaxel, it is necessary to use anhydrous pharmaceutical carriers. This carrier is often used in such cases Cremophor Eh., which in itself has undesirable side effects when administered to man. In line with this, there was some research in order to obtain water-soluble derivatives of paclitaxel, which are disclosed in the following activities.

(a) Haugwitz and others, U.S. patent N 4942184;

(b) Kingston and others, U.S. patent N 5059699;

(c) Stella and others, U.S. patent N 4960790;

(d) Application for Europatent 0558959 AI, published September 8, 1993

(e) Vyas and others , Bioorganic 2 Medicinal Chemistry phosphonoacetate ethers derived taxane and their pharmaceutically acceptable salts. The solubility of these salts facilitates the manufacture of pharmaceutical compositions.

Brief description of the invention

The present invention relates to a derivative taxane having the formula (A):

T - [OCH2(OCH2)mOP(O)(OH)2]n(A)

where T represents taxonomy part, bearing C13-carbon atom substituted 3-amino-2-hydroxypropanoate-group;

n = 1,2 or 3;

m = 0 or an integer from 1 to 6, inclusive;

or their pharmaceutically acceptable salts.

Another variant of the present invention relates to a derivative taxane having the formula (B):

T' - [OCH2(OCH2)mSCH3]n(B)

where T is a T, which is non-reactive hydroxy-group were blocked;

m and n are as defined in formula (A).

In another embodiment, the present invention relates to intermediate compounds having the formula (C):

T'-[OCH2(OCH2)mOP(O)(ORy)2]n< / BR>
where T', m and n are as defined in formula (A);

Ryis phosphonothioic group.

In the following embodiment, the present invention is defined above;

txn is taxanomy part;

or C13the metal alkoxides.

In yet another embodiment, the present invention relates to a method of inhibiting tumor growth in mammals, namely, that the specified mammal host is administered an effective tumor-inhibiting amount of the compounds of formula (A).

In another embodiment, the present invention relates to a method of inhibiting tumor growth in mammals, namely, that the specified mammal is administered an effective tumor-inhibiting amount of the compounds of formula (B'):

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where R1b'is a hydroxy-group, -OCO(O)Rxor-OC(O)ORx;

R3b'is hydrogen, hydroxy-group, -OC(O)ORxC1-6-alkyloxy, or-OC(O)Rx;

one of R6b'or R7b'is hydrogen and the other is a hydroxy-group or C1-6-alkanoyloxy; or R6b'and R7b'together form oxoprop;

R4and R5independently represents a C1-6-alkyl, C2-6alkenyl; C2-6-quinil, or-Z-R6;

Z is a direct bond, C1-6-alkyl or C2-6-alkenyl;

R6is aryl/SUB>-alkyl optionally substituted by 1-6 halogen atoms that can be the same or different, C3-6-cycloalkyl, C2-6-alkenyl, or hydroxy-group; or is a radical of the formula:

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where D is a bond or C1-6-alkyl;

Ra, Rband Rcindependently represent hydrogen, amino, C1-6-alkylamino, di-C1-6-alkylamino, halogen, C1-6-alkyl or C1-6-alkoxy.

Finally, in yet another embodiment, the present invention relates to a pharmaceutical composition which comprises an effective tumor-inhibiting amount of the compounds of formula (B) or (A), and a pharmaceutically acceptable carrier.

If this is not explicitly stated, the terms used in this application have the following meanings. "Alkyl" means a straight or branched saturated carbon chain having from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, isobutyl, so-butyl, n-pentyl, Deut. pencil, isopentyl, and n-hexyl. "Alkenyl" means a straight or branched carbon chain having at least one carbon-carbon double bond, and having from 2 to 6 carbon atoms; for example the extensive carbon chain having at least one carbon-carbon triple bond, and from two to six carbon atoms, for example, ethinyl, PROPYNYL, butynyl, and hexenyl.

"Aryl" means an aromatic hydrocarbon having from 6 to 10 carbon atoms, such as phenyl or naphthyl. "Substituted aryl" means aryl substituted with at least one group selected from C1-6-alkanoyloxy, hydroxy, halogen, C1-6-alkyl, trifloromethyl, C1-6-alkoxy, aryl, C2-6-alkenyl, C1-6alkanoyl, nitro, amino, and amido. "Halogen" means fluorine, chlorine, bromine and iodine.

"Phosphono-" means the group-P(O)(OH)2and "phosphonoacetate" or "phosphonoacetate ether", in General, indicates a group-OCH2(OCH2)mOP(O)(OH)2. "(Methylthio)-thiocarbonyl" means the group-C(S)SCH3. "Methylthiomethyl" (also abbreviated label MTM), mainly refers to the group-CH2SCH3.

"Takanawa part" (also abbreviated denoted txn) means the part containing the main frame of the molecule taxane having 20 carbon atoms, and the following structural formula with absolute configuration

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The numbering system presented above is the standard system of the character CI refers to the carbon atom, marked "1"; C5-C20-oxetan means oxetanone the ring formed by the carbon atoms marked 4, 5 and 20, and an oxygen atom; and C9-hydroxy refers to the oxygen atom linked to the carbon atom labeled "9", where the specified oxygen atom can be oxoprop, or hydroxy group, or - or-alloctype.

"Substituted 3-amino-2-hydroxypropanoate group" means a residue having the formula:

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where X is a group containing no hydrogen;

X' may be hydrogen, or a group that does not contain hydrogen. The stereochemistry of this balance is similar to the side chain of paclitaxel. In the present description, this group is sometimes meant "C13 side chain".

Derived texana" (reduced denoted "T") refers to the compound having taxanomy part, bearing a C13 side chain.

"Heteroaryl" means 5 - or 6-membered aromatic ring containing at least 1 to 4 atoms that are not carbon, and selected from atoms of oxygen, sulfur and nitrogen. Examples of heteroaryl can be thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, TIA is ICA.

"Phosphonate group" means a group that can be used to block or protect the functional phosphonopropyl; moreover, preferred are such a protective group which can be removed by methods that do not have any adverse impact on the rest of the molecule. Suitable phosphonoacetate groups are well known in the art, and as examples of such groups can serve as benzyl and allyl group.

"Hydroxyamine groups" include, but are not limited to, ethers, such as t-butyl, benzyl p-methoxybenzyloxy, p-nitrobenzyloxy, halilovy, trailovic, methoxymethyl, methoxyethoxymethyl, ethoxyethyl, tetrahydropyranyloxy, tetrahydropyranyloxy and trialkylsilyl esters (for example, trimethylsilyloxy, triethylsilyl and t-butyldimethylsilyl ether), esters such as benzoyl, acetyl, phenylacetyl, formyl, mono-, di-, and trigalogenmetany (for example, chloroacetyl, dichloroacetyl, trichloroacetyl, TRIFLUOROACETYL; and carbonates, such as methyl, ethyl, 2,2,2-trichloroethyl, allyl, benzyl and p-nitrophenyl.

Other examples of hydroxy - and phosphonoacetic groups can be found in the so-who plenum Press. These papers also describe methods for introduction and removal of protective groups.

The term "pharmaceutically acceptable salt" means a metal or amine salt of acid phosphonopropyl, where the cations do not adversely affect the toxicity or biological activity of the active compounds. Suitable metal salts are salts of lithium, sodium, potassium, calcium, barium, magnesium, zinc, and aluminum. Preferred are the sodium and potassium salts. Suitable aminovymi salts are, for example, salts of ammonia, tromethamine (TPI), triethylamine, procaine, benzathine, dibenzylamine, chloroprocaine, choline, diethanolamine, triethanolamine, Ethylenediamine, glucamine, N-methylglucamine, lysine, arginine, ethanolamine, etc., Preferred aminovymi salts are salts of lysine, arginine, triethanolamine, and N-methylglucamine. Most preferred is N-methylglucamine salt or triethanolamine salt.

In the present description, the term "-OCH2(OCH2) OP(O)(OH)2refers to both the free acid and its pharmaceutically acceptable salts, if only does not specify what this expression means free acid.

In one Izv>)mOP(O)(OH)2]n(A)

where T represents taxonomy part, bearing C13-carbon atom substituted 3-amino-2-hydroxypropanoate; n = 1, 2, or 3; m = 0 or an integer from 1 to 6, inclusive;

or their pharmaceutically acceptable salts.

In another embodiment, the present invention relates to a derivative taxane formula (B):

T'-[OCH2(OCH2)mSCH3] ()

which can be used to obtain derivatives taxane formula (A).

In one embodiment of the present invention, Takanawa part contains at least the following functional groups: C1is hydroxy, C2-benzyloxy, C4the atomic charges, C5-C20-oxetan, C9is hydroxy, and C11-C12-double bond.

In a preferred embodiment of the present invention, Takanawa part comes from the residue of formula:

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where R2E'is hydrogen;

R2Eis hydrogen, hydroxy, OC(O)Rxor-OC(O)OPx; R3Eis hydrogen, hydroxy, OC(O)Rx, -OC(O)OPxor C1-6-alkyloxy; one of R6thor R7Eis hydrogen and the other is hydroxy or-OC(O)Rx; or R6th
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where R1E'is hydrogen, -C(O)Rxor-C(O)ORx; R4and R5independently represents a C1-6-alkyl, C2-6alkenyl, C2-6-quinil, or-Z-R6;

Z represents a direct bond, C1-6-alkyl or C2-6alkenyl;

R6represents aryl, substituted aryl, C3-6-cycloalkyl, or heteroaryl;

Rxrepresents a C1-6-alkyl, optionally substituted by 1-6 halogen atoms that can be the same or different, C3-6-cycloalkyl, C2-6alkenyl, or hydroxy; or is a radical of the formula:

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where D represents a bond or C1-6-alkyl;

Ra, Rband Rcindependently represent hydrogen, amino, C1-6-alkylamino, di-C1-6-alkylamino, halogen, C1-6-alkyl or C1-6-alkoxy;

p is 0 or 1.

In a preferred embodiment, R4is C1-6-alkyl and p is 1; or R4is - Z - R6and p is 0. More preferably, if R4(O)p is a t-butoxy, phenyl, isopropoxy, n-propyloxy, or n-butoxy.

In another preferable is more preferably if R5represents phenyl, 2-furyl, 2-thienyl, Isobutanol, 2-propenyl, or C3-6-cycloalkyl.

In another embodiment of the present invention, the compound of formula (A) can be, in particular, is represented by the formula (1):

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where R1is hydroxy, OCH2(OCH2)mOP(O)(OH)2, -OC(O)Rxor-OC(O)ORx;

R2is hydrogen;

R2'is hydrogen, hydroxy, -OCH2(OCH2)mOP(O) (OH)2, -OC(O)Rxor-OC(O)ORx;

R3is hydrogen, hydroxy, C1-6-alkyloxy, -OC(O)Rx, -OCH2(OCH2)mOP(O)(OH)2or-OC(O)ORx;

one of R6or R7is hydrogen and the other is hydroxy, C1-6-alkanoyloxy, or-OCH2(OCH2)mOP(O)(OH)2); or R6and R7taken together, constitute oxoprop; provided that at least one of R1, R2, R3, R6and R7is-OCH2(OCH2)mOP(O)(OH)2);

R4, R5, Rx, m and p are as defined above;

or its pharmaceutically acceptable salt.

In the compounds of formula (I), examples of Rxcan serve as a methyl, hydroxymethyl, ,, cyclohexyl, ethynyl, 2-propenyl, phenyl, benzyl, bromophenyl, 4-AMINOPHENYL, 4-methylaminophenol, 4-were, 4-methoxyphenyl, etc., Examples R4and R5are 2-propenyl, Isobutanol, 3-furanyl(3-furyl), 3-thienyl, phenyl, naphthyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-forfinal, 4-triptoreline, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, ethynyl, 2-propenyl, 2-PROPYNYL, benzyl, phenethyl, phenylethenyl, 3,4-acid, 2-furanyl(2-furyl), 2-thienyl, 2-(2-furanyl)ethynyl, 2-methylpropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cyclohexylethyl, etc.

In one embodiment, the present invention relates to a preferred group of compounds of formula (I) in which R5is C2-6-alkenyl or-X-R6where Z and R6defined above. More preferably, if R5is a 3-furyl, 3-thienyl, 2-propenyl, Isobutanol, 2-furyl, 2-thienyl, or C3-6-cycloalkyl.

In another preferred embodiment of the present invention. R4in the compounds of formula (I) represents a C1-6-alkyl, in case p = 1; or R4represents-Z-R6(where Z and R6defined above),-propyloxy, n-butoxy.

In another preferred embodiment implementation of the present invention relates to the compound of formula (I) in which R1represents-OCH2(OCH2)mOP(O)(OH)2. In a more preferred embodiment, P2is hydroxy, -OCH2(OCH2)mOP(O)(OH)2, -OC(O)OPxor-OC(O)Rxand Rxis preferably C1-6-alkyl. In another more preferred embodiment, R3is hydroxy or acetoxy.

In another preferred embodiment implementation of the present invention relates to the compound of formula (I) in which R2represents-OCH2(OCH2)mOP(O)(OH)2; R1represents hydroxy, -OC(O)Rxor-OC(O)ORx; R3represents hydrogen, a hydroxy-group, acetoxy, -OCH2(OCH2)mOP(O)(OH)2or-OC(O)ORxand Rxdefined above. In a more preferred embodiment, R1is hydroxy or-OC(O)Rx, Rxpreferably is C1-6-alkyl; and R3is hydroxy or acetoxy.

In another preferred variant of its implementation of the present invention relates to the hydroxy or-OC(O)OPx; R2is hydrogen, R2is hydrogen, hydroxy, or-OC(O)ORx; and Rxdefined above. In a more preferred embodiment, R1is hydroxy or-OC(O)ORxand Rxis preferably C1-6-alkyl. In another more preferred embodiment, R2is a hydroxy-group.

In another preferred embodiment, m = 0, 1, or 2, if phosphonomethoxy is C7taxanomy part.

Preferred pharmaceutically acceptable salts of the compounds of formula (A) are alkali metal salts, e.g. salts of triethylamine, triethanolamine, ethanolamine, arginine, lysine, and N-methylglucamine. More preferred are the salts of sodium, triethanolamine and N-methylglucamine.

The most preferred derivatives taxane having the formula (A) are the following compounds: (I) phosphonomethylglycine;

(2) (ethoxycarbonyl)-7--phosphonomethylglycine;

(3) phosphonomethylglycine;

(4) (phosphonomethyl)paclitaxel;

(5) 3'-N-desbenzoyl-3'-destiny-3'-N-(t-butyloxycarbonyl)-3'-(2-furyl)phosphonomethylglycine;

(9) phosphonomethylglycine;

(10) paxil;

and their pharmaceutically acceptable salts, in particular salts of sodium, potassium, arginine, lysine, N-methylglucamine, ethanolamine, triethylamine, and triethanolamine.

The compounds of formula (A) can be obtained from tecknologi derived T-[OH]nused as source material, where T' and n are defined above. Identity T'-[OH]nis not strictly limited, because there is at least one reactive hydroxy-group is present either on taxanomy part or on a C13 side chain, and contributing to the formation phosphonoacetate communication. It should be noted that reactive hydroxy-group can be directly linked to C13-propenyloxy-frame (for example, 2-hydroxy-group of paclitaxel) or the Central frame taxane (for example, 7-hydroxy-group of paclitaxel); or it may be present on the substituent in the C13 side chain or substituent in taksanova core. To obtain the compounds of formula (A) can be used in the reaction scheme shown in Scheme I:

Scheme 1.

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In Scheme I, T' represents taxonomie derived, in which the non-reactive hydroxy-group is blocked; Ryis phosphonates is like reactive hydroxyl groups, first, turn to the appropriate methylthiomethyl a simple ester of the formula (B). Using as example paclitaxel, T' can be determined as follows: T' can be very effective (for the implementation of the 2', 7-besmedimmibre), benzyloxycarbonylation; or 2 ethoxycarbonylpyrimidine. The compound of formula (B), where m = 0, can be obtained by processing T'-[OH]nthe sulfoxide/acetic anhydride or dimethyl sulfide and organic peroxide. In more detail, these reactions will be condemned in the next section.

TMT-ether having at least one intermediate melanochroa (i.e., compounds of formula (B), where m = 1) can be obtained in several ways. In one of them, the compound of formula (B), where m = 0, is subjected to reaction with N-iodosuccinimide (NIS) and methylthiomethyl, resulting chain is extended by one melanochroa.

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The analogous reaction of the alcohol with methylthiomethyl group in the presence of NIS described Veeneman and others, Tetrahedron, 1991, T. 47, pp. 1547-1562; the relevant parts of this work are introduced in the present description by reference. As the catalyst preferably use triplet silver. Connection methylthiomethyl and p is the processing of compounds of formula (Aa) base, such as n-utility, diisopropylamide lithium, or hexamethyldisilazide lithium, is subjected to reaction with a simple chloromethylmethylether ether, resulting in the receive connection of the formula (B), in which m = 1.

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Connection (Ae) are obtained by reaction of methylthiomethyl (obtained from methylthiomethyl by treatment with base such as n-utility, diisopropylamide lithium hexamethyldisilazide lithium) chloroiodomethane. Connection (Ae) can also be obtained by treatment with 1,1'-dichlorodimethylsilane (ClCH2OCH2Cl) a stoichiometric amount or less (for example, about 0.8 equivalents) of sodium iodide, and then thiamethoxam sodium. 1,1'-Dichlorodimethyl simple ether described in Ind. J. Chem. , 1989, 28B, pp. 454-456.

In another method, the compound of formula (Aa) is subjected to reaction with bis(MTM)ether, CH3SCH2OCH2SCH3and N1S resulting in the receive connection of the formula (B), where m = 1.

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Bis-(MTM)ether obtained by the reaction of 1,1'-dichlorodimethyl ether with sodium iodide, and then triethoxide sodium.

The procedure described above using methylthiomethyl and NIS can be applied to any reagent with MTM- = 1, can be subjected to reaction with methylthiomethyl and 1 for the compounds of formula (B), where m = 2. This procedure can be repeated in order to obtain compounds of formula (I) in which m = 3, 4, 5 or 6.

In the second stage of scheme 1, methylthiomethyl ether is converted into the corresponding protected phosphonoacetate ether.

To do this, MTM-ether is treated with NIS and protected phosphate HOP(O)(ORy)2. In the third stage, phosphonothioic group and any hydroxyamino group (or groups) are removed and the obtained compound of the formula (A). For example, a suitable phosphonates group is benzyl, which can be removed by catalytic halogenase; and appropriate hydroxyamine groups, is trialkylsilyl, which can be removed with fluoride ion, and trichlorocyanuric, which can be removed with the help of zinc. Removing the protective groups described in reference manuals Green and Wuts, hotective Groups in Organic Synthesis, John Wiley & Sons, 1991; McOnie, Protective in Organic Chemistry, Plenum Press, 1973. Both these stages are described in more detail in a later section of this description.

In the following scheme II shows another variant of the reaction sequence, proillyustrirovannuyu a result get the connection formula (C), which is then subjected to unlock and get the compound of formula (A). The compound of formula (Ca), where m = 0, can be obtained by first processing methylthiomethyl base, such as hexamethyldisilazide sodium, lithium or potassium, with getting methylthiomethyl; and then the desired compound can be obtained by reaction of a specified methoxide protected chlorophosphate, such as dimensionist. The compounds of formula (Ca), in which m = 1, can be obtained by processing the CH3SCH2OCH2Cl diamesinae phosphate salt, for example, dibenzyltoluene salts of sodium, potassium, or Tetra(n-butyl)-ammonium; or CH3SCH2OCH2Cl can be first converted into the corresponding iodosobenzene using sodium iodide, and this iodosobenzene can then be subjected to reaction with the phosphate salt. Alternatively, the compounds of formula (Ca), in which m = 1, can be obtained by processing ClCH2OCH2Cl-sodium iodide, and then thiamethoxam sodium, with the formation of compound CH3CH2OCH2CH3which is then treated NIS and tizamidine phosphate, such as Dienzenhofer, resulting in getting the right product. Any of Viseu what about the reagent with methylthiomethyl and NIS.

In another method of obtaining the compounds (A), T-alkoxide (Ad) is subjected to reaction with idofefetnam, as shown in scheme III.

Scheme III

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In scheme III, iodoheptane compound obtained by reaction ClCH2(OCH2)mCl with diamesinae phosphate salt, which formed the connection ClCH2(OCH2)mOP(O)(ORy)2which is then treated with sodium iodide and get the right product.

In the following scheme IV shows another method that can be used to obtain a subclass of compounds of formula (A), where at least one of phosphonomethoxy associated with taxonomy part.

Scheme IV.

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In scheme IV, m and n are such as defined previously, X is a group containing no hydrogen, P is hydroxyamino group; and txn is taxonomy part. The compounds of formula (I) are 13-alpha-hydroxy-group and one or more methyldiethylamine groups that are directly or indirectly related to taxonomy core; and (C13the alkoxides of the metals of the formula (D). Example of compounds of formula (D) is methylthiopyrimidin III:

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The reaction of interaction of the a, described to obtain the compounds of formula (1d) can also be used to obtain the compounds of formula (Ba)(i.e., compounds of formula (B), in which at least one of the MTM-groups directly or indirectly connected with taxanomy part), if the compound (II) in scheme IV to replace the compound of formula (D). First, Texan preferably turned into C13-the metal alkoxide, such as sodium alkoxide, potassium, or lithium, and more preferably, a lithium alkoxide. Azetidine serves as a precursor C13 side chain. After the reactions proceed with taxonom, hydroxyamino group P is removed, and if necessary, the free hydroxy-group on the side chain can be turned into MTM-ether, or derivatization with the formation of ester or carbonate, as described below.

Azetidinone can be obtained following methods, which are well known to any specialist. The compounds of formula (D) can be obtained using the General procedure described above to obtain compounds of the formula (B) using appropriately protected taxane. However, preferably, these compounds can be obtained from compounds of formula (Ba) by the splitting of the measures the paclitaxel treated with tetrabutylammonium borohydride, resulting in a gain of 7-O-MTM-baccatin III.

The General procedure shown in scheme 1 to obtain the compounds of formula (A), more clearly illustrated in scheme V, where illustrated obtaining the compounds of formula (I') (i.e., compounds of formula (I) in which m = 0). The procedure used in this sequence of reactions can be largely applied to other derivative taxane not specifically relate to compounds of formula (I). In addition, the procedure used in scheme (V), can be modified in accordance with the instructions given in this description and in obtaining derivatives taxane formula (A), where m=1,2, or 3.

However, it should be noted that in scheme V, as well as in other sections of the present description, the term "hydroxyamine group" may include the corresponding carbonates (e.g.,- OC(O)ORxwhere Rxdoes not contain a hydroxy-group); therefore, if a carbonate is used as hydroxyamino

Scheme V

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group, in a later stage, this group should be removed with the formation of the free hydroxy-group; or otherwise kuckucksuhr, protected by a hydroxy-group, -OC(O)Rxor-OC(O)ORx; P2'is hydrogen, R2ais hydrogen, hydroxy-group-protected hydroxy-group, -OC(O)Rxor-OC(O)OR; R3ais hydrogen, hydroxy-group-protected hydroxy-group, C1-6-alkyloxy, -OC(O)Rxor-OC(O)ORx; one of R6aor R7ais hydrogen and the other is a hydroxy-group, protected hydroxy-group, or C1-6-alkanoyloxy; or R6aand R7ataken together form oxoprop, provided that at least one of R1a, R2a, R3a, R6aor R7ais a hydroxy-group. R1bis a hydroxy-group, protected hydroxy-group, -OCH2CH3, -OC(O)Rxor-OC(O)ORx; R2'is hydrogen, R2bis hydrogen, hydroxy-group-protected hydroxy-group, -OCH2CH3, -OC(O)Rxor-OC(O)ORx; R3bis hydrogen, hydroxy-group-protected hydroxy-group, C1-6-alkyloxy, -OC(O)Rx, -OCH2SCH3or-OC(O)ORx; one of R6band R7bis hydrogen and the other is a hydroxy-group, protected hydroxy-group, C1-6-alkanoyloxy, or-OCH21b
, R2b, R3b, R6bor R7bis-OCH2SCH3. R1cis a hydroxy-group, protected hydroxy-group, -OCH2OP(O)(ORy)2, -OC(O)Rxor-OC(O)ORx; R2'is hydrogen, R2cis hydrogen, hydroxy-group-protected hydroxy-group-OCH2OP(O) (ORy)2, -OC(O)Rxor-OC(O)ORx; R3cis hydrogen, hydroxy-group-protected hydroxy-group, C1-6-alkyloxy, -OC(O)Rx, -OCH2OP(O)ORy)2or-OC(O)ORx; one of R6cor R7cis hydrogen and the other is a hydroxy-group, protected hydroxy-group, C1-6-alkanoyloxy, or-OCH2OP(O)(ORy)2; provided that at least one of R1c, R2c, R3c, R6cor R7cis-OCH2OP(O)(ORy)2. R1is a hydroxy-group, -OCH2OP(O)(OH)2, -OC(O)Rxor-OC(O)ORx; R2"'is hydrogen. P2"'is hydrogen, hydroxy-group, OCH2OP(O)(OH)2, -OC(O)Rxor-OC(O)ORx; R3'is hydrogen, hydroxy-group, C1-6-alkyloxy, -OC(O)Rx, -OC(O)ORxor-OCH2OP(O)(OH)2; one of R6'and R7'is in the ina least one of R1', R2", R3', R6'or R7'is-OCH2OP(O)(OH)2, R4, R5, Rxand p are the same as defined above, and Ryis phosphonothioic group.

In the first stage, the free hydroxy-group of compounds of formula (1a) is transformed into the corresponding methyldiethylamine (-OCH2CH3) group. To do this, perform one of two procedures: 1a (dimethylsulfide method) and 1b (dimethylsulfoxide method). Dimethylsulfide method of transformation of alcohols in methylthiomethyl esters described Medina and others (Jet. Lett 1988, page 3773-3776; the relevant parts of this work are introduced in the present description by reference). Dimethylsulfoxide method well known to specialists as the reaction of Pummerer.

It should be noted that the reactivity of the hydroxy-group varies depending on its location on the source connection tecknologi derivative of the formula (1a). Although, usually, 2-hydroxy-group is more reactive acylation reactions than 7-hydroxy-group, which, in turn, is more reactive than 10-hydroxy-group, however, using dimethylsulfide method, it was unexpectedly discovered that 7-reaktivnoi is a tertiary hydroxy-group at C-1. This difference in reactivity of the hydroxyl groups can be used to regulate the location and the extent of methyldiethylamine.

For example, in the case of the compounds of formula (1a), where R1aand R2aare hydroxy groups, primary product methyldiethylamine in dimethylsulfide method will be appropriate methylthiomethyl ether. In order to obtain the compound of formula (1o), where P1ais methylthiomethyl, without conversion of 7-hydroxy-group (if any) in methyldiethylamine group, this 7-hydroxy-group block using traditional hydroxyamino groups, such as triethylsilyl or benzyloxycarbonyl. Similarly, 10-methylthiomethyl ester can also be obtained without making the 7 - and/or 2-hydroxy groups (if they exist), if these groups to block the same or other hydroxyamine groups. Even if 7-hydroxy-group is the preferred place of methyldiethylamine in dimethylsulfide method is still preferable to block 2-hydroxy-group, if 7-monomethylmercury ester is the desired product.

In addition, reaction conditions moguh derivatives taxane. For example, in the case of paclitaxel, increasing the reaction time or the use of excessive amounts of methylthiopyrimidin reagents may lead to a higher content of 2,7-bis(methylthiomethyl)-ether-paclitaxel in the mixture of the final product.

Returning to diagram V, it should be recalled that in the procedure (1a), the compound of formula (1a) is treated with dimethyl sulfide and organic peroxide such as benzoyl peroxide. This reaction is carried out in an inert organic solvent, such as acetonitrile, methylene chloride, etc. at a temperature conducive to the formation of the desired product. Basically, the above reaction is carried out at a temperature of from about - 40oC to about room temperature. Dimethyl sulphide and benzoyl peroxide is used in an excessive amount in relation to the original taxonomy derivative (1a) and dimethyl sulfide is used in an excessive amount relative to the benzoyl peroxide.

The relative quantity of used raw materials depend on the desired degree of methyldiethylamine. For example, if the free hydroxy-group source tecknologi derivative (1a) turn in methyldiethylamine group, Dima is anew derivative (Ia); and preferably, if the amount of dimethyl sulfide in about 2 to 3 times the amount of benzoyl peroxide. If the original compound (1a) has 2'-7-hydroxy-group, the amount of 2',7-bis(methylthiomethyl)ether increases in accordance with the relative amounts of dimethyl sulfide and benzoyl peroxide. If the target product is 2', 7-bis(methylthiomethyl)ether, it is preferable that the amount of dimethyl sulfide at about 15 - 20 times the number of initial connections tecknologi derived, and the amount of benzoyl peroxide is about 5 - 10 times the number of source tecknologi derived.

Alternatively, the compound of formula (Ib) can be obtained by reaction of compounds of formula (Ia) with dimethylsulfoxide and acetic anhydride (procedure (Ib). This procedure can be used to revalidatie group, which is not 2-hydroxy-group, in its methylthiomethyl ether. In the procedure (Ib), the compound of formula (Ia) is dissolved in dimethyl sulfoxide, and the resulting solution was added acetic anhydride. This reaction is mainly carried out at room temperature, for 18 - 24 hours, obtaining monomethylfumarate ether is testwuide protected phosphonoacetate ether. This reaction conversion can be performed using the General method described Veeneman and others , Tetrahedron, 1991, 47 so, pages 1547 - 1562 (the relevant sections of this work are introduced in the present description by reference. For example, the compound of formula (Ib) having at least one methyldiethylamine the group treated with N-iodosuccinimide and protected phosphoric acid, such as Dienzenhofer. This reaction is carried out in an inert organic solvent, such as tetrahydrofuran or a halogenated hydrocarbon such as 1,2-dichloroethane or methylene chloride, and optionally in the presence of a dehydrating reagent, such as a molecular sieve. To accelerate the reaction may also be added to the catalyst, such as trifluromethanesulfonate silver. This reaction is carried out at a temperature from about 0oC and up to about room temperature, preferably at room temperature. N-Iodosuccinimide and protected phosphoric acid is used in approximately the same molar equivalents, as methylthiomethyl ether (Io), however, it is preferable that the amount of these reagents slightly exceeded (for example, from about 1.3 to 1.5 equivalents) number of connections formulay group (if any). This reaction unlock carried out using standard techniques, well known in the art, such as acid or basic hydrolysis, hydrogenolysis, recovery, etc., for Example, catalytic hydrogenolysis can be used to remove the benzyl phosphonates group, and benzyloxycarbonyl hydroxyamino group. Methods unlock described in detail in the well-known manuals Greene and Wutz, or McOmie (see above). Needless to say, if the compound of formula (Ia) contains a hydroxy-group in the radical Rxit is preferable that these hydroxy-group were protected by suitable protective groups described until stage unlock.

As mentioned above, the method illustrated in scheme V, can be modified in accordance with the following instructions, so that this method can be used to obtain derivatives taxane formula A, in which m = 1, 2, or 3.

Listed below are the schemes of Va and Vb, in accordance with which every person is able to modify the above method to obtain the specific compounds of the formula A, in which at least one Deputy represents what ormula (A), in which m = 3.

Scheme Va

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Diagram Vb

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Basic salts of the compounds of formula (I) can be obtained by standard methods, for example, by a reaction between the compounds of formula (I) in the form of the free acid with a metal or aminoven bases. Suitable for this purpose, the metal bases are hydroxides, carbonates, and bicarbonates of sodium, potassium, lithium, calcium, barium, magnesium, zinc and aluminum, and suitable amines are triethylamine, ammonia, lysine, arginine, N-methylglucamine, ethanolamine, procaine, benzathine, dibenzylamine, tromethamine (TRIS), chloroprocaine, choline, diethanolamine, triethanolamine, etc., These basic salts can then be purified by chromatography followed by lyophilization or by crystallization.

Derivatives taxane used as starting materials

To obtain the compounds (A) in the above-described methods can be used derivative taxane formula T-[OH]n. The literature provides many examples of the compounds of formula T-[OH]nand some of them are listed below, namely: (a) paclitaxel; (b) Taxotere; (c) 10-deacetyltaxol; (d) BR> where R1represents-OR6, -SR7or-NR8R9;

R2represents alkyl, alkenyl, quinil, aryl, or heteroaryl;

R3and R4independently represent hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, or acyl, provided, however, that R3and R4are not both acyl;

R5represents-COR10, -COOR10, -COSR10, -CONR8R10, -SO2R11or-POR12R13;

R6represents hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, hydroxyamino group, or a functional group contributing to the increase in water solubility tecknologi derived;

R7represents alkyl, alkenyl, quinil, aryl, heteroaryl, or sulfydryl protective group;

R8represents hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl;

R9represents aminosidine group;

R10represents alkyl, alkenyl, quinil, aryl, heteroaryl, -OR10or-NR8R14;

R12and R13independently represent alkyl, ekenel, quinil, aryl, heteroaryl, -OR10or-NR8R14;

R14present Aut a hydrogen, hydroxy, lower alkanoyloxy, alkanoyloxy, alkanoyloxy, arylisocyanate, or R15and R16taken together , constitute oxoprop;

R17and R18independently represent hydrogen, a hydroxy-group, the lower alkanoyloxy, alkanoyloxy, alkanoyloxy, urinologist; or R17and R18taken together, constitute oxoprop;

R19and R20independently represent hydrogen, a hydroxy-group, the lower alkanoyloxy, alkanoyloxy, alkanoyloxy, or erroroccurred;

R19and R20independently represent hydrogen or lower alkanoyloxy, alkanoyloxy, alkanoyloxy or erroroccurred;

or R21and R22taken together , constitute oxoprop;

R23represents hydrogen, hydroxy, or lower alkanoyloxy, alkanoyloxy, alkanoyloxy, or erroroccurred; or R23and R24taken together, constitute oxoprop or methylene; or R23and R24taken together with the carbon atom to which they are bound, form oxirane ring; or R23and R24taken together with the carbon atom to which they are bound, form oxetanone ring;

R2 is relajarse-group;

R26represents hydrogen, a hydroxy-group, or a lower alkanoyloxy, alkanoyloxy, alkanoyloxy, or urinologist; or R26and R25taken together, constitute oxoprop;

R27represents hydrogen, a hydroxy-group, or lower alkoxy, alkanoyloxy, alkanoyloxy, alkanoyloxy-, or erroroccurred; (e) taxonomie derivatives disclosed in U.S. patent 5227400, 3'-destiny-3'-(2-furyl)- or 3'-(2-thienyl)-derivatives of paclitaxel, Taxotereand (f) taxonomie derivatives disclosed in EP 534709, publ. March 31, 1993 (derivatives of paclitaxel, where the phenyl group in the side chain are independently replaced by naphthyl, styrene, or substituted phenyl). Cm. also PCT 92/09589, published. 11 June 1992; (g) derivative taxane disclosed in EP 534707, publ. 31.3.1993 (derivatives of paclitaxel, in which 3'-N-benzoline group substituted by etoxycarbonyl or methoxycarbonyl); (h) the PCT-application 93/06093, published April 1, 1993 (10 deacetoxy-derivatives of paclitaxel and Taxotere; (i) EP 524093, publ. January 20, 1993 (10-, 7-, or 7,10-bis--(N-substituted carbamoyl derivatives texana); (i) 9-alpha-hydroxy-analogue of paclitaxel, unveiled Klein in "Synthesis of 9-Dihydrotaxol: a new Bioactive Taxane", Tetrahedron Letters, 1993, 34(13): 2047-2050; (� III, disclosed in the 205-th ACS National Meeting in Colorado, 1993. (Med. Chem. Division, Abstract, N 28); and (I) other taxanes, such as C7-verotoxin and various C10-substituted taxanes disclosed in the application as Europatent 577082 A1, publ. January 5, 1994, which is introduced in the present description in its entirety by reference.

