7-halo - 7, 8-mechanotaxis, pharmaceutical composition, intermediate compounds and methods of making intermediates

 

(57) Abstract:

Derivatives tokalov General formula I, where R1is methyl or phenyl, R2- H, NHC(O)H, NHC(O)-alkyl, NHC(O)-phenyl, NHC(O)OCH2-phenyl, NH2, NHC(O)-1-substituted, NHCOO-3-tetrahydrofuranyl, NHCOO-4-tetrahydropyranyl, NHCO-CH2C(CH3)3, NHCOC(CH3)3, NHCONHPh, NHCOC(CH2CH3)CH3, NHCOC(CH3)2CH2Cl

NHCOC(CH3)2CH2CH3phthalimidopropyl, NHC(O)-1-phenyl-1-cyclopentyl, NHC(O)-1-methyl-1-cyclohexyl, NHC(S)NHC(CH3)3, NHC(O)NHC(CH3)3or NHCONHPh; R3-H, NHCO-phenyl, or NHC(O)OC(CH3)3; R4-H, OC(O)OCH2CCl3or NHC(O)-phenyl; R5Is H or OH; R6-H, when R7is a-R71or-R72where one of R71, R72-H and the other is X; X is a halogen atom; R8is methyl; R10- H or C(O)CH3or their pharmaceutically acceptable salts. The compounds of formula I possess anti-tumor activity and is useful in the case of some types of cancer.

7 C. and 12 C.p. f-crystals, 1 table.

Taxol is a connection tecknologi family of diterpenes having the following structure:

< / BR>
Applied for Taxol numerical system recommended by IUPAC (Between ther. Vol.52, pp. 1-34, 1991)] gives an overview of the chemical properties of Taxol as a powerful anticancer diterpenoid and its analogues, with emphasis on selection, analysis, structural modifications, partial synthesis and structural-functional interdependencies.

Clinical pharmacology of Taxol presented in the review of Eric K. Rowinsky & Ross C. Donehower, The Clinical Phabmacology and Use of Antimicrotubule Agents in Cancer Chemotherapeutics (Agents acting on the micro canals, their clinical pharmacology and use in clinical chemotherapy), Pharmac. Ther. vol. 52, pp.35-84, 1991. Review of clinical and preclinical studies of Taxol described in the paper

William J. Slichemayer & Daniel D. von Hoff, Taxol: A New and Effective Anti-Cancer Drug

(Taxol: a new effective anticancer drug), Anti-Cancer Drugs, vol. 2, pp. 519-530, 1991.

Taxol and its analogs are described in various patents, such as U.S. patents NN 4814470, 4857653, 4942184,4924011, 4924012, 4960790, 5015744, 5157049, 5059699, 5136060, 4876399, 5227400, in PCT publication N WO 92109589, in the application for the European patent 90305845.1 (Publication N A2 0400971), 90312366.9 (publication N A1 0428376), 89400935.6 (publication N A1 0366841) and 90402333.0 (publication N 0414610 A1), 87401669.4 (A1 534709), 92308608.6 (A1 0534708), 92308609.4 (A1 534709), and in PCT publications under the numbers WO 91/17977, W 091/17976, WO 91/13066, WO/13053.

In the literature hem. 1991, 56, 5114.

Chen and co-authors (Chen et al.) in the work ("Seren-dipitous Synthesis of a Cyclopropan - Containing Taxol Analog via Anchimeric Participation of a Unactivated Angular Methyl Group, Advance ACS Abstracts, vol. 1, N 2., July 15, 1993) reported the observation of unexpected reactions encountered during the processing of 7-EPI-derived Taxol DAST in dichloromethane, which with the participation of the C-19 methyl group leads to the formation cyclopropanol rings. Cm. also J. Org. Chem., 1993, 58, 4520 (August 13, 1993).

U.S. patent 5248796 (received 28 September 1993) refers to 10-deacetoxy-11,12-dihydroxy-10,12(18)-diene derivatives, and to receive the 10-desiredaccuracy.

The invention relates to 7-deoxy-analogs of Taxol having the formula I:

< / BR>
The compound of the formula I are used to treat the same types of cancer for which was demonstrated the antitumor activity of Taxol; the latter include ovarian cancer human breast cancer, malignant melanoma, lung cancer, stomach cancer, colon cancer, head and neck cancer, and leukemia.

The rules for writing formulas and definition of variables

Chemical formulas, reflecting the different compounds and fragments of molecules in the specification and the claims, may contain, in addition to clearly obozny letters or alphanumeric characters, for example "Z1or Ri"where "i" is an integer. The described variables, the substituents being monovalent or bivalent, denote the group attached to the compound of a specified formula using one or two chemical bonds. For example, the group Z1in the case of attaching her to the formula CH3-C(=Z1)H reflects the bivalent variable. And the group Riand Rjbeing attached to the formula CH3-CH2-C(Ri)(Rj)-H, represent monovalent variable substituents. When chemical formulas are written in linear form as shown above, the variable substituents contained in parentheses are attached to the atom indicated to the left of the variable substituent enclosed in parenthesis. If in brackets sequentially two or more variables Deputy, each of the sequence of variables of the substituents attached to located immediately to the left of the atom, not the prisoner in parentheses. In addition, for molecules with an established system of numbering the carbon atoms to which belongs and Taxol, such carbon atoms denoted as Ciwhere "i" is an integer, it is suitable in accordance with the traditionally accepted numbering.

The chemical formula of the compounds or their parts, written in linear form, represent the atoms in the linear chain. The symbol "-" represents, in General, the bond between two atoms in this chain. Thus, the chain CH3-O-CH2-CH(Ri)-CH3denotes the 2-substituted-1-methoxypropane connection. Similarly, the symbol "= " denotes a double bond, that is, CH2=C(Ri)-O-CH3and the symbol "" represents a triple bond, i.e HCC-CH(Ri)-CH2-CH3. The control group mean one of two ways: -CO - or-C(=O)-, due to the simplicity of the first method is preferred.

The chemical formula of cyclic compounds (rings) or fragments of molecules can also be given in linear form. Thus, the compound 4-chloro-2-methylpyridine can be represented in the form N*= C(CH3)-CH = CCl-CH = C*H2assuming that the atoms marked with an asterisk (*), are connected to each other to form a ring. Likewise, the cyclic molecular fragment, 4-(ethyl)-1-piperazinil can be written in the form N*-(CH2)2- N(C2H5)-CH2-C*H2. Similarly, 2-furyl can be represented by a linear formula C*O-CH = CH-C*H=, and 2-thienyl can be the instrument of the described compounds determines the orientation relative to the plane of the ring for all deputies, attached to each carbon atom of a given rigid cyclic compounds. In the case of saturated compounds which have two substituent attached to a carbon atom that is a member of a cyclic compound, both Deputy-C(X1)(X2can be located either in vertical or in a horizontal plane relative to the ring, and can also change the vertical/horizontal position. However, the position of both of the substituents on ring and relative to each other remains fixed. So, even if the Deputy is often horizontally than the top or bottom of the ring, one of the substituents is greater than the other. In the chemical structural formulas, reflecting such connection, Deputy (X1), which is located "below" another substituent (X2), is defined as being in the alpha configuration, which is denoted as dashed lines or dots, going to the carbon atom, that is, using the symbols "---" or "...". The appropriate Deputy, attached "above" (X2) else (X1) Deputy, is identified as being in beta configuration, which is denoted as continuous the activity can take place either together, either separately, or in different cases valid both. For example, the variable Riattached to a carbon atom as-C(=Ri) may be bivalent and be an oxo - or ketogroup [with the formation of carbonyl groups (-CO)] or two attachable separately from each other monovalent variable Deputy-Ri-jand Ri-k. When a bivalent variable Riis defined as composed of two monovalent variable substituents, for writing such a bivalent variable, use the form "-Ri-j: -Ri-k" or some of its variants. In this case, and-Ri-jand Ri-kjoin one carbon atom with the formation of-C (Ri-j)(-Ri-k)-. For example, if a bivalent variable R6, -C(= R6) is defined as consisting of two monovalent variable substituents, and these monovalent variable substituents are-R6-1:-R6-2,...-R6-9:-R6-10and so on , it is education-C (R6-1)(-R6-2)-,...,-C (R6-9)(-R6-10and so on, Similarly, in the case of bivalent variable R11, -C(=R11), two monovalent variable substituent can be represented in the form-R
As well as the bivalent variable can be defined in two separate monovalent variable substituents, two separate monovalent variable substituent can be represented in a unified form with the formation of the bivalent variable. For example, in formula C1(Ri)H-C2(Rj)H- (C1and C2traditionally define respectively first and second carbon atoms) Riand Rjcan be taken together to denote the resulting (I) a second connection between C1and C2or (2) a bivalent group such in particular as oxo-(O)-, or the formula for determining the epoxide. When Riand Rjare combined to denote formed at more complex structural units such as-X-Y - group, then in such case, the orientation of the group is such that C1in the above formula is attached to X, and C2attached to Y. Thus, in accordance with the agreement, the expression ". .. Riand Rjtaken together with education the case records. . . Riand Rjtaken together, education-CO-O-CH2-CH2-" the rules give the designation of the lactone in which the carbonyl is attached to C1.

The number of carbon atoms in variable substituents indicated in one of two ways. The first method uses a prefix that is appended to the designation of a variable, for example "C1-C4"where "1" and "4" are natural integers, reflecting the minimum and maximum number of carbon atoms in the variable. The prefix spatially separated from the variable. For example, "C1-C4alkyl" means alkyl containing from 1 to 4 carbon atoms (including isomeric forms, if not given any other instructions). In the case of recording a single prefix, this prefix is indicates the total number of carbon atoms in a previously defined variable. Thus, the expression "C2-C4alkylsulphonyl" describes a group CH3-(CH2)n-O-CO-, in which n denotes 0, 1 or 2. In the second method, the number of carbon atoms in each particular part is indicated separately by enclosing the symbol "CiCj" in parentheses and placing it immediately (no spatial interval) pereau (C1-C3)alkylsulphonyl has the same value as C2-C4alkylsulphonyl as "C1-C3" only refers to the content of carbon atoms in the alkoxy group. Similarly, if C2-C6alkoxyalkyl and (C1-C3)alkoxy(C1C3)alkyl determine alkoxyalkyl group containing from 2 to 6 carbon atoms, the two definitions differ in that the first and alkoxy and alkyl part can contain from 4 to 5 carbon atoms each, whereas the second definition restricts all kinds of the number of carbon atoms in each of these three groups.

When claims contains complex (cyclic) Deputy, at the end of the statement, calling/designating a specific Deputy, should be given note (in parentheses), which refers to the same name/designation that appears on circuits and which is further affixed near the structural formula of this Deputy.

More specific, the present invention relates to analogues of 7-deoxy-Taxol with the General formula 1

< / BR>
where R1is selected from the group consisting of

-CH3,

-C6H5or phenyl, Sames the o-, trifluoromethyl-, C2-C6dialkylamino-, hydroxy - or nitro-groups,

-2-furillo, 2-tanila-, 1 dattilo-, 2-aptilo or 3,4-methylenedioxyphenyl groups;

R2is selected from the group consisting of-H, -NHC(O)H, -NHC(O)C1-C10the alkyl (preferably-NHC(O)C4-C6the alkyl), -NHC(O)-phenyl, -NHC(O)-phenyl, substituted by one, two or three C1-C4alkyl, C1-C3alkoxy-, halo-, C1-C3alkylthio, trifloromethyl-, C2-C6dialkylamino, hydroxy or nitro groups, -NHC(O)C(CH3)= CHCH3, -NHC(O)OC(CH3)3, -NHC(O)OCH2-phenyl, -NH2, -NHSO2-4-methylphenyl, -NHC(O)-(CH2)3COOH, -NHC(O)-4-(SO3)H phenyl, -OH, -NHC(O)- 1-adamantyl, -NHC(O)O-3-tetrahydrofuranyl, -NHC(O)O-4-tetrahydropyranyl, -NHC(O)CH2C(CH3)3, -NHC(O)C(CH3)3, -NHC(O)OC1-C10of alkyl, -NHC(O)NHC1-C10of alkyl, -NHC(O)NHPh, -NHC(O)NHPh substituted with one, two or three C1-C4alkyl, C1-C3alkoxy-, halo-, C1-C3-alkylthio, triphenylmethyl, C2-C6dialkylamino or nitro groups, -NHC(O)C3-C8, cycloalkyl, -NHC(O)C(CH2CH3)2CH3, -NHC(O)C(CH3)CH2Cl, -NHC(O)C(CH3)2CH2CH3phthalimido or-NHC(O)NHPh;

R3is selected from the group consisting of-H, -NHC(O)-phenyl, or-NHC(O)OC(CH3), with the overall proviso that one of the two substituents R2and R3represents-H, but both, R2and R3that can't be represented by a radical-H;

R4represents-H or is selected from the group consisting of-OH, -OAc(-OC(O)CH3), -OC(O)OCH2C(Cl)3, -OCOCH2CH2NH+3HCOO-, -NHC(O) phenyl, -NHC(O)OC(CH3)3, -OCOCH2CH2COOH and its farmatsevticheskii acceptable salts, -OCO(CH2)3COOH and its farmatsevticheskii acceptable salts and-OC(O)-Z-C(O)-R' [where Z is an ethylene (-CH2-CH2-), propylene (-CH2-CH2-CH2-), -CH=CH-, 1,2 - cyclohexane or 1,2-phenylene, and R' represents-H, -OH, -OH base, - NR'2R'3, -OR'3, -SR'3, -OCH2C(O)NR'4R'5where R'2represents-H or-CH3,R'3represents -(CH2)nNR'6R'7or (CH2)nN+R'6R'7R'8X-where n has a value of 1-3, R'4represents-H, -C1-C4alkyl, R'5represents-H, -C1-C4alkyl, benzyl, hydroxyethyl-, -CH2CO2H or dimethylaminoethyl, R is the OST NR'6R'7form pyrrolidino-, piperidino, morpholino - or N-methylpiperazine group, R'8represents-CH3, -CH2CH3or benzyl, X-is a halide, and base is presented NH3, (HOC2H4)3N, N(CH3)3CH3N(C2H4)2NH, NH2(CH2)6NH2, N-methylglucamine, NaOH or KOH], -OC(O)(CH2)nNR2R3(where n has a value of 1-3, R2represents-H or-C1-C3alkyl, R3represents-H or-C1-C3alkyl] , -OC(O)CH(R') NH2[where R" is selected from the group consisting of-H, -CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH(CH3)2, -CH2phenyl, -(CH2)4NH2,

-CH2CH2COOH, -(CH2)3NHC(=NH)NH2], the rest of the amino acids Proline, -OC(O)CH= CH2, -C(O)CH2CH2C(O)NH-CH2CH2SO-3Y+, - OC(O)CH2CH2C(O)NHCH2CH2CH2SO-3Y+where Y+represents Na+or N+(Bu)4, -OC(O)CH2CH2C(O)OCH2CH2OH;

R5represents-H or-OH with the overall proviso that when R5represents a different from-H;

R6represents-H:-H, when R7represents where one of R71and R72is-H and the other of R71and R72is-X, where X represents a halo group, and R8represents-CH3;

R6represents-H:-H, when R7represents-H,-R74where R74and R8together with the formation of cyclopropylamino ring;

R10represents-H or-C(O)CH3; and their pharmaceutically acceptable salts, when the compound contains either an acidic or basic functional group.

The preferred option of the object inventions are the compounds of formula I, where R1represents phenyl or phenyl substituted halo-group, R2represents-NHC(O)C6H5, R3and R5represent-H, R4represents-OH, and R10is-H or-CO(O)CH3. Other preferred variants object of the present invention include compounds of formula I, R1is preferably phenyl or phenyl substituted halo-group, R2represents-NHC(O)OC(CH3)3, R3and R5represent-H, R4represents the gain are the compounds of formula I, where R1represents phenyl or phenyl substituted halo-group, R2represents-NHC(O)NHC(CH3)3, R3and R5represent-H, R4represents-OH, and R10is-H or-COCH3.

One of the options object of the present invention are the compounds of formula I, where R1is selected from the group consisting of-CH3, -C6H5or phenyl substituted one, two or three C1-C4alkyl, C1-C3alkoxy, halo, C1-C3alkylthio, trifluoromethyl-, C2-C6dialkylamino, hydroxy or nitro groups, and R2is selected from the group consisting of-H, NHC(O)H, -NHC(O)C1-C10, alkyl (preferably-NHC(O)C4-C6-alkyl), -NHC(O) phenyl, -NHC(O) phenyl substituted one, two or three C1-C4alkyl, C1-C3alkoxy-, halo-, C1-C3-alkylthio, trifluoromethyl-, C2-C6dialkylamino, hydroxy or nitro groups, -NHC(O)C(CH3)=CHCH3, -NHC(O)OC(CH3)3, -NHC(O)OCHH2, phenyl, -NH2, -NHSO2-4-methylphenyl, -NHC(O)(CH2)3COOH, -NHC(O)-4-(SO2(H)phenyl, -OH, -NHC(O)-1-adamantyl, -NHC(O)O-3-tetrahydrofuranyl, -NHC(O)-4-tetrahydrofuranyl, -NHC(O)CH2substituted by one, two or three C1-C4alkyl, C1-C3alkoxy-, halo-, C1-C3alkylthio, trifluoromethyl-, C2-C6dialkylamino - or nitro-groups.

The present invention also relates to Taxol analogs of General formula II

< / BR>
and formula III

< / BR>
where X represents a halogen atom selected from the group consisting of-F, -Br, -Cl and-I; and where R1, R2, R3, R4, R5and R10correspond to the definition given above.

One of the variants of the present invention relates to analogues of 7-deoxy-7,8 - methane-Taxol with General formula II, where:

R1is selected from the group consisting of-CH3, -C6H5or phenyl substituted one, two or three C1-C4alkyl, C1-C3alkoxy, halo, C1-C3alkylthio, trifloromethyl-, C2-C6-dialkylamino, hydroxy or nitro groups;

R2is selected from the group consisting of-H, -NHC(O)C1-C10-alkyl (preferably-NHC(O)C4-C6the alkyl), -NHC(O)phenyl, -NHC(O)phenyl substituted one, two or three C1-C4alkyl, C1-C3alkoxy-, halo-, C1-C3alkylthio-, trifluoromethyl-, C2-C6-dialkyl is ethylphenyl, -NHC(O)(CH2)3COOH, -NHC(O)-4-(SO3(H)phenyl or-OH;

R3is selected from the group consisting of-H, -NHC(O)phenyl or-NHC(O)OC(CH3)3with the overall proviso that one of R2and R3represents-H,but both instead of R2and R3cannot represent-H;

R4represents-H or is selected from the group consisting of-OH, -OAc(-OC(O)CH3), -OC(O)OCH2C(Cl)3, -OCOCH2CH2NH+HCOO-, NHC(O)phenyl, -NHC(O)OC(CH3)3, -OCOCH2CH2COOH and other pharmaceutically acceptable salts, -OCO(CH2)3COOH and pharmaceutically acceptable salts and-OC(O)-Z-C(O)-R' [where Z is an ethylene (-CH2-CH2-), propylene (-CH2-CH2-CH2-), -CH=CH-, 1,2-cyclohexane or 1,2-phenylene, and R' represents-H, -OH, -OH base, -NR'2R'3, -OR'3, -SR'3, -OCH2C(O)NR'4R'5where R'2represents-H or-CH3, R'3represents -(CH2)nNR'6R'7or (CH2)nN+R'6R'7R'8X-where n has a value of 1-3, R'4represents-H or-C1-C4alkyl, R'5represents-H, -C1-C4alkyl, benzyl, hydroxyethyl-, -CH2CO'6and R'7together with the nitrogen NR'6R'7form pyrrolidino-, piperidino, morpholino - or N-methylpiperazine group, R'8represents-CH3CH2CH3or benzyl, X-is a halide, and base is presented NH3, (HOC2H4)3N, N(CH3)3CH3N(C2H4)2NH, NH2(CH2)6NH2, glucamine, NaOH or KOH] , -OC(O)(CH2)nNR2R3[where n has a value of 1-3, R2represents-H or-C1-C3alkyl, R3represents-H or-C1-C3alkyl], -OC(O)CH(R') NH2[where R" is selected from the group consisting of-H, -CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH(CH3)2, -CH2phenyl, -(CH2)4NH2, -CH2CH2COOH, -(CH2)3NHC(= NH)NH2], the rest of the amino acids Proline, -OC(O)CH=CH2, -C(O)CH2CH2C(O)NHCH2CH2SO-3Y+, -OC(O)CH2CH2C(O)NHCH2CH2CH2SO-3Y+where Y+represents Na+or N+(Bu)4, -OC(O)CH2CH2C(O)OCH2CH2OH;

R5represents-H or-OH with the General condition that, when ecstasy a-H, R4- different from-H,

R10represents-H or-C(O)CH3; and their pharmaceutically acceptable salts, when the compound contains either an acidic or basic functional group.