Free hydroxy-group or group derived taxon can be transformed by standard methods into the corresponding ester or carbonate; for example, in compounds of formula (Ia), one of R1a, R2aor R3ais-OC(O)Rxor-OC(O)ORxwhere Rxdefined above. Thus, taxonomie derived T-OH may be subjected to reaction with the compound of the formula L-C(O)ORx(where L is a leaving group) such as chloroformate, in the presence of a base such as tertiary amine, with the formation of the corresponding carbonate. For example, by the reaction of paclitaxel with etelcharge.com in the presence of diisopropylethylamine formed 2' - ethoxycarbonylmethoxy. T-OH can also be subjected to a reaction with a carboxylic acid RxCO2H or allermuir equivalent (e.g., anhydride, active complex ether, or allelochemical) in order to obtain the corresponding ( equivalent contains a hydroxy-group, these groups should preferably be blocked suitable hydroxyamine groups.

In addition, derivatives taxane T-[OH]ncan be obtained by acylation of taxanomy, C13the hydroxy-group, using the appropriately substituted 3-amino-2-hydroxypropanoic acid or its Alliluyeva equivalent, or its predecessor. Suitable precursors of substituted 3-amino-2-hydroxypropanoic acids are, for example, azetidinone formula (III). An example of the acylation reaction may be a reaction accession hydroxyamino baccatin III or hydroxyamino 10-deacetylbaccatin III derived phenylazomethine with the formation of derivatives of paclitaxel, disclosed, for example, in U.S. patents 4924011 and 4924012 (Denis and others); and the reaction accession protected baccatin III and azetidinone with the formation of paclitaxel and its derivatives disclosed in EP-application 400971, published December 5, 1990 (now U.S. patent N 5175315 and 5229526).

The method disclosed in EP 400971 (method of Holton), is that 1-benzoyl-3-(1-ethoxy)ethoxy-4-phenyl-2-azetidinone subjected to reaction with 7-criticallyacclaimed III in the presence of N,N-dimethylamino Xel. An improved method of Holton described Ojima and others in the "New and Efficient Approach to the Semisynthesis of Taxol and its C-13 Side analogs by Means of-Lactam - Synthon Method," Tetrahedron, 1992, 48(34): 6985-7012. The way Ojima is that first obtained the sodium salt of 7-triethylchlorosilane III using sodium hydride, and then, this salt is subjected to reaction with chiral 1-benzoyl-3-(1-ethoxy)ethoxy-4-phenyl-2-azetidinone, and after removal hydroxyamine groups receive paclitaxel. In U.S. patent 5229526 (Holton) discloses the reaction of a merger between metallkarkassiga baccatin III or its derivatives and 2-azetidinone education taxan with M13-side chain. In this work indicates that this method is highly diastereoselective, resulting in this method can be used racemic mixture of the precursor 2-azetidinone with the side chain. Recently, and others in their paper "A Highly Efficient Route to Taxotere by the-Lactam Synthon Method" - Tetrahedron hetters, 1993, 34(26): 4149-4152, opened the reaction presidentialelection,10-bis--(Trichloroisocyanuric)-10-deacetylbaccatin III with chiral 1-(t-butoxycarbonyl)-4-phenyl-3-(protected hydroxy)-2-azetidinone, which, after unlock, received Taxotere. The relevant section is the W baccatin/azetidinone, adapted to obtain the compounds of formula (Ia), illustrated in scheme VI. In this case, the specified method using the appropriate starting materials can be obtained and other derivatives taxane not specifically included in the scope of formula (Ia).

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In scheme VI, R2'is hydrogen, R2dis hydrogen, protected hydroxy-group, -OC(O)Rxor-OC(O)ORx; R3dis hydrogen, -OC(O)RxC1-6-alkyloxyaryl protected by a hydroxy-group, or OC(O)ORxone of P6dand P7dis hydrogen and the other is a hydroxy-group, protected hydroxy-group, or C1-6-alkanoyloxy; or R6dand R7dtaken together, constitute oxoprop; P is hydroxyamino group; M is hydrogen or a metal of group IA, such as lithium, sodium, or potassium; and p, R4, R5and Rxare as defined above. This reaction can be carried out in accordance with the procedure described in EP 400971, where the derived baccatin III of the formula (II) (where M is hydrogen) is subjected to reaction with azetidinone formula (III) in the presence of organic bases such as N, N-dimethylaminopyridine.frame derived a strong base, such as hydrides, alkylamide, and bis(trialkylsilyl)amides of metals of groups IA, as described in U.S. patent 5229526 and work Ojima (see above). More preferably, if the 13-alkoxide is an alkoxide of lithium. The lithium salt can be obtained by reaction of compounds of formula (II), where M is hydrogen, with a strong metal base, such as diisopropylamide lithium, C1-6-alcolici, bis(trimethylsilyl)amide lithium finality, lithium hydride, etc., needless to say, if the compound of the formula (II) contains a hydroxy-group in the radical Rxthese hydroxy-group should preferably be protected by hydroxyamine groups.

The reaction of the merger between taxonom formula (II) and azetidinone formula (III) is carried out in an inert solvent such as tetrahydrofuran at a given temperature in the range from about 0oC to about -78oC. Azetidinone formula (III) can be used in the form of a racemic mixture for the reaction combination with metallocene taxane formula (II) (where M is a metal of group IA); and, in this case, it is preferable that the number of azetidinone was at least 2 EQ is about 3 to about 6 equivalents. Can also be used and chiral azetidinone, and in this case, a sufficient number of azetidinone towards taxane can be 1 equivalent, however, it is preferable that the amount used of azetidinone slightly exceeded (for example, 1.5 EQ.) the number taxane.

Hydroxyamine groups may be similar, or they can be chosen in such a way that they can be selectively removed, without, however, any adverse effects on other groups. For example, in the compound of formula (Id), where R2band PO both can be triethylsilanol, and R3bcan be benzyloxycarbonyl specified benzyloxycarbonyl protective group can be easily removed, while preserving triethylsilyl group by catalytic hydrogenolysis in the presence of palladium charcoal. Thus, hydroxyamine group of compounds of formula (Id) can be selectively removed to obtain the compounds of formula (Ia).

The compounds of formula (II) are either known in the literature (for example, baccatin III, 10-deacetylbaccatin III, and their hydroxyamine derivatives), or they can be obtained from known compounds stout to be obtained in accordance with the procedures described below in the section "Obtaining source materials."

The compounds of formula (III) can be obtained from the compounds (IIIa) in accordance with the General method described in EP 400971 and work Ojima and others Tetrahedion 48: 6985-7012, 1992.

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For example, the compound of formula (IIIa) is first treated with a base, such as n-utility or triethylamine, and then the compound of the formula R4(O)pCO-L, where L is a leaving group, resulting in the receive connection of the formula (III).

The compounds of formula (IIIa) can be obtained in accordance with the General method described in EP 400971, using the intermediate compound 3-acetoxy-4-substituted-2-azetidinone (IIIb); or in accordance with the method described in U.S. Pat. USA N 5229526, using the intermediate compound 3-triethylsilyl-4-substituted-2-azetidinone. In a preferred embodiment, compound (IIIb) can be obtained by condensation of acetoacetanilide with bizimana followed by hydrogenolysis or acid cleavage to remove N-kinoway group. This method is shown in the diagram below, where R5is optionally substituted aryl or heteroaryl group such as furyl and thienyl. Ukazannye description by reference.

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Products (IIIb) obtained in the above reactions, cycloaddition, usually represent a racemic mixture of two CIS-azetidinone. This racemic mixture may be separated by standard methods, such as the transformation into the diastereomers, the differential adsorption on a column Packed chiral adsorbents, or enzymatic separation. For example, a racemic mixture of compounds of the formula (IIIb) may be subjected to interaction with the enzyme that catalyzes the hydrolysis of ester (for example, such an enzyme as the esterase or lipase), and facilitates selective removal of the 3-acyl group of one enantiomer, without, at the same time, the adverse impact on other groups (see, for example, Brilva etc., J. Org. Chem. 1993, 58: 1068-1075, and simultaneously consider the application reg. N 092170, filed July 14, 1993, and EP application N 552041, published July 21, 1993). Alternatively, the racemic mixture can be first subjected to basic hydrolysis to remove 3-icalneu group, and obtain the racemic mixture and the corresponding 3-hydroxy-lactam, and then, this racemic mixture of 3-hydroxy-lactam was subjected to interaction with an enzyme capable of catalyzing about enantiomer, without exerting any influence on the other enantiomer. Or racemic mixture of 3-hydroxy-lactam may be subjected to acylation using a chiral carboxylic acid, and the resulting diastereomers the mixture can then be separated by standard methods, and after removal of the chiral auxiliary compound may be obtained of the desired enantiomer.

Ojima and others, in "J. Org. Chem. 56: 1681 - 1683, 1991; Tet. hetl, 33: 5737 - 5440, 1992" describe the synthesis of some chiral azetidinone formula (IIIa) and/or their respective -(p-methoxyphenyl)-similar, where P is triisopropylsilyl hydroxyamino group; and R5represents a 4-methoxyphenyl; 3,4-dimethoxyphenyl; phenyl; 4-forfinal, 4-trifloromethyl, 2-furyl, 2-phenylethenyl, 2-(2-furyl)ethynyl, 2-methylpropyl, cyclohexylmethyl, isopropyl, phenethyl, 2-cyclohexylethyl, or n-propyl. Other examples of obtaining azetidinone formula (IIIa) and/or (III) can be found in the following works: EP-application 0534709 AI, 0534708 AI and 0534707 AI (all three published March 31, 1993); PCT-application 0 93/06079, published April 1, 1993;

- Bioorgaanic and Medicinal Chemistu hetters, 3 N 11, pp 2475 - 2478 (1993); and Bioerganic and Medicinal chetistry Zetters, 3, N 11, pp 2479 - 2482 (1993); J. Org. Chem., 58, pp. 1068 - 1075; Tetrahedron hetteis 31, No. 44, pp. 6429 - 6432 (1990); Bioorganic and May application for Pat. U.S. reg. N 092170, filed July 14, 1993. The relevant sections of the above-mentioned operations are introduced in the present description by reference. Other azetidinone falling under the definition of formula (III), but not specifically covered in the above works, can be obtained by any specialist by known methods.

Biological tests

The compounds of formula (B) of the present invention are intermediate compounds that can be used to obtain antitumor compounds of the formula (A). In addition, some compounds included in the scope of formula (B), namely, the compounds of formula (B), may themselves be used as antitumor agents. In "the biology part I, below, illustrates the antitumor activity of compounds of the formula (A), and in "the biology part II" (see below) illustrates the antitumor activity of compounds of the formula (B).

The biological part I

Data of in vitro cytotoxicity

The compounds of formula (A) showed cytotoxic in vitro activity against cells HCT-116 and HCT-116/M46 carcinoma human colon. Cells HCT-116/M46 were previously subjected to selection for resistance against the against paclitaxel. Cytotoxicity in cells HCT-116 carcinoma human colon was assessed by analysis using Templ 2,3-bis(2-methoxy-4-nitro-5-sulfenyl)-5-(phenylamino)carbonyl 2H-tetrazole hydroxide, as described in D. A. Scudiero, and others, "Evaluation of a soluble tetrazolium/formazan assay for cell grokth and drug sensitvitu in culture using human and other tumor cell lines", Cancer Res. -48: 4827 - 4833, 1988. These cells were seeded at a density of 4000 cells per well in 96-well plates to micrometrology, and after 24 hours, the wells were added medicines and was carried out by serial dilution. Cells were incubated at 37oC for 72 hours and then added tetrazolium dye, Templ. Dehydrogenase (enzyme) present in living cells, helps to restore Templ until it forms able to absorb light at 450 nm, which can be quantified by spectrophotometry. The higher the optical density, the greater the number of living cells. The results were expressed in the IC50the values represent the concentration of drug required to inhibit cell proliferation (i.e.,). pl. at 450 nm) by 50% compared with untreated control cells. IC50-values for the characteristic is Taxila (example 1a) was also tested in the analysis of cytotoxicity, and the results of this analysis showed that the IC50-value for this connection about 0.003 against HCT-116 - and 0.025 μm against HCT-116/M46/

Antitumor-in vivo activity

Hybrid mice (Balb/CxDBA2F1(CDF1)) subcutaneously (SC) implanted 0.1 ml of 2% (wt./about.)-aqueous composition cell carcinoma of the lung M109 (as described W. ROSE ""Evaluation of Madison 109 Lung Carcinoma as a Model for Screening Antirumor Drugs", Caneer Treatment Reports 65, No. 3 - 4, pp. 299 - 312 (1981). Groups of mice were administered compound and the standard drug, paclitaxel (intravenous); moreover, each group received different doses of the tested compounds and each compound was evaluated at three or four different doses. Mice were daily observed on survival until their death, or approximately 75 days after implantation of the tumor regardless of the outcome of the experiment. One group of mice in this experiment remained untreated and served as control. Once or twice a week also measured the tumor size (in mm), and these measurements are used to assess tumor mass in accordance with the procedure described in the above.

The average survival time of mice treated with the test compound (T), compared with the average time is x mice) was multiplied by 100 and in percentages (i.e., % T/C) systematized in table II for the most common compounds. In addition, table II also shows the difference between the average survival time for the treated groups and the median survival for the control group (expressed in days, T-C) in case of increase of the tumor up to 1 gram. The larger the magnitude of T-C, the greater the deceleration of primary tumor growth. Compounds that demonstrated the value of %T/C to 125% and/or T-C 4.0 days, was considered as active compounds in the investigated model M109SC.

In addition, the compound of example 3 (triethanolamine salt) was tested on models of tumor xenograft mouse and man (M109, A2780/cDDP - carcinoma of the ovary of a person possessing resistance to this drug called cisplatin; and HTC-116 - carcinoma human colon) compared with paclitaxel, used as a positive control. A2780/DDP - model described in the work of Rose and Basler, in vivo 1990, 4: 391-396; HCT-116-model described by Rose and Basler in vivo, 1989, 3:249-254. M109 was subcutaneously injected Balb /C mice, and subcutaneously implanted CDF1 - mice for the analysis of antitumor activity. A2780/cDDP and HCT-116 were cultured in "Nude" mice for experiments on passirovanny (every 2-3 weeks) and experiments in therapy. The compound of example 3 was introduced i the e, containing tween 80, or dissolved in Cremophor/ethanol (50%/50%), and diluted with saline. In trials with subcutaneous injection of M109 tumor, the treatment was performed on the 4th day after the simulation of the tumor and daily for 5 consecutive days. In trials using tumor xenograft human connection was injected 5 times: - once a day every second day (i.e., one day), starting from the moment when the tumor size ranged from 50 to 100 mg.

In one M109 experiment, the compounds of example 3 was injected reached maximum values of % T/C = 155 (T-C=19 days) at 36 mg/kg/injects. (for paclitaxel % T/C= 132 (T-C = 13 days) when 36 or 18 mg/kg/injects. In the same experiment, the compounds of example 3, administered orally reached maximum values of % T/C = 158 (T-C = 22.8 days) at a dose of 160 mg/kg, whereas paclitaxel at the same dose (most use high dose) (suspended in water and Tween 80) did not show any activity. In another M109 experiment, the compound of example 3, administered intravenously, has produced the maximum value of % T/C = 170 (T-C = 17 days) at a dose of 48 mg/kg/injects. (for paclitaxel, max% T/C = 167 (T-C = 14 days) at 48 or 36 mg/kg/inject.). In the same experiment, oral administration Soden the Cremophor/ethanol/saline solution, did not show activity at the dose of 60 mg/kg/injects. In this experiment, paclitaxel dissolved in Cremophor/ethanol/saline solution, may not be introduced at a dose of more than 60 mg/kg/injects., due to poor solubility and toxicity.

In A2780/cDDP experiment, the compounds of example 3, intravenous, showed the maximum value T-C 29.8 days at a dose of 36 mg/kg/injects. (for paclitaxel, max T-C = 26,3 Nam. at 36 mg/kg/injects.) Oral administration of the compound of example 3 gave max T-C = 20 days at the dose of injection of 160 mg/kg In HCT-116 experiment, intravenous dose of 24 or 36 mg/kg/injects. paclitaxel resulted in 6 extracts from 7 or 6 extracts from 8 exhaust mice, respectively; and oral administration of the compound of example 3 at a dose of injection 160 or 240 mg/kg was given 6 or 7 extracts from 8-treated mice, respectively. "Extraction" means the absence of tumors in 80 day after implantation of the tumor.

Triethanolamine salt of the compound of example 1 also showed oral activity in experiments with M109 - and HCT-116-models.

From the literature it is well known that there are sometimes small changes in antitumor activity depending on the specific salt used Faure who (A) has a higher solubility compared with paclitaxel, that allows you to use the above-mentioned salts for the manufacture more convenient to use medicinal compositions. Without pretending to any particular theory, we can only say that phosphonoacetate esters of the present invention are, obviously, a precursor of paclitaxel or its derivatives, where phosphonoacetone part of these precursors is cleaved under the action of in vivo-fosfotazy, which leads to the subsequent production of the initial compounds.

The biological part II

M109 murine model

Hybrid mice (Balb/cxDBA12 F1)was administered intraperitoneally (as described William Roseb" Evaluation of Madison 109 Lung Sagem as a Model for Screening Antitumor Drugs, Cancer Treatment Reports, 65, No. 3-4 (1981)) 0.5 ml of 2% (wt./about.)-composition of carcinoma of the lung M109.

Mice were treated with the test compound by intraperitoneal injection of this compound at various doses, administered via either 1, 5 or 9 days after implantation of the tumor, either on the 5th and 8th day after implantation. Mice were daily observed for survival for approximately 75-90 days after implantation of the tumor. One group of mice in this experiment remained unprocessed and served as the control group. The average time of survival . who compared these two values for each treated group of mice was multiplied by 100 and in percentages (i.e.,% T/C) systematized in table III for the most typical compounds of the formula (B').

As shown above, the compounds of formulas (A) and (B') of the present invention are effective tumor-any abscopal means, and therefore they can be used in medicine and/or veterinary medicine. Thus, in another embodiment, the present invention relates to a method of inhibiting the growth of tumors in humans and other mammals, consists in the fact that the specified person or mammal having a tumor, enter an effective tumor-inhibiting amount of the compounds of formula (A) or (B).

Compounds of the present invention having formulas (A) and (B) may be used in accordance with the same therapeutic scheme, which is commonly used to paclitaxel, and therefore the specialist oncologist can independently, without undue experimentation, to determine the proper dose of a compound of the present invention, with appropriate regimen. Dose, the method and scheme of administration of compounds of the present invention do not have any specific og the present invention can be introduced in any suitable way, preferably parenteral) in the dose component, for example, from about 1 to about 10 mg/kg body weight, or from about 20 to about 500 mg/m2. Compounds of the present invention can also be administered orally in a dose comprising from about 5 to about 500 mg/kg body weight. Specifically used the dose may vary depending on the specific compositions used, how it is administered, the specific site of introduction, from the individual host, and the type of tumor. By separating the desired dose, you must take into account many other factors that can affect the action of the medicinal product, for example, factors such as age, body weight, sex, diet, and physical condition of the patient.

The present invention also relates to pharmaceutical compositions (drug) containing an effective tumor-inhibiting amount of the compounds of formula (A) or (B) in combination with one or more pharmaceutically acceptable carriers, fillers, diluents or adjuvants. As examples of the manufacture of the compositions of the present invention can be taken as examples of the manufacture of drugs paclitaxel and its derivatives, described in U.S. patents NN 49607 what's mixes, capsules, injectively solutions, suppositories, emulsions, dispersions, food additives, and other forms. They can also be made in the form of sterile solid compositions, for example, liofilizovannyh drugs in combination, if necessary, with other pharmaceutically acceptable excipients. Such solid compositions may then be diluted with sterile water, saline solution, or a mixture of water and an organic solvent, such as propylene glycol, ethanol, etc. or any other sterile injectable medium immediately before parenteral administration.

Typical examples of pharmaceutically acceptable carriers are attracted, urea, dextrans, lactose, potato and maize starches, magnesium stearate, talc, vegetable oils, polyalkylene glycols, ethylcellulose, poly(vinylpyrrolidone), calcium carbonate, etiloleat, isopropylmyristate, benzyl benzoate, sodium carbonate, gelatin, potassium carbonate, salicylic acid. The pharmaceutical composition may also contain non-toxic additives, such as emulsifiers, preservatives, wetting agents, etc. as for example, sorbitan-monolaurate, triethanolamine oleate, monostearate polyoxyethylene, tripal the Durach, all temperatures are given in degrees Celsius, if it is not specifically mentioned. Spectral data of nuclear magnetic resonance (NMR) refer to chemical shifts () are expressed in ppm (M. D.) relative to tetramethylsilane was (TMS), used as standard. The relative area specified for various shifts in the data proton NMR correspond to the number of hydrogen atoms of a particular functional type in the molecule. The nature of the shifts and their multipletness marked as follows: (Shir.(C) a broad singlet, (Shir.D.) - broad doublet, (Shir.sq.) - broad Quartet, (s) - singlet, (m) - multiplet, (d) - doublet, (square) Quartet, (t) - triplet, (DD) doublet of doublets, (dt) - doublet of triplets, and (DQC) - doublet of quartets. To obtain the NMR spectra were used the following solvents: acetone-d6(deuterated acetone), DMSO-d6(perdeuteromethoxy), D2O - heavy water, CDCl3(deuterochloroform) and other conventional deuterated solvents. In the IR spectra indicate only the absorption at certain wave numbers (cm-1), which allows the identification of functional group compounds.

"Celite" is a trademark for diato the program: MS (MS) - mass spectrometry; VRMS (HRMS) - mass spectrometry high resolution; Ac is acetyl; Ph is phenyl, vol./about. - volume/volume; FAB - spectrometry by fast atom bombardment; NOBA - m - nitrobenzyloxy alcohol, min = minutes, h - hours (h, hr), NIS N - iodosuccinimide; BOC is t-butoxycarbonyl; CBZ or Cbz - benzyloxycarbonyl; Bn is benzyl; Bz is benzoyl; TES - triethylsilyl; DMSO (DMCO) - sulfoxide; THF (THF - tetrahydrofuran; HMDS - hexamethyldisilazane.

Obtaining raw materials

For various specific raw materials used in the subsequent formation of compounds of formula (A), is illustrated below.

Getting 1:

10-Dezazetilzefotaksima

< / BR>
(a) 2',7-O-bis(2,2,2-Trichloroisocyanuric)-10-deacetyltaxol

10-Deacetyltaxol (140 mg, 0,173 mm) in anhydrous dichloromethane (3.5 ml), at 0oC, was treated with pyridine (0,028 ml, 0,346 mm) and trichlorochloroform (0,0724 ml, is 0.260 mm). After keeping the mixture for 1 hour at the same temperature, the cold bath was removed and the mixture was stirred at room temperature overnight. The solvent is evaporated, and the obtained residue was chromatographically on silica gel (eluent: 30-50% ethyl acetate in hexane), and received the target compounds 25%) and 2.10-O-bis(2,2,2-Trichloroisocyanuric)- 10-deacetyltaxol (output - 16%).

(b) 2',7-O-bis(2,2,2-trichlorocyanuric)-10-deacetoxy-11,12 - dehydroacetate-10,12(18)-Dien

The product obtained in stage (a) (92,3 mg, 0.079 in mm) in anhydrous dichloromethane (2 ml) was treated at room temperature 1,1,2-triflora-2-chloroethylamine (0,0384 ml, 0,238 mm). The resulting solution was stirred over night. The solvent is evaporated, and the residue was purified by column chromatography (eluent: 25% ethyl acetate in hexane), resulting in a received target compound as a white powder (42,8 mg, 47,3%).

(c) 10-Deacetoxy-11,12-dehydroacetate-10,12(18)-Dien

The product of stage (b) (39 mg, 0,034 mm) was dissolved in methanol (0.5 ml) and acetic acid (0.5 ml) and then treated with acid washed zinc dust (66,4 mg, 1,020 mm). The suspension was heated at 40oC for one hour, filtered, and the filtrate evaporated. The residue was chromatographically (eluent: 60% ethyl acetate/hexane), and received the target compound in the form of foam (22 mg, 81%).

(d) 10-Dezazetilzefotaksima

The product of stage (c) (22 mg, 0,028 mm) in ethyl acetate (0.7 ml) was first made at atmospheric pressure in the presence of palladium charcoal (10%, 14,7 mg of 0.014 mm Pd). After keeping the mixture for 5.5 hours at room temperature, it was filtered is ocedure received target product (15,0 mg, 688) as a white foam.

Getting 2:

7-Deoxy-7-Perepelitsa

< / BR>
(a) 2'-O-Benzyloxycarbonyl-7-deoxy-7-Perepelitsa

TRIFLUORIDE diethylaminoethyl (DAST, to 18.7 μl, 0,141 mm) was dissolved in anhydrous dichloromethane (0.5 ml), and the solution was cooled to 0oC. Then was added a solution of 2'--(benzyloxycarbonyl)paclitaxel (71 mg, 0,072 mm) in dichloromethane (1 ml) and the resulting solution was maintained at 0oC for 30 minutes and at room temperature for 4 hours. Then, to terminate the reaction was added water (0.15 ml) and the resulting mixture was concentrated. The resulting residue was subjected to chromatography on a column of silica gel (eluent: 40% ethyl acetate in hexane) and received a mixture of 61 mg (1:1, 85,7%) of target compound and 2'--benzyloxycarbonyl-8-desmethyl-7,8-cyclopropylethanol.

(b) 7-Deoxy-7-Perepelitsa

A mixture of the product of stage (a) (89 mg) was dissolved in ethyl acetate (3 ml), and then gently stirred under hydrogen pressure of 1 ATM, in the presence of palladium charcoal (10% Pd, 29 mg, 0,027 mm). After 12 hours the solvent was removed and the residue was purified by chromatography on silica gel (eluent: 40% ethyl acetate in hexane), resulting in a received 67,7 mg of target compound - chloroapatite used the following HPLC method.

Equipment:

Pump: Series 4 RE

Column: Shandon Hypercarb (graphite carbon), 7 ám, 100 x 4.6 mm, # 59864750 (data size preparative columns can be obtained from the company Keystone Scietific, Bellefonte, PA)

Injector: PEISS - 100

Detector: HP-OM

Conditions

Mobile phase: methylene chloride: hexane = 85:15. The allocation does not give losses in respect of: methylene chloride: hexane: isopropanol = 80:19:1

Flow rate: 2.5 ml/min

Detector: 254 nm

Diluent: Sample dissolved in methylene chloride.

Getting 3:

7-Deoxy-7-forebalkan III

< / BR>
In a dry flask, in an atmosphere of inert gas, was added 2'-O-(benzyloxycarbonyl)paclitaxel (4 g, 4 mm) and anhydrous toluene (80 ml). The resulting suspension was stirred at room temperature, was added one drop of anhydrous tetrahydrofuran (16 ml) before formation of a colorless solution. The above solution was cooled to -78oC in a bath of dry ice and acetone, and then treated with the TRIFLUORIDE diethylaminoethyl (DAST, 1.2 ml, 2.5 EQ.). The reaction mixture was left to stir for 16 hours, gradually warming to room temperature. The resulting suspension was filtered, and the filtrate (diluted with 30 ml of ethyl the shawl magnesium sulfate and concentrated, as a result, we obtained the crude product as a white foam. This crude material was partially purified by column chromatography on silica gel (eluent: 10% CH3CN in CH2Cl2) and received 1.45 g of the mixture (benzyloxycarbonyl)-7-deoxy-7'-Perepelitsa and (benzyloxycarbonyl)-8-desmethyl-7,8-cyclopropylethanol (82:18), defined using the1H-NMR analysis.

The above mixture (1,45 mg) was dissolved in ethyl acetate (60 ml) and was treated with 300 milligrams of palladium charcoal. After 4 hours of agitation in an atmosphere of hydrogen at 50 psi (3,515 kg/cm2), the reaction mixture was purged, filtered through a narrow tube of silica gel and concentrated. Thus was obtained the desired product in the form of a mixture of 7-deoxy-7-Perepelitsa and 8-desmethyl-7,8-cyclopropylethanol as a white foam (1.24 g, yield - 99%, 90:10, defined by the1H NMR analysis). The resulting mixture was dissolved in dry methylene chloride (30 ml) and treated with tetrabutylammonium borohydride (745 mg, 2.9 mm, 2 EQ), and then left to stir for 6 hours. The reaction was suppressed by the addition of acetic acid (1 ml), diluted with 30 milliliters of methylene chloride, and then washed Nasli. Untreated uterine mixture of substituted taxane was partially purified by column chromatography on silica gel (eluent: 10% CH3CN in CH2Cl2) and received a mixture (90: 10, defined using the 1H-NMR analysis) of 7-deoxy-7-forobulgaria III and 8-desmethyl-7,8-cyclopropanation III (510 mg, 60%) as a white foam. The obtained foamy substance was led from hot isopropanol and received 7-deoxy-7-forebalkan III in the form of small white needle crystals (yield - 410 mg) with so pl. 234-236oC (Razlog.).

Getting 4:

10-Deacetoxy-7-deoxy-7-Perepelitsa

< / BR>
(a) 2'-O-Benzyloxycarbonyl-10-dezazetilzefotaksima

10-Dezazetilzefotaksima (27 ml, 0,034 mm) in dichloromethane (1 ml) was treated with benzylchloride (0,0146 ml, is 0.102 mm), and then diisopropylethylamine (0,0177 ml, is 0.102 mm). The reaction mixture was stirred at 0oC for 45 minutes and at room temperature for 12 hours. After evaporation of the solvent and chromatography was carried out on silica gel (eluent: 40% ethyl acetate in hexane), was obtained for 25.5 mg (yield of 81%) of target compound in the form of foam.

(b) 10-Desiccators-7-deoxy-7-Perepelitsa

The product of stage (a) (25,5 mg, 0,028 mm) in dichloromethane (0.8 ml) at 0oC, the reaction mixture was left for reaction for 5 hours at room temperature. The solvent is evaporated, and the mixture was subjected to chromatography and got benzyloxycarbonyl-7-deoxy-7-Perepelitsa in the form of a foamy crude product. This compound was dissolved in ethyl acetate (1 ml) and for 12 hours at room temperature, lightly stirred under hydrogen pressure of 1 ATM in the presence of palladium charcoal (10%, 8,9 mg). The catalyst was removed by filtration and the product was subjected to chromatography on silica gel, resulting in received 10 mg (yield - 40% after two steps) of the desired product in the form of foam.

Getting 5:

10-Deazetil-7-deoxy-7-Perepelitsa

< / BR>
A solution of 2', bi(2,2,2-Trichloroisocyanuric)-10-deacetyltaxol (120 mg, 0,103 mm) in dichloromethane (2 ml) was cooled at 0oC and treated TRIFLUORIDE, diethylamino-sulfur (0,0266 ml, 0,207 mm). The resulting solution was stirred for 30 minutes at 0oC for 4 hours at room temperature. After this reaction was suppressed by addition of water (0.05 ml). The reaction mixture was concentrated, and the residue was purified by chromatography on silica gel (eluent: 30% ethyl acetate in hexane) and received 81 mg (yield of 68%) of 2',10-bis(2,2, was dissolved in dry tetrahydrofuran (20 ml) was added in one portion imidazole (8,7 mg, 0,128 mm). After this was added (at room temperature) sodium hydride (50% in mineral oil, 77 mg, 1,597 mm). After cessation of gas (10 min) was added in one portion) of 4.6 ml of carbon disulfide. After settling for 3 hours at room temperature, the yellow solution was treated with methyliodide (0,238 ml 3,835 mm) and stirred over night. After treatment with ethyl acetate and water, had been the target connection in the form of a crude oily substance.

An alternative procedure

Baccatin III (394 mg, 0,672 mm) was dissolved in tetrahydrofuran (5 ml) and carbon disulfide (1 ml). Then to this solution was added sodium hydride (of 40.3 mg, 60%, with 1.009 mm). After this was added a catalytic amount of imidazole. The resulting reaction mixture was stirred at room temperature for 1.5 hours, and then added methyliodide (122,8 μl, 2,016 mm). After 40 minutes, the solvent was removed in vacuo, and the residue was chromatographically on silica gel (eluent: 20%-50%-60% ethyl acetate in hexano), resulting in a received target product (260 mg, yield - 57,2%) with 7-epibatidine (98,5 mg, 25%).

(b) [(Methylthio)thiocarbonyl]-13-O-triethylcitrate III

The product obtained in stage (a) (in the form of crude maxloop what lilholdem (2.10 ml, 12,78 mm) at room temperature for 15 hours. After this was added water, and the solution was extracted in ethyl acetate. The organic layer was washed thoroughly with water and then drained. After flash chromatography on silica gel (eluent: 20% ethyl acetate in hexane) was obtained target compound in the form of a glassy solid (yield - 20% of two stages; 209 mg).

An alternative procedure

The product obtained in stage (a) (193,4 mg, 0,286 mm) was dissolved in dry dimethylformamide (2,86 ml). To this solution was added imidazole (77.9 mg, 1.14 mm), and then triethylsilane (192 μl, 1.14 mm). The resulting reaction mixture was stirred over night at room temperature. After 12 hours the reaction mixture was diluted with 150 milliliters of ethyl acetate. The organic layer was washed with water (3 x 10 ml), brine (1 x 10 ml), dried and concentrated in vacuum. The obtained residue was chromatographically on silica gel (eluent: 20% ethyl acetate in hexane) was obtained target product (163 mg, yield - 72,0%).

(c) 7-Methoxytrimethylsilane III

The product obtained in stage (a) (182 mg, 0,230 mm) in dry benzene (5 ml) was heated to 80oC in the presence of anti-hydride (0,310 ml, 1,150 mm) and 2', 2'-azobisisobutyronitrile (AK was chromatographically on silica gel (eluent: 20% ethyl acetate in hexane) was obtained target compound in the form of an oily product.

(d) 7-Detectibility III

The product obtained in stage (c) was dissolved in tetrahydrofuran (5 ml) and treated with tetrabutylammonium fluoride (1M in tetrahydrofuran, and 0.50 ml, 0.50 mm) for 2 hours at room temperature. This solution was diluted with ethyl acetate, washed with water and brine, and then was subjected to chromatography on silica gel (eluent: ethylacetate/hexane, 1:1), resulting in a received target compound as a white glassy solid (63 mg, yield 58% of two stages).

Getting 7:

10-Datasetexception III

< / BR>
(a) 10-Deazetil-10--(Pantothenate)thiocarbonyl-7-O-triethylcitrate III

Triethylsilyl-10-deacetylbaccatin III (see Greene and others, J. etm. Chem. Soc. , 110 p. 5917, 1988) was dissolved in dry tetrahydrofuran (5 ml), cooled to -40oC, and treated with n-butyllithium (1,58 M in hexane, 0,384 ml, 0,606 mm). After 40 minutes at the same temperature, to the mixture slowly with a syringe, added pentafluorophenylacetonitrile (0,086 ml, 0,536 mm). The reaction mixture was stirred at -20oC for 90 minutes, was suppressed by adding a saturated solution of ammonium chloride, and extracted with ethyl acetate. An ethyl acetate layer was dried and concentrated. The residue was purified is received (320 mg, the output is 74%).

(b) 10-Deacetoxycephalosporanic III

The product obtained in stage (a) (1119 mg, is 0.135 mm) was dissolved in dry toluene (3 ml) and was treated with 2 milligrams of AIBN. The resulting solution obessively anhydrous nitrogen, and then added the anti-hydride (by 0.055 ml, 0,202 mm). Then the solution was heated for one hour at 90oC. then the solvent is evaporated and the residue was chromatographically on silica gel (eluent: 40% ethyl acetate in hexane) and received 87 mg (yield - 99%) target compound as a colourless foam.

(c) 10-Datasetexception III

The product obtained in stage (b) (120 mg, 0,187 mm) was dissolved in acetonitrile (3.5 ml) and the solution was cooled to -10oC. To the solution was added concentrated hydrochloric acid (36%, to 0.060 ml) and the solution was stirred for 30 minutes. The resulting mixture was diluted with 75 ml ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine, and then dried and concentrated. The residue was purified using flash-chromatography on silica (eluent: 70% ethyl acetate in hexane) and received 10-deacetylbaccatin III in the form of foam (75 mg, yield - 76%).

Getting 8:

10-Deacetoxy-7-detectibility III

< / BR>
(a) [(M is tetrahydrofurane (2 ml) and carbon disulfide (0.5 in MD). Then to the solution was added sodium hydride (60% in mineral oil, 8.5 mg, 0,213 mm), and the mixture was stirred at room temperature for 2 hours. After added iodomethane (0,026 ml, 0,426 mm), the reaction mixture was left over night to continue the reaction. The solvent was removed, and the residue was purified by chromatography on silica gel (eluent: 50% to 70% ethyl acetate in hexane), resulting in a received target compound in the form of foam (46.4 mg, yield - 53%).

(b) 10-Deacetoxy-7-detectibility III

The product obtained in stage (a) (36 mg, 0,058 mm) within 3 hours was heated under reflux in benzene (1 ml) in the presence of AIBN (2 mg) and anti-hydride (0,079 ml, 0,290 mm), and in an argon atmosphere. The reaction well was concentrated, and the residue was subjected to flash chromatography on silica gel (eluent: 40% ethyl acetate in hexane) followed by separation from other components using ghvd (liquid chromatography high pressure), resulting in a received target compound as a foam (yield - 56%; 16,8 mg).

An alternative procedure

To a solution 7-0-[(methylthio)carbonothioyl]-13--triethylenemelamine III (product get 1, stage (b), 0,527 mm, 416,3 mg) in anhydrous toluene (10.5 ml) was added catalytic the Lyali the anti-hydride (708,7 μl, 2,63 m) and the reaction mixture was heated for 2 hours at 100oC, after which was added another portion of the anti-hydride (425,3 μl, 1,581 mm). The resulting reaction mixture was heated at 100oC for 5.5 hours, and then left to cool to room temperature. After chromatography on silica gel (eluent: 20% ethyl acetate in hexane), was obtained 7 deoxy-10-deacetoxy-13(triethylsilyl)baccatin III (320 mg, yield - 97%).

To a solution of the product of the above stage (16.0 mg, 0,255 mm) in dry tetrahydrofuran (2 ml) at room temperature was added tetrabutylammonium fluoride (766 μl, 1M, 0,766 mm). The reaction mixture was stirred for 1 hour at room temperature. The solvent was removed and the residue was chromatographically on silica gel (eluent: 50 - 70% ethyl acetate in hexane), resulting in a received desired target product (115 mg, yield - 87,9%).

9:

(3R, 4S)-1-t-Butoxycarbonyl-4-phenyl-3-triethylsilyl-2-azetidinone

< / BR>
To peremeshannom the solution of (3R, 4S)-4-phenyl-3-triethylsilyl-2-azetidinone (2,200 g, 7.92 mm) in dry tetrahydrofuran was added at 0oC in argon atmosphere) N, N-diisopropylethylamine (1.65 ml, 9,510 mm, 1.2 EQ). The resulting solution was stirred for 5 minutes, followed obavljenimrevizijama 60 minutes at 0oC, and then was diluted with ethyl acetate (25 ml). After this, the solution was washed with saline, 10% NaHCO3, 10% hydrochloric acid, dried with magnesium sulfate and concentrated to obtain the crude product (oily substance). This compound was purified using flash chromatography on silica gel (eluent: 15% ethyl acetate in hexane) was obtained target compound as a white solid (2.4 g, yield of 83%.

10:

()-CIS-3-atomic charges-4-phenylaziridine-2-he

< / BR>
(a) l 3-necked round bottom flask equipped with thermometer, magnetic stirrer and addition funnel, was added hydrobenzoin (30,00 g, 100,5 mm) and ethyl acetate (150 ml). After stirring in an argon atmosphere, the reaction mixture was cooled to 5oC was added triethylamine (16,8 ml, 121 mm). Then drop by drop in the course of 90 minutes, the solution was added acetoxyacetyl (12,4 ml, 116 mm) in ethyl acetate (300 ml). After incubation for 16 hours at the same temperature, the reaction mixture was left to warm to room temperature (1.5 hours) and transferred into a separating funnel. The organic layer was sequentially washed with saturated aqueous NH4Cl (150 ml, 100 ml), saturated aqueous NaHCO3(120 ml) the drying of the organic phase with magnesium sulfate, filtration and removal of solvent in vacuo. Thus obtained crude ()-CIS-3-atomic charges of-1-[(phenyl)(benzylideneamino)methyl] -4-phenyl-azetidin-2-he (quantitative yield) as a red glassy product.

(b) Solution of the compound obtained in part (a) in ethyl acetate (500 ml) in an argon flow, carefully transferred to a 2.0-liter flask Parra containing 6,00 g 10% palladium on charcoal. This mixture was treated with hydrogen (4 ATM) for 20 hours, after which the catalyst was removed by filtration through a layer of Celite. The residue on the filter is suspended in ethyl acetate (200 ml), stirred (10 min) and filtered. After that, the filter cake was washed with ethyl acetate (100 ml) and the filtrates combined. The organic layer was washed with 10% hydrochloric acid (300 ml), and both layers were filtered through a funnel fused glass to remove the white precipitate (dibenzylamino HCl), which was washed with 100 milliliters of ethyl acetate. Then the phases were separated, and the organic layer was washed with another portion of 10% hydrochloric acid (200 ml). Joint 10% HCl leaching was again extracted with ethyl acetate (200 ml) and the combined organic layers were washed with saturated aqueous NaHCO3(300 ml) and brine (250 ml). Organies was cooled to 4oC and the precipitated product was isolated by filtration. The filter cake was washed with hexane (200 ml) and received 16,12 g (the full output from hydrobenzoic - 78,1%) target deposition in the form of white needle-shaped crystals, so pl. 150 - 151oC.

Obtaining 11:

()-CIS-3-Triethylsilyl-4-(2-furyl)-N-t-butoxycarbonylamino-2-he

< / BR>
(a) was Carried out by the procedure described in 10 (part (a), except that instead of hydrobenzoic used hydroformed [(i.e., 2-furyl-CH-N= CH-furyl)2] and the reaction was carried out on the scale 18.6 mm (instead of 100 millimoles). Thus, in the reaction hydroformed (of 5.00 g, 18.6 mm), triethylamine (3,11 ml, 22.3 mm) and acetoacetanilide (2.30 ml, 21,4 mm), received 6,192 g (yield -90,4% ()-CIS-3-atomic charges of-1- [(2-furyl)-2-feniletilamina)methyl] -4-(2-furyl)azetidin-2-it is in the form of a pale red syrupy substance.

(b) was Carried out by the procedure described in 10 (part b), except that the specified product was isolated using preparative TLC and the reaction was carried out at the scale of 2.7 mm from the initial amount of hydroformed. Thus, the crude product obtained in part (a), described above, was again dissolved in ethyl acetate (50 ml) and d the th TLC (2 mm silica gel, eluent: ethylacetat/hexane, 1 : 1) and received 386 mg (total yield from hydroformed was 65,8%) of ()-CIS-3-(atomic charges)-4-(2-furyl)azetidin-2-it is in the form of a yellow solid, which was then recrystallized from ethyl acetate/hexane, so pl. 118 - 119oC.

(c) the Compound obtained in the above paragraph (b) (of 3.78 g of 19.4 mm) in 60% methanol, was stirred with potassium carbonate in 90 minutes (20 mg, of 0.014 mm), and the solution was neutralized resin DOWEX 50W-X8 and filtered. The filtrate was concentrated, and the residue was dissolved in 80 ml of anhydrous THF and stirred (at 0oC) with imidazole (1.44 g, 21,2 mm) and TESCT (3.4 ml, 20,2 mm) for 30 minutes. The solution was diluted with ethyl acetate, washed with brine, dried with magnesium sulfate and concentrated. The residue was chromatographically on silica gel (eluent: hexane/ethyl acetate, 3 : 1) and received 4,47 g (yield of 86%) of ()-CIS-3-triethylsilyl-4-(2-furyl)-azetidin-2-it is in the form of colorless oily substance.

(d) the Product of part (c) (2,05 g, 7.7 mm) in 30 ml of dichloromethane was stirred at 0oC diisopropylethylamine (1.5 ml, 8,6 mm) and di-t-BUTYLCARBAMATE (2.0 g, 9.2 mm) in addition to a catalytic amount of dimethylaminopyridine (DMAP). The resulting solution was diluted with dichloromethane, produced on silica gel (eluent: hexane/ethyl acetate, 8 : 1) and obtained 2.0 g (yield of 70%) of target compound in the form of a waxy solid product.

The racemic mixture obtained in part (b) can be used as a substrate for enzymatic hydrolysis is carried out using lipase, such as PS-30, supplied by the firm of Pseudomonas sp. (Amano International Co. ) to obtain (3R,4R)-3-hydroxy-4-(2-furyl)-azetidin-2-it. Method enzymatic separation using lipase and other enzymes disclosed in our concurrently pending application for U.S. patent, reg. N 092170, filed July 14, 1993, which is entirely introduced into the present description by reference.

Procedures in paragraph (c) and part (d) was performed using (3R, 4R)-3-hydroxy-4-(2-furyl)-azetidin-2-it, the result was obtained (3R, 4R)-N-(t-butoxycarbonyl)-3-triethylsilyl-4-(2-furyl)azetidin-2-it.

Obtaining 12:

()-CIS-3-Triethylsilyl-4-(2-thienyl)-N-t-butoxycarbonylamino-2-he

(a) was Carried out by the procedure described in 10 (stage (a)), except that instead of hydrobenzoic used hydroceramic [(i.e., 2-thienyl-CH-N=CH-2-thienyl)2]. Thus, hydroceramic (30 g, 94,7 mm), triethylamine (15,84 ml, 114 mm) and acetoxyacetyl (to 11.6 ml, 108 mm) machining the form of a viscous oily substance.

(b) To a stirred solution of the product obtained in part (a) (0,431 g of 1.03 mm) in dichloromethane (2,93 ml) (at 25oC) was added in one portion of a 70% aqueous solution of acetic acid (0.35 ml ice-cold acid and 0.15 ml of water). The reaction mixture was heated under reflux and stirred for 2.5 hours. Then the reaction mixture was diluted with 50 ml dichloromethane, and then washed with two 75-ml portions of saturated aqueous sodium bicarbonate and one 50-ml portions of saturated salt solution. The organic extract was concentrated in vacuum to obtain a brown oily product, which was dissolved in minimum amount of dichloromethane and then placed on a column of silica gel having a size of 4 x 0.5 (101,6 x 12.7 mm). In the elution gradient 10% to 60% EtOAc in hexane, received less polar by-products, and then ()-CIS-3-atomic charges-4- (2-thienyl)-azetidin-2-he (0,154 g, yield - 75%) as a white solid.

(c) a solution of the product obtained in paragraph (b) (2.5 g, 11.8 mm) was dissolved in methanol (10 ml) and the resulting suspension was left to stir at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (20 ml) and prominance fractions were dried with magnesium sulfate and concentrated to obtain a yellow solid product (yield - 1.7 g). The crude material was dissolved in anhydrous tetrahydrofuran (20 ml) and the solution was cooled to 5oC ledeno/water bath. After this was added imidazole (752 mg, 1.1 EQ). After stirring for 5 minutes, to the solution drop by drop added triethylchlorosilane (of 1.85 ml, 1.1 EQ. ). The resulting suspension was stirred for 3 hours at the same temperature, and then the solids were removed by filtration. The organic fraction was washed with water (2 x 20 ml), dried with magnesium sulfate and concentrated. The crude product was purified by chromatography on silica gel (eluent : hexane/ethyl acetate, 7 : 3) and receive ()-CIS-3-triethylsilyl-4-(2-thienyl)-azetidin-2-it is in the form of a colorless solid (1.5 g, yield - 45%) with T. pl. 70 - 71oC.

An alternative procedure

The product obtained in paragraph (b) (2.0 g, 9,37 mm) in 40 milliliters of methanol was stirred with potassium carbonate (60 mg, 0,43 mm) for 30 minutes, and the solution was neutralized resin DOWEX 50 W-X8 and filtered. The obtained filtrate was concentrated, and the residue was dissolved in 50 ml of anhydrous THF and then stirred at 0oC with imidazole (0.85 grams, 11,3 mm) and TESCE (1.9 ml, 12.5 mm) for 30 minutes. The solution was diluted with ethyl acetate, washed with brine, dried with received 2,13 g (yield - 86%) of the desired product as colorless oily substance.

(d) a solution of the product obtained in paragraph (c) (427,7 mg, 1,48 mm) was dissolved in dichloromethane (10 ml) and cooled to 5oC in a bath of ice and water. The resulting reaction mixture was treated with a catalytic amount of DMAP, diisopropylethylamine (TESCI, 0.25 ml, 1.0 EQ.), and then di-t-butyl-dicarbonate (of 388.4 mg, 1.2 EQ.). After stirring for 2 hours at the same temperature, the reaction was suppressed saturated aqueous sodium bicarbonate (5 ml), the organic fraction was washed with water (5 ml), then were dried with magnesium sulfate, passed through a short tube with silica gel, and concentrated, resulting in a received desired product as colorless oily substance (523,3 mg, yield - 93%).

13:

(3R, 4R)-3-Triethylsilyl-4-(2-furyl)-N-n-butyloxycarbonyl-2-he

< / BR>
(3R, 4R)-3-Triethylsilyl-4-(2-furyl)azetidin-2-he (0.51 g, 1,91 mm) in 25 ml of dichloromethane, mixed with diisopropylethylamine (0,78 ml, 4.4 mm) and N-propylchloride (4.0 ml, 1.0 M in toluene), 4.0 mm) in addition to a catalytic amount of DMAP. The resulting solution was stirred 1 hour, diluted with dichloromethane, washed with brine, dried with magnesium sulfate and avago connection (output - 96%).

IR (KBr): 1822, 1812, 1716, 1374, 1314, 1186, 1018, 1004, 746 cm-1.

1H-NMR (CDCl3, 300 MHz) : 7,39 (m, 1H), 6.35mm (m, 2H), 5,08 (Avcv., J = the 15.6, 5.6 Hz, 2H), 4,96 (d, J = 10.0 Hz, 1H), 1,25 (d, J = 7,3 Hz, 3H), of 1.17 (d, J = 6.3 Hz, 3H), or 0.83 (t, J = 7.8 Hz, 9H), and 0.50 (m, 6H);

13C-NMR (CDCl3, and 75.5 Hz) : 165,5, 148,6, 147,8, 142,9, 110,5, 109,9, 77,6, 71,1, 55,9, 21,7, 21,6, 6,3, 4,4;

DCI-MS (M+H) for C17H18NO5Si:

Calculated: 354,

Found: 354.

Obtaining 15:

-CIS-3-Triethylsilyl-4-isobutyl-N-t-butoxycarbonyl-azetidin-2-he

(a) N-4-methoxy-N-(3-methyl-2-butenyl)-benzolamide

< / BR>
A solution of p-anisidine (5.7 g, 46,3 mm) was dissolved in diethyl ether (100 ml) and was treated with a catalytic amount of p-toluensulfonate acid (10 mg). To this mixture was added one portion of 3-methyl-2-butenal or 2.67 ml, 50,9 mm) and the reaction mixture was stirred at room temperature for 16 hours. The solvent is then evaporated on a rotary evaporator at 0.5 Torr. , and received need Imin (8.7 g, 100%) as a brown oily substance.

1H-NMR (300 MHz, CDCl3) : scored 8.38 (D., 1H, J = 9.5 Hz), 7,11 (DD., 2H, J = 2,2, 6,7 Hz), to 6.88 (DD, 2H, J = 2,2, 6,7 Hz); 6.22 per 6,18 (m, 1H); 3,81 (s, 3H); 2,01 (C. 3H); 1,95 (s, 3H).

(b) -CIS-N-(4-methoxyphenyl)-3-atomic charges-4-isobutylamides-2-he

< / BR>
Rastertogo gas. To this solution was added triethylamine (7.0 ml, 50,5 mm) for 5 minutes. The obtained white suspension was treated drop by drop within 20 minutes, ethyl acetate and a solution of N-4-methoxy-N-(3-methyl-2-butenyl)-benzenamine (8.7 g, 40 ml). Then, the thus obtained green-brown suspension was gradually heated to room temperature within 4 hours. After that, the suspension was filtered through a layer of celite, and the filtrate was washed with water and then brine. The organic fraction was dried with magnesium sulfate and concentrated to obtain a brown oily substance. The crude product was carefully purified by chromatography on silica gel (eluent: hexane/ethyl acetate, 8:2) and received an orange oily substance, which was utverjdali when defending. Then this substance was recrystallized from dichloromethane/hexane, and obtained the desired product as a pale yellow solid (4.4 g, 32%).

1H-NMR (300 MHz, CDCl3) : to 7.32 (d, 2H, J = 9.1 Hz), 6,86 (d, 2H, J = 9.1 Hz), 5,59 (DD, 1H, J = 3,0, 7,8 Hz), 5,14 - 5,10 (m, 1H), 4,96 (DD, 1H, J = 4,8, and 9.3 Hz), of 3.77 (s, 3H), 2,11 (s, 3H), of 1.81 (s, 3H), of 1.78 (s, 3H).

(c) ()-CIS-3-atomic charges-4-isobutylamides-2-he

< / BR>
A solution of ()-CIS-N-(4-methoxyphenyl)-3-atomic charges-4-isobutylamides-2-she (and a cold solution of ammonium cerium nitrate (26,6 g, 48,6 mm, 50 ml) in one portion). Dark red reaction mixture was left for stirring for 10 minutes, and during this time the color of the mixture gradually became orange tint. The cold solution was transferred into a separating funnel, diluted with water, extracted with ethyl acetate. The organic fraction was washed with several portions of 10% aqueous sodium sulfite, and then saturated aqueous sodium bicarbonate. After that, the organic fraction was dried with magnesium sulfate and concentrated to obtain the desired product (2,71 g, 91%) of yellow-orange, which was used directly in the subsequent stage.

1H-NMR (300 MHz, CDCl3) : 6,11 (Shir.s, 1H); 5,73 (DD, 1H, J = 2.2, while the 4.7 Hz), 5,12 - 5,08 (m, 1H), 4,63 (DD, 1H, 4,7, and 9.1 Hz), is 2.09 (s, 3H), of 1.75 (s, 3H), 1,67 (s, 3H).

(d) ()-CIS-3-Triethylsilyl-4-isobutylamides-2-he

< / BR>
()-CIS-3-atomic charges-4-isobutylamides-2-he (1.47 g, 8.0 mm) was dissolved in methanol (15 ml) and stirred with potassium carbonate (110,5 mg, 0.8 mm) for 3 hours at room temperature. The resulting solution was neutralized with the power of DOWEX 50W-X8, and then filtered. The filtrate was concentrated, and the crude solid product was dissolved in THF (25 ml) and cooled to 5oC in an ice bath. Then add I8,0 mm). The resulting suspension was heated to room temperature and was stirred overnight. The solution was filtered, and the filtrate was washed with water and then brine. The organic fraction was dried with magnesium sulfate and concentrated. Thus obtained crude solid was purified by chromatography on silica gel (eluent: hexane/ethyl acetate, 3: 1) and obtained the desired product (612 mg, 30%) as a pale yellow solid.

1H - NMR (300 MHz, CDCl3) : by 5.87 (Shir.s, 1H), 5,31 - of 5.26 (m, 1H), 4,90 (DD, J = 2.2, while the 4.7 Hz), 4,42 (DD, 1H, J = 4,7, and 9.3 Hz), 1,74 (s, 3H), 1.28 (in s, 3H), 0,98 - of 0.91 (m, 9H), 0,71 is 0.55 (m, 6H).

(e) ()-CIS-3-Triethylsilyl-4-isobutyl-N-t - butoxycarbonylamino-2-he

< / BR>
()-CIS-3-Triethylsilyl-4-isobutylamides-2-he (1.01 g, 3,95 mm) was dissolved in dichloromethane (20 ml) and treated with diisopropylethylamine (0.68 ml, 3,95 mm) and a catalytic amount of dimethylaminopyridine. To this solution was added di-t-BUTYLCARBAMATE (1,02 g, and 4.68 mm), and the solution was left to stir at room temperature for 24 hours. The resulting solution was diluted again with dichloromethane, washed with water and then brine. The organic fraction was dried with magnesium sulfate and concentrated. The residue was purified ambasciatore oily substance.

1H-NMR (300 MHz, CDCl3) : 5,24 (d, 1H, J = 9.6 Hz); a 4.86 (d, 1H, J = 5.7 Hz); 4.72 in (DD, 1H, J = 6,0, 9.9 Hz); of 1.78 (d, 3H, J = 1.1 Hz); of 1.75 (d, 3H, J = 1.1 Hz); of 1.47 (s, 9H), 0,96 - of 0.91 (m, 9H), of 0.64 to 0.55 (m, 6H).

The procedure in the receiving 9, 11(d) 12(d), 13, 14, and 15(e) can be applied to other N-substituted azetidinone that are used in obtaining the compounds of the present invention.

Examples of such azetidinone presented in the following table 4. P represents a hydroxy-protective group, such as triethylsilyl, triisopropylsilyl and ethoxyethyl.

< / BR>
Obtaining 16:

10-Detoxicated

< / BR>
10-Deacetoxy-7--triethylcitrate III (100 mg, 0,156 mm) were placed in the flask (in argon atmosphere) was dissolved in anhydrous tetrahydrofuran (1.5 ml). After cooling to -40oC, one drop was added n-utility (1.45 M in hexane, 0,119 ml, 0,170 mm), and then within 2 minutes was added (3R, 4S)-1-tert.-butoxycarbonyl-4-phenyl-3-triethylsilyl-2-azetidin cases (94.2 mg, 0.25 mm) in tetrahydrofuran (0.5 ml). This mixture was immediately warmed to 0oC and stirred for 45 minutes, after which the reaction was suppressed by the addition of saturated ammonium chloride (3 ml). Then the mixture was extracted with ethyl acetate, dried and concentrated. After chromatography is(125 mg, outlet - 76%). The compound obtained (100 mg, 0,098 mm) was dissolved in acetonitrile (2 ml) at -5oC and treated with hydrochloric acid (0.037 ml, 36%, 12M). The reaction mixture was stirred for 2 hours at -50oC, and then extinguished aqueous bicarbonate, extracted with ethyl acetate, and dried off. The solvent is evaporated, and after chromatography on silica gel (eluent: 75% ethyl acetate in hexane) was obtained target compound in the form of foam (80,5 mg, yield - 80%).

The General procedure used in obtaining 16 can be applied to obtain other compounds of formula (1a), on the basis of the corresponding baccatin III and azetidinone. Examples of other compounds of formula (1a) is illustrated in the following table 5. However, it should be noted that although the following compounds have free hydroxyl groups, however, with the appropriate choice of the various hydroxyl groups, any of these protective groups at the 2'-, 7-, or 10-position, can be selectively removed without any impact on other present protective groups.

Obtaining 17:

Bis(methylthiomethyl)ether

CH3SCH2OCH2SCH3< / BR>
To a solution of 1,1'-dichlorodimethyl ester (3.0 g, 26,3 mm) in acetone (100 ml), at 0is it a mixture of the four portions was added thiamethoxam sodium (1.84 g, 5,23 mm), and the resulting solution was stirred for another 1 hour. After this heterogeneous solution was filtered through a layer of celite, and the filtrate was concentrated in vacuum. The remainder in the form of an oily substance was distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was removed, and then was extracted with ethyl acetate. The combined organic layers were treated with a mixture (1:1, V/V) saturated aqueous sodium bicarbonate and 5% aqueous sodium thiosulfate solution. Then the organic layers were washed with saline, dried with sodium sulfate, and concentrated in vacuum. The residual oily product was purified using flash chromatography (30:1, hexane/ethyl acetate) was obtained 1.9 g of a yellow oily substance, which was then subjected to Kugelrohr distillation (120-130oC, 20 mm RT.cent.), the result that was obtained 1.5 g (45%) of target compound as a colorless oily substance.

1H-NMR (300 MHz, CDCl13) : to 4.73 (4H, s), of 2.15 (6H, s).

Obtaining 18:

Dibenzyldithiocarbamate

CH3SCH2OP(O)(OBu)2< / BR>
To a solution of bis(methylthiomethyl)ester (30 mg, 2,34 mm) and molecular sieves (300 mg) in THF (100 ml), at room temperature, was added dimensios the second mixture was diluted with ethyl acetate and filtered through a layer of celite. The filtrate was treated with a mixture (1:1, V/V) solution of saturated aqueous sodium bicarbonate and 5% aqueous sodium thiosulfate. Colorless organic extract was washed with saline, dried with sodium sulfate and concentrated in vacuo, resulting in a received 600 mg (69%) of target compound

1H-NMR (300 MHz, CDCl3) : to 7.35 (10H, s); of 5.29 (2H, d, J = 12,2 Hz) 5,08 (4H, DD, J = 8.0 a, 1.0 Hz), and 4.68 (2H, s) of 2.10 (3H, s),

Examples.

The following examples illustrate the synthesis of typical compounds of the present invention and should not be construed as a limitation of the scope of the present invention. Every person is able to use the described methods, without undue experimentation, for the synthesis of compounds included in the scope of the present invention but not specifically disclosed in the present description.

Example 1:

7-O-phosphonomethylglycine and its monosodium salt

(a) Obtaining 7-O-methyldiethanolamine

< / BR>
At 0oC, to a vigorously stirred mixture of paclitaxel (0,85 g, 1 mm) and dimethyl sulfide (to 0.72 ml, 8 mm) in anhydrous acetonitrile (10 ml) was added benzoyl peroxide (0,98 g, 4 mm). Stirring was continued for 2.5 hours at 0oC. Over the coursetaxes= 0,38, Rfcont.= 0,64), and if there was observed the formation of more mobile products, the reaction was suppressed by evaporation of the solvents on a rotary evaporator at 30oC. TLC analysis of the reaction mixture indicated the presence of some amount of unreacted paclitaxel and 2', 7-O-bis(methylthiomethyl)of paclitaxel. The isolation of target compounds from the reaction mixture was performed using flash chromatography on a column of silica gel 60(40-63 μm) EM Science (100 ml) (column diameter-2 inches) using the solvent system: ethyl acetate/hexane (1:1, by volume) (RfAve= 0,34 ). The resulting product (552 mg, yield - 60%) was isolated from fractions 12-18 (each fraction was approximately 20 ml).

MC (FAB/NOBA matrix, NaI, KI): [M+H]+m/z : 914, [M+Na]+m/z : 936; [M+K]+m/z 952.

Elemental analysis:

Calculated: C 64,28

Found: 5,85

Elemental analysis for 64,39:

Calculated: 6,07

Found: H 5,85

Calculated: C 1,53; N 1,46

UV (MeOH):max= 226 nm, E(1%/1 cm) = 150, A = 0,2653.

IR (KBr): 3432, 3066, 2940, 1726, 1668, 1602, 1582, 1514, 1484, 1452, 1372, 1242, 1178, 1142, 1108, 1068, 1026, 990, 916, 884, 852, 802, 774, 710, 608, 570, 538, 482 cm-1.

1H-NMR (CDCl3) : to 1.15 (3H, s); 1,19 (3H, s) of 1.73 (3H, s), 1,79 (H, C) 1,90 (3H, d), is 2.09 (3H, is), 5,65 (H, d), 5,77 (H, DD), 6,16 (H, DD), 6.48 in (H, s), 7,07 (H, d), 7.29 trend is 7.50 (10H, m), EUR 7.57 (H, m), 7,73 (2H, d), 8,08 (2H, d).

(b) Obtain 7-O-dibenzylethylenediamine

< / BR>
A solution of N-iodosuccinimide (45 mg, 0.2 mm) and dibenzylamine (55 mg, 0.2 mm) in anhydrous tetrahydrofuran (4 ml) was added to a mixture of 7-O-methyldiethanolamine (119 mg, 0.13 mm) and powdered molecular sieves 4A (about 120 mg) in anhydrous 1,2-dichloroethane (5 ml). The reaction mixture was stirred at room temperature for 16 hours. Over the course of the reaction was observed by TLC (solvent system: toluene/acetone, 2: 1, by volume) (PfAve= 0,48). The molecular sieves were removed by filtration through a layer of celite (Celite 545), and the filtrate was extracted with methylene chloride (100 ml). The organic layer was washed with 1% sodium thiosulfate solution (approx. 100 ml) and 0.5 moles of sodium bicarbonate (100 ml) and then brine. The extract was filtered through Whatman Phase Separator and the solvent evaporated. After purification using flash chromatography on silica gel 60 (methylene chloride/ethyl acetate, 2: 1, by volume) was obtained 7-O-dibenzylethylenediamine at 41.5 mg).

(c) Obtain 7-O-phosphonomethylglycine and its monosodium salt

< / BR>
7-O-Diben ml). The hydrogenation was carried out at 40 psi (275 kPa) for one hour and at room temperature. Over the course of the reaction was observed by TLC in a mixture of chloroform, methanol and water (120:45:8, volume). After purification using preparative TLC (HH,05-cm plate with silica gel in an analytical system), received 7-O-phosphonomethylglycine (26 mg, yield - 75%).

Because the process silikagelevye cleaning was observed decomposition of 7-O-dibenzylethylenediamine, the hydrogenation procedure was modified. Thus, the crude extract 7-O-dibenzylethylenediamine was first made without additional purification. The hydrogenation of the crude extract 7-O-dibenzylethylenediamine was carried out at 60 psi (400 kPa) for 24 hours.

7-O-Phosphonomethylglycine (70 mg) was dissolved in 5 ml of acetone and water (1:1), and was diluted with water to a volume of 50 ml was then added anhydrous sodium bicarbonate (18 mg, 1.2 EQ.). The acetone is evaporated at room temperature using a rotary evaporator and the remaining aqueous solution was liofilizovane. Untreated monosodium salt of 7-O-phosphonomethylglycine was purified using obremenitve colonoy ghvd (15 cm; Jones C18-column, 1 ml/min, 1=230 to 270 nm) in a mixture: acetonitrile/0.05 M buffer of ammonium acetate (45:55 by volume), pH 7, Rt= 2,09 minutes the Fractions containing the desired product were combined, the acetonitrile evaporated, and the residual aqueous solution was liofilizovane, resulting in the received 7-O-phosphonomethylglycine monosodium salt (112 mg).

MC (FAB): [M+H]+m/z 986; [M+Na]+m/z: 1008.

UV (MeOH)max=: 230 nm, E (1%/1 cm) = 248.

IR (KBr): 3430, 3066, 2948, 1724, 1652, 1602, 1580, 1518, 1486, 1452, 1372, 1316, 1246, 1178, 1154, 1108, 1070, 1000, 982, 946, 856, 802, 776, 710, 628, 538 cm-1.

1H-NMR (acetone-d6/D2O) : with 8.05 (2H, d); a 7.92 (2H, d) ; the 7.65 (1H, DD), 7,58-to 7.35 (9H, m, overlapping), of 7.23 (1H, DD), 6,38 (1H, s), between 6.08 (1H, t), the 5.65 (1H, d), the ceiling of 5.60 (1H, d), 5,10 (1H, Shir. C) at 4.99 (1H, d); equal to 4.97 (1H, Shir. C) 4,80 (1H, d), 4,28 (1H, DD), 4,11 (2H, s), with 3.79 (1H, d), to 2.94 (1H, m) to 2.35 (3H, s), 2,35-2,10 (1H, m) to 2.13 (3H, s), of 1.95 (3H, s) of 1.84 (1H, m), and 16.7 (3H, s) of 1.13 (6H, s, overlapped).

Example 2

An alternative way to obtain 7-O-phosphonomethylglycine

(a) Obtaining 2'-O-(benzyloxycarbonyl)of paclitaxel

< / BR>
To a stirred solution of paclitaxel (150 mg, 0,176 mm) and N,N-diisopropylethylamine (93 μl, 0,534 mm, 3 EQ.) in anhydrous methylene chloride (4 ml) at room temperature, was added benzylchloride (75 μl, 0,525 mm, 3 EQ.). Regale on a column of silica gel (eluent: ethyl acetate/hexane) (1:1), and received the target compound as a white powder (150 mg, yield - 86%), so pl. 140-150oC (Razlog.).

(b) Obtaining 2'-O-(benzyloxycarbonyl)-7-O-methyldiethanolamine

< / BR>
To a cooled (in a bath of dry ice/CCI4at a temperature of -30oC) solution of 2'-O-(benzyloxycarbonyl)paclitaxel (4,935 g, 5.0 mm) in dry acetonitrile (80 ml) was added sequentially dimethyldisulfide (3.6 ml, 40 mm) and benzoyl chloride (4.9 g, 20,247 mm). After incubation for 10 minutes at -30oC, the cold bath was removed, and the reaction mixture was vigorously stirred for 2 hours at room temperature. Then the reaction mixture was diluted with ethyl acetate to a volume of 200 ml, and washed with water and brine. The organic layer was dried with magnesium sulfate, and the solvent is evaporated, resulting in the formed residue, which was kept under vacuum for 18 hours to remove the DMSO, which was present as a reaction byproduct. Then the residue was purified on a column of silica gel, using as eluent to remove less polar impurities, ethyl acetate/hexane (1:2), and then ethyl acetate/hexane (1: 1), resulting in a received target compound in the form of foam. Then chapeaurouge solid (5.0 g 95%) with T. pl. 120-122oC).

MC (FAB): [MH]+: m/z: 1048; [M+Na]+m/z; 1070; [M+K]+m/z : 108.

IR (KBr): 3440, 3066, 1750, 1722, 1664, 1602, 1583, 1538 cm-1.

NMR (CDCl3) : 1,177 (3H, s), 1,236 (3H, s), 1,745 (3H, s); 2,023 (3H, s), 2,121 (3H, s) 2,162 (3H, s) 2,436 (3H, s) 3,887 (H, d) 4,134 (H, o) 4,197 (H, o) 4,295 (H, m) 4,964 (H, d), 5,161 (2H, d), 5,450 (H, d), 5,703 (H, d), 5,981 (H, DD), 6,257 (H, t) 6,541 (H, C) 6,920 (H, e), NH), 7,332 is 8.22 (15H, m).

The target compound was also obtained an alternative method, described below.