Another variant of the present invention is analogues of 7-deoxy-7,8 - methane-Taxol with General formula II, where:

R1is selected from the group consisting of-CH3, -C6H5or phenyl substituted one, two or three C1-C4alkyl, C1-C3-alkoxy-, halo-, C1-C3alkylthio-, trifluoromethyl-, C2-C6dialkylamino, hydroxy or nitro groups;

R2is selected from the group consisting of-NHC(O)-1-adamantyl, -NHC(O)O-3-tetrahydrofuranyl, -NHC(O)-O-4-tetrahydropyranyl, -NHC(O)CH2C(CH3)3, -NHC(O)C(CH3)3, -NHC(O)OC1-C10of alkyl, -NHC(O)NHC1-C10of alkyl, -NHC(O)NHPh substituted with one, two or three C1-C4alkyl, C1-C3-alkoxy-, halo-C1-C3alkylthio-, trifluoromethyl-, C2-C6dialkylamino - or nitro-groups, -NHC(O)C3-C8cycloalkyl; and

R3, R4, R5and R10correspond to the definition given above.

The preferred option of the object and is POI, R2represents-NHC(O)C6H5, R3and R5represent-H, and R10is-H or-C(O)CH3. Another preferred object of the invention are the compounds of formula II, where R1represents preferably phenyl or phenyl substituted halo-group, R2represents-NHC(O)OC(CH3)3and R3, R5and R10represent-H. As the preferred option of the object inventions are the compounds of formula II, where R1represents preferably phenyl or phenyl substituted halo-group, R2represents-NHC(O)OC(CH3)3, R3and R5represent-H, and R10represents-C(O)CH3. Another preferred object of the invention are the compounds of formula II, where R1represents preferably phenyl or phenyl substituted halo-group, R2represents-NHC(O)NHC(CH3)3, R3and R5represent-H, R4represents-OH, and R10represents-H or-C(O)CH3.

Additionally, preferred options of the formula II include:

- compounds corresponding to the formula II, and a property named the Il]-7-deoxy-7,8 - methane-Taxol, and

- compounds corresponding to the formula II, namely 10-acetyl-7 - deoxy-7,8 - methane-Taxotere, and

- compounds corresponding to the formula II, namely N - Desbenzoyl - n-(t-butyl)aminocarbonyl-7-deoxy-7,8 - methane-Taxol.

Another option of the present invention are analogs of 7-galatical with the General formula III, where:

X represents a halogen atom selected from the group consisting of-F, -Br, -Cl and-I,

R1is selected from the group consisting of-CH3, -C6H5or phenyl substituted one, two or three C1-C4alkyl, C1-C3alkoxy-, halo-, C1-C3alkylthio-, trifluoromethyl-, C2-C6dialkylamino - hydroxy or nitro groups,

R2is selected from the group consisting of-H, -NHC(O)phenyl, -NHC(O)phenyl substituted one, two or three C1-C4alkyl, C1-C3alkoxy-, halo-, C1-C3alkylthio-, trifluoromethyl-, C2-C6dialkylamino, hydroxy or nitro groups, -NHC(O)C(CH3)=CHCH3, -NHC(O)OC(CH3)3, -NH2, -NHSO2-4-methylphenyl,

-NHC(O)(CH2)3COOH, -NHC(O)-4-(SO3(H)phenyl or-OH,

R3is selected from the group consisting of-H, -NHC(O)-phenyl, or-NHC(O)OC(CH3)3when General ablate a-H,

R4represents-H or is selected from the group consisting of-OH, -OAc(-OC(O)CH3), -OC(O)OCH2C(Cl)3, -OCOCH2CH2NH+3HCOO-, NHC(O)phenyl, -NHC(O)OC(CH3)3, -OCOCH2CH2COOH and pharmaceutically acceptable salts, -CO(CH2)3COOH and pharmaceutically acceptable salts and-OC(O)-Z-C(O)-R' [where Z is an ethylene (-CH2-CH2-), propylene (-CH2-CH2-CH2-), -CH=CH-, 1,2-cyclohexane or 1,2-phenylene, R' represents-H, -OH, -OH base, -NR'2R'3, -OR'3, -SR'3, -OCH2C(O)NR'4R'5where R'2represents-H or-CH3, R'3represents -(CH2)nNR'6R'7or (CH2)nN+R'6R'7R'8X-where n has a value of 1-3, R'4represents-H or-C1-C4alkyl, R'5represents-H, -C1-C4alkyl, benzyl, hydroxyethyl-CH2CO2H or dimethylaminoethyl, R'6and R'7represent-CH3, -CH2CH3, benzyl or R'6and R'7together with the nitrogen of NR'6R'7form pyrrolidino-, piperidino, morpholino - or N-methylpiperazine, R'8represents-CH3, /SUB>)3N, N(CH3)3CH3N(C2H4)2NH, NH2(CH2)6NH2, N-methylglucamine, NaOH or KOH] , -OC(O)(CH2)nNR2R3[where n has a value of 1-3, R2represents-H or-C1-C3alkyl, and R3represents-H or-C1-C3alkyl], -OC(O)CH(R') NH2[where R" is selected from the group consisting of-H, -CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH(CH3)2, -CH2phenyl, -(CH2)4NH2, -CH2CH2COOH, -(CH2)3NHC(= NH)NH2], the remainder of the amino acids Proline, -OC(O)CH=CH2, -C(O)CH2CH2C(O)NHCH2CH2SO-3Y+, -OC(O)CH2CH2C(O)NHCH2CH2CH2SO-3Y+where Y+represents Na+or N+(Bu)4, -OC(O)CH2CH2C(O)OCH2CH2OH;

R5represents-H or-OH with the overall proviso that when R5represents-OH, R4represents-H, and, in addition, provided that when R5represents-H, R4different from-H,

R10represents-H or-C(O)CH3and their pharmaceutically acceptable salts, when the compound contains either KIS is a analogues 7-galatical with the General formula III, where:

X represents a halogen atom selected from the group consisting of-F, -Br, -Cl and-I,

R1is selected from the group consisting of-CH3, -C6H5or phenyl substituted one, two or three C1-C4alkyl, C1-C3alkoxy-, halo-, C1-C3alkylthio-, trifluoromethyl-, C2-C6alkylamino - hydroxy - or nitro-groups,

R2is selected from the group consisting of-NHC(O)-1-adamantyl, -NHC(O)O-3-tetrahydrofuranyl, -NHC(O)O-4-tetrahydropyranyl, -NHC(O)CH2C(CH3)3, -NHC(O)C(CH3)3, -NHC(O)OC1-C10of alkyl, -NHC(O)NHC1-C10of alkyl, -NHC(O)NHPh substituted with one, two or three C1-C4alkyl, C1-C3alkoxy-, halo-, C1-C3alkylthio-, trifluoromethyl-, C2-C6dialkylamino - or nitro-groups, -NHC(O)C3-C8cycloalkyl, and

R3, R4, R5and R10correspond to the definition given above.

The compounds of formula III include y as 7-, and 7 - configuration in the 7-halo-position. However, the halo group include-F, -Br, -Cl and-I

In compounds of formula III: X is preferably F, R3and R5- preferably-H, and R1represents before whom I include:

the compounds according to formula III, where R4represents-H, and R5represents-OH,

the compounds according to formula III, where R4different from-H, and R5represents-H,

the compounds according to formula III, where R3represents-H, and R1is a Ph or substituted phenyl, and

the compounds according to formula III, where X represents-F,

the compounds according to formula III, where X represents --F;

the compounds according to formula III, X is-F, and

R4different o-H, and R5represents-H,

the compounds according to formula III, where X represents-F,

R3represents-H, and R1is a Ph or substituted phenyl, and

the compounds according to formula III selected from the group consisting of 7-deoxy-7-portixol and 2'-[{2,2,2-trichloroethyl)oxy}carbonyl] -7-deoxy-7-portixol, and

the compounds according to formula II, namely N-Desbenzoyl-N-(t - butyl)aminocarbonyl-7-deoxy-7-fluoro-Taxol.

More preferred formula III comprises compounds selected from the group consisting of 7-deoxy - 7 - portixol, 7-deoxy-7 - portixol, 2'-[{(2,2,2-trichloroethyl) -oxy}carbonyl]-7-deoxy-7 - portixol and 2'-[{(2,2,2 - trichlorethyl the compounds of formula III, where R1represents preferably phenyl or phenyl substituted halo-group, R2represents-NHC(O)NHC(CH3)3, R3and R5represent-H or-COCH3.

Examples-NHC(O)C1-C10the include alkyl-NHC(O)-n-pentyl and-NHC(O)CH(CH3)CH2CH3.

Examples of C1-C6of alkyl include straight and branched alkyl chains, presents, in particular, stands, ethyl, isopropyl, t-bootrom, Isobutanol and 2-methyl-Pentium.

Examples of C1-C3alkoxy groups include methoxy, ethoxy-, propoxy group and their isomeric forms.

The halo group refers to-F, -Br, -Cl or-I

Examples of compounds of formula III of the present invention include:

2'-[{ 2,2,2-trichloroethyl)oxy} carbonyl] -7-deoxy-7,8 - methane-Taxol (compound 14AA, compound 11a),

7-deoxy-7,8 - methane-Taxol (compound 11b);

2'-succinyl-7-deoxy-7,8 - methane-Taxol,

2-(- alanyl)-7-deoxy-7,8 - methane-taxonomy ester of formic acid,

2'-glutaryl-7-deoxy-7,8 - methane-Taxol,

2'-[-C(O)(CH2)3C(O)NH(CH2)3N (CH3)2]-7-deoxy-7,8 - methane-Taxol,

2(- sulfopropyl)-7-deoxy-7,8 - methane-Taxol,

2'-the no-Taxol,

2'-(triethylsilyl)-7-deoxy-7,8 - methane-Taxol,

2'-(t-butyldimethylsilyl)-7-deoxy-7,8-/ methane-Taxol,

2'-(N,N-diethylaminopropyl)-7-deoxy-7,8 - mechanotaxis,

2'-(N,N-dimethylglycine)-7-deoxy-7,8 - methane-Taxol,

2'-(glycyl)-7-deoxy-7,8 - methane-Taxol,

2'-(L-alanyl)-7-deoxy-7,8 - methane-Taxol,

2'-(L-leucyl)-7-deoxy-7,8 - methane-Taxol,

2'-(L-isoleucyl)-7-deoxy-7,8 - methane-Taxol,

2'-(L-felled)-7-deoxy-7,8 - methane-Taxol,

2'-(L-i.e. phenylalanyl)-7-deoxy-7,8 - methane-Taxol;

2'-(L-Prol)-7-deoxy-7,8 - methane-Taxol;

2'-(L-lysyl)-7-deoxy-7,8 - methane-Taxol,

2'-(L-glutamyl)-7-deoxy-7,8 - methane-Taxol,

2'-(L-arginyl)-7-deoxy-7,8 - methane-Taxol,

7-deoxy-7,8 - methane-Taxotere

10-acetyl-7,8 - methane-Taxotere (compound 23),

N-desbenzoyl-N-tetrahydrofuran-3-jocstarbunny-7-deoxy-7,8 - mechanotaxis,

N-desbenzoyl-N-(1-adamantoyl)-7-deoxy-7,8 - mechanotaxis,

N-desbenzoyl-N-phenylenecarbonyl-7-deoxy-7,8 - mechanotaxis,

N-desbenzoyl-N-t-butylaminoethyl-7-deoxy-7,8 - mechanotaxis,

N-desbenzoyl-N-(1-methyl-1-cyclohexanol)-7-deoxy-7,8 - mechanotaxis,

N-desbenzoyl-N-(1-phenyl-1-Cyclopentanol)-7-deoxy-7,8 - mechanotaxis,

N-desbenzoyl-N-phthalimido-7-deoxy jocstarbunny-7-deoxy-7,8 - mechanotaxis,

N-desbenzoyl-N-neopentylglycol-7-deoxy-7,8 - mechanotaxis,

N-desbenzoyl-N-(2-chloro-1,1-dimethylethyl)oxycarbonyl-7-deoxy-7,8 - mechanotaxis,

N-desbenzoyl-N-(3-methyl-3-pentyl)oxycarbonyl-7-deoxy-7,8 - mechanotaxis;

3'-destiny-3'-(2-furyl)-7-deoxy-7,8 - mechanotaxis,

3'-destiny-3'-(2-thienyl)-7-deoxy-7,8 - mechanotaxis,

3'-destiny-3'-(1-naphthyl)-7-deoxy-7,8 - mechanotaxis,

3'-destiny-3'-(2-naphthyl)-7-deoxy-7,8 - mechanotaxis,

3'-destiny-3'-(4-methoxyphenyl)-7-deoxy-7,8 - mechanotaxis,

3'-destiny-3'-(4-course)-7-deoxy-7,8 - mechanotaxis,

3'-destiny-3'-(4-bromophenyl)-7-deoxy-7,8 - mechanotaxis,

3'-destiny-3'-(3,4-methylenedioxyphenyl)-7-deoxy-7,8 - mechanotaxis,

3'-destiny-3'-(3,4-acid)-7-deoxy-7,8 - mechanotaxis,

3'-destiny-3'-(4-nitrophenyl)-7-deoxy-7,8 - mechanotaxis,

3'-destiny-3'-(4-forfinal)-7-deoxy-7,8 - mechanotaxis,

N-desbenzoyl-N-(4-bromobenzoyl)-7-deoxy-7,8 - mechanotaxis,

N-desbenzoyl-N-(4-methylbenzoyl)-7-deoxy-7,8 - mechanotaxis,

N-desbenzoyl-N-(4-L-butylbenzoyl)-7-deoxy-7,8 - mechanotaxis,

N-desbenzoyl-N-(4-methoxybenzoyl)-7-deoxy-7,8 - mechanotaxis,

N-desbenzoyl-N-(4-perbenzoic)-3'-destiny-3'-(4-forfinal)-7 - deoxy-7,8 - mechanotaxis,chlorophenyl)-7 - deoxy-7,8 - mechanotaxis,

N-desbenzoyl-N-(4-chlorobenzoyl)-3'-destiny-3'-(4-forfinal)-7 - deoxy-7,8 - mechanotaxis,

N-desbenzoyl-N-(4-bromobenzoyl)-3'-destiny-3'-(4-forfinal)-7 - deoxy-7,8 - mechanotaxis,

N-desbenzoyl-N-(4-methylbenzoyl)-3'-destiny-3'-(4-forfinal)-7 - deoxy-7,8 - mechanotaxis,

N-desbenzoyl-N-(4-perbenzoic)-3'-destiny-3'-(4-methoxyphenyl)-7 - deoxy-7,8 - mechanotaxis,

N-desbenzoyl-N-(4-methylbenzoyl)-3'-destiny-3'-(4-methoxyphenyl)-7 - deoxy-7,8 - mechanotaxis,

N-desbenzoyl-N-(4-perbenzoic)-3'-destiny-3'-(4-chlorophenyl)-7 - deoxy-7,8 - mechanotaxis,

N-desbenzoyl-N-(4-chlorobenzoyl)-3'-destiny-3'-(4-chlorophenyl)-7 - deoxy-7,8 - mechanotaxis,

N-desbenzoyl-N-(4-bromobenzoyl)-3'-destiny-3'-(4-chlorophenyl)-7 - deoxy-7,8 - mechanotaxis,

N-desbenzoyl-N-(4-t-butylbenzoyl)-3'-destiny-3'-(4-chlorophenyl)-7 - deoxy-7,8 - mechanotaxis,

N-desbenzoyl-N-(4-t-butylbenzoyl)-3'-destiny-3'-(4-forfinal)-7 - deoxy-7,8 - mechanotaxis,

N-desbenzoyl-N-(4-chlorobenzoyl)-3'-destiny-3'-(4-methoxyphenyl)-7 - deoxy-7,8 - mechanotaxis,

N-desbenzoyl-N-(4-bromobenzoyl)-3'-destiny-3'-(4-methoxyphenyl)-7 - deoxy-7,8 - mechanotaxis,

N-desbenzoyl-N-(4-t-butylbenzoyl)-3'-destiny-3'-(4-methoxyphenyl)-7 - deoxy-7,8-/ mechanotaxis,

N-desbenzoyl-N-(4-methoxybenzoyl)-3'-destiny-3'-(4-methoxyphenyl is 29),

and their pharmaceutically acceptable salts, when the compound contains either an acidic or basic functional group.

Examples of compounds of formula III of this invention include:

2'-[{2,2,2-trichloroethyl)oxy}carbonyl]-7-deoxy-7-vertical (connection 13AA_ 111c)

7-deoxy-7-vertical (connection 111b);

2'-succinyl-7-deoxy-7-portixol,

formic ester 2-(- alanyl)-7-deoxy--7-portixol,

2'-glutaryl-7-deoxy-7-portixol,

2'-[-C(O)(CH2)3C(O)NH(CH2)3N (CH3)2]-7-deoxy 7-portixol,

2-(- sulfopropyl)-7-deoxy-7-portixol,

2'-(2-sulfonamide)succinyl-7-deoxy-7-portixol,

2'-(3-sulfopropyl)succinyl-7-deoxy-7-portixol,

2'-(triethylsilyl)-7-deoxy-7-portixol,

2'-(t-butyldimethylsilyl)-7-deoxy-7-portixol,

2'-(N,N-diethylaminopropyl)-7-deoxy-7-portixol,

2'-(N,N-dimethylglycine)-7-deoxy-7-portixol,

2'-(glycyl)-7-deoxy-7-portixol,

2'-(L-alanyl)-7-deoxy-7-portixol,

2'-(L-leucyl)-7-deoxy-7-portixol,

2'-(L-isoleucyl)-7-deoxy-7-portixol,

2'-(L-felled)-7-deoxy-7-portixol,

2'-(L-i.e. phenylalanyl)-7-deoxy-7-portixol,

2'-(L-prolyl)-7-deoxy-7-portixol,

2'-(L-R>
7-deoxy-7-fortecstar,

10-acetyl-7-deoxy-7-fortecstar (compound 20),

N-desbenzoyl-N-tetrahydrofuran-3-jocstarbunny-7-deoxy-7-portixol,

N-desbenzoyl-N-pivaloyl-7-deoxy-7-portixol,

N-desbenzoyl-N-n-mexiletineciclovir-7-deoxy-7-portixol,

N-desbenzoyl-N-t-butylaminoethyl-7-deoxy-7-portixol,

N-desbenzoyl-N-(1-methyl-1-cyclohexanol)-7-deoxy-7-portixol,

N-desbenzoyl-N-(1-phenyl-1-Cyclopentanol)-7-deoxy-7-portixol,

N-desbenzoyl-N-phthalimido-7-deoxy-7-portixol,

N-desbenzoyl-N-t-butylaminoethyl-7-deoxy-7-portixol,

N-desbenzoyl-N-t-aryloxyalkyl-7-deoxy-7-portixol,

N-desbenzoyl-N-neopentylglycol-7-deoxy-7-portixol,

N-desbenzoyl-N-(2-chloro-1,1-dimethylethyl)oxycarbonyl-7-deoxy - 7-portixol,

N-desbenzoyl-N-(3-methyl-3-pentyl)oxycarbonyl-7-deoxy-7-portixol;

3'-destiny-3'-(2-furyl)-7-deoxy-7-portixol,

3'-destiny-3'-(2-thienyl)-7-deoxy-7-portixol,

3'-destiny-3'-(1-naphthyl)-7-deoxy-7-portixol,

3'-destiny-3'-(2-naphthyl)-7-deoxy-7-portixol,

3'-destiny-3'-(4-methoxyphenyl)-7-deoxy-7-portixol,

3'-destiny-3'-(4-chlorophenyl)-7-deoxy-7-portixol,

3'-destiny-3'-(4-bromophenyl)-7-methoxyphenyl)-7-deoxy-7-portixol,

3'-destiny-3'-(4-nitrophenyl)-7-deoxy-7-portixol,

3'-destiny-3'-(4-forfinal)-7-deoxy-7-portixol,

N-desbenzoyl-N-(4-bromobenzoyl)-7-deoxy-7-portixol,

N-desbenzoyl-N-(4-methylbenzoyl)-7-deoxy-7-portixol,

N-desbenzoyl-N-(4-t-butylbenzoyl)-7-deoxy-7-portixol,

N-desbenzoyl-N-(4-methoxybenzoyl)-7-deoxy-7-portixol,

N-desbenzoyl-N-(4-perbenzoic)-3'-destiny-3'-(4-forfinal)-7-deoxy-7 - portixol,

N-desbenzoyl-N-(4-perbenzoic)-7-deoxy-7-portixol,

N-desbenzoyl-N-(4-methylbenzoyl)-3'-destiny-3'-(4-forfinal)-7-deoxy-7 - portixol,

N-desbenzoyl-N-(4-chlorobenzoyl)-3'-destiny-3'-(4-forfinal)-7-deoxy-7 - portixol,

N-desbenzoyl-N-(4-bromobenzoyl)-3'-destiny-3'-(4-forfinal)-7-deoxy-7 - portixol,

N-desbenzoyl-N-(4-methylbenzoyl)-3'-destiny-3'-(4-forfinal)-7-deoxy-7 - portixol,

N-desbenzoyl-N-(4-perbenzoic)-3'-destiny-3'-(4-methoxyphenyl)-7-deoxy - 7-portixol,

N-desbenzoyl-N-(4-methylbenzoyl)-3'-destiny-3'-(4-methoxybenzyl)-7-deoxy - 7-portixol,

N-desbenzoyl-N-(4-perbenzoic)-3'-destiny-3'-(4-chlorophenyl)-7-deoxy-7 - portixol,

N-desbenzoyl-N-(4-chlorobenzoyl)-3'-destiny-3'-(4-chlorophenyl)-7-deoxy - 7-portixol,

N-desbenzoyl-N-(4-bromobenzoyl)-3'-destiny-3'-(4-chlorophenyl)-7-dioxindole-N-(4-t-butylbenzoyl)-3'-destiny-3'-(4-chlorophenyl)-7-deoxy - 7-portixol,

N-desbenzoyl-N-(4-chlorobenzoyl)-3'-destiny-3'-(4-methoxyphenyl)-7-deoxy - 7-portixol,

N-desbenzoyl-N-(4-bromobenzoyl)-3'-destiny-3'-(4-methoxyphenyl)-7-deoxy-7-portixol,

N-desbenzoyl-N-(4-t-butylbenzoyl)-3'-destiny-3'-(4-chlorophenyl)-7-deoxy - 7-portixol,

N-desbenzoyl-N-(4-methoxybenzoyl)-3'-destiny-3'-(4-methoxyphenyl)-7 - deoxy-7-portixol,

N-desbenzoyl-N-(4-t-butyl)aminocarbonyl-7-deoxy-7-vertical (compound 28), and

their pharmaceutically acceptable salts, when the compound contains either an acidic or basic functional group.