To a solution of 2'-O-(benzyloxycarbonyl)paclitaxel (2.0 g, 2,0263 mm) in anhydrous dimethyl sulfoxide (10 ml) drop by drop) was added acetic anhydride (10 ml). The resulting mixture was stirred at room temperature for 18 hours under nitrogen atmosphere, was diluted with ethyl acetate (100 ml), and washed with cold 6% sodium bicarbonate solution (g ml), cold water (I ml), and brine. The organic layer was dried with magnesium sulfate, and the solvent is evaporated, resulting in the formation of residue. This residue was purified on a column of silica gel (eluent: methylene chloride, methylene chloride/5% acetonitrile, and methylene chloride/10% acetonitrile) and obtained the desired compound (1.86 g, 87.7 per cent). This compound is identical with the compound obtained previously described method using the helpalliance

< / BR>
To a solution of 2'-O-(benzyloxycarbonyl)-7-O-methyldiethanolamine (5.0 g, 5,5369 mm) in dry 1,2-dichloroethane (120 ml) was added activated powdered molecular sieves 4A (5.0 g). To this mixture drop by drop at room temperature was added a solution mixture of N-iodosuccinimide (1,61 g, 7,1632 mm) and dibenzylamine (1.97 g, 7,1632 mm) in dry tetrahydrofuran (90 ml). After vigorous stirring at room temperature for 30 minutes, the reaction mixture was filtered through a layer of celite, and the filtrate is evaporated to dryness, which formed the red residue. This residue was dissolved in ethyl acetate (100 ml), washed with cold 6% solution of NaHSO3(2x50 ml), cold 6% solution of NaHCO3(2x50 ml), and sileven solution (1x50 ml). The organic layer was dried with magnesium sulfate, and the solvent is evaporated, and received a solid mass, which was pereirae with anhydrous ether and filtered, resulting in a received target compound in the form of a solid substance having ivory (5.9 g, 97%), so pl. 124-127oC

MC (FAB): [MH]+m/z: 1278, [M+Na]+m/z: 1301; [M+K]+m/z 1316.

IR (KBr): 3430, 3066, 3032, 1750, 1726, 1664, 1582, 1532 cm-1< / BR>
NMR (CDCl3) : 1,160 (3H, s), 1,703 (3H, s) 1,985 (3H, s) 2,164 (3H, s) 2,420 (3H, s) 3,854 (H, d), 4,151 (H, d), 4,216 tx2">

(d) Obtain 7-O-phosphonomethylglycine

To a solution of 2'-O-(benzyloxycarbonyl)-7-O-dibenzylethylenediamine (6.0 g, 4,7095 mm) in ethyl acetate (120 ml) was added 10% Pd/C (6.0 g) and the resulting mixture was hydrogenosomal at 60 psi (400 kPa) for 24 hours. The reaction mixture was filtered through a layer of celite, and the solvent evaporated, resulting in a received 4,07 g of crude residue. This residue was purified using a narrow column with silica gel, consistently elwira chloroform/10%, 20% and 40% methanol, and was obtained target compound as white solid (3.2 g, 71%) with T. pl. 155-158oC.

This product had the same value of Rf(TLC) and the same retention time (ghvd), as an authentic sample.

MS (FAB): [MH]+m/z: 964; [M+Na]+m/z: 986; [M+K]+m/z 1002. [M+K++Na+-H]+m/z: 1024, [M+2K-H]+m/z : 1040.

UV (MeOH):max= 230 nm, E (1%/1 cm) = 252,5

IR (KBr): 3432, 3066, 2992, 1722, 1648, 1602, 1580, 1522, 488, 1452, 1372, 1316, 1246, 1178, 1154, 1110, 1070, 1000, 980, 946, 854, 802, 776, 710, 628, 538 cm-1.

NMR (acetone-d6/D2O) : 1,08 (3H, s), 1,10 (3H, s), and 1.63 (3H, s), a 1.88 (3H, s), 1,96 (H, m) to 2.13 (3H, s), 2,32 (3H, s), 2,89 (H, m), 3,76 (H, d), 4,19 (H, m), 4,89 (H, DD), 5,09 (H, DD), 5,55-the ceiling of 5.60 (2H, overlapping with), 6,04 (H, t), 6,32 (H, s), 720 (H, t), 7,34-to 7.67 (10H who helpalliance

(a) Obtaining 2'-O-(etoxycarbonyl)of paclitaxel

< / BR>
To a solution of paclitaxel (4.35 g, 5.1 mm) in anhydrous methylene chloride (51 ml) was added N,N-diisopropylethylamine or 2.67 ml, 15,3 mm), and then ethylchloride (1,46 ml, 15,3 mm). The resulting reaction mixture was stirred at 0oC for 2 hours and then at room temperature for another 1 hour. The reaction mixture was diluted with ethyl acetate (400 ml) and the organic phase was washed with saturated solution of NaHCO3(2x30 ml) and brine (30 ml). The organic phase was dried with magnesium sulfate and received the crude target product (93%) which was used in the subsequent stage without further purification.

MC (FAB/NOBA, NaI, KI): [M+H]+m/z: 926; [M+Na]+m/z: 948; [M+K]+m/z: 964.

HPMC (FAB/NOBA, external standard CSI/GIy): [M+H]+m/z C26, 3588 calculated: 926, 3588,

Analysis for C50H56NO16:

Calculated: 926,3599 (deviation = 1,2 ppm).

1H-NMR (CDCl3) : of 1.13 (3H, s) of 1.23 (3H, s) of 1.30 (3H, t) to 1.67 (3H, s) of 1.92 (3H, s), of 2.21 (3H, s), 2,37 (H, d), a 2.45 (3H, s) 2,54 (H, m), 3,80 (H, d), 4,15-4,32 (4H, m, overlapping), 4,43 (H, DD), 4,93 (H, d), 5,42 (H, d), 5,68 (H, d), 5,98 (H, DD), 6,28 (2H, m, overlapping),7,00 (H, d), 7,34-to 7.59 (11H, overlapping m); 7,74 (2H, d), to 8.12 (2H, d),

***An alternative procedure

Politilena (3,30 ml, 3 EQ. ), and then for 5 minutes on a drop added net ethylchloride (1,81 ml, 3 EQ.). Over the course of the reaction was observed by TLC (50% ethyl acetate in hexane). After incubation for 2 hours at 0oC and 16 hours at room temperature, the reaction was completed, and the resulting yellow-orange solution was diluted with ethyl acetate (300 ml) and washed with saturated sodium bicarbonate (3x75 ml) and brine (75 ml). After drying with magnesium sulfate and evaporation, received the crude target compound, which was purified by precipitation: that is, at first, was added dichloromethane (approx. 100 ml), then cooled and added hexane (approx. 60 ml) to the point of turbidity. After cooling in ice for several hours, the resulting solid substance was collected by filtration (yield of 5.17 g, 88%).

An alternative procedure

In drained flame, odnogolosy three-liter flask was dissolved paclitaxel (99,0 g, 115,9 mm) 3,150 ml of dry methylene chloride, under nitrogen atmosphere. The resulting solution was cooled to - 10oC. then slowly added N, N-diisopropylethylamine (5+4 g, 405,7 mm) (extra time 3 min), and then ClCO2Et (31,45 g, 289,8 mm, more. time 15 minutes). The resulting mixture was stirred overnight (16 Isopropylacrylamide (2,62 g, to 20.28 mm), then ClCO2Et (2.20 g, to 20.28 mm), and the stirring was continued for 3 hours at -4oC. When TLC does not detect the presence of the source material. The cold mixture was diluted with ethyl acetate (1.5 l) and transferred into a separating funnel. Then this mixture is washed with 5% KHSO4(2 x 500 ml), water (1 x 500 ml), 5% KHSO4(1 x 500 ml), again with water (1 x 500 ml), then saturated NaHCO3(2 x 500 ml) and brine (2 x 500 ml). After drying with magnesium sulfate and evaporation of the solvents in vacuo, got 147 g of the crude product. The residue was dissolved in hot methylene chloride (8000 ml, bath temperature -42oC) and under stirring, one drop was added hexane (530 ml), while maintaining the temperature of the 42oC. the resulting crystalline mixture defended for 3 hours at room temperature and then at 0oC during the night in a cold room. The resulting heavy white crystals were collected by filtration and washed hexane/methylene chloride (1: 1, by volume, 2 x 200 ml). After drying on a suction filter for 1 hour, the crystals were dried under vacuum ( 1.0 mm RT. St) during the night, and got to 95.7 g (yield 89 percent) of the target compound (a measure of homogeneity, as measured by Ehud amounted to 98.5%).

3
(3 x 40 mol) and water (2 x 40 ml). The obtained organic layer was dried with magnesium sulfate, and the solvent evaporated in vacuum to dryness. The residue was purified by chromatography on silica gel (eluent: 40% ethyl acetate in hexane) and received the target connection (4,39 g, 94%). MS (FAB/NOBA, NaI, KI):[M+H]+m/z: 986; [M+Na]+m/z: 1008, [M+K]+m/z: 1024.

HPMC (FA/NOBA, external standard CSI/GLy): [M+H]+m/z: 9863646 (Calculated: 9863633, reject = 1,3 ppm).

1H-NMR (CDCl3): of 1.18 (3H, s); of 1.20 (3H, s) of 1.30 (3H, s) of 1.75 (3H, s), 1,84 (H, m), is 2.09 (3H. C) 2,11 (3H, s) of 2.16 (3H, s), 2,24 (H, d), 2,37 (H, d), a 2.45 (3H, s), 2,80 (H, m), 3,68 (H, d), 4,08 -4,33 (5H, m, overlapping) and 4.65 (2H, s), 4,96 (H, d), 5,43 (H, d), 5,69 (HH, d), 5,98 (H, DD), of 6.26 (H, t), 6,55 (H, C) 7,00 (H, d), 7,32-to 7.61 (11H, m, overlapping), 7,73 (2H, DD), 8,11 (2H, DD).

An alternative procedure

2'-O-(Etoxycarbonyl)paclitaxel (2,260 g, 2,4406 mm) was dissolved in anhydrous dimethyl sulfoxide (6 ml), and one portion (at room temperature) was added acetic anhydride (6 ml). Over the course of the reaction was observed using ghvd (analytical C18-column, elwen mawali saturated aqueous bicarbonate (3 times), and then water and brine. After drying with magnesium sulfate and filtering, was obtained the crude product. This product has chromatographically on silica (eluent: 40% ethyl acetate in hexane) was obtained target compound as a white foam (2,030 g, 91%) which had a purity of 90% (ghvd). In addition, part of this compound was purified on the second column (eluent: 5% acetonitrile in dichloromethane), resulting received the product, which had a purity of approximately 97% (ghvd).

An alternative method of obtaining 2'-O-(etoxycarbonyl)-7-O-methyldiethanolamine

2-O-(Etoxycarbonyl)paclitaxel (4,170 g 4,503 mm) was dissolved in anhydrous acetonitrile (68 ml) at -40oC, was added dimethyl sulfide (3.2 ml, 44,10 mm), and then benzoyl peroxide (4,400 g, 18,24 mm). The mixture was placed in an ice bath and stirred at 0oC, after which the progress of the reaction was observed by TLC (40% ethyl acetate in hexane). After 3 hours of starting material was not detected, and therefore the solution was treated by adding ethyl acetate (250 ml) and saturated aqueous sodium bicarbonate (100 ml). In addition, the organic phase is washed with bicarbonate, water and brine, and then dried by magnesium sulfate and filtered. The obtained residue was purified with the e as a white foam (2,571 g, the output is 58%). The purity of this sample was 97% (ghvd).

The NMR spectrum was identical to the spectrum of the first compound described above.

An alternative procedure for obtaining 2-O-(etoxycarbonyl)-7-O-methyldiethanolamine

2 O-(Etoxycarbonyl)paclitaxel (49,3 g, 53,2 mm) were placed in dry fire, odnogolosy liter flask and dissolved in dry acetonitrile (500 ml) at room temperature. Then to the mixture slowly, via syringe, added metilsulfate (39,1 ml, 0,532 M). Stirred the reaction mixture was cooled to -16oC in an ice/salt bath, and to the mixture in one portion was added solid benzoyl peroxide (51,6 g, 0,213 M). (For reaction, until its completion, it requires at least four equivalents). Stirring was continued for 30 minutes, and the temperature was lowered to -10oC., the Reaction medium remained heterogeneous throughout the period (benzoyl peroxide was not completely dissolved). The cooling bath was replaced with an ice/water, the temperature was raised to 0oC, and the remaining benzoyl peroxide was dissolved in approximately 5 minutes, after which it was heated. After stirring at 0oC for 2.5 hours, the reaction was stopped by TLC. Volume Alastor transferred into a separating funnel, where it is washed with heptane (5 x 500 ml). Acetonitrile layer was diluted with ethyl acetate (1.5 l) and washed with a mixture of saturated NaHCO3/5% K2CO3(by volume) (2 x 500 ml), saturated NaHCO3(2 x 500 ml), polysystem salt solution (1 x 500 ml) and brine (1 x 500 ml) and then dried with magnesium sulfate, and the solvent was removed in vacuo, resulting in a received 67,0 g of the crude product. This product was dissolved in acetone (200 ml) was heated to 40oC in a water bath, and drop by drop, with stirring, was added hexane until then, until the solution became turbid (400 ml). After that, the crystalline mixture was defended for 3 hours at room temperature, and then transferred into a cold room (0oC), where he was kept overnight (16 hours). Thus was formed a thick precipitate. This solid product was collected by filtration and washed with hexane/acetone (3:1 by volume) (2 x 50 ml). The obtained white crystals were dried on a suction filter for one hour, and then was dried under vacuum ( 0.5 mm RT. Art.) during the night, resulting in received and 47.5 g (yield - 91%) of target compound (a measure of homogeneity amounted to 94.8%, as measured by ghvd).

(C) Obtaining 2'-O-(etoxycarbonyl)-the one (2,41 g, 8,65 mm) in tetrahydrofuran was added to a mixture of 2-O-(etoxycarbonyl)-7-O-methyldiethanolamine (5,677 g, 5,76 mm) and molecular sieves 4A (5.7 g) in methylene chloride (100 ml) at room temperature. The resulting reaction mixture was stirred for 40 minutes at room temperature. After that, the reaction was considered complete as evidenced by TLC. The reaction mixture was filtered through a layer of celite, and the filtrate was concentrated in vacuum, and received a brown residue, which was diluted with ethyl acetate (800 ml). The organic phase was washed with 1% Na2SO3(2 x 80 ml), and then 5% salt solution (g ml). Then the organic phase was concentrated in vacuum and dried off. The obtained residue was chromatographically (eluent: 50-60% ethyl acetate in hexane), and received the target connection (6,23 g, 89%).

MS (FAB/NOBA, Nal, Kl): [M+Na]+m/z: 1238; [M+K]+m/z: 1254.

A receiver array (FAB/NOBA, external standard CSl/Gly): [M+Na]+m/z: 12154291 (Calculated for C65H71NO20P: 12164307; deviation = 1,3 M. D.).

1H-NMR (CDCl3): of 1.18 (3H, s) to 1.21 (3H, s) of 1.30 (3H, t) to 1.67 (6H, s), 1,80 (H, s), 1.93 and (H, m), 1,99 (3H, d), to 2.18 (3H, s), 2,23 (H, m), 2,38 (H, m), of 2.45 (3H, s), 2,80 (H, m), 3,86 (H, d), 4,14-4,32 (5H, overlapping with), 4,88 (H, d), 5,00 is 5.07 (4H, overlapping with), 5,42 (H, d), 5,68 (H, d), 5,96 (H, DD), 6,26 (H, t To the solution of 2'-O-(etoxycarbonyl)-7-O-methyldiethanolamine (350 mg, 0,355 mm) in anhydrous tetrahydrofuran (8 ml), was added a solution of N-iodosuccinimide (120 mg, 0,532 mm) and dibenzylamine (148 mg, 0,532 mm) in tetrahydrofuran (5 ml). The reaction course was monitored by TLC (C18-column; mixture: 70% acetonitrile/30% 10 mm ammonium phosphate, pH 6). After 2 hours showed less than 5% of the source material, after which the reaction was completed. The solution was diluted with ethyl acetate (75 ml) and washed with 1% aqueous sodium bisulfite (g ml) and brine (50 ml). After a quick drying with magnesium sulfate and filtering, the solvent is evaporated. The residue was subjected to flash chromatography on silica gel (eluent: 45% ethyl acetate in hexane), and received the target compound as a white foam (281 mg, 65%). Ghud-analysis indicated a purity of approximately 95%.

An alternative procedure

Powdered molecular sieves 4a were placed in a dried flame odnogolosy liter flask, which was then connected to the vacuum tubing ( 0.5 mm RT. article). Sieves was heated using a household dryer for about 10 minutes, shaking in this manual. After cooling under vacuum, the flask was injected argon was added 2'-O-(etoxycarbonyl)-7-O-methyldiethylamine (37,5 g, 38,03 mm), and then dimensionful (14.8 g, 53,24 mm) and THF is Shalke. Then, in a separate, dry fire, the flask was loaded N-iodosuccinimide (10.7 g, 47,54 mm) in argon atmosphere), dissolved in THF (50 ml). (In the process of obtaining NIS solution transfer fluid, and during the reaction, the vessel was covered with aluminum foil for protection from light). Then this solution slowly via syringe over 10 minutes was added to the reaction mixture. The flask containing the NIS solution, washed with 5 milliliters of tetrahydrofuran and transferred in the reaction mixture was then stirred 2 hours at room temperature. TLC analysis indicated the absence of starting material. Dark red solution was filtered through a layer of Celitedirectly into the vigorously stirred mixture (two-phase) containing ethyl acetate (500 ml), 10% aqueous sodium thiosulfate (300 ml) and saturated sodium bicarbonate (200 ml). Within two seconds the red color disappeared, and formed colorless solution. Layer Celicawashed with ethyl acetate (approx. 100 ml) and both liquid layer was transferred into a separating funnel. The organic layer was diluted with ethyl acetate (1 l), the layers were separated and the organic layer was washed with a mixture of saturated NaHCO3(2x500 stretch-forming press ml) and 5% K2CO3(the m solution (g ml). The obtained extract was dried with anhydrous magnesium sulfate and filtered. This extract is then processed to 5.0 grams of neutral Norit (coal), stirring during 15 minutes at room temperature. After that, the extract was again filtered through a layer of Celitethe solvent was removed under reduced pressure, and obtained 52 g of the crude product. This product was dissolved in toluene/methylene chloride (280 ml/25 ml) and one drop was added hexane (20 ml). After settling for 3 hours at room temperature, the crystalline mixture was left over night at a temperature of 0oC. Thus, on the walls of the flask were formed pale yellow solid precipitate. After desantirovaniya making solution, the residue was washed with toluene (50 ml), filtered, washed with toluene, and was dried on a suction filter for 30 minutes. Then the residue was transferred into a desiccator Drierite, and was dried under vacuum ( 0.5 mm RT.CT.) within 4 hours, resulting in a received 24.4 g (yield of 53%) of target compound (a measure of homogeneity, as measured by Ehud, 95.9%). The mother liquor is evaporated to dryness, triturated with toluene (100 ml), filtered, washed with toluene and dried on the suction filter homogeneity, measured using Ehud amounted to 97.1%).

(d) Obtaining 2'-O-(etoxycarbonyl)-7-O-phosphonomethylglycine and its monosodium, montalieu, triethylamine, arginine, lysine, ethanolamine, -metilglyukaminovoy and triethanolamine salt

< / BR>
To a solution of 2'-O-(etoxycarbonyl)-7-O - dibenzylethylenediamine (1,23 g, 1,01 mm) in anhydrous ethyl acetate (40 ml) was added 10% palladium carbon (428 mg, 0,404 mm). The reaction mixture was first made (60 psi - 400 kPa) with shaking, for 24 hours. The solid product was filtered through a layer of Celite, and then Celitewashed several times with ethyl acetate. The filtrate was concentrated and received the target connection in the form of the free acid (1.01 g, purity, determined using ghvd, was 80%). In the next stage of the impurities were removed by preparative chromatography on a C18-columns.

MS (FAB/NOBA, NaI, KI): [M+Na]+m/z: 1058, [M+K]+m/z: 1074, [M+Na-H]+m/z: 1080; [M+Na+K-H]+m/z: 1096; [M+2K-N]+m/z: 1112.

MS-analysis (FAB/NOBA, external standard CSl/Gly): [M+Na]+m/z: 10583163 (calculated for C51H58NO20PNa: 10583188; deviation = 2,3, M. D.).

1H-NMR (acetone-d6/D2O): of 1.13 (3H, s), 1,21 (399 (2H, Shir. overlapping with), 5,15 (H, Shir. C) 5,48 (H, d), 5,61 (H, d), of 5.84 (H, DD), 6,07 (H, t), 6,36 (H, s), 7,25 (H, t), 7,28-7,69 (10H, overlapping with), 7,89 (2H, DD), 8,08 (2H, DD), 8,86 (H, d).

An alternative procedure

2'-O-(Etoxycarbonyl)-7-O-(dibenzylideneacetone)paclitaxel (490 mg, 0,402 mm) in ethyl acetate (20 ml) was hydrogenosomal in a Parr shaker at 60 psi (400 kPa) in the presence of palladium charcoal (10% V/V, 150 mg). The reaction course was monitored by TLC and jhud. If you no longer showed no starting material or intermediate compounds (presumably, monobenzoate) (26 hours), then the suspension was filtered through Celiteand evaporated to dryness. Ehud analysis showed the purity of 88-92%.

An alternative procedure

Triethylamine salt of 2'-O-(Etoxycarbonyl)-7-O-phosphonomethylglycine described below (5,4 g, 4.75 mm) energetically distributed between EtOAc (100 ml) and 5% NaHSO4(45 ml) and stirred at 0oC for 30 minutes. The aqueous layer was separated and was extracted with ethyl acetate (20 ml). The combined EtOAc layer was washed half brine (25 ml), brine (25 ml x 2), dried with sodium sulfate and filtered, resulting in a solution of acid ( 4.75 mm) in EtOAc ( 150 ml). Then this EtOAc solution with a yield of 95%. Ghud-analysis showed that the index of homogeneity was 96.1 per cent.

Monosodium salt was prepared as follows:

A sample of 2'-O-(etoxycarbonyl)-7-O-phosphonomethylglycine (1.6 g, 1,55 mm) was dissolved in acetonitrile (30 ml) by ultrasonic treatment. This solution was diluted with water (30 ml) was added 1,1 M solution of NaHCO3(2,11 ml, 2,32 mm), intermittent shaking, and were treated by ultrasound (5-20 minutes) to obtain a solution. The solution some whitish color was applied to a C18-column and washed with two column volumes of water, and then monosodium salt was suirable 25% acetonitrile/water. Then the appropriate fractions were combined, the acetonitrile is evaporated, the aqueous phase liofilizovane, and received monosodium salt of the target compound (850 mg, approx. 50%) with a purity of 97% (ghvd).

MC (FAB/NOBA, NaI, KI): [M +Na]+m/z: 1180.

HP-MC (FAB/NOBA, CSI/Gly-external standard): [M + Na]+m/z: 10802968 (Analysis for C51H57NO20PNa2: calculated: 10803007; deviation D = 3,6 m D.).

Elemental analysis: C 52,65 (calc. 56,72); H is 5.06 (calc. 5,23); 1,20 N (calc. 1,30); Na 2,74 (calc. 2,12).

IR (KBr): 3430, 3066, 2988, 1646, 1722, 1660, 1602, 1582, 1526, 1488, 1452, 1374, 1246, 1178, 1150, 1108, 1070, 1052, 1026, 1002, 966, 912, 834, 792, 776, 710, 628, 538 cm-1.

1C) 2,98 (H, m), 3,74 (H, d), 4,07 (2H, d), 4,13 - 4.26 deaths (3H, m, overlapping), 4,80 (H, Shir. DD), equal to 4.97 (H, d), 5,09 (H, Shir. t), 5,44 (H, d), 5,55 (H, d), 5,99 (H, t) 6,34 (H, s), 7,22 (H, t), 7,43 - 7,69 (10H, m, overlapping); a 7.92 (2H, DD), of 8.06 (2H, DD).

The sodium salt was also obtained in the following way:

The crude 2'-O-(etoxycarbonyl)-7-O-phosphonomethylglycine (89%, 70 mg, 0.060mm) in EtOAc (2 ml) at room temperature was treated with a solution of ethylhexanoate sodium (8,75 mm in EtOAc, 1.0 ml, 0,0875 mm), stirring the while. After stirring at room temperature for one hour, the solution was added hexane (1.2 ml) to the point of turbidity. After storing the mixture at -20oC for 2 hours, fine amorphous powder was filtered with some difficulties very slowly) through a thin filter paper, and received 45 mg (70%) of sodium salt. This salt had a purity of 95.2 per cent (ghvd) and contained a small amount ethylhexanoic acid (NMR analysis).

Triethanolamine salt was prepared as follows:

2'-O-(Etoxycarbonyl)-7-O-phosphonomethylglycine (untreated), obtained by hydrogenation (purity was 89% (ghvd)) (0,69 g, 0,593 mm after amendment on impurity) was dissolved in ethyl acetate (10 ml) and slowly stirred, doba is, actor whitish autoclaved at 0oC for 2 hours and then filtered through fine filter paper and washed with cold ethyl acetate. The result of this procedure received 499 mg (80%) of amorphous, fine, elektrostaticheskogo powder, which was dried in vacuum over night. The analysis, conducted using Ehud showed the purity to 96.6% (C-18, 45% of 5 mm Q12+ 10 mm ammonium phosphate; pH 6; 55% acetonitrile). NMR spectrum (D2O/acetone/DMSO) showed the presence of trace amounts of ethyl acetate and no other obvious impurities. Also tested on 2-3 x hydrate.

In addition, triethanolamine salt, obtained as a result of another experiment, purified using the following procedure. Triethanolamine salt (approximately 2 g) was dissolved in a mixture of about 30% of acetonitrile and water. Then this solution was suirable at low nitrogen pressure on C18-column (Bakerbond) with a gradient of 20 to 40% acetonitrile in water. Fractions containing the desired triethanolamine salt, was collected, and the acetonitrile was removed using a rotary evaporator under reduced pressure. After this aqueous solutions were frozen and liofilizovane during the night, which was obtained 1.4 g triethanolamine salt Chusovoy salt of 2'-O-(etoxycarbonyl)-7-O-phosphonomethylglycine (3.0 g, 2.64 mm) was distributed between EtOAc (60 ml) and 5% NaHSO4(30 ml), vigorously stirring during 15 minutes (0oC). The aqueous layer was separated and was extracted with ethyl acetate (10 ml). United an ethyl acetate layer was washed brine (15 ml), dried sodium sulfate, filtered and obtained acid solution (approx. 2.64 mm) in EtOAc (CA. 70 ml). To this an ethyl acetate solution at room temperature for 5 minutes, one drop was added N - (CH2CH2OH)3(0.35 ml, 2.64 mm), vigorously stirring the while. The resulting suspension was stirred for another 1 hour, and then filtered, washed with ethyl acetate (15 ml × 2) and dried under vacuum, resulting in a 2.8 g triethanolamine salt with a yield of 89%, and so pl. > 157oC (when Razlog. ). The index of homogeneity, as measured by jhud was 98.7 per cent.

Elemental analysis for C56H73N2O23P 2,0 H2O 0,3 EtOAc:

Calculated: C 55,60; H 6,48; N 2,27; KF (H2O) : 2,92.

Found: C 55,94; H 6,59; N 2,43; KF (H2O) : 3,50.

Triethylamine salt was prepared as follows:

To a solution of 2'-O-(etoxycarbonyl)-7-O-dibenzylethylenediamine (10 g, 8,23 mm) in EtOAc (350 ml) at room temperature was added 10% palladium ugou the procedure was repeated 2 more times. Thereafter, the argon was replaced by hydrogen, and perform the same procedure degassing. The resulting suspension was stirred under pressure balloon of hydrogen for 2 to 3 pound per square inch (0,141 - 0,211 kg/cm2) for 16 hours at room temperature, vigorously stirring the while. Hydrogen was pumped out and download the argon (3 times), and then carried out a similar procedure for degassing. The resulting suspension was filtered through a layer of celite. Then it is homogeneous filtrate was slowly added Et3N (8,23 mm to 1.14 ml) (5 minutes), vigorously stirring the while. The obtained fine white suspension was stirred for another 30 minutes, then filtered through a funnel from a sintered material. The filter cake was dried in vacuum (1 mm RT. Art. ) for 16 hours, and was received by 8.22 g of target compound, namely, triethylamine salt with a yield of 88%, and so pl. > 178oC (Razlog.). The index of homogeneity, as measured by jhud was 97,4%.

Elemental analysis for C57H73N2O20P 4,5 H2O:

Calculated: C 56,19; H 6,79; N 2,30; KF (H2): 6,65.

Found: C 56,33; H 6,87; N 2,32; KF (H2O): of 7.96.

An alternative way of obtaining triethylamine salt:

2'-O-(Etoxycarbonyl)-7-O-Deeb is 150 ml). The flask was equipped with a three-position valve and is connected to a vacuum pipe and tubing, through which filed argon. Using this valve, the contents of the flask was partially pumped out, and then the flask was purged with argon. This procedure was repeated 2 more times. Then the flask was added 10% palladium on charcoal (0.85 grams). The pipeline, through which filed argon and associated with three-position valve was replaced with a balloon filled with hydrogen. Using the valve, the contents of the flask was partially deleted and purged with argon. This procedure was repeated 4 more times. The resulting mixture was stirred at room temperature in the atmosphere balloon of hydrogen overnight. TLC analysis after the initial exposure to hydrogen, showed the absence of starting materials. Then the balloon with hydrogen associated with the three-position valve, replaced the pipe, through which filed argon. Using the three-position valve, the flask was partially drained and then purged with argon. This procedure was repeated 2 more times. The contents of the flask were subjected to vacuum filtration through a layer of Celite. Celite was washed with ethyl acetate (2 x 10 ml), and stir the filtrate we use JEM was reduced to 150 ml using a rotary evaporator. The solid product was filtered, washed with ethyl acetate (2 x 10 ml) and dried under vacuum, resulting in a received value of 4.76 g (yield - 90%) target compound as triethylamine salt and in the form of a white powder (a measure of homogeneity, as measured by Ehud amounted to 96.6%).

An alternative way of obtaining triethylamine salt:

2'-O-(Etoxycarbonyl)-7-O-dibenzylethylenediamine (of 5.17 g, 4,25 mm) was added to 250-ml flask and was dissolved in ethyl acetate (150 ml). The flask was equipped with a three position valve, and connected to a vacuum pipe and tubing, through which filed argon. Using this valve, the contents of the flask was partially drained and then purged with argon. This procedure was repeated 2 more times. Then the flask was added 10% palladium on charcoal (0,86 g). The pipeline, through which filed argon, associated with the three-position valve was replaced with a balloon filled with hydrogen. Using the valve, the contents of the flask was partially drained and then purged with argon. This procedure was repeated 5 times. The resulting mixture was stirred at room temperature in the atmosphere balloon of hydrogen. 16-hour TLC analysis of th is p with the three-position valve, replaced the pipe, through which filed argon. Using the three-position valve, the contents of the flask was partially drained and then purged with argon. This procedure was repeated 2 more times. The contents of the flask were subjected to vacuum filtration through a layer of celite. Celite was washed with ethyl acetate (4 x 10 ml). To the stirred filtrate was added Et3N (0,590 ml of 4.25 mm). The resulting suspension was stirred at room temperature for one hour, and then the volume of this suspension was reduced to approximately 140 ml by rotary evaporator. The solid product was filtered, washed with ethyl acetate (10 ml) and dried under vacuum, resulting in a received 4,46 g (yield 92 percent of the target triethylamine salt as a white powder (a measure of homogeneity, defined by jhud was 96,7%).

The lysine salt was prepared as follows:

2'-O-(Etoxycarbonyl)-7-O-dibenzylethylenediamine (15.0 g, 12,34 mm) portions was added to a suspension of 10% palladium carbon (20% load, 3 g) in EtOH (600 ml) tested. 200) at 0oC. the resulting suspension was degirolami by pumping air and purged with argon. This procedure was repeated a further 2 hours. Thereafter, the argon was replaced by hydrogen, and energetic premesis hours. The cooling bath was removed, and the reaction solution was stirred at room temperature for 4.5 hours. The reaction mixture was degirolami by the pumping of hydrogen, and then 3 times was purged with argon. Then the mixture was filtered (in argon atmosphere) through a layer of celite. To the obtained filtrate slowly, with vigorous stirring, was added a solution of lysine (1.63 g, 0,94 EQ.) in a mixture of H2O : EtOH (1 : 1, tested. 200) (20 ml) for 5 minutes. Then, to the obtained white suspension was added distilled water (110 ml) and stirred 30 minutes. This suspension was also heated to about 55oC. the Obtained homogeneous solution was kept in an oil bath at 50oC, and slowly cooled to room temperature for 16 hours and then at 4oC for 3 hours. After filtration and drying on a suction filter, received of 11.8 g (yield 80%) lysine salt so pl. > 170oC ( Razlog.). The index of homogeneity, defined by jhud was 99,0%.

Elemental analysis for C57H72N3O22P 8,0 H2O:

Calculated: C 51,62; H 6,69; N 3,17; KF (H2O): 10,87.

Found: C 51,76; H to 6.57; N 3,48; KF (H2O): 11,42.

Ethanolamine salt was prepared as follows:

2'-O-(This Is 5% NaHSO4(30 ml) with vigorous stirring at 0oC for 15 minutes. The aqueous layer was separated and was extracted with ethyl acetate (15 ml). United an ethyl acetate layer was washed brine (15 ml), dried sodium sulfate, filtered, and received the solution of the free acid ( 2.64 mm) in EtOAc ( 70 ml). To this an ethyl acetate solution at room temperature, one drop and within 5 minutes, was added a solution of H2NCH2CH2OH (0.15 ml, 2.64 mm) in EtOAc (5 ml), vigorously stirring the while. The resulting suspension was stirred for another 1 hour, and then filtered, washed with ethyl acetate (15 ml × 2) and dried under vacuum, resulting in the obtained 2.6 g of the target ethanolamine salt with a yield of 89%, so pl. > 130oC (Razlog.). The index of homogeneity, defined by Ehud-analysis was 97.8 per cent.

Elemental analysis for C53H65N2O21P 2,5 H2O:

Calculated: C 55,73; H 6,18; N 2,45; KF (H2O) 3,94;

Found: C 55,76; H to 6.39; N 2,45; KF (H2O) 6,00.

Arginine salt was prepared as follows:

(Etoxycarbonyl)-7-O - dibenzylethylenediamine (30.0 g, 24,69 mm) portions was added to a suspension of 10% palladium carbon (20% load, 6 g) in EtOH (900 ml) tested. 200) at 0oC. the Floor is 2 more times. Thereafter, the argon was replaced by hydrogen and perform the same procedure degassing, vigorously stirring the while. The resulting mixture was stirred for 2 hours at 0oC. the Cooling bath was removed, and the reaction solution was stirred at room temperature for another 24 hours. The resulting reaction mixture obessively by pumping hydrogen and purging with argon (3 times), then carried out a similar procedure obezvozhivanija. Then the mixture was filtered (in argon atmosphere) through a layer of celite. The filtrate was divided into two equal parts and each part was added EtOH (190 ml, tested. 200). Then to the first part ( 630 ml) was slowly added a solution of arginine (2.0 g, 0,94 EQ.) in a mixture of H2O : EtOH (2 : 1, 20 ml) tested. 200) for 5 minutes and with vigorous stirring. The obtained white suspension was upheld and was added distilled water (100 ml) and then stirred for 30 minutes and heated to about 60oC. After hot filtration, the filtrate was kept in an oil bath at 50oC, and then left for cooling to room temperature, and kept at room temperature for 2 hours and at 4oC for 2 hours. This mixture was filtered, washed with cold 3% solution of H2O in EtOH (100 minoval salt, having the index of homogeneity equal to 96,7%.

This material (12,95 g) was dissolved in a mixture of 15% H2O in EtOH (approx. 700 ml) at 55oC. the resulting solution was cooled and maintained at 30oC for 3.5 hours, then at room temperature for 16 hours, and at 4oC for 3 hours. The obtained crystals were filtered, washed with cold 2% H2O in EtOH (50 ml x 2), dried by suction for 4 hours and then dried in vacuum (1 mm RT. Art.) for 16 hours, and was obtained 10.2 g (yield about 80%) of the target arginine salt, a measure of the homogeneity - of 98.5%) with T. pl. > 176oC (when Razlog.).

Elemental analysis for C57H72N5O22P 6,4 H2O:

Calculated: C 51,65; H 6,45; N 5,28; KF (H2O) 8,7;

Found: C 51,86; H of 6.65; N of 5.53; KF (H2O) 8,72.

N-Methylglucamine salt was prepared as follows:

dibenzyldithiocarbamate (30.0 g, 24,69 mm) portions was added to a suspension of 10% palladium charcoal (6 g, 20% loading) in EtOH (900 ml) tested. 200) at 0oC. the resulting suspension was degirolami by air pumping and purging with argon. This procedure was repeated 2 more times. Then argon was replaced by hydrogen, and continued the same procedure degassed the Cooling bath was removed, and the reaction solution was stirred at room temperature for another 24 hours. The reaction mixture was degirolami by pumping air was purged with argon (three times), and then performed the above procedure degassing. After that, the mixture was filtered (in argon atmosphere) through celite. The filtrate was divided into two equal parts and each part was added EtOH (190 ml, tested. 200). To the first part slowly ( 630 ml) was added during 5 minutes, a solution of N-methylglucamine (2.24 g, 0,94 EQ.) in a mixture of H2O : EtOH (1 : 1, tested. 200) (20 ml), vigorously stirred. To the resulting white suspension was added distilled water (100 ml) and the suspension was stirred for 30 minutes and then was heated to about 49oC. a Transparent homogeneous solution was maintained at 50oC in an oil bath, then left to cool to room temperature for 2 hours, and kept at 4oC for 1.5 hours. The resulting mixture was filtered and washed with 3% H2O in EtOH (100 ml) and then dried by suction at room temperature for 16 hours, and received 9,65 g (yield 64%) of the target N-metilglyukaminovoy salt indicator of homogeneity equal to 96,4%.

This product (9,65 g) was dissolved in a mixture of 15% H2O in EtOH ( 450 ml) at 52 is an increase of 16 hours, and 4oC for 3 hours. The obtained crystals were filtered, washed with cold 2% H2O in EtOH (50 ml x 2), dried by suction for 4 hours and then dried in vacuum (1 mm RT. Art.) for 16 hours, and received the target N-methylglucamine salt (7.5 g, yield about 80%) so pl. > 154oC (when Razlog.). The index of homogeneity, defined by Ehud analysis, amounted to 98.6%.

Elemental analysis for C58H75N2O25P 5,0 H2O):

Calculated: C 52,72; H 6,48; N 2,12; KF (H2O) 6,82.

Found: C 53,09; H 6,50; N 2,08; KF (H2O) 7,12.

Example 4: 2'-O-(phosphonomethyl)paclitaxel

(a) Obtaining 2'-O-methylthiomethyl)-7-O-(triethylsilyl)of paclitaxel

< / BR>
To a cold (0 to 5oC) a solution of 7'-O-(triethylsilyl)paclitaxel (2,46 g, 2,5439 mm) in anhydrous acetonitrile (100 ml) was added dimethyl sulfide (1,348 g of 1.59 ml, 21,6976 mm), and then benzoyl peroxide (2,628 g, 10,8488 mm). The obtained heterogeneous mixture was stirred at 0oC for one hour, and kept at 5oC for 18 hours. The result of this procedure were formed yellow solution. This solution is evaporated to dryness and purified on a column of silica gel (eluent: ethyl acetate/hexane, 1 : 4, 1 : 3 and 1 : 2), ptx2">

MS: [M + H]+: 1028; [M + Na]+: 1050; [M + K]+: 1066.

(b) Obtaining 2'-O-(methylthiomethyl)of paclitaxel

< / BR>
To a cold (-15oC) a solution of the product of part (a) (1.0 g, 0,9737 mm) in anhydrous acetonitrile (30 ml) was added drop of 0.5 N. hydrochloric acid (3 ml). The resulting solution was stirred at -15oC for one hour and 5oC for 18 hours. This solution was diluted with ethyl acetate (20 ml) and washed with cold 6% NaHCO3-solution and brine. After that, the solution was dried with magnesium sulfate and evaporated to dryness. The resulting solution was purified on plates with silica gel (eluent: methylene chloride/15% acetonitrile), and received the pure target compound (280 mg, 31.4 percent).

IR (KBr): 3446, 3064, 2940, 1726, 1666, 1582, 1516, 1486.

NMR (CDCl3): 1,118 (s, 3H); 1,229 (s, 3H); 1,662 (s, 3H); 1,689 (s, 3H); 1,871 (s, 3H); 2,209 (s, 3H); 2,450 (s, 3H); 3,800 (d, H); 4,119 (d, H); 4,305 (d, H); 4,413 (m, H); 4,563 (d, H); 4,703 (d, H); 4,940 (d, H); 4,958 (DD, H); 5,667 (d, H); 5,882 (DD, H); 6,263 (m, 2H); 7,019 (d, H); 7,293 - 8,127 (m, 15H).

MS: [M + H]+: 914; [M + Na]+: 936; [M + K]+952.

BPMC: MH+: 9143394 (calculated: 9143422)

(c) Obtaining 2-O-dibenzylideneacetone)of paclitaxel

< / BR>
To a stirred solution of the product of stage (b) (0,89 g, 0,9748 mm) in anhydrous 1,2-dichloroethane (12 ml) was added to the 4622 mm) and dibenzylamine (0,41 g, 1,4622 mm) in anhydrous tetrahydrofuran (8 ml). The resulting mixture was stirred at room temperature for one hour and then filtered through a layer of celite. The filtrate is evaporated to dryness, and the resulting red residue was dissolved in ethyl acetate (50 ml) and washed with cold 6% NaHSO3cold 6% sodium bicarbonate, and saline. After drying with magnesium sulfate and evaporation, obtained foamy product. This product was purified on plates with silica gel (eluent: methylene chloride/20% acetonitrile), and has obtained the pure product (0,77 g, 69%).

IR (KBr): 3854, 3744, 3362, 3066, 1960, 1722, 1602, 1580.

NMR (CDCl3): 1,075 (s, 3H); 1,167 (s, 3H); 1,651 (s, 3H); 1,799 (s, 3H); 2,209 (s, 3H); 2,296 (s, 3H); 2,464 (m, H); 3,686 (d, H); 4,121 (d, H); 4,240(d, H); 4,293 (m, H); 4,408 - 4,957 (m, 6H); 5,006 (m, H); 5,565 - 5,649 (m, 2H); 6,034 (t, H); 6,194 (3H, s); 7,100 - 8,132 (m, 26H).

MS: [M + H]+: 1144; [M + Na]+: 1166; [M + K]+: 1182.

(d) Obtaining 2'-O-(phosphonomethyl)of paclitaxel

< / BR>
A mixture of the product of stage (c) (0.9 g, 0,8874 mm) and 10% palladium carbon (1.0 g) in ethyl acetate (20 ml) was first made at 60 psi (400 kPa) for 24 hours. The reaction mixture was filtered through celite, and the filtrate evaporated to dryness. The residue was purified on plates with silica gel (eluent : methylene chloride/40% methanol), IR>-1.

NMR (acetone-d6/D2O): 1,081 (s, 6H), 1,571 (s, 3H), 1,847 (s, 3H), 2,115 (s, 3H), 2,357 (s, 3H), 3,707 (d, 1H), 4,08 (m, 2H), 4,275 (m, H), 4,941 - 5,085 (m, 4H), 5,231 (t, H) 5,430 (d, H) 5,544 (d, H) 5,970 (t, H) 6,376 (s, H) 6,961 - 8,017 (m, 16H).

MS: [M + Na]+: 986, [M + K]+: 1002, [M + 2Na - H]+; 1008, [M + Na - K + H]+: 10,24, [M + 2K - H]+: 1040.

BPMC: MNa+, 9862955 (calculated: 9862976).

Example 5: 2'-7-O-bis-(phosphonomethyl)of paclitaxel sodium salt

(a) Obtaining 2',7-O-bis(methylthiomethyl)of paclitaxel

< / BR>
To a stirred solution of paclitaxel (0,853 g, 1 mm) and dimethyl sulfide (1,465 g, 20 mm) in acetonitrile (20 ml) at 0oC) was added solid benzoyl peroxide (1,995 g, 8 mm). The reaction mixture is vigorously stirred at 0oC for 3 hours. Over the course of the reaction was observed by TLC (hexane : ethyl acetate; 1 : 1, by volume, PfTexel= 0,24, Pfproduct= 0,60). After the disappearance of the starting material (approximately 3 hours), the reaction was suppressed by evaporation of solvent to dryness in a low vacuum at 25oC. the Anhydrous residue was isolated using a column with silica gel (EM Science, 40 - 63 µm; 100 ml of anhydrous silica gel; column size: = 3/4 inch; solvent system: hexane/ethylacetat - 53%) was isolated from fractions 15 to 19.

MC (FAB /matrikas. NOBA, NaI, KI): [M + H]+m/z: 974; [M + Na]+: m/z : 996; [M + K]+m/z 1012.

UV (MeOH):max= 204 nm, E (1% /1cm) = 243,45;max= 228 nm, E (1%/1 cm) = 313,99.

IR (KBr): 3440, 3064, 2926, 1724, 1668, 1602, 1582, 1514, 1484, 1452, 1372, 1314, 1266, 1242, 1178, 1142, 1068, 1026, 990, 916, 886, 848, 800, 774, 710, 646, 606, 570, 540, 480 cm-1.

1H-NMR (CDCl3): of 1.17 (3H, s); of 1.20 (3H, s); by 1.68 (3H, s); of 1.74 (3H, s); 1,84 (H, DD); 2,04 (3H, d); of 2.09 (3H, s); of 2.15 (3H, s, overlapped with (H, m); 2,37 (H, DD); of 2.51 (3H, s); 2,79 (H, DDD); 3,78 (H, d); 4,18 (H, d); to 4.28 (H, m); or 4.31 (H, d); 4,53 - 4,74 (4H, two overlapping AB, m); 4,93 (H, d); 4,95 (H, d); 5,68 (H, d); of 5.82 (H, DD); 6,24 (H, DD); 6,54 (H, C); 7,05 (H, d); 7,28 - to 7.59 (10H, overlapping); EUR 7.57 (H, m); 7,76 (2H, d); of 8.09 (2H, d).

(b) Obtaining 2',7'-O-bis(dibenzylideneacetone)of paclitaxel

< / BR>
A solution of N-iodosuccinimide (135 mg, 0.5 mm) and dibenzylamine (167 mg, 0.5 mm) in anhydrous tetrahydrofuran (8 ml), at room temperature, was added to a mixture of 2', 7-bis(methylthiomethyl)paclitaxel (198 mg, 0.2 mm) and molecular sieves 5A (approximately 200 mg) in methylene chloride (12 ml). The reaction mixture was stirred for 1.5 hours, and then the molecular sieve was filtered through celite, washed with methylene chloride (10 ml) and the solvents evaporated to dryness at room temperature in a low vacuum. is I 0.5 moles of sodium bicarbonate (50 ml) and then twice washed with water (2 x 50 ml). The organic phase was dried with magnesium sulfate, evaporated to dryness and again dissolved in ethyl acetate (1 ml). The product was besieged by adding a mixture of 50 ml of ethyl ether/hexane (1 : 1) and washed twice, using the same solvent system (2 x 50 ml). Thus was obtained the crude product (218 mg) with a yield of 74%. This product was purified by loading it methylenechloride solution (3 ml) plates with silica gel ( = 3/4 inch x L = 1 inch) and suirable system of solvents (methylene chloride/ethyl acetate), (3 : 1) (50 ml). Thus received 172,7 mg of target compound (yield - 59,3%).

MC (FAB metric. NOBA / NaI, KI): [M + Na]+m/z : 1456; [M + K]+m/z : 1472.

UV (MeCN):max= 194 nm, E (1%/1 cm) = 1078,36;max= 228 nm, E (1%/1 cm) = 311,95.

IR (KBr): 3430, 3066, 3032, 2958, 1744, 1726, 1664, 1602, 1582, 1532, 1488, 1456, 1372, 1270, 1244, 1158, 1108, 1068, 1016, 1000, 952, 886, 800, 776, 738, 698, 604, 498 cm-1.

1H-NMR (CDCl3): of 1.12 (3H, s); 1,14 (3H, s); 1,56 (H, m); a rate of 1.67 (3H, s); of 1.84 (3H, d); 1,90 (H, m); 2,17 (3H, s); to 2.29 (3H, s); 2,73 (H, m); to 3.73 (H, d); 4,08 (H, d); 4,15 (H, m); 4,20 (H, d); 4,77 (H, m); 4,79 (H, d); 4,91 - 5,04 (10H, overlapping m); 5.25-inch (H, DD); 5,38 (H, DD); 5,54 - to 5.56 (2H, overlapping m); 5,99 (H, Shir. DD); 6,25 (H, C); 7,11 - 7,14 (2H, m); 7.24 to to 7.64 (28H, overlapping the ate

< / BR>
Sample 2'-7-O-bis(dibenzylideneacetone)paclitaxel (112 mg, 0,078 mm) was dissolved in ethyl acetate (7 ml) and was first made at room temperature, in the presence of 10% palladium carbon (50 mg) at 60 psi (400 kPa) for 2 hours. The catalyst was removed by filtration through a layer of celite. Celite was washed with ethyl acetate (10 ml). The filtrate was treated with solid sodium bicarbonate (20 ml, 3 equiv.) and the solvent is then evaporated to dryness. The obtained dry residue was again dissolved in 5 ml of water:acetone (4:1, by volume) and was purified on C-18-columns using reversed-phase chromatography (55 - 105 μm C-18, Jones, 50 ml of dry C-18, = 3/4 inch in the system: water/acetone, 4:1, by volume). Eluent was monitored using analytical jhud on C18-columns Jonex (15 cm, 1 ml/min, = 230 mn) in acetonitrile:phosphate buffer (pH 6, a 50/50 by volume) mixture of Q12-ion pairs (Regis), Rt = 4,7 min Fractions containing the desired product were combined, the acetone evaporated under conditions of low vacuum at 20oC, and the solution was liofilizovane. Thus was obtained the desired product (44,2 mg, 58.8% of output).

MS FAB metric. NOBA /NaI, KI): [M + H]+m/z : 1118; [M + Na]+: m/z 1140.

UV (MeCN):max= 192 nm, E (1%/1 cm) = 129,73;max= 230 nm, E (1%/1 cm) = 26,43.">

1H-NMR (acetone-d6/D2O): 0,97 (3H, s); of 1.02 (3H, s); 1,47 (H, m), and 1.54 (3H, s); 1,70 (H, m); a 1.75 (3H, s); 1,85 (H, m); 2,11 (3H, s); of 2.30 (3H, s); 2,88 (H, m); 3,64 (H, d); 4,03 (H, m); 4,06 (H, d); 4,16 (H, d); 4,74 (H, m), a 4.86 (H, m); 5,11 (H, Shir. t); 5,22 (H, d); 5,42 (H, d); 5,90 (H, Shir. t); 6,21 (H, C); 7,06 (H, Shir. t); 7,32 - 7,69 (10H, overlapping m); 7,80 (2H, d); to 7.93 (2H, d).

Example 6. 7'-O-Methylthiopyrimidin III (7-MTM-baccatin III)

< / BR>
To a solution of 2'-O-ethoxycarbonyl-7-O-methyldiethanolamine (compound of example 3 (b), 27 g, 27,4 mm) in 100 ml of THF and 500 ml of methanol, was added sieroty potassium carbonate (2.7 g, 19 mm). The resulting solution was stirred for 30 minutes, neutralized resin IP-120 (H+), filtered and concentrated. The crude filtrate was dissolved in 200 ml dichloromethane and stirred for 24 hours with tetrabutylammonium borohydride (10 g). Then the solution was diluted with dichloromethane and washed with water, saturated bicarbonate and brine. After that, the organic fraction was dried with magnesium sulfate and concentrated. The residue was chromatographically on silica gel (eluent: hexane/ethyl acetate, 1:1) and obtained 9.4 g of target compound (53%) with T. pl. 269oC.

FAB-MS (NOBA): [M + H]+for C33H43NO11: calculated: 647. Found: 647.

IR (KBr): 3474, 1746, 1724, 1712, 1270, 5 (with, 1H); 4,94 (d, J = 8,1 Hz, 1H); of 4.83 (q, J = 5,1 Hz, 1H); 4,66 (AB kV, J = 14,7, 12.3 Hz, 2H); 4,30 (m, 2H): 4,13 (d, J = 8,4 Hz, 1H); 3,91 (d, J = 6,6 Hz, 1H); and 2.79 (m, 1H); 2,27 (c, 3H); to 2.25 (m, 2H); 2,19 (s, 3H); 2,16 (c, 3H); 2,10 (s, 4H); is 1.81 (m, 1H); 1,72 (s, 3H); to 1.61 (m, 2H); to 1.16 (s, 3H); of 1.03 (s, 3H).

13C-NMR (CDCL3, and 75.5 Hz): 202,3, 170,8, 169,3, 167,0, 144,2, 132,6, 132,1, 130,1, 129,4, 128,6, 83,9, 80,9, 78,7, 75,7, 74,5, 73,9, 57,9, 57,6, 47,6, 42,7, 38,3, 26,7, 22,6, 21,0, 20,1, 15,2, 15,0, 10,8.

Example 7. Triethanolamine salt of 3'-N-desbenzoyl-3'-destiny-3'-N-(t-butoxycarbonyl)-3'-(2-furyl)-2'-O - ethoxycarbonyl-7-O-phosphonomethylglycine

(a) Obtaining 3'-Dibenzoyl-3'-destiny-3'-N-(t - butyloxycarbonyl)-3'-(2-furyl)-7-O-methyldiethanolamine

< / BR>
To a solution of HMDS (and 0.40 ml, 1,90 mm) in 15 ml THF was added a solution of n-utility (0.75 ml, 2.5 M in hexane, of 1.88 mm) and was stirred for 5 minutes at -55oC. To this solution add baccatin III 7-MTM (compound of example 6, of 1.03 g, 1,59 mm) in 10 ml THF and stirred for 10 minutes, after which was added 10 ml of a solution of (3R, 4R)-1-(t-butyloxycarbonyl)-4-(2-furyl)-3-(triethylsilyl)-2 - azetidinone (883 mg, 2.40 mm). The cold bath was removed and was replaced with a bath so 0oC, and the reaction mixture was stirred for 30 minutes. The resulting solution was diluted with ethyl acetate and washed with saturated solution of NH4Cl, drained sulfate MAGN is made of 1.5 g of the product of the joining of the 3'-N-desbenzoyl-3'-destiny-3'-N-(t-butyloxycarbonyl)-3'-(2-furyl)-7-O-methylthiomethyl-2'-O-criticalimportance (93%).

FAB-MS (NOBA) [M+Na] for C50H71NSSiO16:

Calculated: 1036; Found: 1036.

IR (film): 3446 (), 1720, 1368, 1242, 1166, 1144, 1124, 1066 cm-1.

1H-NMR (CDCl3, 300 MHz): 8,07 (d, J = 7.2 Hz, 2H); 7,56 (m, 1H); 7,46 (t, J = 7.5 Hz, 2H); of 7.36 (m, 1H); 6,56 (s, 1H); 6,33 (m, 1H); of 6.20 (m, 2H); 5,67 (d, J = 6,9 Hz, 1H); from 5.29 (Shir. s, 2H); 4,94 (d, J = 7.8 Hz, 1H); 4.75 V (s, 1H) and 4.65 (s, 2H); to 4.28 (m, 2H); 4.16 the (d, J = 8,1 Hz, 1H); to 3.89 (d, J = 6,9 Hz, 1H); 2,80 (m, 1H); to 2.46 (s, 3H); is 2.37 (m, 1H); 2,22 (m, 1H); of 2.16 (s, 3H); of 2.10 (s, 3H); 2,04 (c, 3H); of 1.84 (m, 1H); 1,74 (s, 3H); of 1.65 (m, 1H); of 1.33 (s, 9H); of 1.20 (s, 3H); 1,19 (s, 3H); 0,81 (t, J = 7.8 Hz, 9H); 0,47 (m, 6H).

13C-NMR (CDCl3, and 75.5 Hz): 202,0, 171,2, 170,3, 169,3, 167,1, 155,3, 152,0, 141,9, 141,0, 133,6, 132,9, 130,2, 129,2, 128,7, 110,7, 107,3, 84,0, 81,1, 80,2, 78,7, 76,1, 75,7, 74,1, 72,4, 71,1, 57,4, 52,8, 47,1, 43,3, 35,2, 33,0, 28,1, 26,3, 22,9, 21,2, 21,0, 15,0, 14,5, 10,9, 6,5, 4,3.

To a solution of 2-triethylsilyl ether obtained above (330 mg, 0.32 mm) in 7 ml of THF was added tetrabutylammonium fluoride (0.35 ml, 1.0 M in THF, 0.35 mm) and stirred 10 minutes. The solution was diluted with ethyl acetate, washed with brine, dried with magnesium sulfate and concentrated. The residue was chromatographically on silica gel (eluent: hexane/ethyl acetate, 2:1), and received 301 mg of target compound (95%).

FAB-MS (NOBA) [M + H] for C45H58NO16S: Calculated: 900; Found: 900.

IR (film): 3442, 1720, 1242, 1066, 1026 cm-1.

13C-NMR (CDCl3, and 75.5 Hz): 202,0, 172,6, 170,3, 169,2, 167,0, 155,2, 151,3, 142,4, 140,4, 133,7, 133,2, 130,2, 129,1, 128,7, 110,7, 107,4, 83,9, 81,2, 80,5, 78,6, 76,5, 76,1, 75,4, 74,6, 74,0, 72,5, 71,8, 57,4, 51,7, 47,2, 43,2, 35,2, 32,8, 28,1, 26,4, 22,6, 20,9, 15,2, 14,6, 10,9, 8,3.

(b) Obtaining 3'-N-desbenzoyl-3'-destiny-3'-N-(t - butoxycarbonyl)-3'-(2-furyl)-2'-O-ethoxycarbonyl-7-O - methyldiethanolamine

< / BR>
To a solution of the product of stage (a) (864 mg, 0.96 mm) in 50 ml of dichloromethane at 0oC, was added diisopropylethylamine (2.0 ml, 11.5 mm) and ethylchloride (0,50 ml, 5.25 mm), and then the resulting solution was stirred for 4 hours. After this, the solution was diluted with dichloromethane and washed deep bicarbonate, dried with magnesium sulfate and concentrated. The residue was chromatographically on silica gel (eluent: hexane/ethyl acetate, 1:1) and received 884 mg of target compound (2-ethylcarbonate) with access 95%.

FAB-MS (NOBA) [M + H] for C48H62NO18S: Calculated: 9723668; Found: 9723654.

IR (film): 1752, 1720, 1370, 1244, 1196, 1176, 1064 cm-1.<(m, 1H); 6,27 (m, 1H); from 6.22 (t, J = 7.8 Hz, 1H); 5,67 (d, J = 7.2 Hz, 1H); 5,51 (d, J = 9.9 Hz, 1H); of 5.34 (d, J = 2.4 Hz, 1H); 5.25-inch (d, J = 10,2, Hz, 1H); 4,95 (d, J = 8.1 Hz); the 4.65 (s, 2H); 4,30 (m, 2H); 4,22 (m, 2H); 3,88 (d, J = 7.2 Hz, 1H); of 2.81 (m, 1H); to 2.41 (s, 3H); 2,36 - of 2.21 (m, 2H); of 2.16 (s, 3H); 2,11 (s, 3H); of 2.09 (s, 3H); to 1.83 (m, 1H); 1,74 (s, 3H); 1,67 (c, 3H); 1,59 (s, 1H); of 1.34 (s, 9H); of 1.29 (t, J = 7.2 Hz, 3H); of 1.20 (s, 3H); 1.18 to (s, 3H).

13C-NMR (CDCl3, and 75.5 Hz): 202,1, 169,9, 169,1, 167,6, 167,0, 154,0, 150,1, 142,6, 141,0, 133,6, 132,9, 130,2, 129,2, 128,7, 110,7, 107,5, 83,9, 81,1, 80,7, 78,7, 76,0, 75,7, 75,1, 74,7, 74,2, 71,8, 65,1, 57,4, 49,7, 46,1, 43,2, 35,0, 33,0, 28,1, 26,3, 22,6, 21,1, 20,9, 15,1, 14,5, 14,1, 10,9.

(c) Obtaining 3'-Dibenzoyl-3'-destiny-3'- (t-butyloxycarbonyl)-3'-(2-furyl)-2'-O-ethoxycarbonyl-7-O-dibenzyl-phosphonomethylglycine

< / BR>
To a solution of the product of stage (b) (230 mg, 0,236 mm) in 10 ml of anhydrous THF, was added 300 mg of molecular sieves 4A 270 mg (0,98 mm) dibenzylamine and 62 mg (0.28 mmol) of recrystallized NIS. To this solution was added 45 mg (0.17 mm) trifluromethanesulfonate silver, and the solution was stirred for 3 hours. Then the solution was filtered through celite and diluted with ethyl acetate, washed with 10% NaS2O8, saturated bicarbonate and brine, then were dried with magnesium sulfate and concentrated. The residue was chromatographically on silica gel (eluent: 15% acetonitrile/chloroform), resulting floor is keno: 1224; Found: 1224.

IR (film): 3422 (Shir. ), 1750, 1722, 1370, 1244, 1160, 1036, 1016, 1000, 976, 944 cm-1.

1H-NMR (CDCl3, 300 MHz): 8,08 (d, J = 6,9 Hz, 2H); 7,58 (t, J = 7.2 Hz, 1H); 7,46 (t, J = 7.8 Hz, 2H); 7,39 (s, 1H); 7,31 (m, 10H); 6,35 (m, 2H); 6,28 (s, 1H); 6,21 (t, J = 7.8 Hz, 1H); 5,64 (d, J = 6,9 Hz, 1H); 5,50 (d, J = 10.5 Hz, 1H); of 5.39 (d, J = 6,6 Hz, 1H); 5,32 (d, J = 2.4 Hz, 1H); 5.25-inch (d, J = 9.9 Hz, 1H); free 5.01 (DD, J = 8,1, 6,3 Hz, 5H); a 4.86 (d, J = 8,4 Hz, 1H); 4,29 - 4.09 to (m, 4H); of 3.85 (d, J = 8,4 Hz, 1H); 2,77 (m, 1H); is 2.40 (s, 3H); 2,30 (m, 2H); of 2.16 (s, 3H); 1,99 (s, 3H); of 1.94 (m, 1H); to 1.70 (s, 3H); 1,67 (s, 1H); and 1.54 (s, 1H); of 1.34 (s, 9H); of 1.28 (t, J = 7.2 Hz, 3H); of 1.20 (s, 3H); 1,17 (s, 3H).

13C-NMR (CDCl3, and 75.5 Hz): 201,8, 169,9, 169,2, 167,7, 167,0, 155,1, 154,0, 150,0, 142,74, 141,1, 133,7, 132,9, 130,2, 129,1, 128,7, 128,5, 128,4, 128,0, 110,7, 107,6, 93,8, 84,1, 81,6, 80,8, 80,7, 78,8, 76,3, 75,1, 74,6, 71,8, 69,3, 69,2, 65,1, 57,0, 49,7, 46,7, 43,2, 35,0, 28,1, 26,4, 22,6, 21,2, 20,8, 14,6, 14,1, 10,5.

(d) Receiving triethanolamine salt of 3'-N-desbenzoyl-3'-N-Deshanel-3'-N-(t-butoxycarbonyl)-3'-(2-furyl)-2'-O - ethoxycarbonyl-7-O-phosphonomethylglycine

< / BR>
To a solution of the product of stage (c) (311 mg, 0,259 mm) in 25 ml of ethyl acetate was added 60 mg of 10% palladium charcoal and the resulting solution was stirred in hydrogen atmosphere for 30 minutes. The catalyst was removed by filtration through celite, and the filtrate was concentrated in vacuum. The residue was dissolved in 3 ml of ethyl acetate was added triethanolamine (2.3 ml, 0.1 M in 40% acetonitrile/water) and liofilizovane, as a result, we received 205 mg phosphatidylethanolamine salt (67%).

FAB-MS (NOBA) [M+Na] for C47H60HPO22Na: calculated: 1044 found: 1044.

IR (film): 3432 (Shir. ), 1752, 1722, 1372, 1246, 1158, 1108, 1096, 1070, 1002 cm-1.

1H-NMR (d6-acetone/D2O, 300 MHz): of 8.09 (d, J = 7.2 Hz, 2H); a 7.62 (m, 2H); 7,52 (t, J = 7.5 Hz, 2H); 6.48 in (d, J = 3.3 Hz, 1H); 6.42 per (m, 2H); 6,16 (t, J = 8.7 Hz, 1H); the 5.65 (d, J = 6,9 Hz, 1H); 5,46 (d, J = 3.6 Hz, 1H); and 5.30 (d, J = 3.6 Hz, 1H); 5.17 to (Shir.s, 1H); 5,01 (Shir.d, J = 9.0 Hz, 1H); 4,19 (Shir.s, 1H); 4,18 (m, 5H); 3,95 (m, 4H); a 3.87 (d, J = 6,9 Hz, 1H); 3,68 (s, 10H); 3,50 (Shir.triplet, J = 4,8 Hz, 4H); 2.95 and (m, 1H); of 2.44 (s, 3H); to 2.41 (m, 2H); of 2.16 (s, 3H); 1,99 (s, 3H); of 1.94 (m, 1H); by 1.68 (s, 3H); of 1.34 (s, 9H); to 1.24 (t, J = 6.9 Hz, 3H); of 1.17 (s, 6H).

Example 8. Triethanolamine salt of 3'-N-desbenzoyl-3'-destiny-3'-N-(butyloxycarbonyl)-3'-(2-thienyl-2'-O-ethoxycarbonyl-7-O-phosphonomethylglycine

(a) Obtaining 3'-N-desbenzoyl-3'-destiny-3'-N-(t-butyloxycarbonyl)-3'-(2-thienyl)-7-O-methyldiethanolamine

< / BR>
To a solution of HDMS (0.5 ml, 2.4 mm) in 18 ml of THF at -55oC, was added n-utility of 0.85 ml, 2.5 M in hexane, 2.1 mm). After 10 minutes, to the solution drop by drop) was added baccatin III 7-MTM (1,15 g, 1,78 mm) in 18 ml of THF, and the resulting solution was stirred cold for 10 minutes. After that I added ()-CIS-1-(t-butyloxycarbonyl)-4-(2C within 30 minutes. The solution was diluted with ethyl acetate and washed with saturated solution of NH4Cl was dried by magnesium sulfate and concentrated. The residue was chromatographically on silica gel (eluent: hexane/ethyl acetate, 3: 1) and received 1,87 g selected lactam (eluent: hexane/ethyl acetate, 3: 1) and 1.44 g of the product of the joining - 3'-N-desbenzoyl-3'-destiny-3'-N-(t-butyloxycarbonyl)-3'-(2-thienyl)- 7-O-methylthiomethyl-2'-O-criticalimportance (output - 78%).

FAB-MS (NOBA) [M + Na] for C51H71NO15S2SiNa:

Calculated: 1052; Found: 1052.

IR (film): 3442 (Shir. ), 1720, 1490, 1368, 1270, 1242, 1162, 1110, 1064, 1024, 984, 754 cm-1.

1H-NMR (CDCl3, 300 MHz): of 8.09 (d, J = 7.2 Hz, 2H); EUR 7.57 (t, J = 7,6 Hz, 1H); 7,47 (t, J = 7.8 Hz, 2H); 7,22 (m, 1H), 6,95 (m, 2H); 6,55 (s, 1H); 6,21 (t, J = 9,3 Hz, 1H); of 5.68 (d, J = 6,9 Hz, 1H); 5,49 (Shir.d, 1H); 5,39 (Shir. d, J = 9.6 Hz, 1H); 4,94 (d, J = 7.8 Hz, 1H); with 4.65 (s, 2H); of 4.57 (s, 1H); to 4.28 (m, 2H); 4,17 (d, J = 8,4 Hz, 1H); 3,88 (d, J = 6,9 Hz, 1H); 2,80 (m, 1H); to 2.46 (s, 3H); is 2.37 (m, 1H); of 2.20 (m, 1H); 2,17 (s, 3H); 2,10 (s, 3H); 2,03 (s, 3H); of 1.84 (m, 1H); 1,74 (s, 3H); 1,68 (s, 1H); of 1.62 (s, 1H); to 1.31 (s, 9H); of 1.20 (s, 6H); from 0.84 (t, J = 7.8 Hz, 9H); 0,50 (m, 6H).

13C-NMR (CDCl3, and 75.5 Hz): 201,9, 171,1, 170,7, 170,1, 169,3, 167,0, 155,1, 142,8, 140,9, 133,6, 132,9, 130,2, 129,2, 128,7, 126,9, 124,6, 83,9, 81,2, 80,1, 78,8, 77,4, 76,0, 75,7, 75,2, 74,8, 74,1, 71,3, 57,4, 53,8, 47,0, 43,3, 35,3, 33,3, 28,1, 26,3, 23,0, 21,3, 20,9, 14,9, 14,4, 10,9, 6,6, 4,5.

To a solution of 2'-triethylsilyl Astor was stirred for 30 minutes, was diluted with ethyl acetate, washed with brine, dried with magnesium sulfate and concentrated. The residue was chromatographically on silica gel (eluent: hexane/ethyl acetate, 1:1) and got to 1.16 g of target compound (92%).

FAB-MS (NOBA) [M + Na] for C45H57NO15S2Na:

Calculated: 938; Found: 938.

IR (film): 3440 (Shir.), 1720, 1368, 1242, 1168, 1106, 1066, 710 cm-1.

1H-NMR (CDCl3, 300 MHz): 8,08 (d, J = 7.2 Hz, 2H); to 7.59 (m, 1H); 7,47 (t, J = 7.8 Hz, 2H); from 7.24 (m, 1H), 7,07 (m, 1H); 6,99 (m, 1H); 6,53 (s, 1H); 6,18 (t, J = 8,1 Hz, 1H); to 5.66 (d, J = 6,9 Hz, 1H); 5,49 (d, J = 9.6 Hz, 1H); 5,32 (d, J = 9.6 Hz, 1H); to 4.92 (d, J = 7.8 Hz, 1H); 4,63 (m, 3H); to 4.28 (m, 2H); 4,15 (d, J = 8,4 Hz, 1H); 3,86 (d, J = 6,9 Hz, 1H); 3,47 (d, J = 5.4 Hz, 1H); 2,78 (m, 1H); of 2.36 (s, 3H); 2,34 (s, 2H); 2,17 (s, 3H); 2,10 (s, 3H); 2,00 (s, 3H); to 1.83 (m, 1H); 1,74 (s, 3H); 1,72 (s, 1H); to 1.61 (s, 1H); of 1.33 (s, 9H); to 1.21 (s, 3H); 1.18 to (s, 3H).

13C-NMR (CDCl3, and 75.5 Hz) 201,9, 172,3, 170,3, 169,2, 167,0, 154,0, 141,5, 140,2, 133,7, 133,3, 130,2, 129,1, 128,7, 127,0, 125,4, 83,9, 81,3, 80,4, 78,6, 76,1, 75,4, 74,5, 74,0, 73,4, 72,5, 57,5, 52,8, 47,2, 43,2, 35,3, 32,9, 28,2, 26,4, 22,6, 20,9, 15,1, 14,7, 10,8.