The present invention also provides a method of obtaining oxazolidines by the formula 5

< / BR>
in which

R1corresponds to the previously given description.

R9selected from C1-C6Akilov, R11represents phenyl, substituted -(OC1-C2alkyl)nwhere n takes values from 1 to 3,

R12is selected from the group consisting of-C(O)C1-C10the alkyl (preferably-C(O)C4-C6the alkyl), -C(O)phenyl, -C(O)phenyl substituted one, two or three C1-C4alkyl, C1-C3alkoxy-, halo-, C1-C3alkylthio-, trifluoromethyl-, C2-C6dialkylamino, methylphenyl, -C(O)(CH2)3COOH, -C(O)-4-(SO3(H)phenyl, -C(O)-1-adamantyl, -C(O)O-3-tetrahydrofuran, -C(O)O-4-tetrahydropyranyl, -C(O)CH2C(CH3)3, -C(O)OC1-C10of alkyl, -C(O)NHC1-C10of alkyl, -C(O)NHPh substituted with one, two or three C1-C4alkilani, C1-C3alkoxy-, halo-, C1-C3alkylthio, trifluoromethyl-, C2-C6-dialkylamino-, or nitro groups, or-C(O)C3-C8cycloalkyl, -C(O)C(CH2CH3)2CH3, -(C(O)C(CH3)2CH2Cl, -C(O)C(CH3)2CH2CH3, -C(O)-1-phenyl-1-cyclopentyl, -C(O)-1-methyl-1-cyclohexyl, -C(S)NHC(CH3)3, -C(O)NHCC(CH3)3or-C(O)NHPh, which involves the reaction of hydroxy-amine of formula 3

< / BR>
in which R1and R3correspond to the previously given description, and R2is selected from the group consisting of-NHC(O)H, -NHC(O)C1-C10the alkyl (preferably - NHC(O)C4-C6the alkyl), -NHC(O)phenyl, -NHC(O)phenyl substituted one, two or three C1-C4alkyl, C1-C3alkoxy-, halo-, C1-C3alkylthio-, trifluoromethyl-, C2-C6dialkylamino, hydroxy or nitro groups, -NHC(O)C(CH3)=CHCH3, NHC(O)OC(CH3)3, -NHC(O)OCH2-phenyl, -NHSO2A, NHC(O)O-4-tetrahydropyranyl, -NHC(O)CH2C(CH3)3, -NHC(O)C(CH3)3, - NHC(O)OC1-C10of alkyl, -NHC(O)NHC1-C10of alkyl, -NHC(O)NHPh substituted with one, two or three C1-C4alkilani, C1-C3alkoxy-, halo-, C1-C3alkylthio-, trifluoromethyl-, C2-C6dialkylamino-, or nitro groups, or-NHC(O)C3-C8cycloalkyl, NHC(O)C(CH2CH3)2CH3, -NHC(O)C(CH3)2CH2Cl, -NHC(O)C(CH3)2CH2CH3,

-NHC(O)-1-phenyl-1-cyclo-pentile, -NHC(O)-1-methyl-1-cyclohexyl, -NHC(S)NHC(CH3)3, -NHC(O)NHCC(CH3)3or-NHC(O)NHPh;

(1) electron-enriched benzaldehyde of formula 4A

< / BR>
or (2) electron-enriched acetone formula 4

< / BR>
where n takes on the values 1-3.

In addition, the present invention relates to a method of obtaining

< / BR>
which involves the reaction of the free acid of oxazolidine formula 7

< / BR>
connection baccatin formula 8

< / BR>
in the presence of a dehydrating agent. Thus R10and R14can be the same or different and are selected from the group consisting of-C(O)C1-C6the alkyl (preferably-C(O)CH3), - C(O)OC1-C6
20represents a C1-C6alkyl) or Si(R20)3; and R11and R12determined in accordance with the above description.

Compounds of the present invention receive in accordance with the methods shown in schemes A, A', B, and C.

The starting point of the method shown in the diagram And is a Taxol derivative or analog of Taxol a-1. The reaction of the compound a-1 with the same reagent as diethylaminosulfur (will GIVE), with the same reagent as diethylaminosulfur (will GIVE), dimethylaminomethylphenol (Matildas), bis(dimethylamino)sulfonitric, bis(diethylamino)sulfonitric or (diethylamino(dimethylamino)sulfonitric, provides 7-deoxy-7,8 - methane-similar to A'-2 (chart A-II), and 7-deoxy-7-fluoro-analogue of A"-2 (chart A-III). The preferred method for this conversion is a method comprising GIVE or Matildas. The reaction to GIVE or Matildas is performed in an aprotic solvent such as methylene chloride (CH2Cl2), chloroform (CHCl3), ferrichloride (freon IIR), dimethyl ether (glyme), 2-methoxyethylamine ether (diglyme), pyridine, hydrocarbons such as pentane, hexane or isooctane, tetrahydrofuran (THF), benzene, tremperature from -100oC to 100oC and above. In General, the reaction starts at a low temperature, for example -78oC, and then passes at a higher temperature, in particular at 25oC. the Reaction is stopped by the addition of water, emit crude product using standard methods of extraction and clean standard chromatographic methods and/or by crystallization. [In the case when R4represents-OC(O)OCH2C(Cl)3processing A'-2 (chart A-II) with activated zinc in a solution of methanol : acetic acid is used to remove the protective group and obtain the desired 7-deoxy-7,8-/ methane-Taxol or similar 7-deoxy-7,8 - methane-Taxol A"-3 (scheme A-II). When R4represents-OC(OCH2C(Cl)3processing A"-2 (chart A-III) with activated zinc in a solution of methanol : acetic acid is used to remove the protective group and obtain the desired 7-deoxy-7-portixol or similar 7-deoxy-7-portixol A"-3 (scheme A-III)]. The techniques used for the introduction of various protecting groups in the Taxol and Taxol analogues and removal of such groups can be found in: Greene, T. W. and P. G. M. Wuts, "Protective Groups in Organic Synthesis", 2nd Ed., pages 10-142, Wiley, N. Y., 1991.

Alternatively, compounds (formula II) this is about was described in the work of Chen and co-authors (Chen et al., Serendipitous Synthesis of a Cyclopropane - Containing Taxol Analog via Anchimeric Participation of an Unactivated Angular Methyl Group, Advance ACS Abstracts, Vol. 1, No. 2, July 15, 1993 and J. Org. Chem., 1993, 56, 4520, (August 13, 1993).

Compounds (formula II) of the present invention can be also obtained by using the method shown in figure B-11. In this method, when Z' = H in formula II (when Z' = H, R10= -C(O)CH3this structure of the formula II are known, as well as baccatin III) processing baccatin III or suitably protected (Z' = Troc) molecules B-1 baccatin III by the method described above, provides 7-deoxy-7,8 - methane-baccatin III (B-2) after removal of the protective group. Response B-2 with an activated side chain precursor B-3 using one of several methods described in the literature (see: Kingston, D. G. I. Pharmac. Ther., 1991, 52, 1-34, Commercon, A.; Bezard, D.; Bernard, F. ; Bourzat, J. D. Tetrahedron Lett., 1922, 33, 5188, Georg, G. I.; Cheruvallath, Z. S.; Himes, R. H.; Mejillano, M. R. Bio Med. Chem. Lett. 1992, 2, 295) gives B-4. For example, the binding of 7-deoxy-7,8 - methane-baccatin III (4S,5R)-N-BOC-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate acid in accordance with the procedure of Commerson with co-authors yields an intermediate product that can be used for further transformations of 7-deoxy-7,8 - methane-Taxol, 7-deoxy-7,8 - methane-Taxotere (compound of formula II, where R1

Compounds (formula II) of the present invention can be obtained also from Taxol or Taxol analogues with in position C-7 as a substituent group having a high mobility, that is, (a) the precursor ion, page, such as-NH2(b) ether sulfonate, -OSO2R (where R represents a group such as-CH3, -CF3C6H4-(p)-Br, C6H4-(p) -NO2or (b) one of the halogen is iodine or bromine (-I or-Br). Amine Deputy in position C-7 by reaction with nitrous acid (HNO2turns into ion page. Ion page spontaneously loses nitrogen, which leads to the formation of 7,8 - methane-functional groups. C-7-Sulphonate ester, when dissolved in a polar solvent (such as methanol: water, ethanol: water, triperoxonane acid) undergoes ionization, leading to the formation of 7,8 - methane-functional groups. The ionization of the C-7-sulfatase ether can be enhanced by adding to the reaction medium dinucleophiles base (such as potassium carbonate, potassium bicarbonate, 1,4-diazobicyclo-[2.2.2]-octane (DABCO)] . C-7-Iodide or bromide is also subjected to ionization with the formation of 7,8 - metafunctional group in a polar solvent in the presence is t silver.

Compounds (formula III) of the present invention can be also obtained by using the method shown in scheme B-III. In this method, when Z' = H in formula II (when Z' = H, R10= -COCH3this structural formula II also known as baccatin III), fluoridation baccatin III or suitably protected (Z' = troc) molecule 8-1 baccatin III according to the method described above gives 7-herbacetin III (B-2) after removal of the protective group. Response B-2 activated side chain precursor B-3 one of the methods described in the literature (see: Kingston, D. G. I. Pharmac. Ther., 1991, 52, 1-34; Commercon, A. ; Berard, D.; Bernard, F.; Bourzat, J. D.'; Tetrahedron Lett. , 1992, 33, 5185, Georg, G. I.; Cheruvallath, Z. S.; Himes, R. H.; Mejillano, M. R. BioMed. Chem. Lett. 1992, 2, 295), gives B-4. For example, the binding of 7-herbacetin III c (4S,5R)-N-BOC-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate acid and subsequent transformation procedure of Commerson with co-authors yields an intermediate product that can be used for further transformations of 7-deoxy-7,8 - portixol, 7-deoxy-7,8 - fortecstar (compound of formula III, where R1= Ph, R2= NHC(O)O-t-Bu; R3= R5= H, R4= OH, R10= -C(O)CH3] or other analogues of 7-deoxy-7,8 - cortexone.

Compounds (formula I, including formulae III and III) on the x A', B and C. Obtaining esters 1 3 azido-2-hydroxy-carboxylic acid may be carried out as described in the literature (see: Denis, J-N.; Correa, A. ; Greene, A. E. J. Org. Chem. 1990, 55, 1957). These substances easily hydrogensource with formation of free amines 2, although the data from literature, avoid using this intermediate product to obtain a hydroxy-acylated intermediate before restoring azide. Amin 2 is quite stable, so there are no problems selecting it and direct use to obtain the N-acylated free hydroxy compounds 3. Compound 3 was used to protect the hydroxy groups, for hydrolysis of the ester to the acid and direct condensation with the derived baccatin III or after conversion in oxazine (European Patent 0428376 A1, U.S. 436235). These procedures are not perfect, as they require a large excess of cilleruelo agent and, as a rule, do not allow to spend more than 60%. Described and other procedures that use of beta-lactam intermediate, however, they also require a large excess of the reagent or the introduction of very strong bases such as LDA, which complicates the conduct of the process and makes it unfit of glidevale was described very effective condensation process, including the conversion of the hydroxy-amine derivative 3 in oxazolidin with two substituents different from hydrogen in the 2 position (Commercon, A.; Berard, D.; Bernard, F.; Bourzat, J. D. in Tetrahedron Lett., 1992, 33, 5185, and Patent WO 92/09589). The condensation process gives a very high output, however, to remove the protecting group is required is a sufficiently strong acid, so sensitive analogues of Taxol dissolved in such hard conditions deprotection. We have modified and improved this procedure by education oxazolidines 5 not through the ketone, as did the above-mentioned researchers, and through enriched with electrons benzaldehyde 4. Oxazolidine obtained through the benzaldehyde 4, to form a mixture of diastereomers, but in some cases they were able to share and to show that all the diastereomers have the same properties, useful for synthesis. Oxazolidine 5 easily hydrolyzed with the formation of salts 6 and acids 7. Acid labile, so you must use it immediately after receiving. Both isomers of oxazolidine equally effective in the condensation reaction with the protected bucketname 8, resulting in a reaction a good way protected oxazolidinone analogues 9 Taxol. More significant is the fact that both isomagic acidic conditions, that allows deprotection without undesirable transformation of the derivatives of Taxol, highly sensitive to acid, such as 10, which are the object of the present invention. In the literature there are references to the use of electron-rich aldehydes for the protection of 1,2-diols, in particular, dioxolanes, but no data about the use of such aldehydes to protect 2-hydroxy-protected amines. Deprotection can be carried out so that oxazolidin, and 7-protected hydroxyl 9 can be removed either at the same time or independently of each other. Figure 8 additionally describes how deprotection of a number of analogues 10 urethane to obtain the free amine 11. Thus, the compounds can be re-transformed into many different aminoacylating analogues 10.

It is known that the process of conversion of azide 1 Amin 2 impact of restorative agents. Thus, the reaction can be carried out by hydrogenation in the presence of many hydrogenation catalysts such as palladium, platinum, rhodium or ruthenium. Alternatively, the azide can be recovered in the processing of a phosphine, such as triphenyl or tributylphosphine, or acid, such as hydrochloric These reactions may be conducted in solvents such as ethanol, ethyl acetate, methyl t-butyl ether, tetrahydrofuran, etc., the conversion of amine 2 in its acylated derivative 3 promotes processing of amine in pyridine or a non-basic solvent such as methylene chloride or tetrahydrofuran containing Quaternary amine, such as triethylamine or ethyldiethanolamine, together with azetiliruet agent. If 3 is a urethane, 2 treated with such agents as benzylchloride, 2,2,2-trichlorocyanuric, di-tert-BUTYLCARBAMATE or other forming urethane agent known in the art. If 3 - is an amide, 2 is treated with Alliluyeva agent such as acyl-halide or acyl-anhydride, or other known in the art alleluya agents. If 3 is a urea or thiourea, 2 treated with this agent, as the alkyl - or aryl-isothiocyanate, or others known in the art agent, forming urea or thiourea.

Hydroxyamide or urethane 3 turn in oxazolidin 5 by treatment enriched with electrons with benzaldehyde or its acetals, such as dimethyl - or diethyl-acetal 4, and an acidic catalyst such as p-toluensulfonate acid, p-toluensulfonate pyridinium. or other the ID, or other aprotic solvent. Examples of electron-rich benzaldehydes include, but are not limited, however, by them, 2-, 3-, 4-methoxybenzaldehyde, 2,4-, 3,5-, 2,5-dimethoxybenzaldehyde, 2,4,6-trimethoxybenzaldehyde and 4-ethoxybenzaldehyde. The preferred benzaldehyde is 2,4-dimethoxybenzaldehyde. Education oxazolidine carried out usually by heating at the boiling point under reflux to distillation of both solvents and distillation of water or alcohol. Ether 5 hydrolyzing to salt 6 by treatment with alkali or hydroxide of Quaternary amine or carbonate of an alkali metal, or other basis, known in the art, in a solvent such as water, methanol, ethanol or another proton solvent. The reaction can be conducted at a temperature of from -78oC to 100oC. the Product 6 is stable and can be isolated by evaporation of solvents and stored later in the form of solids, or the reaction can be directed to the transformation of 6 into acid 7 by treatment with acid. In the General case, 7 is obtained by treatment of an aqueous solution of 6 in a separating funnel sufficient amount of acid, such as hydrochloric, sulphuric, potassium bisulfate and other distribution scopariinae solvent. The resulting acid 7 is clean enough and stable to use in the next reaction, but usually not enough stable for the purposes of long-term storage. Acid 7 is condensed with a derivative baccatin 8 with the formation of ester 9 in the presence of a dehydrating agent. Most preferred for this procedure is carbodiimide, such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, di-p-taylorbodiesmade, hydrochloric acid salt of ethyldiethanolamine and the like, as well as the basic catalyst, preferably 4-dimethylaminopyridine. In General, the reaction is carried out in an aprotic solvent such as toluene, benzene, tetrahydrofuran, dioxane and the like, at a temperature of 25oC to 100oC. For education 9 can be applied to other procedures dehydration, in particular, turning 7 in its mixed with ether sulfonic acid, reaction with toluensulfonate or benzosulphochloride or the formation of halide acid from dry 6 in the presence of oxaliplatin in accordance with what is known in the technique relative to the carboxylic acids that are sensitive to acid. Oxazolidine 9 can be subjected deprotection thus, h is sledovatelno, or together, depending on finding a protecting group in position 7, and the reaction conditions. If R14represents an acid labile group, such ether silila, the hydrolysis of oxazolidine can be performed at mild acidic conditions and lead to deprotection 7 position with education directly 10MZ. The necessary conditions for such transformations include hydrolysis in aqueous acetic acid, aqueous alcohol acid with a concentration from 0.01 to 0.1 N at a temperature of from 0oC to 50oC or alcoholic acid with a concentration from 0.01 to 0.1 N at a temperature of from 0oC to 50oC. alternatively, the patronage in the 7-position can be removed in the second stage, if the connection is not cyclotourism. For example, trichlorocarbanilide group in position 7 can be removed from 10MY (scheme B) by means known in the art method of recovery eventually 10MZ. Depending on the nature of the group protecting the nitrogen (i.e. R2or R3in 10MZ (scheme B), the protecting group can be removed with getting 11Z. For example, when R2represents PhCH2OC(O)NH, it can be removed using a mild hydrogenolysis. The conditions necessary for such a transformation, on the solvent, which may be ethanol or ethyl acetate, at room temperature, under pressure from one to three atmospheres. In engineering and other known methods of carrying out such a process. The obtained amine 11Z can be again converted into amide or urethane 10MZ (scheme B) using the procedure acylation as described above for the conversion of 2 into 3. Product 10MZ can be protected 2'-hydroxyl group with the formation of the 12MZ (scheme B). For example, the 2'-hydroxyl group can be allerban using trichlorocarbanilide in pyridine or other solvents on the basis of aromatic amines or non-basic solvent, such as toluene, methylene chloride or tetrahydrofuran containing base Quaternary amine. The reaction can be carried out in the temperature range from -50oC to 100oC. In technology there are also other methods for these acylation.

The reaction of Taxol analogues of Taxol 10MZ (R15is an acetate or other suitable acyl group), baccatin III or analogues 8 baccatin III (R6is an acetate or other suitable acyl group) with hydrazine based on a very convenient method used to obtain the 10-deazetil Taxol, anal is At that time, as is known in the literature method (Samaranayake. G., et al., J. Org. Chem., 1991, 56, 5114) removal of acetyl groups from this position taxonomy and bakalinova structures by means of zinc bromide in methanol provides many other products in addition to the required NO2- product diallylamine described reaction with hydrazine gives practically only the desired product diallylamine. The reaction may be conducted at room temperature in an organic solvent, and requires, as a rule, from a minimum of 15 minutes to a maximum of 24 hours depending on the substrate. The preferred solvent for the reaction is 95% ethanol, and the preferred form of the reagent - 98% hydrazine.