(b) Obtaining 3'-Dibenzoyl-3'-destiny-3'-N-(t-butyloxycarbonyl)-3'-(2-thienyl)-2'-O-ethoxycarbonyl-7-O-methyldiethanolamine

< / BR>
To a solution of the product of stage (a) (621 mg, 0,677 mm) in 35 ml of dichloromethane, at 0oC, was added diisopropylethylamine (1.20 ml, 6,89 mm) and ethylchloride (0, is giving 2 hours and was diluted with dichloromethane, was washed with saturated bicarbonate, dried with magnesium sulfate, and concentrated. The residue was chromatographically on silica gel (hexane/ethyl acetate, 1:1), and received 528 mg of target compound (79%).

FAB-MS (NOBA) [M + Na] for C48H61NO17S2Na:

Calculated: 1010; Found: 1010.

IR (film): 3510, 3440, 1752, 1720, 1370, 1244, 1198, 1170, 1026, 988, 756 cm-1.

1H-NMR (CDCl3, 300 MHz): of 8.09 (d, J = 7.2 Hz, 2H); 7,58 (m, 1H); of 7.48 (t, J = 7.8 Hz, 2H); 7,26 (m, 1H), 6,99 (m, 2H); 6,55 (s, 1H); 6,23 (t, J = 8.0 Hz, 1H); of 5.68 (d, J = 6,9 Hz, 1H); 5,33 (d, J = 9.9 Hz, 1H); 5.25 in (d, J = 2.4 Hz, 1H); 4,94 (d, J = 7.8 Hz, 1H); 4,65 (c, 2H); 4,33 - 4,08 (m, 5H); 3,88 (d, J = 6,9 Hz, 1H); 2,80 (m, 1H); 2.40 a (s, 3H); 2.40 a - 2,20 (m, 2H); of 2.16 (s, 3H); 2,11 (s, 3H); 2,07 (s, 3H); to 1.83 (m, 1H); of 1.74 (s, 3H); 1.69 in (s, 1H) and 1.60 (s, 1H); of 1.33 (s, 9H); to 1.31 (t, J = 7.2 Hz, 9H); of 1.20 (s, 3H); 1,19 (s, 3H).

13C-NMR (CDCl3, and 75.5 Hz): : 202,0, 169,7, 169,1, 167,5, 167,1, 154,0, 140,9, 133,6, 132,9, 130,2, 129,2, 128,7, 127,2, 125,4, 125,3, 83,9, 81,2, 80,6, 78,8, 76,9, 76,0, 75,7, 74,7, 74,2, 72,8, 72,0, 65,2, 57,4, 50,9, 47,1, 43,3, 35,1, 33,0, 28,1, 26,4, 22,7, 21,2, 20,9, 15,1, 14,5, 14,1, 10,9.

(c) Obtaining 3'-N-desbenzoyl-3'-destiny-3'-N-(t-butyloxycarbonyl)-3-(2-thienyl)-2'-O-ethoxycarbonyl-7-O - dibenzylethylenediamine

< / BR>
To a solution of the product of stage (b) (516 mg, 0,522 mm) in 15 ml of anhydrous tetrahydrofuran was added 530 mg of molecular sieves 4A, 576 mg (2,09 mm) dibenzylamine and 136 mg per the obtained solution was stirred for 1 hour. After this, the solution was filtered through celite, diluted with ethyl acetate, washed with 10% NaS2O8, saturated bicarbonate and brine, dried with magnesium sulfate and concentrated. The residue was chromatographically on silica gel (15% acetonitrile/chloroform) and received 535 mg of target compound (84%).

FAB-MS (NOBA) [M + Na] for C61H72NO21PSNa:

Calculated: 1240; Found: 1240.

IR (film): 3424 (Shir.), 1750, 1722, 1370, 1244, 1016, 1000, 944 cm-1.

1H-NMR (CDCl3, 300 MHz): 8,08 (d, J = 7,0 Hz, 2H); 7,58 (m, 1H); 7,47 (t, J = 7.5 Hz, 2H); 7,28 (m, 11H), of 6.99 (m, 2H); 6,33 (s, 1H); from 6.22 (t, J = 7.8 Hz, 1H); to 5.66 (m, 2H); of 5.39 (t, J = 6,6 Hz, 1H); of 5.34 (d, J = 12 Hz, 1H); with 5.22 (d, J = 2.4 Hz, 1H); free 5.01 (d, J = 8,1, 6,0 Hz, 5H); a 4.86 (d, J = 7.8 Hz, 1H); 4,29 - 4,08 (m, 5H); of 3.85 (d, J = 6,6 Hz, 1H); was 2.76 (m, 1H); 2,39 (s, 3H); 2,35 - to 2.18 (m, 2H); of 2.16 (s, 3H); of 1.97 (s, 4H); 1.69 in (C, 4H); of 1.33 (s, 9H); of 1.30 (t, J = 7.2 Hz, 3H); of 1.20 (s, 3H); 1,17 (s, 3H).

13C-NMR (CDCl3, and 75.5 Hz): 197,4, 165,4, 164,9, 163,3, 162,7, 150,6, 149,7, 136,7, 136,0, 129,4, 128,6, 125,9, 124,7, 124,3, 124,2, 124,1, 123,6, 122,9, 121,1, 121,0, 89,4, 79,8, 77,3, 76,5, 76,3, 74,4, 72,0, 70,7, 70,3, 67,7, 64,9, 60,9, 52,7, 46,5, 42,3, 38,9, 30,7, 23,8, 22,0, 13,3, 17,0, 16,4, 10,3, 9,8, 6,2.

(d) Receiving triethanolamine salt of 3'-N-desbenzoyl-3-destiny-3'-N-(t-butyloxycarbonyl)-3'-(2-thienyl)-2-O-ethoxycarbonyl-7-O-phosphonomethylglycine

< / BR>
To a solution of the product of stage (c) (512 mg, is within 3 hours. The catalyst was removed by filtration through celite, and the filtrate was concentrated in vacuum. The residue was dissolved in 2 ml of ethyl acetate was added triethanolamine (4,0 ml, 0.1 M in ethyl acetate, 0.40 mm). The resulting solution was concentrated, and the residue was chromatographically on C18-columns (eluent: 40% acetonitrile/water), and then liofilizovane, and received 280 mg phosphatidylethanolamine salt (56%). The purity of the salt was determined using ghud-analysis was 96%.

FAB-MS (NOBA) [M + Na) for C47H60NO21PS:

Calculated: 1060; Found: 1060.

IR (KBr): 3422 (Shir.), 1750, 1720, 1372, 1246, 1162, 1096, 1068, 1000 cm-1.

1H-NMR (d6-acetone/D2O, 300 MHz): of 8.06 (d, J = 7.2 Hz, 2H); 7,63 (t, J = 7.2 Hz, 1H); 7,52 (t, J = 7.8 Hz, 2H); 7,38 (d, J = 4,2 Hz, 1H); 7,16 (d, J = 3.5 Hz, 1H); 7,01 (DD, J = 5,1, 3.6 Hz, 1H); 6,37 (s, 1H); 6,11 (t, J = 8.7 Hz, 1H); 5,61 (d, J = 6,9 Hz, 1H); ceiling of 5.60 (s, 1H); 5,26 (d, J = 4.5 Hz, 1H); 5,14 (t, J = 6,6 Hz, 1H); 5,00 (d, J = 8,4 Hz, 1H); a 4.86 (DD, J = 12,0, 6.3 Hz, 1H); 4,17 (m, 5H); 4,00 (s, 7H); to 3.92 (t, J = 4,8 Hz, 6H); a-3.84 (d, J = 6,9 Hz, 1H); of 3.48 (t, J = 4,8 Hz, 6H); to 2.94 (m, 1H); to 2.42 (s, 3H); of 2.36 (m, 1H); and 2.27 (m, 1H); of 2.15 (s, 3H); 1,95 (s, 4H); of 1.66 (s, 3H); of 1.30 (s, 9H); of 1.23 (t, J = 7.2 Hz, 3H); 1.14 in (s, 6H).

Example 9. 10-Deacetyl-3'-N-desbenzoyl-3'-N-(t-butyloxycarbonyl)-10-O-(phosphonomethyl)paclitaxel

(a) Receiving 10-deacetyl-10-O-benzyloxycarbonyl-7-O-triethylenemelamine III
balali anhydrous tetrahydrofuran (30 ml), and the solution was cooled to -70oC. To this solution drop by drop) was added 2,38 mm (3,81 mm) 1.6 M n-utillity. After 15 minutes, to this solution drop by drop added benzylchloride (of 0.91 ml, 6.35 mm). The resulting mixture was stirred for 3 hours while gradually warming to room temperature. The reaction was suppressed by adding 25 ml of saturated NH4Cl, washed with saline, and was dried in vacuum magnesium sulfate. After flash chromatography (silica gel, 30 to 45% ethyl acetate/hexane) received 2.24 g (89%) of target compound as a white foam.

1H-NMR (300 MHz, CDCl3): 8,10 (d, J = 8.0 Hz, 2H); 7,63 - 7,58 (m, 1H); 7,47 (t, J = 8.0 Hz, 2H); 7,41 - 7,26 (m, 5H); of 6.29 (s, 1H); 5,61 (d, J = 7,0 Hz, 1H); 5,20 (sq, J = 12,2 Hz, 2H); 4,96 (d, J = 9.0 Hz, 1H); 4,87 - 4,84 (m, 1H); 4,48 (DD, J = 6,7, 10.4 Hz, 1H); 4,30 (d, J = 8.5 Hz, 1H); 4,14 (d, J = 8.5 Hz, 1H); of 3.84 (d, J = 7,0 Hz, 1H); 2,58 - 2,48 (m, 1H); to 2.29 (m, 4H); of 2.20 (s, 3H); 2,03 (d, J = 5.0 Hz, 1H); 1,92 of - 1.83 (m, 1H); by 1.68 (s, 3H); of 1.17 (s, 3H); 1.04 million (s, 3H); of 0.91 (t, J = 7.5 Hz, 9H); 0,57 (sq, J = 7,4 Hz, 6H).

(b) Receiving 10-deacetyl-10-O-benzyloxycarbonyl-3'-N-desbenzoyl-3'-N-(t-butyloxycarbonyl)-2',7-bis-O - criticalimportance

< / BR>
In a dry flask containing the product of stage (a) (3.50 g, 4,42 mm), was added a small amount of toluene, and the solution was concentrated in vacuum. Then the flask was placed in an atmosphere of argon, was added to the mm). After stirring for 20 minutes, to a solution of one drop of solution was added (3R, 4S)-1-(t-butyloxycarbonyl)-4-phenyl-3-triethylsilyl-2-azetidinone (2.58 g, 7,07 mm) in 10 ml dry THF. The reaction mixture was stirred for 3.5 hours, gradually warming to room temperature. After this reaction was suppressed by adding 70 ml of saturated NH4Cl, washed with saline, dried with magnesium sulfate and concentrated. After flash chromatography (silica gel, 5 to 15% ethyl acetate/hexane), was obtained 5,12 g (99%) target compound as a white foam.

1H-NMR (300 MHz, CDCl3): 8,11 (d, J = 8.0 Hz, 2H); 7,60 - 7,58 (m, 1H); of 7.48 (t, J = 8.0 Hz, 2H); 7.24 to 7,26 (m, 10H); 6,32 - of 6.26 (m, 2H); 5,69 (d, J = 7,0 Hz, 1H); 5,47 (Shir. d, J = 9.7 Hz, 1H); 5,31 - 5,10 (m, 3H); 4,94 (d, J = 8.5 Hz, 1H); 4,56 (s, 1H); to 4.46 (DD, J = 6,9 J = a 10.6 Hz, 1H); or 4.31 (d, J = 8,3 Hz, 1H); 4,17 (d, J = 8,3 Hz, 1H); 3,81 (d, J = 7,0 Hz, 1H); 2,53 (s, 3H); 2,48 is 2.33 (m, 1H); 2,22 - 2,17 (m, 1H); of 2.09 (s, 3H); 1,95 is 1.86 (m, 1H); to 1.70 (s, 3H); 1,95 is 1.86 (m, 1H); 1,65 (s, 1H); of 1.52 (s, 1H); of 1.30 (s, 9H); 1.26 in - 1,19 (m, 6H); of 0.94 - 0.87 (m, 9H); the 0.80 to 0.75 (m, 9H); 0,61 - of 0.53 (m, 6H); 0,48 - 0,30 (m, 6H).

(c) Receiving 10-deacetyl-3'-N-desbenzoyl-3'-N-(t-butyloxycarbonyl)-7-O - criticalimportance

< / BR>
The product of stage (b) (5,12 g, 4,40 mm) was dissolved in 100 milliliters of ethyl acetate, transferred into a vessel Parra and was placed in an atmosphere of argon. Then dobavljal - 3,867 kg/cm2within 8 hours. The reaction mixture was filtered through a layer of celite and concentrated. After flash chromatography (silica gel; 15 - 20% ethyl acetate/hexane), was obtained 3,24 g (79%) of target compound as a white foam. As a result of hydrolysis of 2'-triethylsilyl product group stage (b) in a Parr apparatus, received acid residues in trace quantities.

1H-NMR (300 MHz, CDCl3): 8,10 (d, J = 8,0 2H); 7,63-7,58 (m, 1H); 7,49 (d, J = 8,0, 2H); 7,39 - 7,26 (m, 5H); 6,27 - of 6.17 (m, 1H); 5,64 (d, J = 7,2); 5,42 (d, J = 9,4, 1H); 5,28 - a 5.25 (m, 1H); 5,12 (s, 1H); to 4.92 (d, J = 8,6, 1H); 4,62 (Shir. s, 1H); to 4.38 - to 4.28 (m, 3H); 4,17 (d, J = 8,5, 1H); of 3.85 (d, J = 6,7, 1H); to 3.36 (d, J = 5,3, 1H); 2,49 - to 2.40 (m, 1H); of 2.36 (s, 3H); 2,25 (Shir. the doublet. J = 8,7, 2H); 1,99 is 1.91 (m, 1H); of 1.85 (s, 3H); 1,74 (s, 3H); 1.69 in (s, 1H); 1,67 (s, 1H); to 1.35 (s, 9H); 1,22 (s, 3H); 1,11 (s, 3H); of 0.93 (t, J = 7.5 Hz, 9H), and 0.61 - 0,49 (m, 6H).

(d) Receiving 10-desacetyl-2'-O-benzyloxycarbonyl-3'-N-desbenzoyl-3'-N-(t-butyloxycarbonyl)-7-O-criticalimportance

< / BR>
Into the flask containing the product of stage (C) (3,24 g, 3,51 mm) was added 30 ml of dry dichloromethane. After the flask was placed in an atmosphere of argon and cooled to 0oC. To the reaction mixture were added N,N-diisopropylethylamine (1,22 ml, 7,02 mm), and then one drop was added benzylchloride (1,00 ml, 7,02 mm). After 15 minutes the cooling bath was removed, and the reaction zabavlenia 30 ml of saturated NH4Cl, washed with saline and dried with magnesium sulfate. After flash chromatography (silica gel, 7-20% ethyl acetate/hexane) received 3,24 g (89%) of target compound as a white solid.

1H-NMR (300 MHz, CDCl3): 8,10 (d, J = 8,0, 2H); 7,62-EUR 7.57 (m, 1H); of 7.48 (t, J = 8,0, 2H); 7,40 - 7,26 (m, 10H); 6,33 - 6,27 (m, 1H); to 5.66 (d, J = 7,0, 1H); 5,49 - 5,42 (m, 5H); 5,31 (s, 1H); 5,22 - 5,13 (m, 3H); is 4.93 (d, J = 9.4 Hz, 1H); to 4.38 (DD, J = 6,5, J = 10,7, 1H); 4,34 - to 4.28 (m, 2H); 4,18 (d, J = 8,3, 1H); 3,90 (d, J = 6,7, 1H); 2,52 - of 2.30 (m, 4H); 2,24 - of 2.20 (m, 1H); 1,97 - to 1.87 (m, 3H); 1,74 (s, 3H); to 1.59 (s, 3H); 1.32 to (s, 9H); 1.26 in (s, 3H); 1,11 (s, 3H); 0,96 - to 0.88 (m, 9H); 0,61 - of 0.48 (m, 6H).

(e) Receiving 10-desacetyl-2'-O-benzyloxycarbonyl-3'-N-desbenzoyl-3'-N-(t-butyloxycarbonyl) 10-O-(Dibenzoyl-phosphonomethyl)-7-O-criticalimportance

< / BR>
The product of stage (d) was dissolved in 13.5 ml (54%) DMSO, is 8.75 ml (35%) of acetic anhydride and 2.75 ml (11%) glacial acetic acid and then placed in an atmosphere of argon. The reaction mixture was stirred for 56 hours, after which it was diluted with ethyl acetate to a volume of 60 ml the Solution was washed with saturated sodium bicarbonate until then, until it became neutral, which was indicated pH-filter paper and then washed with saline. The organic fraction was dried with magnesium sulfate and concentrated. After flash chromatographically product (so that is , 10-desacetyl-2'-N-O-benzyloxycarbonyl-3'-N-desbenzoyl-3'-N- (t-butyloxycarbonyl)-10-O-(methylthiomethyl)-7-O - criticalimportance, based on 70% of the material (NMR analysis).

The above crude mixture (3,12) was dissolved in 1,2-dichloroethane (61 ml) and placed in an atmosphere of argon. After this was added powdered molecular sieves 4A (3.12 g) and the resulting heterogeneous mixture was vigorously stirred. To this stirred mixture was added a solution of recrystallized N-jodatime (0,830 g, 3,69 mm), and then by kanalirovaniya added dimensionful (of 1.027 g of 3.69 mm) in anhydrous THF (46 ml). The resulting mixture was stirred 5 hours, filtered through a layer of celite, and was diluted with ethyl acetate to a volume of 250 ml. After washing with cold 2% NaHSO3(G ml), cold 6% NaHCO3(G ml) and brine, the organic phase was dried with magnesium sulfate, and concentrated. After flash chromatography (silica gel; eluent: 25-35% ethyl acetate/hexane), was obtained 1.52 g (40%) of target compound as a white solid.

1H-NMR (CDCl3), 300 MHz): 8,08 (d, J = 7,0, 2H); to 7.59 - of 7.55 (m, 1H); 7,46 (t, J = 7,2, 2H); 7,38 - 7,25 (m, 20H); 6,30 (t, J = 8,5, 1H); the 5.65 (d, J = 6,8, 1H); 5,49 of 5.39 (m, 4H); 5,32 (s, 1H); 5,18 - 4,19 (m, 4H); is 4.93 (d, J = 9,2, 1H), of 4.44 (DD, J = 6,6, J = 10,2, 1H); or 4.31 (d, J (H); of 0.93 (t, J = 7,4, 9H), 0.55 and (sq, J = 7,8, 6H).

13C-NMR (CDCl3, 75.5 MHz): 204,1, 169,7, 157,9, 167,1, 151,1, 140,7, 135,7, 133,6, 130,2, 129,2, 128,9, 128,8, 128,7, 128,6, 128,5, 128,4, 128,3, 128,2, 128,0, 127,8, 126,4, 90,4, 84,2, 81,1, 80,4, 79,3, 78,8, 74,9, 72,8, 72,0, 70,5, 69,2, 69,1, 69,0, 58,1, 46,8, 43,2, 37,1, 35,0, 28,1, 26,5, 22,8, 21,0, 14,1, 10,0, 6,9, 5,5.

MC (FAB) m/z + : 1345

(f) Receiving 10-desacetyl-2-O-benzyloxycarbonyl-3'-N-desbenzoyl-3'-N-(t-butyloxycarbonyl)-10-O-(dibenzyl-phosphonoacetate)of paclitaxel

< / BR>
In argon atmosphere, a solution of the product of stage (e) (50,8 mg, 0.038 mm) in anhydrous THF (2.5 ml) was cooled to -40oC. To this solution drop by drop) was added tetrabutylammonium fluoride (0,057 ml 0,057 mm) in THF (1.0 M). The reaction mixture was stirred for 1.5 hours, was gradually heated to -20oC. Then the reaction mixture was extinguished by 15 ml of saturated NH4Cl and diluted with 30 ml EtOAc. The organic phase is washed with sodium bicarbonate (g ml) and brine. After that, the mixture was dried with magnesium sulfate and concentrated. After preparative chromatography (silica gel; 50% ethyl acetate/hexane), was obtained 36 mg (77%) of target compound in the form of a white powder.

1H-NMR (CDCl3, 300 MHz): 8,10 (d, J = 8,5, 2H); 7,60 - of 7.55 (m, 1H); 7,49 - 7,44 (m, 2H); of 7.36 - to 7.18 (m, 20H); 6,27 - to 6.22 (m, 1H); 5,78 (s, 1H); 5,67 (d, J = 7,0, 1H); 5,44 - of 5.34 (m, 3H); 5,27 ,87 (m, 5H); 1,73 was 1.69 (m, 4H); of 1.30 (s, 9H); 1,22 - of 1.15 (m, 6H).

MC (FAB) m/z: 1231.

(g) Receiving 10-deacetyl-3'-N-desbenzoyl-3'-N-(t-butyloxycarbonyl)-10-O- (phosphonomethyl)of paclitaxel triethanolamine salt

< / BR>
500-Ml flask Parra download 10-desacetyl-2-O-benzyloxycarbonyl-3'-N-desbenzoyl-3'-N- (t-butyloxycarbonyl)-10-O-(dibenzylideneacetone)paclitaxel (264,9 mg, 0,215 mm) and ethyl acetate (20 ml). The flask was purged with argon was added 10% palladium carbon (318 mg). The resulting mixture was placed in a Parr apparatus under hydrogen pressure of 55 pounds per square inch (3,586 kg/cm2). The reaction course was monitored using ghvd (70: 30, CH3CN/Q8-buffer; pH of 6.0, and 1.00 ml/min, C-18 column Bond, 25,0 cm = 230 nm) until the disappearance of starting material (12.5 hours). The resulting mixture was filtered through celite and washed with ethyl acetate and a small amount of dichloromethane. The obtained filtrate was concentrated, and the residue was dissolved in dichloromethane (5 ml). By adding hexane, formed white precipitate, in the form of the free acid (80% purity by ghvd), which was allocated 140,3 mg of a white solid. This material is directly used in the next stage.

Into the flask containing the above free acid (140 mg, is lazette (1,16 ml, 0,116 mm), resulting in the solution has gained a muddy color. Then add approximately 2 ml of hexane and the mixture was left overnight at -20oC. the precipitate was filtered through a funnel fused glass (4,0-5,5 µm). The formed solid product was removed and placed in vacuum for 4 hours. So, got to 69.9 mg (42%) target triethanolamine salt in the form of a grey powder (ghvd-purity: 95 - 96%; TR= 2,05 min, eluent: CH3CN/ Q8-buffer; pH of 6.0, and 1.00 ml/min, C-18-column Bond - 25,0 cm = 230 nm).

1H-NMR (d6-acetone /D2O, 300 MHz): 8,03 (d, J = 7,4, 2H); the 7.65 (t, J = 7,3, 1H); rate of 7.54 (t, J = 7,6, 2H); 7,42 - 7,33 (m, 5H); 7,21 (t, J = 7,0, 1H); 6,09 (t, J = 9,0, 1H); 5,88 (s, 1H); 5,59 (d, J = 7,0, 1H); 5,12 (Shir. s, 2H); is 4.93 (d, J = 8,4, 2H); 4,56 (d, J = 4,9, 1H); or 4.31 - 4.26 deaths (m, 1H); 4,11 (s, 2H); 3,41 - 3,37 (m, 6H); 2,42 of - 2.32 (m, 5H); 2,15 (Shir. s, 1H); of 1.97 (s, 3H); 1.77 in - of 1.64 (m, 2H); was 1.58 (s, 3H); of 1.13 (s, 9H); 1,15 - of 1.07 (m, 6H).

13C-NMR (d6-acetone, D2O, 75,6 MHz): 171,6, 166,9, 156,6, 141,8, 135,1, 134,2, 131,0, 130,7, 129,4, 129,3, 128,4, 128,1, 88,3, 85,4, 81,9, 79,7, 78,6, 78,1, 76,8, 76,0, 74,8, 71,9, 71,2, 47,4, 44,0, 37,1, 36,3, 28,5, 27,0, 23,1, 22,0, 14,7, 10,4.

BPMC: MNA+for C44H56NO18PNa: calculated: 9403142; found: 9403133.

Example 10. 2'-O-Phosphonomethylglycine

(a) Obtaining 2'-O-(methylthiomethyl)-7-O-triethyl-silicagel

< / BR>

1H-NMR (300 MHz, CDCl3): 8,12 - 7,20 (15H, m);? 7.04 baby mortality (1H, d, J = 8,9 Hz); 6,41 (1H, s); of 6.25 (1H, m); of 5.81 (1H, DD, J = 8,9, and 2.4 Hz); of 5.68 (1H, d, J = 7,0 Hz); is 4.93 (1H, d, J = 7,0 Hz); 4,79 (2H, m); 4,71 (1H, d, J = 2.4 Hz); of 4.45 (1H, DD, J = 10,5, and 6.6 Hz); 4,30 (1H, d, J = 8,3 Hz); 4,28 (1H, d, J = 11.7 Hz); 4,17 (1H, d, J = 8,3 Hz); Android 4.04 (1H, d, J = 11.7 Hz); of 3.80 (1H, d, J = 6.9 Hz); 2,48 - 1,13 (25H, m, including singlets at 2,51, 2,13, 2,05, 2,01, 1,69, 1,19, 1,16); 0,98 - 0,85 (9H, m); 0,65 - of 0.50 (6H, m);

(b) Obtaining 2'-O-(dibenzylideneacetone)-7 - criticalimportance

< / BR>
To a solution of the product obtained in stage (a) (15 mg, 0,0141 mm) and molecular sieves (15 mg) W mm), and the solution was stirred for 1 hour. At this time TLC analysis of the reaction mixture indicated the presence of only the source material. Then to the solution in three portions were added triplet silver (5.0 mg, 0,019 mm) (within 2 hours), and the reaction mixture was stirred for another 1 hour. Then the reaction mixture was diluted with ethyl acetate, and the resulting solution was filtered through a layer of celite. Thereafter, the filtrate was treated with a mixture (1:1, by volume) solution of saturated aqueous sodium bicarbonate and 5% aqueous sodium thiosulfate solution. The organic extract was washed with saline, dried with sodium sulfate and concentrated in vacuum. The residual oily product was purified using flash-chromatography (hexane/ethyl acetate, 1:1), and received 5.0 mg (33%) of target compound.

1H-NMR (300 MHz, CDCl3): 8,08 - 7,16 (25H, m), 7,18 (1H, d, J = 8,8 Hz); 6.41 (1H, s); 6,21 (1H, m); of 5.82 (1H, DD, J = 9,0, 3.1 Hz); to 5.66 (1H, d, J = 7,0 Hz); 5,01 - 4,65 (10H, m); 4,56 (1H, DD, J = 14,7, 5,6 Hz); 4,43 (1H, DD, J = 10,4, 6,7 Hz); the 4.29 (1H, d, J = 8,3 Hz); 4,16 (1H, d, J = 8,3 Hz); of 3.78 (1H, d, J = 8,3 Hz); 2,60 - 1,13 (22H, m, including singlets at 2,49, 2,15, 1,93, 1,66, 1,15, 1,13, and 3H-each) of 0.95 is 0.84 (9H, m); 0,63 - 0,45 (6H, m).

(C) Obtaining 2'-O-phosphonomethylglycine

< / BR>
The product of stage (b) was treated with fluoride tetrabutyl is In accordance with the procedure described in the previous examples, the thus obtained compound was subjected to catalytic hydrogenation, and received the target connection.

Example 11. 2-O-Phosphonomethylglycine (Alternative procedure)

(a) Obtaining 2-O-Criticalimportance

< / BR>
To a solution of paclitaxel (20,0 g, 0,0234 M) and imidazole (3,59 g, 0,052 M) in 150 ml of DMF, at 0oC, was added triethylsilane (6,0 ml, 0,053 M) of 2.0-ml portions over 20 minutes. The reaction mixture was stirred at 0oC for one hour. Then the mixture was diluted with ethyl acetate and saturated aqueous ammonium chloride. The organic layer was removed, washed with saline, dried with magnesium sulfate and concentrated in vacuum to obtain a yellow oily substance. This crude product was purified using flash-chromatography (hexane/ethyl acetate, 1:3, and then hexane/ethyl acetate, 1:1), and received 21,07 g (yield 98%) of target compound as a colorless solid.

1H-NMR (300 MHz, CDCl3): 8,15 (2H, m); of 7.70 (2H, m); the 7.65 7,30 (11H, m); to 7.15 (1H, d, J = 8,9 Hz); 6,30 (1H, s); of 6.25 (1H, m); 6,70 - 6,10 (2H, m); 4,94 (1H, d, J = 7.9 Hz); of 4.67 (1H, d, J = 2.0 Hz); however, 4.40 (1H, m); the 4.29 (1H, d, J = 8,4 Hz); 4,18 (1H, d , J = 8,4 Hz); 3,81 (1H, d, J = 7,1 Hz); 2,65 - 1,10 (22H, including singlets at 2,55, 2,BR>
To a solution of 2-O-criticalimportance (22,3 g, 24,1 mm) in THF (250 ml), cooled to -50oC, drop by drop within 10 minutes, was added utility (1.6 M in hexane, 12.9 sludge of 8.06 mm). The resulting solution was stirred 20 minutes, and the temperature was maintained in the range from -50oC to -35oC. Then the reaction mixture was cooled to -50oC, and drop in for 5 minutes was added benzylchloride (5,08 g, 29,8 mm). Then the reaction mixture was maintained at -40oC for 30 minutes and then for 30 minutes vigorously stirred to a temperature of 0oC. the resulting mixture was diluted with ethyl acetate and saturated aqueous ammonium chloride. The obtained organic layer was washed with saline, dried with sodium sulfate and concentrated in vacuum.1H-NMR analysis of the crude reaction mixture indicated the presence of the desired 2'-O-triethylsilyl-7-O-benzyloxycarbonylglycine, and 2'-O-triethylsilyl-7-epigallocatechol (respectively, the ratio is 3:1). This product (mixture) used in the subsequent stage without further purification, and then the isomers were separated. An analytical sample of the first product-2'-0-triethylsilyl-7-0-benzyloxycarbonylglycine was purified using flash-chromatography the,52 (1H, m); 5,24 (1H, d, J = 12.3 Hz); 5,16 (1H, d, J = 12.3 Hz); of 4.95 (1H, d, J = 8.7 Hz); 4,69 (1H, s); of 4.35 (1H, d, J = 8,3 Hz); 4.25 in (1H, d, J = 8,3 Hz); 3,94 (1H, d, J = 6.8 Hz); 2,70 - 1,12 (22H, including singlets at 2,54, 2,14, 2,01, 1,80, 1,20, 1,15, 3H each); 0,81 - to 0.73 (9H, m); 0,55 - 0,31 (6H, m).

(c) obtaining the 7-On-benzyloxycarbonylglycine

< / BR>
To a solution of the product of stage (b) (24,0 g, 22,6 mm) in acetonitrile (250 ml), cooled to 0oC, was added hydrochloric acid (6N 1.0 ml, 6.0 mm). After 10 minutes, TLC analysis (hexane/ethyl acetate, 1:1) indicated complete reaction. The reaction mixture was diluted with saturated aqueous sodium bicarbonate and then with ethyl acetate, and the organic layer was removed, washed with saline, dried with sodium sulfate and concentrated in vacuum. The residual oily substance was purified using flash-chromatography (hexane/ethyl acetate, 1:3, and then hexane/ethyl acetate, 1:1), and obtained 11.4 g (yield in relation to the two phases were 48%) of target compound and 4.8 g (yield - 20%) 7-epigallocatechol.

1H-NMR (300 MHz, CDCl3): of 8.09 (2H, m); 7,71 (2H, m); the 7.65 7,27 (16H, m), 7,10 (1H, d, J = 8,9 Hz); to 6.39 (1H, s); 6,16 (1H, m); of 5.81 (1H, d, J = 8,9, and 2.4 Hz);); the 5.65 (1H, d, J = 6.9 Hz); 5,49 (1H, DD, J = 10,6, 7,2 Hz); 5,20 (1H, d, J = 11,9 Hz); 5,12 (1H, d, J = 11,9 Hz); 4,91 (1H, d, J = 8,4 Hz); 5,78 (1H, m); 4,30 (1H, d, J = 8,4 Hz); 4,15 (1H, d, J = 8,4 Hz); 3,91 (1H, d, J = 6,8 is dimethylmethoxy)-7-O-benzyloxycarbonylglycine

< / BR>
To a solution 7-0-benzyloxycarbonylglycine (5.53 g, 5,71 mm), 1', 1'-decimalisation ester (7.8 g, 57,1 mm) N-iodosuccinimide (6,35 g, 28.3 mm) and dried in an oven, powdered molecular sieves (5.0 g) in THF (110 ml) at room temperature, was added triflate silver (300 mg, 1,17 mm). TLC analysis (hexane: ethyl acetate, 1:1) reaction mixture after 20 minutes pointed to the conversion of approximately 40% of the source material in a higher fraction of the product. Then added triplet silver (150 mg, 0,585 mm) and the reaction course was monitored by TLC, which is 30 minutes later testified about 65% completion of reaction. After that, the mixture was diluted with ethyl acetate (100 ml), filtered through a layer of celite, and the obtained filtrate was poured into a separating funnel containing 200 ml of a saturated aqueous solution of sodium bicarbonate and 50 ml of 5% aqueous sodium thiosulfate solution. The organic layer was removed, washed with saline, dried with sodium sulfate and concentrated in vacuum. The remainder in the form of an oily product was purified using flash chromatography (eluent: gradient of ethyl acetate/hexane, 4: 1 - 3:2), and received 3.0 g (yield of 54%) of the desired product as a pale yellow solid.

1H, Is, J = 6.9 Hz); the 5.51 (1H, d, J = 11,9 Hz); a total of 5.21 (1H, d, J = 11,9 Hz); 5,14 (1H, d, J = 11,9 Hz); 4.92 in (1H, m); 4,79 (2H, m); and 4.68 (1H, d, J = 2.5 Hz); or 4.31 (1H, DD, J = 11.8 Hz); 4,30 (1H, d, J = 11.8 Hz); 4,16 (1H, d, J = 8.5 Hz); 4,10 (1H, d, J = 11.8 Hz); 3,93 (1H, d, J = 6.9 Hz); 2,65 - 1,10 (25H, including singlets at each 2,50, 2,15, 2,05, 1,74, 1,72, 1,20, 1,15, 3H).

(e) Obtaining 2-O-(dibenzylideneacetone)-7-O-benzyloxycarbonylglycine

< / BR>
To a solution of 2'-O-(methylthiomethyl)-7-O-benzyloxycarbonylglycine (1.06 g, 1,07 mm) and dried in an oven, powdered molecular sieves (1.0 g) in THF (20 ml) at room temperature, was added dimensionful (1,49 g, 5,30 mm), and then immediately added N-iodosuccinimide (2.65 g, 1,18 mm). TLC analysis (eluent: hexane/ethyl acetate, 1:1) reaction mixture after 2.5 hours, suggesting that the reaction was completed by approximately 60%. After adding N-iodosuccinimide (175 mg, 0,78 mm), the reaction mixture was stirred for another 30 minutes, after which TLC analysis indicated completion of reaction. The reaction mixture was diluted with ethyl acetate (50 ml) and filtered through a layer of celite. Thereafter, the filtrate was poured into a separating funnel containing 100 ml of a saturated aqueous solution of sodium bicarbonate and 20 ml of 5% aqueous sodium thiosulfate solution. The organic layer was removed, PR is th product was purified using flash chromatography (eluent: gradient mixture of hexane/ethyl acetate, 3:1 - 1:1), resulting in a received 750 mg (yield of 62%) of target compound as a white solid.