Preparation of N1:

Preparation of methyl ester (2R,3S) -- phenyl-azaserine (2)

Methyl ester (2R,3S)-3-azido-2-hydroxy-3-phenylpropionic acid (1, 0.5 g) hydrogenized in the presence of 10% palladium on coal (0.1 g) in ethanol at atmospheric pressure for 1 hour.

Then the reaction mixture is filtered and evaporated to obtain the desired amine. So pl. =- 106-108oC.

NMR (CDCl3TMS): 2,1 (SHS), 3,80 (C., 3H), or 4.31 (m, 2H), 7,28 was 7.45 (m, 5H).

The preparation of N2:

Obtaining methyl ester (4S,5R)-N-Benzoyl-2(2,4-dimethoxyphenyl) dissolved in dry THF (10 ml) and benzene (10 ml), then the solution is treated with dimethyl acetal of 2,4-dimethoxybenzaldehyde (4, 0,420 g, 1.98 mm) and p-toluensulfonate pyridinium (12 mg), and the solution was heated and refluxed. After 30 min the reaction mixture was cooled to room temperature and left to stand over night. Then again heated for the purpose of slow distillation 1/2 of the solvent for one hour. TLC shows that the reaction to this end. The reaction mixture was concentrated in vacuo and chromatographic the residue on 50 g of silica gel in a mixture (5:95) methanol: toluene. Column elute with a mixture (5:95) methanol:toluene. Collect fractions with a volume of 12 ml Product eluted as a mixture. Next, the fractions containing the mixture 5Aa and 5Ab, again combined and evaporated. The remainder (about 0.90 g) rechromatography on silica gel (100 g). Column elute with a mixture of ethyl acetate:toluene (500 ml of a mixture of 15:85 and 500 ml of a mixture of 20:80). Fractions of 20 ml are collected and analyzed by TLC. The fractions containing each of 5Aa and 5Ab are pooled and evaporated under vacuum.

Less polar isomer 5Aa

A mixture of the less polar and more polar isomers 5Aa and 5Ab

The more polar isomer 5Ab

Isomer 5Ab crystallized from EtOAc to obtain white crystals (142 mg, MP. = 138 - 141< (CDCl3TMS): , of 3.69 (s, 3H), of 3.77 (s, 3H), 3,86 (s, 3H), is 4.93 (d, 1H), 5,6 (MS, 1H), 6,28 - 6,37 (m, 2H), 6.90 to (s, 1H), 7,03 (d, 1H), 7,15 - of 7.55 (m, 9H).

Data for 5Ab:

TLC: silicagel: 20% EtOAc: 80% toluene, Rf: 0,41.

1H NMR (CDCl3TMS): , 3,62 (CL, 3H), 3,75 (MS, 6H) and 4.65 (D., 1H), 5,68 (SHS, 1H), 6,2 - 6,5 (m, 2H), 6,8 - of 7.55 (m, 11H).

UV: EtOH, 229 (16,000), 277 (3,240), 281 sh (3,170).

Analytical data:

Calculated (Percent): C - 69,79, H - 5,63, N - 3,13.

Found (percent): C - to 69.61, H 5,61, N - 2,93

Drug N 3:

Obtaining potassium salt of (4S,5R)-N-benzyl-2-(2,4-acid) -4-phenyl-5-oxazolidinecarboxylate acid 6Ab

Methyl ester of (4S,5R)-N-benzyl-2-(2,4-acid)-4-phenyl-5 - oxazolidinecarboxylate acid (Preparation N 2, 5Ab, 355 mg, 0.96 mm) was dissolved in 9 ml of methanol. To the solution was added water (350 μl) and potassium carbonate (155 mg, 1,12 mm). After stirring for 5 hours no undissolved components, and TLC showed only a very small number of remaining methyl ester. The solvent was concentrated in vacuo and added to the oil water (10 ml). The solution is dried by freezing to obtain 500 mg of a light crystalline powder of white colour, containing 374 mg of the potassium salt.

TLC: silica gel 60, 1:2, EtOAc: hexane,Rf: start

Agents who nd acid (9AbA)

A solution of potassium salt of (4S, 5R)-N-benzyl-2-(2,4-acid)-4-phenyl-5-oxazolidinecarboxylate acid (6Ab, drug N 3, with 91.4 mg, about 0.15 mm) in ethyl acetate, washed with 5% aqueous NaHSO4. An ethyl acetate solution is dried and evaporated to obtain the corresponding acid 7Ab. The residue is dissolved in methylene chloride (0.8 ml) and toluene (1.75 ml) and combined with 7-triethylsilyl-bakatina 111 (68 mg). The mixture is treated with 4-dimethylaminopyridine (6.3 mg) and 1,3-dicyclohexylcarbodiimide (34 mg). The reaction mixture is heated to 80oC for 90 minutes, cooled, filtered and chromatographic on silica gel in a mixture of ethyl acetate: hexane. The result was achieved in 86% yield of the combined product 9AbA.

NMR (CDCl3TMS) : 0,58 (m, 6H), of 0.90 (m), 1,73 (C., 3H), of 1.87 (m, 1H), 2,03 (m, 3H), 2,17 (CL, 3H), of 2.20 (s, 3H), of 2.23 (m, 2H), 2,50 (m, 1H), 3,76 (CL, 3H), of 3.80 (s, 3H), 3,85 (D., 1H), 4,13 (D., 1H), 4,27 (D., 1H), 4,50 (m, 1H), 4,90 (m, 2H), 5,63 (SHS, 1H), of 5.68 (d, 1H), from 6.25 6.48 in (m, 3H), of 6.50 (s, 1H), 6,86 (s, 1H), to 7.09 (m, 1H), 7,15-the 7.65 (m, 13H), with 8.05 (d, 2H),

Preparation of N 5:

Preparation of Taxol (compound 10AA)

Ether 7-TES-baccatin 111-13-(4S, 5R)-N-Benzoyl-2-(2,4-dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylate acid 9AbA), subject to deprotection under stirring in 0.1 M HCl in methanol for 10 minutes. After dilution with ethyl acetate the solution and acetone: hexane. To natural Taxol NMR data for proton and carbon are identical.

Drug N 6:

Obtaining methyl ester (4S, 5R)-N-BOC-2-(2,4-acid)-4-phenyl-5-oxazolidinecarboxylate acid (5Ba and 5Bb)

Methylene ether N-SIDE -- phenylazomethine (3B) (0.5 g, 1,69 mm) dissolved in dry THF (10 ml) and toluene (10 ml) and concentrated to dryness to remove any water, including crystallization. Then the residue is dissolved in dry THF (10 ml) and the resulting solution is treated with dimethylacetal 2,4-dimethoxybenzaldehyde (4) (0,425 g, 2.0 mm) and p-toluensulfonate pyridinium (12 mg), and the solution was heated and refluxed. After 30 minutes the reaction mixture is cooled to room temperature and left to stand overnight. Then again heated and refluxed for 3 hours. The course of the reaction is monitored by TLC, when it was found that the reaction is incomplete. Next, the reaction mixture is heated to 85oC the purpose of distillation, approximately 2/3 of THF. Then add fresh THF (10 ml) and acetal (200 mg) and boil the reaction mixture under reflux for another 2 hours. The results of the TLC shows that the reaction is finished. Then the reaction mixture was concentrated in in the Yu acetone:hexane (500 mg, 15:85 and 500 ml of 20:80). Collecting fractions of 20 ml.

Isomers of the desired product come in the form of a mixture. Fractions containing a mixture of 5Ba and 5Bb, combined and concentrated in vacuo to obtain a white foamy substance. Then foamy substance re chromatographic through 100 g of silica gel and elute with a mixture (10:90) EtOA:toluene. Collecting fractions of 20 ml and analyzed by TLC. Thus was allocated 34 mg of the less polar isomer 5VA, 187 mg of the mixture of the less polar and more polar isomers 5Ba and 5Bb and 500 mg of the more polar isomer 5Bb.

Isomer 5Bb crystallized from EtOA:hexane to obtain white crystals (378 mg).

The mixture of isomers also crystallized from EtOA:hexane to obtain crystalline 5Bb (113 mg) with purity, confirmed by TLC, the same as in the mother solution, which was crystallized isomer 5Bb. These crystals and the mother liquor solutions are combined and subjected to re-crystallization from EtOA:hexane to obtain more pure 5Bb (160 mg).

Data for 5Ba:

TLC: silica gel 60, 10% EtOAc: 90% toluene, Rf: 0,44.

1H NMR (CDCl3TMS): 1,26 (C., 9H), 3,80 (C., 3H), 3,84 (C., 3H), 3,85 (s, 3H), 4,86 (D., 1H), 5,24 (s, 1H), 6,40 (DD., 1H), 6,47 (D., 1H), 6,72 (S.,1H), 7,12 (D., 1H), 7,30-the 7.43 ( m, 3H), 7,53 (D., 2H).

(C., 9H), 3,52 (sm., 3H), 3,81 (C., 3H), a 3.87 (C., 3H), 4,54 (D., 1H), 5,43 (CL., 1H), 6.48 in (S., 2H), for 6.81 (SHS, 1H), 7,13 (CL., 1H), 7,30-of 7.48 (m, 5H).

UV: EtOH, 233 (10,600), 260 sh(1010), 277 (2840), 281 sh (2680).

Analytical data:

Calculated (Percent): C-65,00, H-6,59, N-3,16.

Found (Percent): C-64,86, H-6.42 Per, N-3,24.

Drug N 7

Obtaining potassium salt of (4S, 5R)-N-BOC-2-(2,4-acid)-4-phenyl-5-oxazolidinecarboxylate acid 7Ba

100 mg (0.23 mmol) of methyl ester of (4S, 5R)-N-BOC-2-(2,4-acid)-4-phenyl-5-oxazolidinecarboxylate acid (preparation No. 6, 5Ba) was stirred at room temperature under nitrogen atmosphere in 3 ml of MeOH. Add 0.1 ml of water and 43 mg (0,31 mm) of potassium carbonate. After 1 hour, TLC data showed the absence of starting material. The mixture was stored in the freezer over night. The next morning, the solvent is evaporated to obtain the potassium salt of (4S, 5R)-N-BOC-2-(2,4-acid) -4-phenyl-5-oxazolidinecarboxylate acid (68a). The residue is distributed between methylene chloride and water containing 0.9 ml of 1N HCl. The phases are separated and the aqueous layer was subjected to re-extraction with methylene chloride. The combined organic phases, dried over sodium sulfate and evaporated. This gives (4S, 5R)-N-BOC-2-(2,4-acid)-4-phenyl-5-oxazolidinecarboxylate acid (7Ba) in the form of a white solid is TMS) : 1,26 (C., 9H), 3,76 (C., 6H), 4,77 (S., 1H), 5,34 (S. , 1H), 6,33-6,45 (D. , 2H), 6,60 (S., 1H), 7,07-7,16 (D., 1H), 7.24 to 7,40 (m, 3H), 7,42-7,54 (D., 2H).

Drug N 8:

Obtaining ester of 7-TES-baccatin 111-13-(4S, 5R)-N-BOC-2-(2,4-acid)-4-phenyl-5-oxazolidinecarboxylate acid (9BaA)

0.23 mm (4S, 5R)-N-BOC-2-(2,4-acid)-4-phenyl-5-oxazolidinecarboxylate acid (preparation 7, 7Ba) dissolved in a mixture of 1.5 ml of methylene chloride and 3 ml of toluene. To the resulting mixture are added 106 mg (0.15 mm) of 7-TES-baccatin 111 (8A), 11 mg (0.09 mm) DMAP and 49 mg (0.24 mm) DCK. The reaction mixture was stirred in nitrogen atmosphere and heated to 75oC for 90 minutes, then cooled to room temperature. Obtained by-product in the form of urea is removed by filtration, and the filtrate is evaporated in vacuum. The remainder chromatographic on 20 g of silica gel, elwira mixture 30:70 EtOAc : hexane. Collect fractions of 5 ml and analyze them with TLC. Faction 17-34 containing the desired product are combined and evaporated. Ether 7-TES-baccatin III-13-(4S, 5R)-N-BOC-2-(2,4-acid)-4-phenyl-5-oxazolidinecarboxylate acid (9BaA) are obtained in the form of a white solid.

TLC: silica gel 60: 30% EtOAc: 70% hexane, Rf:0,56.

Mass spectrum (FAB, m/z) 1112, 1012, 874, 328, 284, 115, 105, 87.

1H NMR (CDCl3TMS) : 0,52-0,66 (, H), of 4.49 (m, 1H), a 4.83-is 4.93 (m, 2H), 5,31 (D., 1H), 5,67 (D., 1H), 6,29 (t , 1H), 6,38-6,53 (m, 3H), 6,69 (S., 1H), 7,13 (D., 1H), 7,29-the 7.65 (m, 8H), 8,05 (D., 2H).

Drug N 9:

13-(N-SIDE -- phenylisopropyl)-baccatin III (10BA)

0.1 M HCl solution is prepared in a mixture of 0,071 ml acetylchloride and 9,929 ml MeOH and incubated before use 30 minutes.

To 57 mg (0,051 mm) ester of 7-TES-baccatin-III-13-(4S, 5R)-N-BOC-2-(2,4-acid)-4-phenyl-5-oxazolidine carboxylic acid (Preparation No. 8, 9BaA) add 0.5 ml of the above methanolic HCl under stirring in nitrogen atmosphere. As shown by TLC, the reaction ends after 75 minutes. The reaction mixture is distributed in a mixture of ethyl acetate: 5% sodium bicarbonate. The layers are separated and the aqueous layer was subjected to re-extraction with ethyl acetate. The organic extracts are combined dried over sodium sulfate and evaporated in vacuum.

The obtained crude product is subjected to chromatographicaliy 10 g silicagel using for elution of a mixture of 50:50 ethyl acetate:toluene. Collect fractions of 2 ml and analyze them with TLC. Pure product find in fractions 19 to 42, which are combined and evaporated. 13-(N-SIDE -- phenylisopropyl)baccatin III (10BA) are obtained in the form of a white solid.

the ski calculation for C45H56N1O15850, 3650: m/z 794, 569, 509, 105, 57.

1H NMR (CDCl3TMS) : 1,14 (C., 3H), 1.27mm (C., 3H), 1,33 (C., 9H), 1,67 (C. , 3H), 1,84 (C., 3H), 2,24 (C., 3H), of 2.38 (SD, 3H), 3,44 (D., 1H), 3,81 (D., 1H), 4,17 (D., 1H), 4,30 (D., 1H), to 4.41 (m, 1H), 4.63 to (CL., 1H), 4.95 points (D., 1H), 5,26 (sm., 1H), 5,43 (sm., 1H), 5,67 (D., 1H), 6,23 (t, 1H), 6,28 (S. , 1H), 7,27 was 7.45 (m, 5H), to 7.50 (t, 2H), a 7.62 (t, 1H), 8,11 (D., 2H)

Drug N 10:

Obtaining potassium salt of (4S, 5R)-N-BOC-2-(2,4-acid)-4-phenyl-5-oxazolidinecarboxylate acid (6Bb)

A solution of methyl ester (4S, 5R)-N-BOC-2-(2,4-acid)-4 - phenyl-5-oxazolidinecarboxylate acid (preparation No. 6, 5Bb, 374 mg, 0.84 mm) in MeOH (11 ml) was stirred at room temperature under nitrogen atmosphere and add water (and 0.37 ml) and potassium carbonate (161 mg, 1,17 mm). After 2 hours, TLC shows that the reaction was about 70%. After stirring over night the reaction, as shown terminates. The solvent is evaporated and the resulting residue is dissolved in 10 ml of water and dried by freezing. As a result of this process is getting 507 mg of a light crystalline solid white, which contains the potassium salt of (4S,5R)-N-BOC-2-(2,4-acid)-4-phenyl-5-oxazolidinecarboxylate acid (6Bb, 393 mg).

TLC: silica gel, 20% EtOAc: 80% hexane, Rfstart.


0.12 mm of the crude preparation of potassium salt of (4S,5R)-N-BOC-2-(2,4-acid)-4-phenyl-5-oxazolidinecarboxylate acid (preparation No. 10, 6Bb) distributed between ethyl acetate: 5% sodium bisulfate. The layers separated, and the aqueous layer was subjected to re-extraction with ethyl acetate. The organic extracts are combined dried over sodium sulfate and evaporated under vacuum.

The resulting acid 7Bb dissolved in a mixture of 0.8 ml of methylene chloride: 1.5 ml of toluene together with 53 mg (0.076 mm) of 7-TES-baccatin III (8A, see Denis, J.-N. , Greene, A. E.; Guenard, D., Gueritte-Vogeline F., Mangatal, L.; Potier, P. J. Am. Chem. Soc. 1988, 110 N, 59167), 6 mg (0,049 mm) 4-dimethylaminopyridine (DMAP) and 25 mg (0.12 mmol) of dicyclohexylcarbodiimide (DCC). The reaction mixture was stirred in nitrogen atmosphere and heated to 75oC for 90 minutes. Then the reaction mixture is cooled to room temperature and filtered by-product urea. The resulting filtrate is evaporated in a vacuum.

The remainder chromatographic on 15 g of silica gel, elwira mixture 30:70 EtOAc: hexane. Fractions with a volume of 7 ml are taken and analyzed by TLC. Faction 16-38 containing the desired product are combined and evaporated. Ether 7-TES-baccatin III-13-(4S, 5R)-N-BOC-2-(2,4 - acid)-4-phenyl-5-oxazolidinecarboxylate acid (9BbA) is

Mass spectrum (FAB, m/z): 1112, 1012, 384, 328, 284, 115, 105, 87, 57.

1H NMR (CDCl3TMS): from 0.50 to 0.61 (m, 6H), from 0.84 to 0.97 (m, 9H), 1,08 (C., 9H), 2,21 (C., 3H), 3,67 (D., 1H), 3,80 (C., 3H), 3,90 (C., 3H), 4,07 (D., 1H), 4,23 (D., 1H), and 4.40 (m, 1H), 4.53-in (sm., 1H), 4,87 (D., 1H), 5,44 (sm., 1H), ceiling of 5.60 (D., 1H), 6,34 (S., 1H), 6,44 (CL., 1H), 6.48 in (S., 1H), 7,20 (CL., 1H), 7,30-to 7.50 (m, 7H), 7,60 (t, 1H), 8,01 (D., 2H).

Drug N 12:

13-(N-SIDE -- phenylisopropyl)-baccatin III (10BA)

0.1 M HCl solution is prepared in a mixture of 0,071 ml acetylchloride and 9,929 ml MeOH and incubated before use 30 minutes.

To 45 mg (0,040 mm) ester of 7-TES-baccatin III-13-(4S,5R)-N-BOC-2-(2,4 - acid)-4-phenyl-5-oxazolidinecarboxylate acid (preparation No. 11, 9BbA) add 0,395 ml of the above methanolic solution of HCl under stirring in nitrogen atmosphere. As shown by TLC, the reaction ends after 20 minutes.

After 30 minutes the reaction mixture was partitioned between ethyl acetate phases: 5% sodium bicarbonate. The layers are separated and the aqueous layer was subjected to re-extraction with ethyl acetate. The organic extracts are combined dried over sodium sulfate and evaporated in vacuum.

The coarse product chromatografic on 5 g of silica gel, using for the elution mixture of 50:50 ethyl acetate:toluene. Collect fractions of 5 ml and analysera Soderini)-baccatin III (10BA) are obtained in the form of a white solid.

TLC: silica gel 60, 50:50, EtOAc:toluene, Rf: 0,42.

1H NMR (CDCl3TMS): 1,15 (C., 3H), 1.27mm (C., 3H), 1,33 ((C., 9H), 1,68 (C. , 3H), 1,85 (C., 3H), 2,25 (C., 3H), of 2.38 (SD, 3H), 3,44 (D., 1H), 3,80 (D., 1H), 4,17 (D., 1H), 4,30 (D., 1H), to 4.41 (m, 1H), 4,62 (CL., 1H), 4.95 points (D., 1H), 5,26 (sm., 1H), 5,43 (sm., 1H), 5,67 (D., 1H), 6,23 (t, 1H), 6,29 (S. , 1H), 7,13 was 7.45 (m, 5H), 7,49 (t, 2H), a 7.62 (t, 1H), 8,11 (D., 2H).