1H-NMR (360 MHz, CDCl3): 8,10 (2H, m); 7,79 (2H, m); 7,65 - 7,24 (26H, m), 7,10 (1H, m); 6,41 (1H, s); of 6.20 (1H, m); 5,79 (1H, DD, J = 8,8, 3.6 Hz); the 5.65 (1H, d, J = 7,0 Hz); 5,52 (1H, m); 5,20 (1H, d, J = 11.8 Hz); 5,11 (1H, d, J = 11.8 Hz); 5,04 - 4,85 (6H, m); 4.75 V - 4,60 (4H, m); 4,30 (1H, d, J = 8,4 Hz); 4,15 (1H, d, J = 8,4 Hz); to 3.92 (1H, d, J = 8,4 Hz); 2,65 - 1,10 (22H, including singlets at 2,48, 2,19, 1,95, 1,80, 1,20, 1,10, 3H - each).

(f) Obtaining 2'-O-phosphonomethylglycine triethanolamine salt

To a solution of 2'-O-(dibenzylideneacetone)-7-O-benzyloxycarbonylglycine (500 mg, 0,382 mm) in ethyl acetate (40 ml), placed in a vessel Parra, was added 10% palladium angle. The vessel was attached to a Parr apparatus, and the reaction mixture was subjected to interaction with hydrogen at a pressure of 50 psi (3,515 kg/cm2), then the reaction mixture was shaken for 6.5 hours, and then filtered through a funnel fused glass. To the obtained filtrate was added triethanolamine (0.1 N. in ethyl acetate, 4,0 ml) and the resulting solution was concentrated in vacuum. The crude solid product is suspended in ethyl acetate (approximately 5.0 ml) and the solvent decantation. This procedure povtoreva about the purity of salt 87%. In addition, this compound was purified by chromatography on C18-columns (eluent: water/acetonitrile, 3:1) and obtained target compound (120 mg, 34%) with a purity of 95% (ghvd).

1H-NMR (300 MHz, CD3COCD3D2O): 9,05 (1H, d, J = 8.7 Hz); 8,15 - 7,12 (21H, m); 6,40 (1H, m); 6,05 (1H, m); 5,69 - of 5.55 (2H, m); 5,01 - 4,85 (6H, m); of 4.35 (1H, m), 4,14 (2H, m); 3.96 points - of 3.85 (6H, m); of 3.25 (1H, d, J = 7,1 Hz); 3,30 - 3,15 (6H, m); 2,50 was 1.04 (22H, including singlets at each 2,49, 2,15, 2,05, 1,81, 1,60, 3H).

Example 12. 3'-N-Desbenzoyl-3'-N-(isopropoxycarbonyl)-7-O-methyldiethylamine

< / BR>
To a solution 7-0-methylthiopyrimidine III (408 mg, 0,630 mm) in 10 ml of THF at -60oC, was added n-utility (0,30 ml, 2.5 M, 0.75 mm) and stirred 10 minutes. Then to the solution drop by drop) was added (3R, 4S)-3-triethylsilyl-4-phenyl-N - isopropoxycarbonyl-2-he (320 mg, 0,88 mm) in 6 ml of THF, and then the reaction was brought to 0oC for 30 minutes. The reaction solution was suppressed by the addition of saturated NH4Cl was extracted with ethyl acetate, shaken with 1.0 milliliters (1.0 M, 1.0 mm) Bu4NF, and then washed with saline solution, dried by magnesium sulfate, and concentrated. The residue was chromatographically on silica gel (eluent: hexane/ethyl acetate, to 1.5:1); and received 545 mg of product, which crystallizability of acetone is - 4%.

IR (KBr): 3460, 1720, 1266, 1244, 1230 cm-1.

1H-NMR (CDCl3, 300 MHz): 8,07 (d, J=7.2 Hz, 2H); to 7.59 (t, J=7.2 Hz, 1H); 7,47 (t, J=7.5 Hz, 2H); 7,32 (m, 5H); 6,51 (s, 1H); 6,18 (t, J=8.7 Hz, 1H); the 5.65 (d, J=6,6 Hz, 1H); 5,50 (d, J=9,3 Hz, 1H); 5,28 (d, J=8,4 Hz, 1H); 4,91 (d, J= 8,1 Hz, 1H); of 4.77 (m, 1H); with 4.64 (Shir. s, 3H); 4.26 deaths (m, 2H); 4,15 (d, J= 8,4 Hz, 1H); 3,83 (d, J=6,9 Hz, 1H); 3,44 (d, J=5,1 Hz, 1H); 2,78 (m, 1H); of 2.34 (s, 3H); 2,25 (d, J=9.0 Hz, 2H); 2,17 (s, 3H); 2,14 (s, 1H); 2,10 (s, 3H); 1,96 (s, 3H); to 1.83 (m, 1H); at 1.73 (s, 3H); to 1.15 (m, 12H).

13C-NMR (CDCl3, and 75.5 Hz): 201,8, 170,4, 169,2, 167,0, 156,3, 140,1, 138,3, 133,7, 133,3, 130,2, 129,1, 128,8, 128,6, 128,1, 126,8, 83,8, 81,4, 78,7, 76,0, 75,5 74,5, 74,0, 73,6, 72,2, 68,9, 57,5, 56,4, 47,1, 43,2, 35,3, 32,9, 26,6, 22,6, 22,0, 21,9, 20,9, 15,1, 14,6, 10,9.

MC (FAB) (NOBA) [M+Na] for C46H57NSO15:

Calculated: 918; Found: 918.

Elemental analysis for C46H57NO15: Calculated: C 61,66; H 6,41; 1,56 N; Found: C 61,63; H 6,36; N, 1,68.

Example 13. 3'-N-Desbenzoyl-3'-N-(t-butyloxycarbonyl)-7-O-methyldiethylamine

< / BR>
To a solution of 7-O-methylthiopyrimidine III (425 mg, 0.66 mm) in 10 ml of THF at -60oC, was added n-utility (0,30 ml, 2.5 M, 0.75 mm), and the solution was stirred for 10 minutes. Then to the solution drop by drop) was added (3R, 4S)-3-triethylsilyl-4-phenyl-N-(n-butyloxycarbonyl)azetidin-2-he (350 mg, 0,93 mm) in 6 ml of THF, and the reaction was brought to 0oC for 30 minutes. The reaction is rajawali with 1.0 milliliters (1.0 M, 1.0 mm) Bu4NF and washed with saline, dried with magnesium sulfate and concentrated. The residue was chromatographically on silica gel (eluent: hexane/ethyl acetate, to 1.5:1) and received 581 mg of the target product, which was led from toluene/hexane, resulting in received 464 mg of a white solid (77%).

IR (KBr): 3444, 1722, 1372, 1242, 1108, 1066, 1026, 988 cm-1.

1H-NMR (CDCl3, 300 MHz): 8,08 (d, J=7.2 Hz, 2H); to 7.59 (t, J=7.5 Hz, 1H), 7,47 (t, J=7.2 Hz, 2H); 7,39 - 7,11 (m, 5H); 6,51 (s, 1H); of 6.20 (t, J= 8.7 Hz, 1H); the 5.65 (d, J=6,9 Hz, 1H); to 5.56 (d, J=9,3 Hz, 1H); from 5.29 (d, J=8,4 Hz, 1H); 4,91 (d, J=8,1 Hz, 1H); 4,65 (Shir. s, 3H); 4,27 (m, 2H); 4,15 (d, J=8,4 Hz, 1H); of 3.97 (m, 2H); of 3.84 (d, J=6,9 Hz, 1H); of 3.45 (d, J=4,8 Hz, 1H); 2,78 (m, 1H); of 2.33 (s, 6H); 2,25 (d, J=8,7, 2H); 2,17 (s, 3H); 2,10 (s, 3H); 1,96 (s, 3H); to 1.83 (m, 1H); 1,74 (s, 3H); of 1.62 (s, 1H); to 1.48 (m, 2H); 1,19 (m, 5H); or 0.83 (t, J=7.2 Hz, 3H).

13C-NMR (CDCl3, and 75.5 Hz): 201,9, 172,3, 170,5, 169,2, 167,0, 156,3, 140,1, 138,4, 133,8, 133,4, 130,2, 129,2, 129,0, 128,9, 128,7, 128,2, 126,8, 125,3, 83,9, 81,4, 78,8, 77,3, 76,0, 75,6, 74,1, 73,7, 72,2, 65,4, 57,5, 56,5, 47,2, 43,2, 35,4, 26,6, 22,6, 21,5, 21,0, 18,9, 15,1, 14,7, 13,7, 10,9.

MC (FAB) (NOBA) [M+H] for C47H60NSO15:

Calculated: 910; Found: 910.

Elemental analysis for C47H59NSO15:

Calculated: C 62,03; H 6,53; N 1,54;

Found: C 62,16; H Of 6.45; N, 1,57.

Example 14. 3'-N-Desbenzoyl-3'-N-(t-butoxycarbonyl)-7-O - methylthiomethyl

< / BR>
To a solution of HMDS (0,275 ml, 1,30 mm) in 8 ml THF was added a solution of n-utility (of 0.48 ml, 2.5 M in hexane, 1.20 mm) and stirred 5 minutes at -55oC. To this solution was added 7-O-methylthiopyrimidin III (639 mg, 0,99 mm) in 8 ml of THF and stirred for 10 minutes, after which was added 8 ml of a solution of (3R, 4S)-3-triethylsilyl-4-phenyl-N-(t-butoxycarbonyl)azetidin-2-it (1.52 mm). The cold bath was removed and was replaced with a bath temperature of 0oC and then the reaction mixture was stirred for 30 minutes. The resulting solution was diluted with ethyl acetate, washed with saturated solution of NH4Cl, dried magnesium sulfate, and concentrated. The residue was chromatographically on silica gel (hexane/ethyl acetate, 3:1), and received 1.0 g of the target product (yield was 98%).

1H-NMR (CDCl3, 300 MHz): of 8.09 (d, J=6,9 Hz, 2H); EUR 7.57 (m, 1H); 7,46 (t, J=7.8 Hz, 2H); 7,35 (m, 2H); 7,26 (m, 3H); 6,55 (s, 1H); of 6.25 (t, J=9.6 Hz, 1H); of 5.68 (d, J=6,9 Hz, 1H); 5,45 (Shir. d, J=9,3 Hz, 1H); 5,27 (Shir. d, 1H); 4,95 (d, J=7,8, 1H); with 4.65 (s, 2H); 4.53-in (s, 1H); 4,29 (m, 2H); 4,17 (d, J= 8,4 Hz); the 3.89 (d, J=6,9 Hz, 1H); of 2.81 (m, 1H); of 2.51 (s, 3H); is 2.37 (DD, J= 15,3 and 9.6 Hz, 1H); 2,17 (s, 3H); 2,10 (s, 3H); 2,03 (s, 3H); of 1.85 (m, 1H); 1,74 (s, 3H); and 1.63 (d, J=14.1 Hz, 1H); of 1.29 (s, 9H); 1,21 (c, 6H); from 0.76 (t, J=7.8 Hz, 9H); 0,36 (m, 6H).

13C-NMR (CDCl3, and 75.5 Hz): 202,0, 171,6, 170,1, 169,3, 167,1, 155,2, 141,0, 139,0, 133,6, 132,8, 130,2, 129,2, 128,7, 128,5, 127,7, 126,4, 83 C get.,), 1720, 1242, 1120, 1056 cm-1.

MS(FAB) (NOBA) [M+H]: for C53H74NSSiO15:

Calculated: 10244549. Found: 10244583.

(b) Obtaining 3'-N-desbenzoyl-3'-N-(t-butoxycarbonyl)-7-O-methyldiethanolamine

< / BR>
To a solution of 3'-N-desbenzoyl-3'-N-(t-butoxycarbonyl)-2-O-triethylsilyl-7-O - methyldiethanolamine (269 mg, 0,26 mm) in 6 ml THF was added tetrabutylammonium fluoride (0.3 ml, 1.0 M in THF, 0.3 mm) and the resulting mixture was stirred for 10 minutes. The resulting solution was diluted with ethyl acetate, washed with brine, dried with magnesium sulfate, and concentrated. The residue was subjected to chromatography on silica gel (eluent: hexane/ethyl acetate, 1:1), and received 240 mg of the desired product (95%).

IR (film): 3440, 1720, 1370, 1242, 1170, 1108, 1066, 756, cm-1.

1H-NMR (CDCl3, 300 MHz): of 8.06 (d, J = 7.2 Hz, 2H); EUR 7.57 (t, J = 7.2 Hz, 1H); 7,46 (t, J = 7.8 Hz, 2H); 7,35 (m, 5H); 6,52 (c, 1H); 6,16 (t, J = 7.8 Hz, 1H); 5,64 (d, J = 6,9 Hz, 1H); 5,43 (width, d, J = 9,3 Hz, 1H); 5,24 (W, d, J = 8,1 Hz, 1H); 4,91 (d, J = 8,1 Hz, 1H); 4,63 (m, 3H); 4.26 deaths (m, 2H), 4,14 (d, J = 8,4 Hz, 1H), 3,83 (d, J = 6,9 Hz, 1H); 3.46 in (d, J = 5.4 Hz, 1H); 2,77 (m, 1H); of 2.34 (s, 3H); and 2.27 (d, J = 8.7 Hz, 2H); 2,16 (c, 3H); 2,09 (c, 3H); of 1.97 (s, 3H); to 1.79 (m, 2H); 1,72 (s, 3H); 1.32 to (c, 9H); 1,19 (c, 3H); 1.18 to (s, 3H).

13C-NMR (CDCl3, and 75.5 Hz): 202,0, 172,7, 170,3, 169,2, 167,0, 155,3, 140,3, 138,4, 133,7, 133,2, 130,2, 129,1, 128,8, 128,7, 128,0, 126,7, 83,9, 81,3, 60,2, 78NO15S:

Calculated: 9103684. Found: 9103706.

Example 15. 3'-N-Desbenzoyl-3'-N-(t-butoxycarbonyl)-2-O-ethoxycarbonyl-7-O-methyldiethylamine

< / BR>
To a solution of 3'-N-desbenzoyl-3'-N-(t-butoxycarbonyl)-7-O-methyldiethanolamine (428 mg, 0.47 mm) in 10 ml of dichloromethane, was added diisopropylethylamine of 0.85 ml, 4.8 mm) and DMAP (20 ml) and the resulting solution was cooled to 0oC. then was added ethylchloride (0.25 ml, 2.6 ml) and the solution was stirred for 1 hour. The solution was diluted with ethyl acetate, washed with bicarbonate and brine, dried with magnesium sulfate and concentrated. Thus obtained residue was chromatographically on silica gel (hexane/ethyl acetate, 1:1), and received 428 mg of the target ethylcarbonate (92%).

IR (film): 3448 (m), 1750, 1720, 1370, 1244, 1064 cm-1.

1H-NMR (CDCl3, 300 MHz): of 8.09 (d, J = 7.2 Hz, 2H); to 7.59 (t, J = 7.2 Hz, 2H); of 7.48 (t, J = 7.8 Hz, 2H); 7,39 (m, 2H); 7,31 (m, 3H); 6,55 (s, 1H); of 6.25 (t, J = 9.0 Hz, 1H); of 5.68 (d, J = 7.2 Hz, 1H); 5.40 to (W, m, 2H); 5.25 in (c, 1H); 4,95 (d, J = 8,1 Hz, 1H); with 4.65 (d, 2H); 4,29 (m, 2H); 4,15 (m, 3H); 3,88 (d, J = 6,9 Hz, 1H); of 2.81 (m, 1H); 2,43 (s, 3H); 2,32 (m, 1H); of 2.21 (m, 1H); of 2.16 (s, 3H); 2,11 (s, 3H); of 2.08 (s, 3H); of 1.84 (m, 1H); 1,74 (s, 3H); of 1.62 (s, 1H); 1.32 to (c, 3H); of 1.28 (t, J = 7.2 Hz, 3H); of 1.20 (s, 6H).

13C-NMR (CDCl3, and 75.5 Hz): 202,0 169,7, 169,1, 168,1, 167,0, 155,1, 154,1, 141,0, 137,2, 133,6, 132,9, 130,2">

FAB-MS (NOBA) [M + N]: for C50H64NSO17:

Calculated: 9823895. Found: 9823874.

Example 16. 3'-N-Desbenzoyl-3'-N-(t-butoxycarbonyl)-7-O-methylthiomethyl-10-deazetil-10-hydroxymethyluracil (paclitaxel)

(a) Obtaining 7-O-Triethylsilyl-10-deazetil-10-benzyloxycarbonylglycine III

< / BR>
To a solution of 7-O-triethylsilyl-10-methoxyacetanilide III (3,85 g, 5,85 mm) in 40 ml of THF at -60oC, was added n-utility (2.6 ml, 2.5 M in hexane, 6.5 mm) and was stirred for 5 minutes, then added benzyloxyacetophenone (1.0 ml, 6.5 mm). After stirring for 30 minutes at -60oC and subsequent heating to room temperature the solution was diluted with ethyl acetate and washed with bicarbonate. After that, the solution was dried with magnesium sulfate and concentrated, and the obtained residue was chromatographically on silica gel (eluent: hexane/ethyl acetate 2:1, hexane/ethyl acetate, 1:1), resulting in a received 4,36 g of product (92%).

IR (film): 3478 (Shir.), 1724, 1270, 1244, 1136, 1110, 1070 cm-1.

1H-NMR (CDCl3, 300 MHz): 8,08 (d, J = 7.2 Hz, 2H); 7,60 - of 7.23 (m, 8H), is 6.54 (s, 1H); ceiling of 5.60 (d, J = 6,9 Hz, 1H); 4,94 (d, J = 7.8 Hz, 1H); 4,79 (width, square, 1H); 4,69 (s, 2H); of 4.49 (DD, J = 10,5, and 6.6 Hz, 1H); 4.26 deaths (m, 2H); of 4.12 (m, 1H); of 3.85 (d, J = 6,9 Hz, 1H); 2,52 (m, 1H); and 2.26 (s, 3H); of 2.23 (m, 2H); to 2.18 (s, 3H); 2,10 58SiO12:

Calculated: C 65,49; H 7,24

Found: C 65,33; H 7,27.

FAB-MS (NOBA) M + N: for C44H59SiO12:

Calculated: 807; Found: 807.

(b) 3'-N-Desbenzoyl-3'-N-(t-butoxycarbonyl)-10-methoxyacetyl-10-benzyloxycarbonyl (paclitaxel)

< / BR>
To a solution of 7-O-triethylsilyl-10-methoxyacetyl-10-benzyloxycarbonylglycine III (1,21 g of 1.66 mm) in 50 ml of THF at -60oC, was added n-utility (0.7 ml, 2.5 M in hexane, to 1.75 mm), and the solution was stirred for 5 minutes, followed by addition of (3R, 4S)-3-triethylsilyl-4-phenyl-N-(t-butoxycarbonyl)azetidin-2-it, (1.2 g, 3.2 mm). After stirring for 5 minutes at -60oC and then for 30 minutes at 0oC, the solution was diluted with ethyl acetate and washed with saturated NH4Cl. After that, the solution was dried with magnesium sulfate and concentrated. The residue was subjected to chromatography on silica gel (hexane/ethyl acetate, 3:1, then hexane/ethyl acetate, 1:1), and received 980 mg of product (53%). This product was dissolved in 6 ml of acetonitrile and cooled to 0oC, and then mixed with 0,60 milliliters of 6 N. hydrochloric acid for 19 hours. After this, the solution was diluted with ethyl acetate, washed with saturated bicarbonate, dried with magnesium sulfate and chromatographia): 3448 (Shir. ), 1716, 1496, 1368, 1316, 1270, 1246, 1176, 1108, 1070, 1026 cm-1.

1H-NMR (CDCl3, 300 MHz): 8,08 (d, J = 7.5 Hz, 2H); to 7.59 (t, J = 7.8 Hz, 1H); 7,47 (t, J = 7.8 Hz, 2H); of 7.36 (m, 10H); 6,38 (s, 1H); of 6.20 (t, J = 9.0 Hz, 1H); the 5.65 (d, J = 6,9 Hz, 1H); 5,39 (Shir. d, J = 9,3 Hz, 1H); is 4.93 (d, J = 7.8 Hz, 1H); 4,69 (s, 2H); 4,60 (Shir. s, 1H); 4,39 (m, 1H); to 4.28 (m, 3H); 4,15 (d, J = 8,4 Hz, 1H); of 3.78 (d, J = 6,9 Hz, 1H); 3.40 in (lat. s, 1H); to 2.54 (m, 1H); 2,43 (m, 1H); 2,36 (s, 1H); 2,28 (m, 2H); of 1.84 (s, 4H); 1,72 (m, 1H); to 1.67 (s, 3H); to 1.31 (s, 9H); of 1.23 (m, 1H); to 1.21 (s, 3H); 1,10 (s, 3H).

Elemental analysis for C52H61NO16:

Calculated: C 65,33; H To 6.43; N, 1,46.

Found: C 64,97; H 6,44; N, 1,43.

FAB-MS (NOBA) M+Na: for C52H61NO16Na: Calculated: 978; Found: 978.

(c) Obtaining 3'-N-desbenzoyl-3'-N-(t-butoxycarbonyl)-2-O - benzyloxycarbonyl-7-O-methylthiomethyl-10-deacetyl-10 - benzyloxycarbonyl (paclitaxel)

< / BR>
To a solution of 3'-N-desbenzoyl-3'-N-(t-butoxycarbonyl)-10-deacetyl - 10-benzyloxycarbonyl (paclitaxel) (570 mg, 0,59 mm) in 10 milliliters of methylene chloride, at 0oC, was added diisopropylethylamine (0.15 ml, 0,86 mm) and CbzCl (0.10 ml, 0.70 mm). The resulting solution was stirred for hours, slowly warming to room temperature. The solution was washed with bicarbonate, dried with magnesium sulfate and concentrated. The obtained residue in 10 ml acetonuria to room temperature for 75 hours. After this, the solution was diluted with ethyl acetate, washed with saturated bicarbonate, dried with magnesium sulfate, and was chromatographically on silica gel (eluent: hexane/ethyl acetate, 2:1), resulting in a received 412 mg of the desired product (65%).

IR (film): 3438, 1754, 1722, 1368, 1272, 1244, 1176, 1110, 1066, 1028 cm-1.

1H-NMR (CDCl3, 300 MHz): 8,11 (d, J = 7.2 Hz, 2H); to 7.61 (t, J = 7.2 Hz, 1H); 7,49 (t, J = 7.8 Hz, 2H); 7,35 (m, 15H); to 6.67 (s, 1H); of 6.26 (t, J = 8.7 Hz, 1H); 5,69 (d, J = 6,6 Hz, 1H); 5,41 (Shir. m, 2H); from 5.29 (s, 1H); 5,14 (AB sq, J = 12 and 5.7 Hz, 2H); to 4.98 (d, J = 8 Hz, 1H); 4.72 in (m, 4H); 4,32 (m, 3H); 4,19 (m, 2H); 3,90 (d, J = 6.0 Hz, 1H); to 2.85 (m, 1H); of 2.45 (m, 1H); of 2.44 (s, 3H); of 2.34 (m, 1H); of 2.24 (m, 1H); of 2.15 (s, 3H); 2,12 (s, 3H); to 1.87 (m, 1H); or 1.77 (s, 3H); of 1.33 (s, 9H); to 1.19 (s, 6H).

13C-NMR (CDCl3, 75.5 MHz): 201,6, 169,7, 168,7, 168,0, 167,0, 155,1, 154,1, 141,6, 137,1, 134,4, 133,7, 132,5, 130,2, 129,2, 128,9, 128,8, 128,7, 128,5, 128,4, 128,2, 128,0, 128,0, 126,4, 83,9, 81,2, 80,4, 78,8, 77,2, 76,2, 75,8, 74,7, 74,3, 73,4, 72,0, 70,6, 67,1, 57,4, 54,1, 47,1, 43,2, 35,2, 32,9, 28,1, 26,4, 22,7, 21,3, 15,2, 14,6, 10,9.

MS (FAB) (NOBA) (M+Na) for C62H71NO18SNa: Calculated: 1172 Found: 1172.

(d) Obtaining 3'-N-desbenzoyl-3'-N-(t-butoxycarbonyl)-7-O - methylthiomethyl-10-deazetil-10-hydroxymethyluracil (paclitaxel)

< / BR>
To a solution of 3'-N-desbenzoyl-3'-N-(t-butoxycarbonyl)-2-O - benzyloxycarbonyl-7-O-methylthiomethyl-10-deazetil-10 - benzyloxycarbonyl (publicationfile hydrogen within 120 hours. The catalyst was removed by filtration through celite, and the solution was concentrated. The residue was chromatographically on silica gel (eluent: 20% CH3CN /79% CH2Cl2/1% MeOH), and has obtained 190 mg of the desired product (65%).

IR (film): 3444 (Shir.), 1724, 1368, 1246, 1174, 1096, 1070, 1026, 988 cm-1.

1H-NMR (CDCl3, 300 MHz): 8,07 (d, J = 7.2 Hz, 2H); to 7.59 (t, J = 7.2 Hz, 1H); 7,47 (t, J = 7.8 Hz, 2H); 7,35 (m, 5H); of 6.65 (s, 1H); 6,17 (t, J = 8.7 Hz, 2H); the 5.65 (d, J = 6,6 Hz, 1H); 5,39 (Shir. d, J = 9.6 Hz, 1H); 5,26 (Shir. d, 1H); is 4.93 (d, J = 8,4 Hz, 1H); of 4.67 (m, 3H); 4,28 (m, 5H); a 3.83 (d, J = 6.0 Hz, 1H); 3,44 (d, J = 5,1 Hz, 1H); 2,77 (m, 1H); 2.50 each (m, 1H); of 2.36 (s, 3H); to 2.29 (d, J = 8,4 Hz, 2H); 2.13 in (lat. s, 3H); for 2.01 (s, 3H); to 1.82 (s, 3H); 1,74 (s, 3H); of 1.33 (s, 9H); 1.18 to (s, 3H); to 1.16 (s, 3H).

13C-NMR (CDCl3, 75.5 MHz): 201,5, 171,5, 170,3, 167,0, 155,4, 141,3, 133,7, 132,7, 130,2, 129,0, 128,8, 128,7, 128,1, 126,8, 83,8, 81,3, 80,2, 78,6, 75,0, 74,4, 74,0, 73,6, 72,3, 60,6, 57,4, 56,2, 47,2, 43,2, 35,3, 32,6, 28,2, 26,5, 22,6, 21,0, 15,5, 14,7 10,8.

FAB-MS (NOBA) (M+Na) for C47H59NO16SNa:

Calculated: 948; Found: 948.

Example 17. 3'-N-Desbenzoyl-3'-N-(t-butoxycarbonyl)-7-O-methylthiomethyl-3'-methoxyphenyl-3'-isobutyrylacetate

< / BR>
To a solution of 7-O-methylthiopyrimidine III (1.5 g, 2.3 mm) in 30 ml of THF at -60oC, was added n-utility (1.0 ml, 2.5 M in hexane, 2.5 mm), and the resulting solution was stirred for 10 minutes. Then to this solution n the ml THF. After this solution was stirred at 0oC for 30 minutes and extinguished a saturated solution of NH4Cl and then extracted with ethyl acetate. The resulting solution was dried with magnesium sulfate, concentrated, and the residue was chromatographically on silica gel (eluent: hexane/ethyl acetate, 3:1). The obtained product was dissolved in 100 ml of THF was shaken with 2 or 3 ml (1.0 M in THF, 2.3 mm) Bu4NF was diluted with ethyl acetate and washed with saline. Then the solution was dried with magnesium sulfate and concentrated, and the residue was chromatographically on silica gel (eluent: hexane/ethyl acetate, 1,5:1), which was obtained 1.6 g of the desired product (78%).

IR (film): 3452 (Shir.), 1724, 1370, 1242, 1096, 1066 cm-1.

1H-NMR (CDCl3, 300 MHz): 8,07 (d, J = 7.2 Hz, 2H); to 7.59 (t, J = 7.5 Hz, 1H); 7,45 (t, J = 7.8 Hz, 2H); is 6.54 (s, 1H); 6,11 (t, J = 9,3 Hz, 1H); to 5.66 (d, J = 6.0 Hz, 1H); from 5.29 (d, J = 6.0 Hz, 1H); 4,94 (d, J = 8,1 Hz, 1H); 4.75 V (m, 2H); with 4.64 (AB kV, J = 12,0, 2.7 Hz, 2H); 4,29 (m, 2H); 4,20 (m, 2H); 3,86 (d, J = 6.0 Hz, 1H); 3,37 (Shir.d, 1H); and 2.79 (m, 1H); to 2.35 (s, 6H); of 2.16 (s, 3H); 2,10 (s, 3H); 2,04 (s, 3H); to 1.82 (m, 1H); 1,74 (s, 9H); of 1.34 (s, 9H); of 1.23 (s, 3H); of 1.20 (s, 3H).

13C-NMR (CDCl3, 75.5 MHz): 202,0, 170,2, 169,2, 166,9, 155,4, 140,6, 138,0, 133,7, 133,1, 130,1, 129,2, 128,6, 120,6, 83,8, 81,2, 79,9, 78,7, 77,2, 76,1, 75,5, 74,6, 74,0, 73,7, 72,2, 57,7, 57,4, 51,5, 47,1, 43,2, 35,4, 32,9, 28,2, 26,4, 25,8, 22,4, 21,0, 18,6, 15,1, 14,8, 10,9.

Tyl-3'-methoxyphenyl-3'-isobutyrylacetate

In accordance with the procedure described in example 17, the target connection poluchalis-O-methylthiopyrimidine()-CIS-3-triethylsilyl-4-isobutyl-N-benzoylation-2-it.

Example 19. 3'-Methoxyphenyl-3'-(2-furyl)-2'-O - ethoxycarbonyl-7-O-methyldiethylamine

In accordance with the procedures described in examples 7(a) and 7(b), the target compound can be obtained from (3R, 4R)-1-benzoyl-4-(2-furyl)-3-triethylsilyl-2-azetidinone and 7-O-methylthiopyrimidine III.

Example 20. 2-O-n-Propylboronic-7-O-phosphonomethylglycine

(a) Obtaining 2-O-n-propylmalonate

< / BR>
To a solution of paclitaxel (15.0 g, 17.5 mm) and diisopropylethylamine (18.3 ml, 105 mm) in dichloromethane (175 ml), cooled to 0oC, drop by drop within 2 minutes added butyrylcholine (5,49 ml, 52,4 mm). The reaction mixture was heated to room temperature and was stirred for 16 hours. Then the reaction mixture was distributed between ethyl acetate and saturated aqueous ammonium chloride. The organic phase was washed with a saturated solution of sodium bicarbonate, then brine, then dried with sodium sulfate and concentrated in vacuum. The oily residue was purified using flash chromemate.

1H-NMR (CDCl3, 300 MHz): 8,13 - with 8.05 (2H, m); 7,75 - the 7.65 (2H, m); a 7.62 7,30 (11H, m); to 6.88 (1H, d, J = 9.0 Hz); of 6.26 (1H, s); 6,23 (1H, DD, J = 8,4 Hz); of 5.92 (1H, DD, J = 9,3, 6,0 Hz); the 5.65 (1H, d, J = 7,1 Hz); of 5.48 (1H, DD, J = 10,4, a 6.5 Hz); 4,94 (1H, d, J = 7.9 Hz); is 4.21 (1H, DD, J = 10,4, 6.5 Hz); 4,28 (1H, d, J = 8,4 Hz); 4,17 (1H, d, J = 8,4 Hz); of 3.78 (1H, d, J = 7,0 Hz); 2,64 - 1,02 (26H, m, including singlets at each 2,43, 2,19, 1,91, 1,65 1,65, 1,20, 1,10, 3H); of 0.87 (3H, DD, J = 8,2 Hz).

(b) Obtaining 2'-O-n-propylboronic-7-O - methyldiethanolamine

< / BR>
To a solution of 2'-O-n-propylmalonate (14.4 g, 15,6 mm) and dimethyl sulfide (9,23 ml of 124.8 mm) in acetonitrile (312 ml), cooled to -40oC, was added benzoyl peroxide (15,1 g, 62,3 mm) and the reaction mixture was heated to room temperature within one hour. At this time TLC analysis (eluent: hexane/ethyl acetate) indicated completion of the reaction. After the reaction mixture was diluted with ethyl acetate and the resulting organic solution was washed three times with a saturated solution of sodium bicarbonate, and then brine. The organic phase was dried with sodium sulfate and concentrated in vacuum. The oily residue was purified using flash chromatography (eluent: hexane/ethyl acetate), and received the target compound (14.4 g, 93%) as a white solid.

1H-NMR (CDCl35,51 (1H, d, J = 3.2 Hz); 4.92 in (1H, d, J = 8,2 Hz); 4,68 - 4,59 (2H, m); 4,32 - 4.26 deaths (2H, m); 4,15 (1H, d, J = 8,3 Hz); 3,86 (1H, d, J = 6.8 Hz); 2,77 (1H, m); 2,50 - 1,05 (25H, m); of 0.87 (3H, d, J = 7,3 Hz).

(c) Obtaining 2'-O-n-propylboronic-7-O-(dibenzylideneacetone)of paclitaxel

< / BR>
To a solution of 2'-O-n-propylboronic-7-O-methyldiethanolamine (10.7 g, 11,0 mm), dibenzylamine (15.3 g, 55,0 mm) and 5 g dried in an oven Angstrom sieves 3 in THF (200 ml), at room temperature, one portion was added N-iodosuccinimide (4.9 g, 21,8 mm), and the resulting mixture was stirred for 1 hour. At this time TLC analysis (eluent: hexane/ethyl acetate) indicated completion of the reaction. This reaction mixture was diluted with ethyl acetate to a volume twice the original volume and filtered through celite. Then the filtrate was poured into a saturated solution of sodium bicarbonate containing 1% sodium thiosulfate (by weight). The organic layer was washed four times with saturated aqueous sodium bicarbonate, and then brine. The aqueous layer was again extracted with ethyl acetate, and the combined organic extracts were dried with sodium sulfate and concentrated in vacuum. The residual oily substance was purified using flash chromatography (eluent: hexane/ethyl acetate) and the received target deben is m); 7,74 - 7,71 (2H, m); to 7.61 - 7,25 (21H, m); 6,94 (1H, d, J = 9.0 Hz); of 6.31 (1H, s); of 6.20 (1H, DD, J = 8.7 Hz); 5,91 (1H, DD, J = 9,0, 3.1 Hz); 5,64 (1H, d, J = 6.9 Hz); 5,49 (1H, d, J = 3.0 Hz); of 5.39 (1H, DD, J = 6.6 Hz); of 5.05 - to 4.98 (5H, m); a 4.86 (1H, d, J = 6.6 Hz); 4.26 deaths - of 4.12 (3H, m); a-3.84 (1H, d, J = 8,4 Hz); 2,82 - a 2.71 (1H, m); 2,52 - 1,05 (26H, m, including singlets at each 2,43, 2,18, 1,97, 1,69, 1,22, 1,20, 3H); 0,90 - of 0.85 (3H, DD, J = 7,3 Hz).

(d) Obtaining 2'-O-n-propylboronic-7-O-phosphonomethylglycine

< / BR>
In purged with nitrogen, the flask for hydrogenation Parra, was added 2.5 g of 10% palladium carbon, and then pure ethyl acetate (150 ml) and a solution of 2'-O-n-propylboronic-7-O- (dibenzylideneacetone)paclitaxel (4.9 g, 4,14 mm) in ethyl acetate (40 ml). Then, the reaction vessel was connected to hydrogenization Parra, was placed under vacuum and submitted hydrogen at a pressure of 50 psi (3,515 kg/cm2). The obtained heterogeneous mixture was stirred with shaking for 5 hours, after which TLC analysis (eluent: hexane/ethyl acetate) indicated the complete depletion of the source material. Then the reaction mixture was placed in a vacuum, after which it was purged with nitrogen. The resulting mixture was filtered through a funnel of sintered glass and the filtrate was concentrated in vacuo, resulting in a received target compound (3.7 g, yield - 91%), which was purified with the aid of which impolitical

To a solution of 2'-O-n-propylboronic-7-O-phosphonomethylglycine (1.1 g, 1,09 mm) in dichloromethane (50 ml), was added a 0.1 M solution of triethanolamine (10.9 ml, of 1.09 ml) in ethyl acetate, and the resulting mixture was stirred for 5 minutes at room temperature. The reaction mixture was concentrated in vacuo and the resulting white solid was purified by first dissolving the crude material in a minimum amount of a mixture of methylene chloride and ethyl acetate, and then to this solution was added hexane, which formed the desired amine salt as a white solid. Then this mixture decantation, and received amine salt as a white solid, which had a purity (defined using Ehud analysis) more than 95%.

1H-NMR (acetone-d6D2O, 300 MHz): 8,09 - 8,07 (2H, m); 7,86 - to 7.84 (2H, ); 7,69 - 7,24 (11H, m); from 7.24 (1H, DD, J = 7.5 Hz); 6,36 (1H, s); 6,05 (1H, DD, J = 8,4 Hz); of 5.85 (1H, d, J = 6,7 Hz); 5,61 (1H, d, J = 7,0 Hz); 5,49 (1H, d, J = 6.9 Hz); 5,15 - 5,13 (1H, m); to 4.98 (1H, d, J = 8,2 Hz); 4,87 (1H, DD, J = 12.1 Hz, 6.4 Hz); 4,12 (W, s, 2H); 3,89 - of 3.80 (7H, m); 3,36 - 3,30 (6H, m); 2.95 and - of 2.93 (1H, m); 2,42 - 1,50 (25H, m, including singlets at each 2,42, 2,22, 1,93, 1,66, 3H); 1,13 (Shir. s, 6H); 0,86 - 0,81 (2H, DD, J = 7,4 Hz).

Example 21. 2'-O-Methylcarbamyl-7-O-phosphonomethylglycine

(a) Obtaining 2'-O-armetale (140 ml), cooled to 0oC, drop by drop within 2 minutes added acetylchloride (1.0 ml, 14,1 mm). The reaction mixture was heated to room temperature and was stirred for 10 hours. The resulting reaction mixture was distributed between ethyl acetate and saturated aqueous ammonium chloride. The organic phase was washed with a saturated solution of sodium bicarbonate, then brine, then dried with sodium sulfate and concentrated in vacuum. The residual oily product was purified using flash chromatography (eluent: hexane/ethyl acetate), and received 2-O-acetylacetone (7.7 g, 92%) as a white solid.

1H-NMR (CDCl3, 300 MHz): 8,10 - 8,08 (2H, m); 7,92 - of 7.90 (1H, m); 7,89 - of 7.70 (2H, m); 7,60 - 7,29 (11H, m): 6,94 (1H, d, J = 9,2 Hz); of 6.26 (1H, s); 6,23 (1H, DD, J = 9.5 Hz); to 5.93 (1H, DD, J = 9,2, 3.1 Hz); the 5.65 (1H, d, J = 7.8 Hz); of 5.48 (1H, d, J = 3.2 Hz); 4,94 (1H, d, J = 7.8 Hz); was 4.42 (1H, DD, J = 10,8 Hz and 6.6 Hz); 4,28 (1H, d, J = 8,4 Hz); 4,16 (1H, d, J = 8,4 Hz); of 3.78 (1H, d, J = 6.9 Hz); 2,60 - 1,02 (25H, m, including singlets at each 2,42, 2,19, 2,12, 1,90, 1,65, 1,25, 1,11 and 3H).

(b) Obtaining 2'-O-acetyl-7-O-methyldiethanolamine

< / BR>
To a solution of 2'-O-acetylacetonate (7.7 g, 8,60 mm) and dimethyl sulfide (5,1 ml, 68,8 mm) in acetonitrile (200 ml), cooled to -40oC, was added benzoyl peroxide (8,3 g, 34,4 mm), and R is latitat, 1 : 1) indicated complete reaction. The reaction mixture was diluted with ethyl acetate, and the organic solution was three times washed with a saturated solution of sodium bicarbonate, and then brine. The organic phase was dried with sodium sulfate and concentrated in vacuum. The residual oily substance was purified using flash chromatography (eluent: hexane/ethyl acetate), and the received target methylthiomethyl ether (7,39 g, 90%) as a white solid.

1H-NMR (CDCl3, 300 MHz): 8,10 - 8,08 (2H, m); to 7.77-7,73 (2H, m); 7,65 - 7,26 (11H, m); 6,53 (3H, 2); of 6.20 (1H, DD, J = 8,3 Hz); of 5.92 (1H, DD, J = 12,2, 3.1 Hz); 5,67 (1H, d, J = 7,0 Hz); the 5.51 (1H, d, J = 3.2 Hz); 4,94 (1H, d, J = 8,2 Hz); 4,69 - 4,60 (3H, m); 4,33 - to 4.28 (2H, m); 4,27 (1H, d, J = 8,4 Hz); 3,86 (1H, d, J = 6.9 Hz); 2,84 - to 2.74 (1H, m); 2,50 - 1,1 (28H, m, including singlets at each 2,41, 2,15, 2,13, 2,11, 2,06, 1,73, 1,18, 1,15, 3H).

(c) Obtaining 2'-O-acetyl-7-O-(dibenzylideneacetone)-paclitaxel

< / BR>
To a solution of 2-O-acetyl-7-O-methyldiethanolamine (5.0 g, 5,23 mm), dibenzylamine (5.0 g, 5,23 mm) and 5 g dried in an oven Angstrom sieves 3 in THF (104 ml) at room temperature, one portion was added N-iodosuccinimide (1.75 g, a 7.85 mm), and the resulting mixture was stirred for 1.5 hours. At this time TLC analysis (eluent: hexane/ethyl acetate, 1 : 1) indicated Segodnya volume, and filtered through a layer of celite. Then the filtrate was poured into a saturated solution of sodium bicarbonate containing 1% sodium thiosulfate (by weight). The organic layer was washed four times with saturated aqueous sodium bicarbonate, and then brine. After that, the aqueous layers was extracted again with ethyl acetate and the combined organic extracts were dried with sodium sulfate and concentrated in vacuum. The residual oily substance was purified using flash chromatography (eluent: hexane/ethyl acetate), resulting in a received target dimensionful (4.9 g, 80%) as a white solid.

(d) Obtaining 2'-O-acetyl-7-O-phosphonomethylglycine

< / BR>
In the vessel Parr hydrogenation (purged with nitrogen) was added 700 mg of 10% palladium carbon, and then 130 ml of pure ethyl acetate, and the solution of 2'-O-acetyl-7-O-(dibenzylideneacetone)paclitaxel (1.0 g, 0.84 mm) in ethyl acetate (40 ml). The reaction flask was connected to hydrogenization Parra, was placed in a vacuum, and served hydrogen at a pressure of 50 psi (3,515 kg/cm2). Then the reaction mixture was stirred with shaking for 6 hours, after which TLC analysis (eluent: hexane/ethyl acetate) indicated the complete depletion of Agency the solution was filtered through a funnel fused glass, and the filtrate was concentrated in vacuum, and received 848 mg of a white solid product. This substance was subjected to1H-NMR analysis, which indicated the presence of a mixture of target compound (50%) and 2-O-acetylacetonate.

(e) Obtaining 2'-O-acetyl-7-O-phosphonomethylglycine triethanolamine salt

To a solution of 2'-O-acetyl-7-O-phosphonomethylglycine (424 mg, 0,42 mm) and the aforementioned by-product 2-O-acetylacetonate in dichloromethane (15 ml), was added a 0.1 M solution of triethanolamine (3,7 ml, 3.8 mm) in ethyl acetate, and the resulting mixture was stirred at room temperature for 10 minutes. Then the reaction mixture was concentrated in vacuo and the resulting white solid was purified by chromatography on C18-columns (eluent: water/acetonitrile, 2,3:1), resulting in a received desired amine salt (310 mg, 72%), the purity of which was (ghvd analysis) more than 96%.

1H-NMR (acetone-d6D2O, 300 MHz): 8,05 - 8,08 (2H, m); 7,86 - 7,83 (2H, m); 7,69 - 7,24 (11H, m); 7.23 percent (1H, DD, J = 7,4 Hz); 6,35 (1H, s); of 6.02 (1H, DD, J = 8,3 Hz); 5,69 (1H, d, J = 6.9 Hz); 5,59 (1H, d, J = 7,1 Hz); the 5.45 (1H, d, J = 8,4 Hz); a 4.86 (1H, DD, J = 11,5, 6.5 Hz); 4,24 - 4,18 (1H, m); of 4.12 (2H, Shir.C); 3,92 - to 3.89 (6H, m); 3,80 - of 3.77 (1H, m); 3.46 in - 3,43 (6H, m); 3,00 - 2,89 (6H, m); 2,39 - 1,65 (21H, including singlets at each 2,39, 2,1 who phenoxymethylpenicillin

(a) Obtaining 2'-O-methoxycarbonylethyl

< / BR>
To a solution of paclitaxel (8.0 g, 9,60 mm) and diisopropylethylamine (5.0 ml, 28.8 mm) in dichloromethane (96 ml), cooled to 0oC, drop by drop within 2 minutes added chloromethylketone (1,11 ml, 14.4 mm). The resulting reaction mixture was heated to room temperature and was stirred for 20 hours. Then the reaction mixture was distributed between ethyl acetate and a saturated solution of ammonium chloride. The organic phase was washed with a saturated solution of sodium bicarbonate, then brine, then dried with sodium sulfate and concentrated in vacuum. The residual oily product was purified using flash chromatography (eluent: hexane/ethyl acetate), and received the target compound (7.8 g, 91.3 percent) as a white solid.

1H-NMR (CDCl3, 300 MHz): 8,12 - of 8.09 (2H, m); 7,72 - of 7.70 (2H, m); a 7.62 7,30 (11H, m); of 6.96 (1H, d, J = 9,3 Hz); 6,29 - 6,23 (3H, m); 5,95 (1H, DD, J = 9,3, 2,5 Hz); to 5.66 (1H, d, J = 7,1 Hz); 5,38 (1H, d, J = 2.6 Hz); 4,94 (1H, d, J = 7.8 Hz); to 4.41 (1H, DD, J = 10,8, and 6.6 Hz); 4,28 (1H, d, J = 7.8 Hz); 4,17 (1H, DD, J = 10,8, and 6.6 Hz); 3,79 - of 3.78 (3H, m); 2,60 was 1.04 (22H, m, including singlets at each 2,43, 2,19, 1,90, 1,65, 1,22, 1,10, 3H).

(b) Obtaining 2'-O-methoxycarbonyl-7-O-methyldiethanolamine

< / BR>
To a solution of 2'-O-metaxis, added benzoyl peroxide (of 7.48 g, 32,4 mm) and the reaction mixture was heated to room temperature within one hour. At this time TLC analysis (eluent: hexane/ethyl acetate) indicated completion of the reaction. The reaction mixture was diluted with ethyl acetate and the resulting organic solution of 3 times washed with a saturated solution of sodium bicarbonate, and then brine. The organic phase was dried with sodium sulfate and concentrated in vacuum. The remainder in the form of an oily substance was purified using flash chromatography (eluent: hexane/ethyl acetate), and received the target compound (7.4 g, 95%) as a white solid.

1H-NMR (CDCl3, 300 MHz); 8,25 - 8,23 (2H, m); 7,87 - to 7.77 (2H, m); 7,60 - 7,30 (11H, m); 6,93 (1H, d, J = 9,2 HZ); 6,53 (1H, s); of 6.25 (1H, DD, J = 8,2 Hz); 5,95 (1H, DD, J = 11,7, 2,4 Hz); of 5.68 (1H, d, J = 6.9 Hz); of 5.40 (1H, d, J = 2,6 Hz); of 4.95 (1H, d, J = 8.1 Hz); 4,69 - 4,60 (2H, m); or 4.31 - 4.26 deaths (2H, m); 4,16 (1H, d, J = 8,4 Hz); 3,86 (1H, d, J = 6.9 Hz); with 3.79 (3H, s); 2,84 - to 2.74 (1H, m); 2,43 - 1,10 (25H, including singlets at each 2,44, 2,15, 2,10, 0,08, 1,73, 1,19, 1,16, 3H).

(c) Obtaining 2'-O-methoxycarbonyl-7-O-(dibenzylideneacetone)of paclitaxel

< / BR>
To a solution of 2'-O-ethoxycarbonylpyrimidine (5,04 g, 5,18 mm), dibenzylamine (7.2 g, 25,8 mm) and 5 g dried in an oven molecular sieves Angstron 3 in THF (100 ml), kV 1.5 hours. At this time TLC analysis (eluent: hexane/ethyl acetate, 1:1) indicated complete reaction. The reaction mixture was diluted with ethyl acetate to a volume twice the original volume and filtered through a layer of celite. The filtrate was poured into a saturated solution of sodium bicarbonate containing 1% sodium thiosulfate (by weight). After that, the organic layer four times washed with saturated aqueous sodium bicarbonate, and then brine. The aqueous layer was again extracted with ethyl acetate, and the combined organic extracts were dried with sodium sulfate and concentrated in vacuum. The residual oily substance was purified using flash chromatography (eluent: hexane/ethyl acetate), and received the target compound (5.1 g, 96%) as a white solid.

1H-NMR (CDCl3, 300 MHz): 8,12 - 8,08 (2H, m); 7,73 - of 7.70 (2H, m); a 7.62 7,27 (21H, m); 7,00 (1H, d, J = 9,2 Hz); of 6.31 (1H, s); 6,24 - 6,21 (1H, m); 5,96 - of 5.92 (1H, m); 5,66 - 5,64 (1H, m); 5.40 to and 5.36 (2H, m); of 5.05 - 4,93 (5H, m); 4,87 - 4,84 (1H, m); 4,29 - of 4.05 (3H, m); 3,85 - a 3.83 (1H, m); of 3.77 (3H, s); 2,81 - a 2.71 (1H, m); 2,62 - 1,05 (22H, m, including singlets at each 2,43, 2,19, 2,01, 1,73, 1,22, 1,15, 3H).

(d) Obtaining 2'-O-methoxycarbonyl-7-O-phosphonomethylglycine

< / BR>
In a nitrogen purged vessel Parr hydrogenation, EXT is phosphonoacetate)paclitaxel (3.4 g, of 3.32 mm) in ethyl acetate (40 ml). Then the reaction vessel was connected to hydrogenization Parra, pomesali in vacuum, and served hydrogen at a pressure of 50/pound/square inch (3,515 kg/cm2). The mixture was mixed by shaking for 8.5 hours, after which TLC analysis (eluent: hexane/ethyl acetate) indicated the complete depletion of the source material. After the reaction mixture pomesali in vacuum and then purged with nitrogen. The heterogeneous solution was filtered through a funnel of sintered glass and the filtrate was concentrated in vacuum, the result was obtained 2.9 g of white solid. In the1H-NMR analysis showed the presence of a mixture of the desired product (67%) and 2-O-ethoxycarbonylpyrimidine (33%).

(e) Obtaining 2'-O-methoxycarbonyl-7-O-phosphonomethylglycine triethanolamine salt

To a solution of 2'-O-methoxycarbonyl-7-O-phosphonomethylglycine (1,91 g, 1,87 mm) and the aforementioned by-product 2-On-methoxycarbonylethyl in dichloromethane (11 ml) was added a 0.1 M solution of triethanolamine (18,9 ml, 1,89 mm) in ethyl acetate, and the resulting mixture was stirred for 5 minutes at room temperature. Then the reaction mixture was concentrated in vacuo and the resulting white solid fuel after lyophilization, received triethanolamine salt. This salt was analyzed using ghvd, which indicated the purity of the salt, which is 97%.

1H-NMR (acetone-d6D2Oh, 300 MHz): 8,08 - of 8.06 (2H, m); 7,88-of 7.55 (2H, m); 7,69-7,24 (11H, m); from 7.24 (1H, DD, J=7,3 Hz); 6,36 (1H, m); 6,05 (1H, DD, J= 8,8 Hz); of 5.82 (1H, d, J=6.8 Hz); the ceiling of 5.60 (1H, d, J=7,1 Hz); 5,46 (1H, d, J= 6.9 Hz); to 5.13 (1H, DD, J=6.5 Hz); 5,98 (1H, d, J=8.1 Hz); 4,87 (1H, DD, J= 11.8 Hz, 6.3 Hz); is 4.21(1H, DD, J=10,3, 6,9 Hz); 4,13 (Shir. s, 6H); 3,92-to 3.89 (6H, m); 3,81 (1H, d, J=7,02); 3,76 (3H, s); 3.46 in-of 3.42 (6H, m); 3,01 - 2,90 (1H, m); to 2.42 (3H, s); 2,20-of 1.80 (10H, including singlets at 2,20, 1,93); of 1.66 (3H, s); of 1.12 (6H, Shir. C).

Example 23. Obtaining 2'-O-phosphonomethoxy-7-O-phosphonomethylglycine

(a) Obtaining 2'-O-methyltrimethoxysilane

< / BR>
To a solution of 2'-O-methylthiomethyl-7-O-benzyloxycarbonylglycine (1.2 g, 1,11 mm) in ethyl acetate (100 ml) and ethanol (70 ml), placed in a Parr flask was added 3 g of 10% palladium charcoal. This reaction vessel was connected to the apparatus Parra, and the reaction mixture was placed in an atmosphere of hydrogen under a pressure of 50 psi (3,515 kg/cm2). Then the reaction mixture was stirred with shaking for 20.5 hours, filtered through a funnel of sintered glass and the filtrate was concentrated in vacuum. The residual oily in(0,98 g, 93%).

1H-NMR (CDCl3; 300 MHz); 8,12-8,10 (2H, m); 7,76 - 7,73 (2H, m); to 7.61-7,27 (11H, m), 7,03 (1H, d, J= 8,9 Hz); 6,40 - 6,27 (11H, m); and 6.25 (1H, s); 5,80 (1H, DD, J=8,9, and 2.4 Hz); to 5.66 (1H, d, J=7,1 Hz); 4,98-4,94 (1H, m); a 4.86-rate 4.79 (2H, m); 4.75 V - and 4.68 (1H, m); 4,43 - 4,39 (1H, m); of 4.05 (1H, d, J= 11.7 Hz); of 3.78 (1H, d, J=7,1 Hz); 2,60 was 1.06 (25H, m, including singlets at each 2,45, 2,21, 2,02, 1,85, 1,66, 1,22, 1,11, 3H).

(b) Obtaining 2'-O-methylthiomethyl-7-O-methyldiethanolamine

< / BR>
In the solution of 2'-O-methyltrimethoxysilane (0,98 g of 1.03 mm) and dimethyl sulfide (0.6 ml, 8,11 mm) and acetonitrile (20 ml), cooled to -40oC, was added benzoyl peroxide (1.0 g, 4,13 mm) and the reaction mixture was heated to room temperature within 30 minutes. At this time TLC analysis (eluent: hexane/ethyl acetate) indicated completion of the reaction. After the reaction mixture was diluted with ethyl acetate and the resulting organic solution was washed three times with a saturated solution of sodium bicarbonate, and then brine. The organic phase was dried with sodium sulfate and concentrated in vacuum. The oily residue was purified using flash chromatography (eluent: ethyl acetate/hexane), and received the target product (0,945 g, 91%) as a white solid.

1H-NMR (CDCl3, 300 MHz): 8,13 - 8,11 (2H, m), 7,79 - 0 (1H, m); 2,55 - 1,05 (27H, m, including singlets at 2,51, 2,18, 2,11, 1,80, 1,21, 1,20, 3H-each).

(c) Obtaining 2'-O-dibenzyldithiocarbamate-7-O-(dibenzylideneacetone)of paclitaxel

< / BR>
To a solution of 2'-0-methylthiomethyl-7-0-methyldiethanolamine (0,92 g, 0,916 mm), dibenzylamine (2,03 g, 7,30 mm) and 1 g dried in an oven Angstrom molecular sieves 3 in THF (18 ml) at room temperature, one portion was added N-iodosuccinimide (of 0.615 g, 2,74 mm), and the resulting mixture was stirred for 30 minutes. At this time TLC analysis (eluent: hexane/ethyl acetate) indicated completion of the reaction. Then the reaction mixture was diluted with ethyl acetate to a volume twice the original volume and filtered through a layer of celite. The filtrate was poured into a saturated solution of sodium bicarbonate containing 1% sodium thiosulfate (by weight). The organic layer is 4 times washed with saturated aqueous sodium bicarbonate, and then brine. After that, the organic layer was again extracted with ethyl acetate, and the combined organic extracts were dried with sodium sulfate and concentrated in vacuum. The residual oily product was purified using flash chromatography (eluent: hexane/ethyl acetate), and received the target connection 65 - 7,27 (11H, m); 6,30 (1H, c); 6,25 - 6,18 (1H, m); of 5.82 (1H, DD, J= 9,1, 3,4 Hz); 5,63 (1H, DD, J=6.9 Hz); 5,38 (1H, DD, J=6.6 Hz); 5,10 - 4,60 (15H, m); 4,30 - 4,10 (3H, m); of 3.80 (1H, d, J=6.8 Hz); 2,85 - to 2.65 (1H, m); 2,50 - 1,60 (22H, m, including singlets at each 2,47, 2,16, 1,91, 1,72, 1,88, 1,15, 3H).

(d) Obtaining 2'-O-phosphonomethoxy-7-O-phosphonomethylglycine

< / BR>
In a nitrogen purged vessel Parr hydrogenation, was added 1.3 g of 10% palladium carbon, and then added to pure ethyl acetate (110 ml) and a solution of 2-O-dibenzylideneacetone-7-O-(dibenzylideneacetone)paclitaxel (0,721 g, 0,498 mm) in ethyl acetate (40 ml). This reaction vessel was connected to the apparatus Parra, pomesali in vacuum, and then filed hydrogen at a pressure of 50 psi (3,515 kg/cm2). The obtained heterogeneous mixture was stirred with shaking for 16 hours, after which TLC analysis (eluent: hexane/ethyl acetate) indicated the complete depletion of the source material. After the reaction mixture was placed in a vacuum and purged with nitrogen. Then the mixture was filtered through a funnel of sintered glass and the filtrate was concentrated in vacuo, resulting in a received 0,413 g of the target product, which had a purity of 60% (ghvd analysis).

(e) Obtaining bis-triethanolamine salt 2-O-ximity-7-O-phosphonomethylglycine (413 mg) in dichloromethane (10 ml) was added a 0.1 M solution of triethanolamine (7,6 ml, 0.076 mm) in ethyl acetate, and the resulting mixture was stirred for 5 minutes at room temperature. Then the reaction mixture was concentrated in vacuo and the resulting white solid was purified by chromatography on C18-columns (eluent: water/acetonitrile, 9:1 - 5,6: 1). The eluent fractions containing the desired salt (ghvd-purity was more than 96%) were combined and the acetonitrile was removed on a rotary evaporator. The resulting aqueous solution of amine salt was liofilizovane, resulting in a received desired salt (0,210 g, yield to the two stages of 30%) as a white solid.

1H-NMR (acetone-d6/D2O, 300 MHz): 7,97 - 7,94 (2H, m); 7,79 - 7,76 (2H, m); to 7.67 - 7,33 (11H, m); 7,12 - 7,07 (1H, m); of 6.26 (1H, s); of 5.89 (1H, DD, J = 8.6 Hz); of 5.48 (1H, d, J=7.9 Hz); 5,00 - 4,79 (8H, m), 4,70 (1H, d, J = 8.1 Hz); 4,15 - a 4.03 (3H, m); 3,74 - 3,66 (7H, m); 3,14 - 2,86 (8H, m), 2,33 - 1,00 (20H, m, including singlets at each 2,33, 2,10, 1,88, 1,56, 1,02, 1,00, 3H).

Additional examples

General procedures presented in the previous examples and descriptions were used to obtain the following compounds included in the scope of formula (A) (table 6).

1. Phosphonoacetate esters derived taxane General formula

T-[OCH2(OCH2)mOP(o)(OH)2]nThat
m = 0 or 1;

n = 1, 2,

or its pharmaceutically acceptable salt.

2. Connection on p. 1, where the specified Takanawa part differs in that it contains at least11-C12double bond, WITH1is hydroxy, C2-benzoyloxy WITH4the atomic charges, WITH9is hydroxy and C5-C20-oxetan.

3. Connection on p. 1, where the specified Takanawa part is derived from a residue having the formula

< / BR>
where R2E'is hydrogen;

R2Eis hydrogen, hydroxy, -OC(O)or SIGx;

R3Eis hydrogen, hydroxy, -OC(O)Rx, -OC(O)OR SIGxor acetylamino;

R6thand R7Etaken together, constitute oxoprop; Rxrepresents a C1-6-alkyl, or Rxrepresents a radical of the formula

< / BR>
where D represents C1-6-alkyl;

Rand, Rinand Rwithindependently represent hydrogen.

4. Connection on p. 1, where the specified substituted 3-amino-2-hydroxypropanoate is derived from a residue having the formula

< / BR>
where R1represents hydrogen or C(O)Rx; -C(O)OR SIGx;

R4and R5regardless, not only 6 represents aryl or heteroaryl;

p = 0 or 1,

Rxsuch as that previously defined.

5. Connection on p. 1, where the specified Takanawa part differs in that it contains at least11-C12-double bond, WITH1is hydroxy, C2-benzoyloxy WITH4the atomic charges, WITH9is hydroxy and C5-C20-oxetan;

specified substituted 3-amino-2-hydroxypropanoate is derived from a residue having the formula

< / BR>
where R1, R4and R5and p are as defined above.

6. Connection on p. 1 having the formula

< / BR>
where R1is hydroxy, -och2(OCH2)mTHE OP(O)(OH)2, -OC(O)Rxor-OC(O)or SIGx;

R2'is hydrogen;

R2is hydrogen, hydroxy, -och2(OCH2)mTHE OP(O)(OH)2; -OC(O)OR SIGx;

R3is hydrogen, hydroxy, acetyloxy, -OC(O)Rx, -OCH2(OCH2)mTHE OP(O)(OH)2or-OC(O)or SIGx;

R6and R7taken together, constitute oxoprop, provided that at least one of R1, R2, R3, R6and R7are-och2(OCH2)is trading above;

and its pharmaceutically acceptable salt.

7. Connection on p. 6, where R2'is hydrogen, and R2is-och2THE OP(O)(OH)2; or its pharmaceutically acceptable salt.

8. Connection on p. 7, where R1is hydroxy, -OC(O)Rxor OS(O)or SIGx; Rxis such as defined above.

9. Connection on p. 8, where Rxrepresents a C1-6-alkyl.

10. Connection on p. 8, where R3represents hydrogen, a hydroxy-group or acetoxy.

11. Connection on p. 8, where R4(OH)pis a phenyl or t-butoxypropyl.

12. Connection on p. 8, where R5is phenyl, 2-fullam or 2-tanila.

13. Connection on p. 1, which is (etoxycarbonyl)(phosphonomethyl)paclitaxel or its pharmaceutically acceptable salt.

14. Connection on p. 13, which is a sodium salt.

15. Connection on p. 13, which represents triethanolamine salt.

16. Connection on p. 13, which represents triethylamine salt.

17. Connection on p. 13, which represents an arginine salt.

18. Soedinenii ethanolamine salt.

20. Connection on p. 13, which is an N-methylglucamine salt.

21. Connection on p. 1, which is (phosphonomethyl)paclitaxel, or its pharmaceutically acceptable salt.

22. Connection on p. 21, which is a sodium salt.

23. Connection on p. 1, which is 3'-N-Dibenzoyl-3'-methoxyphenyl-3'-N-(t-butyloxycarbonyl)-3'-(2-furyl)-2'-0-ethoxycarbonyl-7-0-phosphonomethylglycine, or its pharmaceutically acceptable salt.

24. Connection on p. 23, which represents triethanolamine salt.

25. Connection on p. 1, which is 3'-N-Dibenzoyl-3'-methoxyphenyl-3'-N-(t-butyloxycarbonyl)-3'-(2-thienyl)methoxycarbonylmethpoxyimiono.

28. Connection on p. 1, which represents methylcarbonylethylthioethyl.

29. Connection on p. 1, which is n-propylbromoacetate.

30. Connection on p. 6, where R1represents-och2THE OP(O)(OH)2or its pharmaceutically acceptable salt.

31. Connection on p. 30, where R2'is hydrogen, R2is hydrogen, Hydra is SUP>3is hydrogen, hydroxy-group or acetoxypropionyl.

33. Connection on p. 31, where R4(OH)pis a phenyl or t-butoxypropyl.

34. Connected by p. 31, where R5is phenyl.

35. Connection on p. 1, which is (phosphonomethyl)paclitaxel or its pharmaceutically acceptable salt.

36. Connection on p. 6, where both R1and R2are-och2THE OP(O)(OH)2or its pharmaceutically acceptable salt.

37. Connection on p. 1, which is 2', bis(phosphonomethyl)paclitaxel, or its pharmaceutically acceptable salt.

38. Connection on p. 37, which is a sodium salt.

39. Connection on p. 6, where R1represents-och2(OCH2)OP(O)(OH)2or its pharmaceutically acceptable salt.

40. Connection on p. 1, which represents phosphonomethyliminodiacetic.

41. Connection on p. 1, which represents phosphonomethylglycine, or its pharmaceutically acceptable salt.

42. Connection on p. 41, which is triethanolamine salt.

43. With the ASS="ptx2">

44. Connection on p. 1, which is a 10-methoxyacetyl-3'-N-methoxybenzoyl-3'-N-(t-butyloxycarbonyl)-10

where R2E, R2E', R3E, R6thand R7Eare as defined above.

48. Connection on p. 46, having the formula

< / BR>
or WITH13the metal alkoxide.

49. Diprosone taxane having the formula IN

T'-[OCH2(OCH2)mSCH3]n< / BR>
where T' represents T, which is non-reactive hydroxy-group is blocked;

m and n are defined above.

50. Connection on p. 49, having the formula IN'

< / BR>
where R1Bis a hydroxy-group, protected hydroxy-group, -OCH2SCH3, -OC(O)Rxor-OC(O)or SIGx;

R2'is hydrogen;

R2Bis hydrogen, hydroxy-group-protected hydroxy-group, -OCH2SCH3or-OC(O)or SIGx;

R3bis hydrogen, hydroxy-group, acetyloxy, -OC(O)or SIGx, -OC(O)Rxor-OCH2SCH3;

R6Vand R7btaken together, constitute oxoprop; provided that at least one of R1B, R2B, R3b, R6Vor R7bare-OCH2SCH

52. Connection on p. 50, which is a 2 methyldiethylamine.

53. Connection on p. 50, which is a 2 methyldiethylamine.

54. Connection on p. 50, which represents a 2'(triethylsilyl)paclitaxel.

55. Connection on p. 50, which represents a 2'(methylthiomethyl)paclitaxel.

56. Connection on p. 50, which is 2', bis(methylthiomethyl)paclitaxel.

57. Connection on p. 50, which represents a 3'-N-desbenzoyl-3'-destiny-3'-N-(t-butyloxycarbonyl)-3'-(2-furyl)methyldiethylamine.

62. Connection on p. 50, which represents a 3'-N-desbenzoyl-3'-N-(n-butyloxycarbonyl)methyldiethylamine.

63. Connection on p. 50, which represents a 3'-N-desbenzoyl-3'-N-(t-butoxycarbonyl) methyldiethylamine.

64. Connection on p. 50, which represents a 3'-N-desbenzoyl-3'-N-(t-butoxycarbonyl) methyldiethylamine.

65. Connection on p. 50, which represents a 3'-N-desbenzoyl-3'-N-(t-butoxycarbonyl) methylthiomethyl-10-deazetil-10-hydroxymethyluracil(paclitaxel).

66. Swedisherotica.

67. Connection on p. 50, which represents a 3'-N-desbenzoyl-3'-N-(t-butoxycarbonyl)ethoxycarbonyl-7-0-methyldiethylamine.

68.Soedineniya.50,kotorayaraspolagaetsya-3'-methoxyphenyl-3'-isobutyrylacetate.

69. Connection on p. 50, which represents a 3'-methoxyphenyl-3'(2-furyl)methyldiethylamine.

70. Connection on p. 49, having the formula:

< / BR>
where R2', R2B, R3b, R4, R5, R6V, R7band R are the same as defined above.

71. Connection on p. 70, which represents criticalimportance.

72. Connection on p. 70, which represents benzyloxycarbonylglycine.

73. Ester proizvodnye phosphonoacetate esters derived taxane having the formula (C):

T'-[OCH2(OCH2)mThe OP(o)(or SIGy)2]n(C)

where M', m and n are such as defined above;

Ry- phosphonoamidate group.

74. Connection on p. 73 having the formula

< / BR>
where R1Cthe hydroxy - group, a protected hydroxy-group, -och2THE OP(O)(OCH2Ry)2, -OC(O)Rxor-OC(O)or SIGx;

SUB>2
Ry)2, -OC(O)Rx;

R3sis hydrogen, the hydroxy-group, acetyloxy or-och2THE OP(O)(OCH2Ry)2;

R6sand R7Ctaken together, constitute oxoprop; provided that at least one of R1C, R2C, R3s, R6sor R7Cis-och2THE OP(O)(OCH2Ry)2; R, R4, R5, Rx, Ryare as defined above.

75. Connection on p. 73 having the formula

< / BR>
where R2', R2C, R3s, R4, R5, R6s, R7C, Ryand p are as defined above.

76. Pharmaceutical composition having inhibitory tumor activity, comprising an active agent and a pharmaceutically acceptable carrier, characterized in that it contains an effective amount of the compounds under item 1.

77. Method of inhibiting tumor growth in a mammal host, including the introduction of an active agent, wherein the active agent is administered inhibiting tumor growth, the number of connections on p. 1.

78. The method according to p. 77, characterized in that the specified mammal orally administered inhibiting the growth op is including the introduction of active agenta, characterized in that the active agent is administered inhibiting tumor growth amount of the compounds of formula (In') on p. 50

< / BR>
where R2'is hydrogen;

R2Bis the co2SCH3;

R1Bthe hydroxy - group, -OC(O)Rxor-OC(O)or SIGx;

R3bis-OC(O)Rx;

R6Vand R7btaken together, constitute oxoprop;

R4, R5R and Rxare the same as defined above, provided that the compound of this formula cannot be 3'-N-desbenzoyl-3'-destiny-3'-N-(t-butoxycarbonyl)-3'-(2-furyl)-7-0-methyldiethanolamine or 3'-N-desbenzoyl-3'-destiny-3'-N-(t-butoxycarbonyl)-3'(2-furyl)methyldiethanolamine.

80. The method according to p. 79, characterized in that as the active agent used 3'-N-desbenzoyl-3'-N-(t-butoxycarbonyl)-7-0-methyldiethylamine.

81. The method according to p. 79, characterized in that as the active agent used 3'-N-desbenzoyl-3'-N-(t-butoxycarbonyl)-2'-0-ethoxycarbonyl-7-0-methyldiethylamine.

Priority points:

17.08.93 - PP.1-26, 30-39, 41-43, 46-51, 70, 73-78;

24.11.93 - PP.40, 44, 45, 52-60, 71, 72;

17.05.94 - PP.27, 28, 29,

 

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-chloropropionate" target="_blank">

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The invention relates to a new method of obtaining 7-trialkylsilyl-baccatin III General formula 1

< / BR>
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< / BR>
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FIELD: chemistry.

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31 cl

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EFFECT: improved preparing method, enhanced and valuable medicinal properties of compound.

10 cl, 7 tbl, 6 ex

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