Drug N 13:

Obtaining ester 7-(2,2,2-trichlorocyanuric)-baccatin-III - 13-(4S, 5R)-N-BOC-2-(2,4-acid)-4-phenyl-5-oxazolidinecarboxylate acid (9BaB, 9BbB)

0,39 mm potassium salt of (4S,5R)-N-BOC-2-(2,4-acid)-4-phenyl - 5-oxazolidinecarboxylate acid (6Ba, 6Bb) are distributed between the phases ethyl acetate: 5% sodium bisulfate. The phases are separated and the aqueous phase re-extracted with ethyl acetate. The organic extracts are combined dried over sodium sulfate and evaporated under vacuum.

The remainder of the acid 7Ba, 7Bb dissolved under stirring in nitrogen atmosphere to a mixture of 2 ml of methylene chloride: 6 ml of toluene. To the resulting solution was added 187 mg (0,245 mm) 7-(2,2,2-trichlorocyanuric)-baccatin III (8B, see, for example, Mangatal, L.; Adeline, M.-T.; Guenard, D., Gueritte-Vogelein, F.; Potier, P. Tetrahedron 1989, 45, 4177), then added 22 mg (0.18 mm) DMAP and 80 mg (0,39 mm) DCK. Soon after you add all of these components in the solution starts falling out the live reaction by TLC. After cooling to room temperature, the insoluble fraction is separated by filtration, and the filtrate is evaporated in vacuum. The coarse product is subjected to chromatographicaliy 50 g of silica gel by elution successively with 400 ml of 30:70, 200 ml of 40:60, 100 ml of 70:30 mixture of ethyl acetate: hexane. Fraction volume of 15 ml is collected and analyzed by TLC. The following fractions are combined and evaporated under vacuum to obtain a white solid.

Fractions 14-20, less polar isomer 9BaB

Fractions 21-26, mixture of isomers 9BaB, 9BbB

Faction 27-32, the more polar isomer 9BbB

Faction 37-44, the output of the source of alcohol 8B

Data for isomer 9BaB:

TLC: silica gel 60, 40:60 ethyl acetate:hexane, Rf: 0,67.

1H NMR (CDCl3TMS): 1,26 (C.), 1,82 (C., 3H), 2,12 (C., 3H), 2,19 (C. , 3H), 2,58 (m, 1H), 3,81 (C., 3H), 3,91 (C., 3H), 3,97 (D., 1H), 4,13 (D., 1H), 4,28 (D., 1H), 4,66 (D., 1H), 4.92 in (m, 2H), 5,03 (D., 1H), are 5.36 (D., 1H), of 5.83 (m, 1H), 5,67 (D., 1H), 6,32 (m, 1H), 6,40 (S., 1H), 6,51 (D., 1H), 6,69 (S., 1H), 7,16 (D., 1H), 7,37 to 7.62 (m, 8H), 8,02 (D., 2H).

Data for isomer 9BbB:

TLC: silica gel 60, 40:60 ethyl acetate:hexane, Rf: 0,55.

1H NMR (CDCl3TMS): 2,17 (SHS.), 3,47 (m), 3,79-of 3.94 (m,), 4,08 (doctor ), 4,27 (d), 4,54 (m) and 4.65 (m), 4,89 (doctor), 5,01 (m), of 5.40 (m), 5,50 (m ), 5,62 (doctor), 6,24 (SHS.), of 6.49 (SHS.), 7,37-the 7.65 (m), 8,03 (d).

0.1 M solution of HCl in MeOH prepared in a mixture of 0,071 ml acetylchloride and 9,929 ml MeOH and incubated before use 30 minutes.

252 mg (0,216 mm) ester 7-(2,2,2-trichlorocyanuric)-baccatin III-13-(4S, 5R)-N-BOC-2-(2,4-acid)-4-phenyl-5-oxazolidinecarboxylate acid (preparation N 13, 9BaB, 9BbB) was stirred at room temperature under nitrogen atmosphere with 2.2 ml of above 0.1 M solution of HCl in MeOH. The progress of the reaction is followed by TLC and because after 20 minutes it is completed, add another 0.5 ml of the HCl solution and continue to carry out reaction for 15 minutes.

Then the reaction mixture was diluted with ethyl acetate and washed with 5% sodium bicarbonate. The layers are separated and the aqueous fraction is re-extracted with ethyl acetate. The organic extracts are combined dried over sodium sulfate and evaporated under vacuum. The coarse product chromatografic on 30 g of silica gel by elution successively with 200 ml of 35:65 and 300 ml of a 40:60 mixture of ethyl acetate:hexane. Fractions of 5 ml are collected and analyzed by TLC. Faction 25-54, containing the pure product, are combined and dried under vacuum to obtain 7-(2,2,2-trichlorocyanuric)- 13-N-SIDE-phenylisoxazol-baccatin III 10BB in the form of a solid substance.

TLC: si is ri 1024, 2656, the calculation for C48H57Cl3N1O17is 1024, 2692, 1024, 968, 924, 743, 683, 105, 57.

1H NMR (CDCl3TMS): 1,17 (C., 3H), 1,24 (C., 3H), 1,34 (C., 3H), 1,34 (C. , 9H), 1,83 (C., 3H), 1.91 a (C., 3H), 2,17 (C., 3H), 2,39 (C., 3H), 2,62 (m, 1H), 3,60 (D., 1H), 3,94 (D., 1H), 4,16 (D., 1H), 4,30 (D., 1H), 4,63 and 5,04 (2D., 2H), 4,62 (CL., 1H), 4.95 points (D., 1H), 5,26 (sm., 1H), the 5.45 ceiling of 5.60 (m , 2H), 5,66 (D., 1H), of 6.20 (t, 1H), 6,36 (S., 1H), 7.24 to 7,44 (m, 5H), 7,49 (t, 2H), to 7.61 (t, 1H), 8,08 (D., 2H).

Drug N 15:

13-(N-SIDE -- phenylisopropyl)-baccatin III (10BA) and 7-(2,2-dichlorocarbene)-13-(N-SIDE -- phenylisopropyl)-baccatin III 10BG.

150 mg (0,146 mm) 7-(2,2,2-trichlorocyanuric)-13-(N-SIDE -- phenylisopropyl)-baccatin III (preparation No. 14, 10BB) was stirred at room temperature under nitrogen atmosphere in a mixture of 13.5 ml of MeOH and 1.5 ml OHAc. To the mixture was added 150 mg of activated zinc and heat it to 50oC for 60 minutes. The progress of the reaction is followed by TLC, the results of which add zinc 4 more times portions 150 mg, heating the reaction mixture after each addition for 45 minutes. Then the reaction mixture is filtered and the filtrate is evaporated under vacuum. The resulting residue is distributed between methylene chloride fractions: water. Fractions are separated and the aqueous layer was re-extracted with methylenechloride chromatographic on 20 g of silica gel, elwira successively with 200 ml of 70:30, and 200 ml of 70:30 mixture of ethyl acetate : hexane. Fractions of 5 ml are collected and analyzed by TLC. The following fractions are combined and evaporated under vacuum to obtain white solids.

Fractions 9 - 13, 7-(2,2-dichlorocarbene)-13-(N-SIDE) -- phenylisopropyl)-baccatin III 10BG.

Fractions 14 to 44, 13-(N-SIDE -- phenylisopropyl)-baccatin II (10BA)

Data for 7-(2,2-dichlorocarbene)-13-(N-SIDE -- phenylisopropyl)-baccatin III 10BG:

TLC: silica gel 60, 50:50 ethyl acetate : hexane, Rf: 0,81 (in this TLC system this product and source material go together).

1H NMR (CDCl3TMS): 1,17 (s, 3H), 1,24 (C., 3 H), 1,35 (C., 9H), 1,61 (C., 3H), 1,81 (C., 3H), 2,19 (C., 3H), 2,39 (C., 3H), 2,52 of 2.68 (m, 1H), 3,37 (D. , 1H), 3,92 (D., 1H), 4,16 (D., 1H), 4,32 (D., 1H), 4.53-in (m, 2H), 4,63 (SHS. , 1H), 4.95 points (D., 1H),) 5,26 (sm., 1H), 5.40 to (SD., 1H), 5,48 (m, 1H), 5,67 (D., 1H), 5,96 (m, 1H), of 6.20 (t, 1H), 6,45 (S., 1H), 7,28 - 7,44 (m, 5H), to 7.50 (t, 2H), a 7.62 (t, 1H), 8,10 (D., 2H).

Data for 10BA:

TLC: silica gel 60, 50:50 ethyl acetate : hexane, Rf: 0,32

1H NMR (CDCl3TMS): 1,14 (C., 3H), 1,24 (s, 3H), 1,32 (C., 9H), 1,67 (C., 3H), 1,84 (C., 3H), 2,23 (C., 3H), 2,37 (C., 3H), 2,44 at 2.59 (m, 1H), 2,64 (sm., 1H), 3,70 (CL., 1H), 3,78 (D., 1H), 4,15 (D., 1H), 4,28 (D., 1H), and 4.40 (m , 1H), br4.61 (CL., 1H), 4,94 (D., 1H), 5.25-inch (sm., 1H), 5,57 (sm., 1H), the 5.65 (d, 1H), from 6.22 (t, 1H), 6,29 (S., 1H), 7.24 to 7,44 (m, 5-2-(2,4-acid)-4-phenyl-5-oxazolidinecarboxylate acid (9bC)

Rough preparation of the potassium salt of (4S,5R)-N-BOC-2-(2,4 - acid)-4-phenyl-5-oxazolidinecarboxylate acid (preparation N 10 6b) (0,089 mm) are distributed between the phases of the mixture ethyl acetate: 5% NaHSO4. The layers are separated and the aqueous fraction is re-extracted with ethyl acetate. The organic extracts are combined dried over sodium sulfate and evaporated under vacuum to obtain (4S,5R)-N-BOC-2-(2,4 - acid)-4-phenyl-5-oxazolidinecarboxylate acid (7b). The residue is stirred at room temperature in a nitrogen atmosphere in a mixture containing methylene chloride (0.8 ml) and toluene (1.5 ml). To this mixture add 7,10-bis-Troc-10-deacetylbaccatin III (8C, see, for example, Senilh, V., Gueritte-Vogelein, F., Guenard, D., Colin, M., Potier, P. C. R. Acad. Sci. Paris 1984, 229, 4177), 50 mg, 0,056 mm. The resulting solution was treated with 4-dimethylaminopyridine (5 mg, 0.04 mm) and 1,3-dicyclohexylcarbodiimide (18 mg, 0,087 mm), and then heat the mixture to 75oC (25 minutes). After 15 minutes of heating, the results of the analysis carried out using TLC shows completion of the reaction.

Besieged dicyclohexylphosphino filtered. The filtrate is applied on silica gel (1 g) and chromatographic on silica gel 10 g), which elute with a mixture of ethyl acetate : hexane (30:70). Fractions of 4 ml gather and analyze is OK-baccatin III-13-(4S,5R)-N-BOC-2-(2,4 - acid)-4-phenyl-5-oxazolidinecarboxylate acid (8BbC) as a white solid.

TLC (silica gel 60): 40% EtOAc: 60% hexane, Rf: 0,56.

Mass spectrum (FAB, m/z): 1304, 1306, 1308, (M+H), 1024, 875, 683, 384, 328, 284, 105 (base), 57.

1H NMR (CDCl3TMS): 1,07 (C., 3H), 1.14 in (C., 3H), 1,22 (C., 3H), 1,79 (C. , 3H), of 2.56 (m, 1H), 3,79 (D., 1H), 3,81 (C., 3H), 3,89 (C., 3H), 4,08 (D., 1H), 4,25 (D., 1H), 4,54 (D., 1H), 4,59 and 4,88 (2D, 2H), 4,78 (S., 2H), 4,89 (units, 1H), 5,43 (m, 1H), 5,50 (m, 1H), 5,62 (D., 1H), 6,05 (CL., 1H), 6,12 (S. , 1H), 6,47 (D., 1H), of 6.49 (s, 1H), 6.75 in (CL., 1H), 7,21 (m, 1H), 7,35 - 7,53 (m, 7H), a 7.62 (t, 1H), 8,01 (D., 2H).

Drug N 17:

Getting 7,10-bis-Troc-13-(N-SIDE -- phenylisopropyl)-baccatin III (10BC)

Acetylchloride (0,071 ml, 80 mg, 0,056 mm) was added to methanol (10 ml) and the solution allowed to stand for 30 minutes, obtaining in the end a 0.1 N HCl solution. Ether 7,10-bis-Troc-Baccatin III-13-(4S, 5R)-N-BOC-2- (2,4-acid)-4-phenyl-5-oxazolidinecarboxylate acid (product No. 16, 9BbC) (73 mg, 0,056 mm) dissolved in the above methanolic HCl solution (0,553 ml) and left to stand for 25 minutes. After the reaction mixture is diluted with EtOAc and washed with 5% sodium bicarbonate. The layers are separated and the aqueous fraction is re-extracted with EtOAc. The organic extracts are combined dried over sodium sulfate and evaporated under vacuum. The coarse product is applied on silica gel (1 g) and chromatographic on silica gel (10 g). The elution from the column carry out smallfraction 10 - 20, which are combined and evaporated. Not enough pure product in fractions 7 to 9 again chromatographic, as described above. Fractions 11 - 26, containing the pure product are pooled with the product obtained from the first column. The result 7,10-bis-Troc-13-(N-BOC- -- phenylisopropyl)-baccatin III (10BC) as a white solid.

TLC (silica gel 60): 30% EtOAc: 70% toluene, Rf: 0,59, a by-product of 2,4-dimethoxybenzaldehyde is on the chromatogram ahead of the desired product and to the right of the starting material.

Mass spectrum (FAB, m/z) 1156, 1158, 1160 (M+H), 1100, 1056, 701, 685, 105 (base), 57.

1H NMR (CDCl3TMS): 1,20 (C., 3H), 1.27mm (C., 3H), 1,35 (C., 9H), 1,85 (C. , 3H), 1,95 (C., 3H), 2,35 (C., 3H), 3,41 (d, 1H), 3,90 (D., 1H), 4,17 (D. , 1H), 4,33 (D., 1H), 4,60 and 4.93 (2D., 2H), 4,62 (CL., 1H), 4,78 (S., 2H), 4.95 points (D., 1H), 5,26 (sm., 1H), 5,42 (sm., 1H), 5,54 (DD., 1H), 5,69 (D. , 1H), 6,21 (t, 1H), 6,24 (S., 1H), 7,12 - 7,42 (m, 6H), 7,49 (t, 2H), a 7.62 (t, 1H), 8,09 (D., 2H).

Drug N 18:

Obtain 7-(2,2-dichlorocarbene)-13-(N-SIDE -- phenylisopropyl)-baccatin III (10BD),

10-(2,2-dichlorocarbene)- 13-(N-SIDE -- phenylisopropyl)-baccatin III (10BE) and

13-(N-SIDE -- phenylisopropyl)-baccatin III (10BF, Taxotere)

7,10-bis-Troc-13-(N-SIDE -- phenylisopropyl)-baccatin III (preparation N 17: 10BC) (48 mg, 0,041 mm) is stirred at comacina (85 mg). After 30 minutes there is a clouding of the reaction mixture. Add another 1 ml of a mixture of MeOH : HOAc, after which the reaction mixture becomes transparent. The results of TLC after 30 and 60 minutes look about the same, namely: no notes source material, and there are two minor product, and one more polar product in large enough quantities. After 70 minutes after the start of the reaction is filtered solid zinc. The filtrate is evaporated under vacuum. The residue is distributed between the phases of methylene chloride and water. The layers are separated and the aqueous layer was re-extracted with methylene chloride. The organic extracts washed again with water, dried over sodium sulfate, combined and evaporated under vacuum. The mixture is coarse product is applied on silica gel (1 g) and chromatographic on silica gel with 5 Column, elute with a mixture of EtOAc: hexane (100 ml 40:60, 50:50, 60:40 and 70:30). Fractions of 4 ml are collected and analyzed by TLC. The following fractions are combined and evaporated under vacuum.

Fractions 12 to 24, 10BD

Fractions 29 - 42 - 10BE

Faction 48 - 84, 10BF

Data for 10BD:

TLC (silica gel 60): 60% EtOAc: 40% hexane, Rf: 0,92.

Mass spectrum (FAB, m/z) 948, 950, 952 (M + H), 892, 848, 830, 667, 649, 105 (base), 57

1H NMR (CDCl< (doctor, 1H), 4,33 (D., 1H), 4,48 (m, 2H), 4.62, and 4,93 (2D., 2H), and 5.30 (m, 1H), lower than the 5.37 (SD, 1H), 5,46 (D., 1H), 5,68 (D., 1H), of 5.83 (t, 1H), 6,21 (t, 1H), 7,3 was 7.45 (m, 6H), to 7.50 (t, 2H), a 7.62 (t, 1H), 8,10 (D., 2H).

Data for 10BE:

TLC (silica gel 60): 60% EtOAc: 40% hexane, Rf: 0,65.

Mass spectrum (FAB, m/z) 948, 950, 952 (M+H), 892, 848, 667, 527, 509, 105 (base), 57.

1H NMR (CDCl3TMS): 1,16 (C., 3H), 1.27mm (C., 3H), 1,33 (C., 9H), 1.70 to (C. , 3H), 1,89 (C., 3H), 2,39 (C., 3H), 2.57 m (m, 1H), 3,40 (D., 1H), 3,75 (D. , 1H), 4,17 (D., 1H), 4,33 (D., 1H), 4,35 (m, 1H), 4,56 (DD., 2H), with 4.64 (m , 1H), 4.95 points (D., 1H), 5,28 (m, 1H), lower than the 5.37 (D., 1H), 5,68 (D., 1H), of 5.92 (D., 1H), 6,16 (S., 1H), and 6.25 (t, 1H), 7,20 was 7.45 (m, 6H), to 7.50 (t, 2H), to 7.64 (t, 1H), 8,10 (D., 2H).

Data for 10BF:

TLC (silica gel 60): 60% EtOAc: 40% hexane, Rf: 0,23.

Mass spectrum (FAB, m/z) 808 (M+H), 790, 752, 708, 527, 509, 105 (base), 57.

1H NMR (CDCl3TMS): 1,12 (C., 3H), 1,23 (C., 3H), 1,33 (C., 9H), 1,74 (C. , 3H), 1,84 (C., 3H), 2,37 (C., 3H), of 2.56 (m, 1H), 3,60 (CL., 1H), 3,89 (D. , 1H), 4,18 (D., 1H), 4,21 (m, 1H), 4,30 (D., 1H), 4,32 (S., 1H), 4,62 (CL., 1H), 4,94 (D., 1H), 5,23 (S., 1H), 5,28 (CL., 1H), 5,54 (D., 1H), 5,66 (D., 1H), of 6.20 (t, 1H), 7,25 was 7.45 (m, 6H), to 7.50 (t, 2H), to 7.61 (t, 1H), 8,09 (D., 2H).

Drug N 19:

Obtaining methyl ester (2R,3S)-N-carbobenzoxy -- phenylazomethine (3C)

A solution of methyl ester (2R,3S) -- phenylazomethine (2) (product No. 1, 2 mm) in pyridine containing a small amount of DMAP, cooled in an ice bath and obrabotati the reaction mixture was diluted with ethyl acetate, washed with 5% solution of sodium bisulfate, dried and evaporated. The pure product is obtained after applying chromatography on silica gel with elution with mixtures of ethyl acetate : hexane.

So pl. = 120 - 121oC.

NMR (CDCl3TMS): / 3,26 (m, 1H), 3,79 (C., 3H), 4,47 (m, 1H), is 5.06 (m, 2H), 5,27 (D., 1H), of 5.75 (m, 1H), 7,20 is 7.50 (m, 10H).

Drug N 20:

Obtaining methyl ester (4S,5R)-N - Carbobenzoxy-2-(2,4-dimetilfenil)-4-phenyl-5-oxazolidinecarboxylate acid 5Cb

Methyl ester of N-Carbobenzoxy -- phenylazomethine (product No. 19, 3C, 0.375 g, 1.14 mm), dissolved in dry THF (10 ml), treated with a solution dimethylacetal 2,4-dimethoxybenzaldehyde (4, 0,300 g, 1,42 mm) and p-toluensulfonate pyridinium (10 mg) and heated the reaction mixture to distillation THF and methanol. After distillation 1/2 THF add another 10 ml of THF and again distilled off 1/2 of the volume of the reaction mixture. The process was repeated three times. Then the reaction mixture was concentrated in vacuo and chromatographic residue on 75 g of silica gel, elwira column with a mixture of acetone : hexane (300 ml of 20:80 and 300 ml of 25:75). Fractions of 20 ml are collected and analyzed by TLC. The following fractions are combined and evaporated under vacuum.

Fractions 26 to 44, 543 mg, isomer 5Cb' (other shared components, as is Xan, Rf: 0,19.

1H-NMR (CDCl3TMS): 3,51 (CL, 3H), 3,81 (MS, 6H), 4,56 (d, 1H), 4,8 (sm, 1H), 4,94 (D., 1H), 5,54 (d, 1 H), 6,4 (CL., 2H), 6,78 (D., 3H), 7,05 is 7.50 (m, 9H).

Drug N 21:

Obtaining potassium salt of (4S,5R)-N-CBZ-2-(2,4-acid) -4-phenyl-5-oxazolidinecarboxylate acid 6Cb

Methyl ester of (4S,5R)-N-CBZ-2-(2,4-acid)-4-phenyl-5-oxazolidinecarboxylate acid (preparation N 20, 5Cb, 444 mg, 0,93 mm) dissolved in 10 ml of methanol. To the resulting solution was added water (400 μl) and potassium carbonate (200 mg, 1,45 mm). After stirring over night the reaction mixture does not remain insoluble components, and TLC data show a very small remnant of the methyl ester. The solution was concentrated in vacuo and add to the oil with water (20 ml). The solution is dried by freezing, getting 6,38 mg light white crystalline powder, containing 466 mg of the potassium salt 6Cb.

TLC: silica gel 60, 1:4 EtOAc:toluene, Rfstart.

Drug N 22:

Getting ether 7-Triethylsilyl-Baccatin III-13-(4S,5R)-N - CBZ-2-(2,4-acid)-4-phenyl-5-oxazolidinecarboxylate acid, 9CbA

Rough preparation of the potassium salt of (4S,5R)-N-CBZ-2-(2,4 - acid)-4-phenyl-5-oxazolidinecarboxylate acid (preparation N 21, 75 mg, 0,11 mm) are distributed between the phases musicheskie extracts filtered through anhydrous sodium sulfate and concentrated in vacuo, getting 51 mg of (4S,5R)-N-CBZ-2-(2,4-acid)-4-phenyl-5 - oxazolidinecarboxylate acid (7Cb).

7-Triethylsilyl-baccatin III (8A, 50 mg, 0.07 mmol) is dissolved in 700 μl of toluene. All (4S, 5R)-N-CBZ-2-(2,4-acid)-4-phenyl-5 - oxazolidinecarboxylate acid is added to a solution of CH2Cl2. To the solution was added also DCC (25 mg, 0,11 mm) and DMAP (4 mg, 0.04 mm) and heated the reaction mixture to 80oC to remove CH2Cl2. The progress of the reaction is controlled by TLC and, as shown by its data, 1.5 hours are found only very small amounts of 7-triethylsilyl-baccatin III. The reaction mixture is cooled and filtered from the slurry. The filtrate was concentrated in vacuo and chromatographic on the column with 7 g of silica gel in a mixture of 1:3 EtOAc: hexane. Column elute with 40 ml of a mixture of 1:3 EtOAc: hexane and 75 ml of a mixture of 1:2 EtOAc: hexane, collecting fractions of 3 ml of the Desired product is found in fractions 17 - 32.

Mass spectrum (FAB-High resolution)

Calculated: 1146, 4882

Found: 1146, 4915

1H-NMR (CDCl3TMS): 0,51 - 0,59 (m, 6H), from 0.88 to 0.94 (m), 1,13 (C., 3H), 1,18 (C. , 3H), 1,79 - 1,89 (m, 1H), 2,17 (C., 3H), 2.40 a - 2,50 (m, 1H), 3,67 (D., 1H), 3,80 (CL., 6H), 4,07 (D., 1 H), 4,22 (D., 1H), 4,39 (m, 1H), 4,54 (D. , 1H), 4,77 (D., 1H), 4,86 (D., 1H), 4,94 (d, 1H), 5,54 (D., 1H), 5,61 (D., 1H), 5,90 (m, 1H), 6,33 (S., 1H), gold 6.43 (m, 2H), 6,78 (m, 3H), 7,12 - 7,21 (who and III 10CA and 10-deazetil-13-(N-CBZ-phenylisopropyl)-baccatin III SW

Ether 7-Triethylsilyl-Baccatin III-13-(4S,5R)-N-CBZ-2- (2,4-acid)-4-phenyl-5-oxazolidinecarboxylate acid (9CbA, drug N 22, 630 mg, 0.55 mm) dissolved in 10 ml of 0.1 N HCl solution in methanol. a 0.1 N HCl solution prepared by dilution 71 μl acetylchloride to 10 ml with methanol followed by reaction for at least 0.5 hour. The progress of the reaction is controlled by TLC, this shows the lack of after 0.5 hours of source material. The reaction mixture was partitioned between brine, 5% solution of NaHCO3and EtOAc. The layers are separated and the organic layer is extracted with 5% solution of NaHCO3. The combined aqueous layers extracted with EtOAc and the combined organic extracts are filtered through anhydrous sodium sulfate. The solvent was concentrated in vacuo and the residue chromatographic on a column of 60 g of silica gel in a mixture of 1:1 EtOAc:hexane. Column elute with 500 ml of a mixture 1:1 EtOAc:Hexane, 250 ml of a mixture of 3:2 EtOAc:hexane, 240 ml of a mixture of 2:1 EtOAc:hexane, collecting fractions with a volume of 25 ml.

Fractions 16 -36, 13-(N-CBZ- -- phenylisopropyl)-baccatin III, 10CA.

Faction 44 - 52, 10-deazetil-13-(N-CBZ-phenylisopropyl)-baccatin III, 10CB

Data for 10CA:

Mass specr (FAB-High resolution)

Calculated: 884, 3493

Found: 884, 3490

1H-NMR (CDCl3H), 4,90 is equal to 4.97 (m, 1H), 4,94 (D., 1H), of 5.05 (D., 1H), 5,34 (D., 1H), 5,64 (D., 1H), 5,75 (D., 1H), 6,23 (m , 1H), 6,25 (S., 1H), 7,17 (CL., 2H), 7,25 (CL., 3H), 7,29 - 7,41 (m, 5H), to 7.50 (m, 2H), to 7.61 (m, 1H), 8,21 (D., 2H).

Data for 10CB

Mass spectrum (FAB-High resolution)

Calculated: 842, 3388

Found: 842, 3364

1H-NMR (CDCl3TMS): 2,37 (C., 3H), 2.57 m (m, 1H), 3,40 (D., 1H), a 3.87 (D. , 1H), 4,18 - 4,32 (m) and 4.65 (CL., 1H), 4.92 in (D., 1H), 4.95 points (D., 1H), 5,06 (D. , 1H), 5,18 (S., 1H), 5,35 (D., 1H), 5,65 (D., 1H), 5,78 (D., 1H), 6,20 (m , 1H), 7,18 (m, 1H), 7,22 - 7,46 (m), to 7.50 (m, 2H), to 7.61 (m, 1H), 8,11 (D., 2H).

Drug N 24:

13 -(- phenylisopropyl)-baccatin III (IIA) from 13-(N-CBZ-phenylisopropyl)-baccatin III (10CA)

405 mg (0.45 mm) 13-(N-CBZ-phenylisopropyl)-baccatin III (preparation N 23, 10CA) was stirred at room temperature and hydrogenizing at atmospheric pressure in the presence of 40 ml of absolute ethanol and 100 mg of 10% Pd/C (palladium on coal). The reaction, monitored by TLC, ends in 5 hours.

The reaction mixture was filtered through Celite and washed with ethyl acetate. The combined filtrate and wash the mixture is evaporated under vacuum. The residue is treated with a small amount of ethyl acetate and a few large amount of hexane and evaporated twice more. 13 -(- phenylisopropyl)-baccatin III (11A) are obtained in the form of a white solid Veh">

1H-NMR (CDCl3TMS): 1,13 (C., 3H), 1,24 (C., 3H), 1,66 (C., 3H), 1,88 (C., 3H), 2,23 (C., 3H), 2,24 (C., 3H), 2,45 - 2,61 (m, 1H), 3,75 (D., 1H), 4,14 (D., 1H), 4,23 - to 4.33 (m, 3H), and 4.40 (m, 1H), 4,93 (D., 1H), 5,63 (D., 1H), 6,13 (t, 1H), 6,27 (S., 1H), 7,26 (m, 1H), 7,39 (D., 4H), 7,52 (t, 2H), 7,65 (t, 1H), 8,06 (D., 2H).

Drug N 25:

Obtaining ester (2R, 3S)-N-(2,2,2-trichlorocyanuric) -- phenylazomethine (3D)

Following the General procedure of obtaining the drug N 19 (methyl ester (2R, 3S)-N-carbobenzoxy -- phenylazomethine (3C)), but from the reaction of acylation of methyl ester -- methylisourea (2) by using 2,2,2-trichlorocarbanilide get the desired methyl ether N-(2,2,2-trichlorocyanuric) -- phenylazomethine (3D).

Drug N 26:

Obtaining methyl ester (4S, 5R)-N-(2,2,2-trichlorocyanuric)-2-(2,4-acid)-4-phenyl-5-oxazolidinecarboxylate acid 5Da and 5Db

Following the General procedure 20 (receipt methyl ester (4S, 5R)-N-Carbobenzoxy-2-(2,4-acid)-4-phenyl-5 - oxazolidinecarboxylate acid (5Cb), but starting the reaction with methyl ester 2,2,2-trichlorocyanuric -- phenylazomethine (3D), get your desired product methyl ether (4S, 5R)-N-(2,2,2 - trichlorocyanuric)-2-(2,4-acid)-4-phenyl-5 - oxazolidinecarboxylate acid (5Da and 5Db)

Drug N 27:

Received (6Da and 6Db)

Following the General procedure of obtaining the drug N 21 (potassium salt of (4S, 5R)-N-carbobenzoxy-2-(2,4-acid)-4-phenyl-5 - oxazolidinecarboxylate acid (6Cb), but starting the reaction with methyl ester (4S,5R)-N-(2,2,2-trichlorocyanuric) 2-(2,4-acid)-4-phenyl-5-oxazolidinecarboxylate acid (5Da and 5Db), get the required product - potassium salt of (4S, 5R)-N-(2,2,2 - trichlorocyanuric)-2-(2,4-acid)-4-phenyl-5 - oxazolidinecarboxylate acid ( 6Da and 6Db).

Drug N 28:

Getting ether 7-Triethylsilyl-Baccatin III-13-(4S, 5R)-N-2 (2,2,2-trichlorocyanuric)-2-(2,4-acid)-4 - phenyl-5-oxazolidinecarboxylate acid (9DaA, 9DbA)

Following the General procedure of obtaining the drug N 22 (ether 7-Triethylsilyl-baccatin-III-13-(4S, 5R)-N-CBZ-2-(2,4-acid) -4-phenyl-5-oxazolidinecarboxylate acid, 9CbA), but starting the reaction with (4S,5R)-N-(2,2,2-trichlorocyanuric)-2-(2,4-acid)-4 - phenyl-5-oxazolidinecarboxylate acid (6Da, 6Db), get the desired ether 7-Triethylsilyl-Baccatin III-13-(4S,5R)-N-2-(2,2,2 - trichlorocyanuric)-2-(2,4-acid)-4-phenyl-5 - oxazolidinecarboxylate acid (9DaA, 9DbA).

Drug N 29:

13-(N-(2,2,2-trichlorocyanuric) -- phenyl-azaserine)baccatin III (10DA)

Following the General procedure of obtaining ven is akkarin III-13-(4S,5R)-N-2-(2,2,2 - trichlorocyanuric)-2-(2,4-acid)-4-phenyl-5 - oxazolidinecarboxylate acid (9Da, 9Db), get the required product - 13-(N-(2,2,2-trichlorocyanuric) -- phenyl-azaserine)-baccatin III (10DA).

Drug N 30:

13 -(- phenyl-azaserine)-baccatin III (11A) from 13-(N- (2,2,2-trichlorocyanuric) -- phenyl-azaserine)-baccatin III (10DA)

13 -(- (2,2,2-Trichlorocyanuric) -- phenyl-azaserine)-baccatin III (preparation No. 29, 10DA, 1 g) is dissolved in methanol 950 ml), and the solution was treated with zinc powder (2 g) and ammonium chloride (2 g) under stirring at room temperature. After stirring for 3 hours the reaction mixture is filtered and the filtrate is evaporated under vacuum (less than 20 mm RT.cent.). The residue is distributed between ethyl acetate and 5% aqueous sodium bicarbonate solution. The organic layer is separated, dried (sodium sulfate) and concentrate under vacuum to obtain the desired product 13 -(- phenyl-azaserine)-baccatin III (11A).

Drug N 31:

13-(N-SIDE -- phenylisopropyl)-baccatin III (10BA)

68 mg (0.09 mm) 13 -(- phenyl-azaserine)-baccatin III (preparation N 24, 11A) is stirred at room temperature in a nitrogen atmosphere in 0.5 ml of dry THF. To this mixture is added 20 mg (0,092 mm) of di-t-butyl bicarbonate in 0.2 ml of dry THF and of 0.013 ml (0,093 mm) of triethylamine. The mixture is left for the PE the second mixture is distributed between ethyl acetate and brine. The layers are separated and the aqueous layer was subjected to re-extraction with ethyl acetate. The organic extracts are combined dried over sodium sulfate and evaporated under vacuum.

The coarse product chromatografic on 10 g of silica gel, elwira a mixture of 60:40 ethyl acetate: hexane. Fractions of 2 ml are collected and analyzed by TLC. Faction 12-30 containing the desired product are combined and evaporated under vacuum. This procedure gives the desired connection - 10AB - in the form of a white solid.

TLC: silica gel 60, 60:40, EtOAc: hexane, Rf: 0,46.

1H NMR (CDCl3TMS) to 1.15 (SD, H), 1,33 (C., 9H), 1,85 (C., 3H), 2,25 (C., 3H), 2,30 (m), of 2.38 (SD, 3H), 2,54 (MT), 3.46 in (D., 1H), 3,80 (D., 1H), 4,17 (D., 1H), or 4.31 (D., 1H), to 4.41 (m, 1H), 4.63 to (CL., 1H), 4.95 points (D., 1H), 5,28 (sm, 1H), 5,42 (sm., 1H), 5,67 (D., 1H), 6,24 (t, 1H), 6,29 (S., 1H), 7,18 (D., 1H), 7,38 (m, 5H), to 7.50 (t, 2H), a 7.62 (t, 1H), 8,10 (D., 2H).

Example N 32:

13-(N-(1-adamantoyl) -- phenylisopropyl)-baccatin III (10EA)

44 mg (0.06 mm) 13 -(- phenylisopropyl)-baccatin III (preparation N 24; 11A) is stirred at a temperature of 0oC in nitrogen atmosphere in 1 ml of dry pyridine. To this mixture is added 0.2 ml of methylene chloride containing 13 mg (0.06 mmol) of 1-adamantane-carbonylchloride. 30 minutes after start of the reaction, TLC shows that the reaction is completely the head of the new solution, dried over sodium sulfate and evaporated under vacuum.

The remainder chromatographic on 5 g of silica gel, elwira mixture 65:35 EtOAc: hexane. Fractions of 2 ml are collected and analyzed by TLC. The desired product find in fractions 8-23, which are combined and evaporated, receiving 33 mg (60% yield) of a white solid. Data spectral analysis still showed some presence of 1-adamantanecarbonyl acid.

The crude product is dissolved in 1 ml swietojanska THF. Then add excess diazomethane and leaving the reaction mixture for 30 minutes. After that the reaction mixture is evaporated under vacuum and chromatographic, as described above. Pure product find in fractions 6-25, which is evaporated, receiving 13-(N-(1-adamantoyl) -- phenylisopropyl)-baccatin III IOEA in the form of a solid substance.

TLC: silica gel 60, 50:50, EtOAc:hexane, Rf:0,48.

Mass spectrum (FAB, m/z): (M+H) measured at 912, 4168, the calculation for C51H62N1O14is 912, 4170; 912, 852, 834, 569, 551, 509, 344, 326, 298, 268, 180, 135, 105

1H NMR (CDCl3TMS): 1,16 (C.), 1.27mm (C.), 1,60 - 2,10 (m), 2,24 (C., 3H), 2,30 (m), 2,36 (C., 3H), 2,52 (m), 3,54 (D., 1H), of 3.77 (D., 1H), 4,18 (D. , 1H), 4,29 (D., 1H), and 4.40 (m, 1H), and 4.68 (m, 1H), 4,94 (D., 1H), 5.56mm (DD. , 1H), 5,68 ((N-(3-tetrahydropyranyloxy) -- phenyl-azaserine)-baccatin III (10FA)

13 -(- Phenyl-azaserine)-baccatin III (preparation N 24: IIA, 16,8 mg, 0,022 mm) handle racemic mixture of 3-tetrahydroprotoberberine (5.0 mg, 0,023 mm), pyridine (5 ml) and methylene chloride (180 μl). The reaction mixture was stirred at room temperature for 2 days. Then it is diluted with ethyl acetate and washed with 5% aqueous solution of sodium bisulfate and 5% aqueous sodium bicarbonate solution. The organic solution is dried and evaporated, obtaining a mixture of diastereomers of 13-(N-(3-tetrahydropyranyloxy) -- phenylisopropyl)-baccatin III (10FA).

TLC: silica gel 60; 50:40 acetone:hexane: Rf:0,16.

1H NMR (CDCl3TMS): 1,16 (C.), 1.27mm (C.), of 1.66 (SD+m) and 1.83 (C.), 1,90 (m ), of 2.25 (SD+m), 2,37 (C.), to 2.55 (m), 3,7 - 4,0 (m), 4,18 (D., 1H), 4,30 (D., 1H), 4,43 (m, 1H), with 4.64 (m, 4H), of 4.95 (DD., 1H), 5,09 (m, 1H), and 5.30 (m , 1H), 5,67 (m, 2H), 6,28 (C.+ m, 2H), 6,39 (m, 5H), to 7.50 (t, 2H), 7.62mm (m, 1H), 8,12 (D., 2H).

Drug N 34:

13-(N-(4-tetraphenylsilane) -- phenylisopropyl)-baccatin III (10GA)

13 -(- Phenyl-azaserine)-baccatin III (preparation N 24, 11A, 10 mg, 0,013 mm) is treated with 4-tetrahydroprotoberberine (3,3 mg of 0.014 mm), pyridine (5 ml) and methylene chloride (100 ml). The mixture is stirred over night at room temperature. Then reactio is sodium carbonate. An ethyl acetate solution is dried and evaporated, getting to 10.3 mg of the crude product. Cleaning chromatographytandem on a column of silica gel in a mixture (40:60) acetone:hexane gives pure 13-(N-(4-tetraphenyl-oxycarbonyl) -- phenylisopropyl)-baccatin III (10GA).

TLC:silica gel 60, 40:60 acetone:hexane, Rf:0,17.

1H NMR (CDCl3TMS) : 1,15 (C), 1.27mm (C.), 1,5 - 1,8 (m), 1,68 (C.), 1,84 (C.), 1,89 (m), of 2.1 - 2.4 (m in), 2.25 (C., 3H), 2,41 (C., 3H), 2.49 USD (D. , 1H), to 2.55 (m, 1H), is 3.08 (m, 1H), 3.27 to (m, 1H), 3.33 and (D., 1H), 3,70 (m, 1H), 3,80 (D. + m,2H), 4,16 (D., 1H), 4,29 (D., 1H), 4,42 (m, 1H), 4,66 (m , 2H), 4,94 (D., 1H), 5,33 (m, 1H), 5,67 (m, 1H), 5,65 (D. 1H), 6,28 (C. + m, 2H) 7,37 (m, 5H), 7,51 (m, 2H), to 7.61 (m, 1H), 8,14 (D., 2H).

Drug # 35:

13-(N-(tert-butylacetyl) -- phenylisopropyl)-baccatin III (10HA) and

2'-t-butylacetyl-13-(N-(tert. -butylacetyl) -- phenylisopropyl)-baccatin III (12CA)

51 mg (0,068 mm) 13 -(- phenylisopropyl)-baccatin III (preparation N 24; 11A) is stirred in nitrogen atmosphere at a temperature of 0oC in 1 ml of dry pyridine, 0.01 ml (9.1 mg, 0,068 mm) of tert-butylacetamide dissolved in 0.1 ml of methylene chloride. This solution is added dropwise to the original amine. The mixture is left to react at a temperature of 0oC for 3 hours and placed overnight in the freezer.

The reaction mixture is diluted with etelaat the Organic extracts are combined dried over sodium sulfate and evaporated under vacuum.

The crude product chromatographic 7 g of silica gel, elwira a mixture of 50: 50 and 70:30 EtOA:hexane. Fractions of 2 ml are collected and analyzed by TLC. The following fractions are combined and evaporated under vacuum.

Faction 11-21, crude 2'-t-butylacetyl-13-(N-(tert-butylacetyl) -- phenylisopropyl)-baccatin III - (12CA)

Faction 22-45, 13-(N-tert-butylacetyl) -- phenylisopropyl)baccatin III (10HA) in the form of a white solid.

12CA, still representing the crude product is re-chromatographic on 3 g of silica gel, elwira a mixture of 10:90 acetone:methylene chloride. Fractions of 1 ml are collected and analyzed by TLC. Faction 11-28 containing the desired product are combined and evaporated under vacuum, obtaining pure 2'-t-butylacetyl-13-(N-(tert-butylacetyl) -- phenylisopropyl)-baccatin III (12CA) as a white solid.

Data for 12CA:

TLC: silica gel 60: 60:40 ethyl acetate:hexane, Rf: 0,70.

Mass spectrum (FAB, m/Z): (M+H) measured at 946, 4618,

the calculation for C52H68N1O15is 946, 4589, 946, 509, 378, 360, 280, 262, 234, 105, 99, 57, 43.

1H NMR (CDCl3TMS) : 0,98 (C.), 1,28 (C., 3., 1H), of 6.31 (SD, 1H), 7,28 was 7.45 (m, 5H), 7,51 (t, 2H), to 7.61 (t, 1H), 8,11 (D., 2H).

Data for 10HA:

TLC: silica gel 60: 60:40 ethyl acetate:hexane; Rf:0,27

Mass spectrum (FAB, m/Z): (M+H) measured at 848, 3863

the calculation for C46H58N1O14is 848, 3857, 848, 830, 788, 770, 569, 551, 509, 280, 262, 234, 182, 136, 115, 105, 99, 57, 43.

1H NMR (CDCl3TMS): 0,97 (C.), 1,26 (C., 3H), 2,24 (C., 3H), 2,33 (C. , 3H), 2,52 (m, 2H), 3,60 (D., 1H), 3,78 (D., 1H), 4,18 (D., 1H), 4,29 (D., 1H), 4,39 (m, 1H) and 4.65 (m, 1H), 4,93 (D., 1H), 5,55 (DD, 1H), 5,67 (D., 1H), to 6.19 (t, 1H), 6,28 (S., 1H), 7,39 (m, 5H), to 7.50 (t, 2H), a 7.62 (t, 1H), 8,10 (D., 2H).

Drug N 36:

13-(N-(pivaloyl) - phenylisopropyl)-baccatin III (10IA)

44 mg (0.06 mm) 13 -(- phenylisopropyl)-baccatin III (preparation N 24, 11A) is stirred at a temperature of 0oC in nitrogen atmosphere in 1 ml of dry pyridine. To this mixture is added over 5 minutes a solution of 8 mg (0.06 mm) trimethylacetylchloride in 0.2 ml of methylene chloride. 30 minutes after start of the reaction TLC shows that a large part of the amine reacted.

The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated under vacuum.

The coarse product chromatografic on 5 g of silica gel, elwira mixture 65:35 which are combined and evaporated under vacuum, getting the desired connection.

Data spectral analysis shows the presence in the product of a small number trimethylhexanoic acid. Therefore, the product is dissolved in ethyl acetate, washed with 5% sodium bicarbonate solution, dried over sodium sulfate and evaporated under vacuum. This gives 101A in the form of a white solid.

TLC: silica gel 60; 50:50 EtOAc: hexane, Rf: 0,29.

Mass spectrum (FAB, m/z): (M+H) measured at 834, 3712,

the calculation for C45H56N1O14is 834, 3700, 834, 816, 774, 569, 551, 509, 387, 327, 266, 248, 220, 190, 105, 57.

1H NMR (CDCl3TMS) : 1,16 (C.), 1,23 (C.), 2,23 (C., 3H), 2,29 (d, 1H), 2,35 (C., 3H), of 2.51 (m, 1H), of 3.77 (D., 1H), 4,17 (D., 1H), 4,28 (D., 1H), to 4.38 (m, 1H), 4,68 (D., 1H), 4,93 (D., 1H), 5.56mm (DD., 1H), 5,66 (D., 1H), 6,17 (m , 1H), 6,28 (S.,1H), 6,54 (D.,1H), 7,35 (m, 5H), 7,49 (m, 2H), 7,60 (m,1H), 8,10 (D., 2H).

Drug N 39:

Getting 7-fluoro-13-(N-CbZ-phenyl-azaserine)-baccatin III (18) of 7-fluoro-13-(N-CbZ-phenyl-azaserine)-2-Troc-baccatin III(13BA)

A solution of 7-fluoro - 13-(N-CbN -- phenyl-azaserine)-2'- Troc-baccatin III (13BA, example 3) (0,079 g) in a mixture of 9:1 methanol/acetic acid (20 ml) and ethyl acetate (8 ml) is stirred with activated zinc (0,153 mg) at room temperature for two hours. After that, the obtained crude product Hrol)-baccatin III(18): mass spectrum 886, 571, 511, 371, 347, 329, 316, 298, 105, 91 m/z.

Drug N 40:

Getting 7-fluoro-13 -(- phenylisopropyl)-baccatin III (19)

23,5 mg (0,027 mm) 7-fluoro-13- (N-CbZ-phenyl-azaserine) baccatin III(18) (product No. 39, 18) is dissolved in 3 ml of absolute ethanol, treated with the resulting solution of 7 mg of 10% palladium on coal (Pd/C) and hydrogenizing at atmospheric pressure and room temperature for 4.5 hours. The disappearance of the starting material followed by means of TLC. The reaction mixture was filtered through Celite, washing the Celite with ethyl acetate. The combined filtrate and washing liquid is evaporated under vacuum. The residue is twice treated with a mixture of ethyl acetate:hexane and evaporated under vacuum. These procedures yield 7-fluoro-13 -(- phenyl-azaserine)-baccatin III (19) in the form of a white solid.

TLC: silica gel 60, 50:50 ethyl acetate:hexane, Rf: 0,11.

1H NMR (CDCl3TMS): 2,20 (C., 3H), 2.26 and (c. 3H), of 2.54 (m, 1H), 3,99 (D. , 1H), 4,24 (D., 1H), 4,27 was 4.42 (m, 3H), 4,55 (DD., J =48 Hz, 1H), 4,99 (d,1H), 5,72 (D., 1H), 6,11 (m, 1H), 6,55 (c. 1H), 7,27 (c. 1H), 7,39 (m , 4H), 7,51 (m,2H), to 7.64 (m, 1H), 8,08 (D.,2H).

Drug N 41:

Getting 7-fluoro-13-(N-SIDE -- phenylisopropyl)-baccatin III (20) and

7-fluoro-2'-BOC-13-(N-SIDE -- phenylisopropyl)-baccatin III(13CA)

0,027 mm 7-fluoro-13 -(- phenyl what th temperature in nitrogen atmosphere. Then add 6 mg (0,027 mm) of di-tert-butylboronic and 0,004 m (0.029 mm) of triethylamine. Mixture to reaction for 20 hours.

The reaction mixture is distributed between ethyl acetate and brine. The layers are separated and the aqueous layer was subjected to re-extraction with ethyl acetate. The organic extracts are combined dried over sodium sulfate and evaporated under vacuum.

The mixture of products chromatographic on 3 g of silica gel, elwira mixture 30:70 ethyl acetate: hexane to exit the column first product, passing then to a mixture of 50:50 ethyl acetate:hexane. The following fractions are combined and evaporated, getting a white solid.

Fractions 16-30, 13CA

Faction 32-46, 20

Data for 13CA:

TLC: silica gel 60, 50:50 ethyl acetate:hexane, Rf:0,83.

Mass spectrum (FAB, m/z) 952 (M+H), 878, 822, 778, 571, 511, 389, 329, 106, 162, 105, 57.

1H NMR (CDCl3TMS): 1,17 (c. 3H), 1,24 (c. 3H), 1,25 (c. 9H), 1,90 (c. 9H), 2,08 (c. 3H), 2,22 (c. 3H), 2,0-2,7 (m,4H), was 4.02 (D., 1H), 4,24 (D. , 1H), 4,36 (D., 1H), 4,59 (DD., J=48 Hz, J = 5 Hz, 1H), 4,77 (CL., 1H), 5,02 (D., 1H), 5,22 (CL., 1H), of 5.68 (m, 1H), 5,77 (D., 1H), 6,27 (m, 1H), 6,57 (S.,1H), 7,27-of 7.70 (m, 9H), 8,09 (D.,2H).

Data for 20:

TLC: silica gel 60, 50:50 ethyl acetate:hexane, Rf:0,54.

Mass spectrum (FAB, m/z): (M+H) measured at 8x2">

1H NMR (CDCl3TMS): 1,17 (c. 3H), 1,23 (C., 3H), 1,34 (C., 9H), 2,22 (C. , 3H), 2,39 (C.,3H), 2,0 - 2,7 (m, 4H), to 3.36 (m, 1H), 4.04 the (doctor, 1H), 4,28 (D. , 1H), 4,37 (D., 1H), 4,48-and 4.68 (m, 2H), 5,01 (D., 1H), and 5.30 (m, 1H), the 5.45 (m, 1H), 5,76 (D., 1H), 6,21 (m, 1H), 6,56 (S., 1H), 7,30-of 7.70 (m, 9H), 8,13 (D., 2H).

Drug N 42:

13-(N-Benzyloxycarbonyl -- phenyl-azaserine)-7-deoxy-7,8 - methanobactin III (21) from 13-(N-Benzyloxycarbonyl -- phenyl-azaserine)-2'-Troc-7-deoxy-7,8 - methanobactin III (14BA)

A solution of 13-(N-benzyloxycarbonyl -- phenyl-azaserine) -2' -Troc-7-deoxy-7,8 - methanobactin III (14BA example 3) (0,040 g) in a mixture of 9:1 methanol/acetic acid (10 ml) was stirred at room temperature with activated zinc (0,144 g) for 3 hours. The resulting crude reaction product chromatographic on silica gel by elution with 40% EtOAc in hexane, obtaining in the end, 13-(N-Benzyloxycarbonyl -- phenyl-azaserine)-7-deoxy-7,8 - methanobactin III (21):

mass spectrum

Found: 866, 3423, C48H51NO14+H requires 866, 3388, 848, 806, 788, 551, 533, 491, 105, 91 m/z.

Drug N 43:

13 -(- phenylisopropyl)-7-deoxy-7,8 - methanobactin III (22)

14 mg (0,016 mm) 13-(N - Benzyloxycarbonyl -- phenylisopropyl)-7-deoxy-7,8 - methanobactin III (preparation No. 42, 21) dissolved in 2 atmosfernom pressure for 6 hours. The progress of the reaction is followed by TLC and when complete, filter the mixture through Celite, rinsing it with ethyl acetate. The filtrate and washing liquid are combined and evaporated under vacuum. Double-add a mixture of ethyl acetate: hexane and re-evaporation, receiving 22 as a white solid. After storage in the freezer over night it is used for the preparation of N 44.

TLC: silica gel 60, 50:50, EtOAc:hexane, Rf: the band from the start a few up over the plate.

1H NMR (CDCl3TMS): 5,62 (D., 1H), 6,11 (t, 1H), of 6.31 (SD, 1H), 7,39 (m), 7,53 (m, 2H), 7,66 (m, 1H), 8,08 (D., 2H).

Drug N 44:

13- (N-SIDE -- phenylisopropyl)-7-deoxy-7,8 - methanobactin III (23) and 13- (N-BOC-2'-SIDE-- -phenylisopropyl)-7-deoxy-7,8 - methanobactin III (14CA)

0,016 mm 22 (preparation 44) is dissolved with stirring in nitrogen atmosphere of 0.12 ml of dry THF. To this mixture is added 3.5 mg (0,016 mm) of di-t-butylboronic in 0.05 ml of dry THF and 0.0025 ml (0.018 mm) of trimethylamine in 0,015 ml of dry THF. The mixture is left to react for 27 hours, after which TLC indicates almost complete reaction.

The reaction mixture is distributed between ethyl acetate and brine. The layers are separated and Vodytsia and evaporated under vacuum.

A mixture of crude products chromatographic on 3 g of silica gel. The elution is carried out in a gradient from 30:70 to 50:60 mixture of EtOAc:hexane. Fractions of 1 ml are collected and analyzed by TLC. The following fractions are combined and evaporated, getting a white solid.

Fractions 16-30, 14CA

Faction 33-53, 23

23 is not a pure product, in connection with which it is subjected to repeated chromatographicaliy on 1 g of silica gel, conducting elution in a gradient from 40:60 to 50:50 mixture of EtOAc:hexane. Fractions of 0.5 ml are collected and analyzed by TLC. Pure product is found in fractions 11-20, which are combined and evaporated under vacuum, obtaining the result desired product in the form of 4 mg of a white solid.

Data for 14CA:

TLC: silica gel 60, 50:50, EtOAc:hexane, Rf:0,87.

Mass spectrum (FAB, m/z) 858, 803, 798, 551, 491, 369, 327, 206, 105, 57.

1H NMR (CDCl3TMS) : 1,25 (C.), 2,01 (C., 3H), 2,21 (C., 3H), 2,43 (m ), 4,01 (D., 1H), 4,07 (D.,1H), 4,28 (D., 1H), 4,70 (m, 2H), 5,18 (SHS. 1H), 5,64 (m,2H), and 6.25 (m, 1H), 6,33 (S.,1H), 7,39 (C.,5H), 7,51 (m,2H), to 7.64 (m, 1H), 8,09 (D.,2H).

Data for 23:

TLC: silica gel 60, 50:50 EtOAc: hexane, Rf:0,77.

Mass spectrum (FAB, m/z):(M+H) measured: 832, 3588, the calculation for C45H54N1O14is 832, 3H), of 2.26 (m), 2,39 (C., 3H), 2,47 (m), 3,30 (m, 1H), 4,06 (m ,2H), or 4.31 (D.,1H), 4,63 (m,1H), 4,74 (D.,1H), and 5.30 (m, 1H), are 5.36 (D., 1H), 5,66 (D.,1H), 6,28 (m,1H), 6,33 (S., 1H), 7,37 (m,5H), 7,51 (m, 2H), to 7.61 (m,1H), 8,15 (D.,2H).

Drug N 45:

13- (N-prilocaine -- phenyl-azaserine)-baccatin III; 13 -(- phenylisopropyl)-baccatin III N-phenylacetone (10JA)

48 mg (0,064) 13 -(- Phenyl-azaserine)-baccatin III (preparation N 24 11A) is dissolved in 700 μl of THF and added dropwise to 6.5 μl (0.060mm) phenylisocyanate. TLC does not detect amine in the reaction mixture. The solution was diluted with EtOAc and extracted with saturated CuSO4. The organic phase is filtered through Na2SO4, concentrated in vacuo and chromatographic on a column of 5 g of silica gel in the mixture: 1:1 EtOAc:hexane. Column elute sequentially with 20 ml 1:1 EtOAc:hexane, 20 ml of 3:2 EtOAc:hexane and 20 ml of 2:1 EtOAc:hexane, collecting fractions of 3 ml of the Desired products are in fractions 17-31.

Mass spectrum (FAB-high resolution)

Calculated: 869, 3512

Found: 869, 3512

1H NMR (CDCl3TMS) : of 1.13 (s, 3H), 1,19 (s, 3H), 1,81 (C., 3H), 2,19 (C. , 3H), and 2.27 (m), is 2.37 (s, 3H), of 2.51 (m, 1H), 2,66 (m, 1H), 3,76 (D., 1H), 4,18 (D., 1H), 4,28 (D., 1H), 4,37 (m, 1H), 4,67 (m, 1H), 4,93 (D., 1H), 5,49 (DD., 1H), 5,67 (D., 1H), 6,21 (m, 1H), 6,27 (S., 1H), 6,93 (m, 2H), 7,07 (m, 2H), 7,19 (m, 3H), 7,26-7,40 (m), of 7.48 (m, 1H), 7,60 (m, 1H), 8,10 (D., 2H).

Drug N 46:

P IS/BR> N-desbenzoyl-N-(t-butyl)aminocarbonyl-Taxol (51 mg, 0.07 mmol). Drug N 24, 11A) is dissolved in 700 μl of THF and add 7 µg (0,061 mm) t-utilizationof. TCX detects the presence of amine in the reaction mixture, so add another 3 ml. This procedure is repeated twice more (3 µl and 4 µl) up until TCX will not show a very small amount of residual amine. The solution was concentrated in vacuo and chromatographic on a column of 5 g of silica gel in a mixture of 1: 1 EtOAc:hexane. Column elute sequentially with 50 ml 1:1 EtOAc: hexane, 25 ml of 3: 2 EtOAc:hexane and 25 ml of 2:1 EtOAc:hexane, collecting fractions of 3 ml of the Desired product is found in fractions 21-40.

Mass spectrum (FAB-High resolution)

Calculated: 849, 3809

Found: 849, 3809

1H NMR (CDCl3TMS) : 1,14 (C., 3H), 1,22 (C.), 1,24 (C.) and 1.83 (C., 3H), 2,23 (C., 3H), 2,44 (C., 3H), of 2.50 (m, 1H), of 3.77 (D., 1H), 4,17 (D., 1H), 4,29 (D., 1H), to 4.38 (m, 1H), br4.61 (m, 1H), 4,94 (D., 1H), from 5.29 (m, 2H), 5,67 (D., 1H), 6,18 (m, 1H), 6,29 (c. 1H), 7,33 (m, 5H), 7,49 (m, 1H), to 7.61 (m, 1H), 8,09 (D., 2H).

Drug N 47:

13-(N-1-methyl-1-cyclohexane -- phenyl-azaserine)- baccatin III 13-(N-(1-methyl-1-cyclohexanol) -- phenyl-azaserine)- baccatin III (10MA)

30 mg (0.04 mm) 13 -(- phenyl-azaserine)-baccatin III (preparation N 24, 11A) is dissolved in 400 μl of pyridine and cooled to 0oC. Immediately after otak as TCX then show the presence of some amount of remaining amine, add 10 ál of the above solution. After this, TCX shows a small amount of residual amine. Then the reaction mixture was diluted with EtOAc and extracted with saturated CuSO4. The organic phase is filtered through Na2SO4, concentrated in vacuo and chromatographic on the column with 3 g of silica gel in a mixture of 1:1 EtOAc:hexane. For elution is used sequentially with 50 ml 1:1 EtOAc:hexane and 20 ml of 3:2 EtOAc:hexane, collecting fractions of 2 ml of the Desired product is found in fractions 11-28.

Mass spectrum (FAB-high resolution)

Calculated: 874, 4013

Found: 874, 4011

1H NMR (CDCl3TMS) : 1,12 (C., 3H), 1,15 (C., 3H), 1.26 in (C., 3H), 1,81 (C. , 3H), of 1.87 (m, 3H), 2,24 (C., 3H), 2,36 (C., 3H), of 2.54 (m, 1H), 3,78 (D. , 1H), 4,18 (D., 1H), 4,29 (D., 1H), and 4.40 (m, 1H), 4,70 (D., 1H), 4,94 (doctor, 1H), 5,61 (DD., 1H), 5,67 (D., 1H), to 6.19 (m, 1H), 6,28 (S., 1H), 6,51 (D. 1H), 7,38 (m, 5H), to 7.50 (m, 2H), to 7.61 (m, 1H), 8,11 (D., 2H)

Drug N 48:

13-(N-1-phenyl-1-cyclopentane -- phenyl-azaserine)- baccatin III 13-(N-(1-phenyl-1-Cyclopentanol) -- phenyl - azaserine)-baccatin III (10NA)

26 mg (0,035 mm) 13 -(- phenyl-azaserine)-baccatin III (preparation N 24, 11A) is dissolved in 400 μl of pyridine and cooled to 0oC. Immediately after cooling, add 20 ál (0,033 mm) solution of 350 mg/ml 1-phenyl-1-cyclopentanecarbonitrile in CH2Cl4. The organic phase is filtered through a NaSO4, concentrated in vacuo and chromatographic on a column of 3 g of silica gel in a mixture of 1:1 EtOAc:hexane. For elution is used sequentially with 50 ml 1:1 EtOAc:hexane and 20 ml of 3:2 EtOAc:hexane, collecting fractions of 2 ml of the Original product is found in fractions 12-29.

Mass spectrum (FAB - high resolution)

Calculated: 922, 4013

Found: 922, 4022

1H NMR (CDCl3TMS) : 1,16 (C., 3H), 1.27mm (C., 3H), 1.77 in (C., 3H), 1.60-to 2,10 (m in), 2.25 (C., 3H), 2,35 (C., 3H), 2,25-to 2.65 (m in), 3.75 (D., 1H), 4,19 (D. , 1H), 4,28 (D., 1H), to 4.38 (m, 1H), 4,59 (D., 1H), 4.92 in (D., 1H), 5,49 (DD., 1H), 5,66 (D., 1H), 6,10 (m, 2H), 6,26 (S., 1H), was 7.08 (m, 2H), 7,29 (m), 7,53 (m, 2H), 7,63 (m, 1H), 8,12 (D., 2H).

Drug N 49:

13-(N-phthalimide -- phenyl-azaserine)-baccatin III 13 -(- phenyl-azaserine)-baccatin III N-phthalimide (10PA)

29 mg (0.04 mm) 13 -(- phenyl-azaserine)-baccatin III (preparation N 24, 11A) is dissolved in 400 μl of pyridine and 15 mg (0.07 mmol) of carbamaxepine. The progress of the reaction is controlled using TCX showing through 72 hours total absence of amine. Next, the reaction mixture was diluted with EtOAc and extracted with saturated CuSO4. The organic phase filter is:1 EtOAc: hexane. For elution is used sequentially with 20 ml 1:1 EtOAc:hexane, 20 ml of 3: 2 EtOAc:hexane, 20 ml of 2:1 EtOAc:hexane and 20 ml of 4:1 EtOAc:hexane, collecting fractions of 2 ml of the Desired product is found in fractions 16-28.

1H NMR (CDCl3: TMS) : 1,09 (C., 3H), 1,16 (C., 3H), 1,81 (C., 3H), 2,21 (C. , 3H), 2,44 (C., 3H), 2,52 (m, 2H), 3,76 (D., 1H), 4,15 (D., 1H), 4,28 (D. , 1H), to 4.41 (m, 2H), 4,96 (D., 1H), 5,31 (m, 1H), 5,61 (D., 1H), 5,76 (doctor , 1H), between 6.08 (m, 1H), 6,24 (S., 1H), 7.23 percent (m, 1H), was 7.36 (m, 2H), 7,52 (m, 4H), 7,66 (m, 1H), 7,80 (m, 4H), 8,10 (D., 2H).

Drug N 50:

Obtaining N-desbenzoyl-N-(t-butyl)iminodicarboxylate (10LA)

24 mg (0,032 mm) 13 -(- phenyl-azaserine)-baccatin III (preparation N 24, 11A) is stirred at room temperature in a nitrogen atmosphere in 0.2 ml of dry THF. Then add 4 ál (0,032 mm) t-butyl-isothiocyanate. After 5 hours the TLC results show that the reaction is not completed. Add 4 μl of t-butyl-isothiocyanate and the reaction proceeds during the night. The crude product is applied onto 0.5 g of silica gel and chromatographic on 3 g of silica gel by elution of a mixture of 60:40 ethyl acetate:hexane. Fractions of 1 ml are collected and analyzed by TLC. Faction 7-20 containing the desired product are combined and evaporated under vacuum, obtaining the desired product.

TLC: silica gel 60, 60:40, EtOAc:hexane, Rf

Mass spectrum (FAB, m/z) : (M+H) measured at 865, 3577, calculation for C45H57N2O13S is 865, 3581, 865, 569, 509, 297, 251, 133, 105, 77, 57.

Drug N 51:

Receiving Taxotere (10BF) from 10-Acetylacetone (10BA)

25 mg (0.029 mm) 10-acetylacetone (preparation 1, 10BA) was stirred at room temperature under nitrogen atmosphere in 1.0 ml of 95% ethanol. Then add 2 drops of anhydrous hydrazine and leave the mixture to undergo reaction for 1.5 hours, after which time TLC shows that the reaction is almost complete. The reaction mixture is distributed between water and methylene chloride. The aqueous layer was subjected to re-extraction with methylene chloride. The organic extracts are combined dried over sodium sulfate and evaporated under vacuum.

The crude product chromatografic on 3 g of silica gel by elution of a mixture of 70:30 ethyl acetate:hexane. Fractions of 1 ml are collected and analyzed by TLC. Faction 14-28 containing the desired product are combined and evaporated under vacuum.

TLC: silica gel 60, 70:30, EtOAc:hexane, Rf:0,33.

1H NMR (CDCl3, TMS62 (CL., 1H), 4,94 (D., 1H), 5,23 (S., 1H), 5,28 (CL., 1H), 5,52 (D., 1H), 5,66 (D., 1H), of 6.20 (t , 1H), 7,25 was 7.45 (m, 6H), to 7.50 (t, 2H), to 7.61 (t, 1H), 8,11 (D., 2H)

Drug N 52:

13 -(- phenyl-azaserine)-baccatin III N-t - imilarity (10RA)

Part a:

Getting t-amyl 4-nitrophenylarsonic

A solution of t-amyl alcohol (0.54 ml, 5.0 mm) in pyridine (1 ml) is treated at 0oC 4-nitrophenylphosphate (1,00 g, equal to 4.97 mm). After adding 1.5 ml of methylene chloride, the reaction mixture was stirred at room temperature overnight. Then it is diluted with toluene and filtered. Impurities crystallized in a mixture of methylene chloride:hexane.

NMR 0,981 (t, 3H), and 1.54 (C., 6H), 1,88 (K., 2H), was 7.36 (D., 2H), 8,28 (D., 2H).

Part B:

29 mg (0,039 mm) 13 -(- phenyl-azaserine)-baccatin III (preparation N 24, 11A) and t-amyl 4-nitrophenylarsonic (13 mg, 0,051 mm) in pyridine (0.10 ml) was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate and washed with 5% aqueous sodium bisulfate. An ethyl acetate solution is dried over anhydrous sodium sulfate, evaporated and chromatographic on a column of silica gel (3 g, 230 - 400 mesh.). Column elute with a mixture of ethyl acetate:hexane. The desired product is not completely clean, so it again chromatographic in SIM., 4H), of 2.25 (SD + m, 4H), of 2.38 (s,., 3H), of 2.53 (m, 2H), 3,37 (D., 1H), 3,80 (D., 1H), 4,17 (D., 1H), 4,30 (D. , 1H), to 4.41 (m, 1H), 4,63 (m, 1H), 4.95 points (d, 1H), and 5.30 (m, 1H), 5.40 to (m, 1H), 5,67 (D., 1H), 6,24 (m, 1H), 6,29 (S., 1H), 7,31 - to 7.68 (m, 8H), 8,11 (D., 2H)

13C-NMR (CDCl3TMS): 8,16; 9,53; 14,85; 20,85; 21,86; 22,61; 25,25; 25,71; 25,91; 26,73; 33,22; 35,42; 35,56; 43,18; 45,59; 56,05; 58,53; 72,14; 72,36, 73,57; 74,94; 75,55; 76,44; 79,03; 79,28; 81,05; 82,68; 84,37; 126,67; 128,05; 128,68; 128,84; 128,91; 130,16; 132,95; 133,69; 138,28; 142,28; 155,25; 167,03; 170,16; 171,27; 172,92; 203,66.

MS (FAB): (m + H)+= 864. Large ions m/z 794, 569, 527, 509, 345, 327.

Drug N 53:

13 -(- phenyl-azaserine)-baccatin III N-neopentyl - urethane (10UA)

Part a:

Getting Neopentyl 4-Nitrophenylarsonic

The solution neopentylene alcohol (0.54 ml, 5,01 mm), pyridine (1 ml), 4-nitrophenylphosphate (1,00 g, 5.0 mm) and distilled THF (2 ml) dried over a fire flask was stirred at room temperature for 40 hours. The reaction mixture was diluted with hexane, filtered and evaporated. Product chromatographic on silica gel using a mixture of ethyl acetate:hexane. Product suirvey with speakers, then subjected to recrystallization from a mixture of methylene chloride:hexane.

NMR (CDCl3TMS): 1,02 (C., 9H), 3,99 (S., 2H), 7,39 (D., 2H), 8,29 (d, 2H).

Part B:

20 mg (0,027 mm) 13 -(- phenyl-azaserine)-baccatin III (preparation N 24, Uchenie night. The reaction mixture was diluted with atelephone and washed with 5% aqueous solution of sodium bisulfate. The organic solution is dried over anhydrous sodium sulfate and concentrated. The crude product is twice chromatographic on silica gel, initially in the system acetone:hexane, and then in the system ethyl acetate:hexane, obtaining the result desired product.

NMR (CDCl3TMS) : / 0,82 (c. 9H) and 1.15 (s, 3H), 1.26 in (C., 3H), 1,68 (C. , 3H), 1,84 (C. + m, 4H), of 2.25 (SD + m, 4H), of 2.38 (SD, 3H), 2,52 (m, 2H), 3,40 (d, 1H), 3,61 (d, 1H), and 3.72 (m, 1H), 3,79 (D., 1H), 4,18 (d, 1H), 4,29 (D. , 1H), to 4.41 (m, 1H), of 4.66 (m, 1H), 4,94 (D., 1H), 5,33 (m, 1H), 5,59 (m, 1H), 5,66 (D., 1H), 6,28 (+m, 2H), 7,30 - of 7.70 (m, 8H), 8,12 (D., 2H).

13C-NMR (CDCl3TMS): 9,45, 14,74, 20,73, 21,79, 22,47, 26,09, 26,72, 31,32, 35,46, 43,05, 45,50, 45,38, 58,45, 72,03, 73,47, 74,57, 75,42, 76,36, 79,02, 81,00, 84,28, 126,61, 128,09, 128,58, 128,79, 128,96, 130,11, 132,97, 133,61, 138,10, 141,97, 156,30, 166,91, 170,23, 171,14, 172,47, 203,50.

MC (FAB):(m + H)+= 864. Large ions m/z 569, 551, 509, 327, 296, 250.

Drug N 54:

13 -(- phenyl-azaserine)-baccatin III N-(2-chloro-1,1 - dimethylethyl)urethane (10SA)

PART A:

A solution of 1-chloro-2-methyl-2-propanol (0.51 ml, 5.0 mm), 4-nitrophenylphosphate (0,999 g, 5.00 mm), pyridine (400 μl., 5.00 mm) and THF (2 ml) in a dry flask was stirred at room temperature for 40 hours. The reaction mixture was diluted with hexane and ASS="ptx2">

NMR (CDCl3TMS): 1,64 (C., 6H), a 3.87 (SD, 2H), 7,38 (D., 2H), 8,28 (D., 2H)

PART B:

28 mg (0,037 mm) 13 -(- phenyl-azaserine)-baccatin III (preparation N 24, 11A) and chloro-t-butyl-4-nitrophenylarsonic (12.0 mg, 0,044 mm) in pyridine (0.10 ml) was stirred at room temperature overnight. Then the reaction mixture was diluted with ethyl acetate and washed with 5% aqueous solution of sodium bisulfate. The organic phase is dried over anhydrous sodium sulfate and evaporated. The coarse product is cleaned by chromatographytandem on a column of silica gel in the system acetone:hexane.

NMR (CDCl3TMS): 0,82 (C., 9H), 1,15 (C., 3H), 1.26 in (C., 3H), 1,68 (C. , 3H), 1,84 (C. + m, 4H), of 2.25 (SD + m, 4H), of 2.38 (SD, 3H), 2,52 (m, 2H), 3,40 (d, 1H), 3,61 (D., 1H), and 3.72 (m, 1H), 3,79 (D., 1H), 4,18 (D., 1H), 4,29 (D., 1H), to 4.41 (m, 1H), of 4.66 (m, 1H), 4,94 (D., 1H), 5,33 (m, 1H), 5,59 (m, 1H), 5,66 (D., 1H), 6,28 (C. + I., 2H) 7,30 - of 7.70 (m, 3H), 8,12 (D., 2H)

13C-NMR (CDCl3TMS): 9,45, 14,74, 20,73, 21,79, 22,47, 26,09, 26,71, 31,32, 35,46, 43,05, 45,50, 56,38, 58,45, 72,03, 73,47, 74,57, 75,42, 76,36, 79,02, 81,00, 84, 28, 126,61, 128,09, 128,58, 128,79, 128,96, 130,11, 132,97, 133,61, 138,10, 141,97, 156,30, 166,91, 170,23, 171,14, 172,47, 203,50.

MC (FAB): (m + H)+= 864. Large ions m/z 569, 551, 509, 327, 296, 250.

Drug N 55:

13 -(- phenyl-azaserine)-baccatin III N-(3-methyl-3 - pentyl)urethane (10TA)

PART A:

Obtaining 3-methyl-3-pentyl-4-nitrophenylarsonic

€ At room temperature for 40 hours. Add acetonitrile (2 ml) and continue stirring overnight. Then the reaction mixture is diluted with methylene chloride and hexane, filtered and evaporated. The resulting product chromatographic on silica gel in a mixture of ethyl acetate: hexane.

NMR (CDCl3TMS): of 0.95 (t, 6H), 1,50 (C., 3H), 1,90 (m, 4H), 7,35 (D., 2H), 3.27 to (doctor, 2H).

PART B:

32 mg (0,043 mm) 13 -(- phenyl-azaserine)-baccatin III (preparation N 24, 11A) and 3-methyl-3-pentyl-4-nitro-phenylcarbamate (12.5 mg, 0,047 mm) in pyridine (0.15 ml) was stirred at room temperature for 60 hours. Then the reaction mixture was diluted with uitilization, washed with 5% aqueous sodium bisulfate, dried over anhydrous sodium sulfate and evaporated. The resulting product is distilled chromatographytandem on a column of silica gel in a mixture of acetone:hexane.

NMR (CDCl3TMS): 0,76 (t, 6H), 1,15 (C., 3H), 1,24 (C., 3H), 1.27mm (C. , 3H), 1,50 - 1,98 (3C. + m, 12H), of 2.25 (SD + m, 5H), of 2.38 (SD, 3H), of 2.53 (m, 2H), 3,37 (CL., 1H), 3,80 (D., 1H), 4,17 (D., 1H), 4,30 ( D., 1H), to 4.41 (m , 1H), with 4.64 (m, 1H), 4.95 points (D., 1H), from 5.29 (m, 1H), 5,42 (m, 1H), 5,66 (D., 1H), 6,24 (m, 1H), 6,29 (S., 1H), 7,30 - of 7.70 (m, 8H), 8,11 (D., 2H).

13C-NMR (CDCl3TMS): 7,61, 9,27, 14,58, 20,58, 21,63, 22,35, 22,58, 26,46, 30,18, 30,26, 35,15, 35,29, 42,91, 45,31, 55,68, 58,26, 71,88, 72,13, 73,27, 74,71, 75,29, 76,31, 78,78, 80,79, 84,10, 84,95, 126,38, 127,77, 128,41, 128,58, 128,81, 129,90, 132,71, 133,41, 138,06, 142,03, 154,86, 16:

Obtain methyl ester of N-(t-butylaminoethyl) -- finalization (ZK)

Methyl ester (2R,3S) -- phenyl-azaserine (4.35 g, 22 mm) was dissolved in 100 ml of dry THF and cooled flask to 0oC. To the solution was added t-utilizationa (2.8 ml, 25 mm). After 15 minutes, TLC shows the presence of some amount of starting material, therefore, add another 0.5 ml of the isocyanate. After 1 hour, TLC already not detected in the reaction solution of the source material, so that the solution was concentrated in vacuo, obtaining the methyl ester of N-(t-butylaminoethyl) -- phenylazomethine (3K).

Proton NMR (CDCl3TMS) : 1,27 (C., 9H), 3.43 points (doctor, 1H), 3,81 (C., 3H), 4,34 (CL., 1H), 4,48 (m, 1H), 5,27 (m, 1H), 5,32 (m, 1H), 7,29 (m, 29), 7,34 (m, 3H).

Mass spectrum (FAB-high resolution)

Calculated for C15H22N2O4+ H : 295, 1658

Found: 295, 1663.

Drug N 57:

Obtaining methyl ester (4S,5R)-N-(t-butylaminoethyl)-2- (2,4-acid)-4-phenyl-oxazolidin - carboxylic acid (5Ka and 5Kb)

Methyl ester of N-(t-butylaminoethyl) -- phenyl-azaserine (68 mg, 0.23 mmol, 3K, drug N 56) dissolved in 5 ml of dry T GF, process the resulting solution was dimethylacetal 2,4-dimethoxybenzaldehyde (70 mg, 0.33 mm) and n-toluensulfonate pyridinium who eat about 2 ml of solvent, each time adding 2 ml of fresh THF, by this time, TLC does not detect in the solution of the starting materials. The solution was concentrated in vacuo and chromatographic on the column with 7 g of silica gel in a mixture of 1:3 EtOAc: hexane. Column elute with 80 ml of 1:3 EtOAc: hexane, 45 ml of 1:2 EtOAc:hexane, 35 ml of 2:3 EtOAc:hexane and 30 ml of 1:1 EtOAc: hexane, collecting fractions of 3 ml

Less polar isomer methyl ether (4S,5R)-N-(t - butylaminoethyl)-2-(2,4-acid)-4-phenyl-5 - oxazolidinecarboxylate acid (5Ka) - find in fractions 21 to 31.

Proton NMR (CDCl3TMS): 1,19 (C., 9H), 3,82 (C., 3H), 3,85 (C., 3H), 3,89 (C., 3H), 4,68 (CL., 1H), 4,88 (d, 1H), 5,52 (D., 1H), 6,46 (m), 6,70 (S., 1H), 7,25 - 7,50 (m).

Mass spectrum (FAB-high resolution)

Calculated for C24H31N2O6+ H: 443,2182

Found: 443,2172

The more polar isomer methyl ether (4S, 5R)-N-(t - butylaminoethyl)-2-(2,4-acid)-4-phenyl-5 - oxazolidinecarboxylate acid (5Kb) - find in fractions of 33 - 42.

Proton NMR (CDCl3TMS): 0,99 (m, 9H), 3,53 (m, 3H), 3,81 (m, 3H), 3,38 (m, 3H), of 4.05 (m, 1H), 4,55 (m, 1H), the 5.45 (m, 1H), 6.48 in (m, 2H), 6,79 (m, 1H), 7,25 - 7,50 (m).

Mass spectrum (FAB-high resolution)

Calculated for C24H31N2O6+ H: 443, 2182

Found the Il-5-oxazolidinecarboxylate acid (6Ka) and its free acid (7Ka)

100 mg (0.23 mmol) of the less polar isomer methyl ester (4S,5R)-N-(t-butylaminoethyl)-2-(2,4-acid)-4-phenyl-5 - oxazolidinecarboxylate acid (preparation N 57, 5Ka) was stirred at room temperature under nitrogen atmosphere in 3 ml of MeOH. To this mixture is added 0.1 ml of water and 43 mg (0,31 mm) of potassium carbonate. After 1 hour TCX data showed the absence of starting material. During the night the mixture was kept in the freezer. The next morning, the solvent is evaporated, receiving potassium salt of (4S,5R)-N-(t-butyl-aminocarbonyl)-2-(2,4-acid)-4 - phenyl-5-oxazolidinecarboxylate acid (6Ka).

Proton NMR (d6-DMSO): 1,20 (C., 9H), 3,51 (s, 1H), 3,76 (C., 3H), 3.96 points (C., 3H), 4,32 (D., 2H), 4,80 (S., 1H), from 5.29 (D., 1H), 6,60 of 6.68 (m, 2H), of 6.71 (D. , 1H), 7,26 (D., 1H), 7,35 (5, 1H), 7,45 (t, 2H), 7,53 (D., 2H).

Drug N 59:

Receipt of (4S, 5R)-N-(t-butylaminoethyl)-2-(2,4 - acid)-4-phenyl-5-oxazolidinecarboxylate acid (7Ka)

Potassium salt of (4S, 5R)-N-(t-butylaminoethyl)-2-(2,4 - acid)-4-phenyl-5-oxazolidinecarboxylate acid (6Ka, preparation 58) are distributed between the phases of methylene chloride and water containing 0.9 ml of IN HCl. The layers are separated and the aqueous phase is subjected to re-extraction with methylene chloride. The organic extracts are combined dried over sodium sulfate about acid (7Ka) as a white solid.

Drug N 60:

Obtaining ester of 7-TES-baccatin 111-13-(4S, 5R)-N-(t - butylaminoethyl)-2-(2,4-acid)-4-phenyl-5 - oxazolidinecarboxylate acid (9KaA)

(4S, 5R)-N-(t-butylaminoethyl)-2-(2,4-acid)- 4-phenyl-5-oxazolidinecarboxylate acid (1,07 mm, the preparation 59, 7Ka) dissolved in a mixture of 1.5 ml of methylene chloride and 3 ml of toluene. To the obtained mixture is added 7-TES-baccatin III (500 mg, 0.71 mm, 8A), DMAP (45 mg, 0.36 mm) and DCC (240 mg, 1.15 mm). The reaction mixture was stirred in nitrogen atmosphere for 1 hour at room temperature. The resulting by-product in the form of urea is removed by filtration, and the filtrate is evaporated under vacuum. The remainder chromatographic on silica gel (80 g), elwira it consistently mixtures 25:75 EtOAc:hexane (200 ml) and 33:67 EtOAc:hexane (1 liter). Fractions of 20 ml are collected and analyzed by TCX. Fractions 28 to 47 containing the desired product are combined and evaporated. Ether 7-TES-baccatin 111-13-(4S,5R)-N-(t-butylaminoethyl)-2-(2,4 - acid)-4-phenyl-5-oxazolidinecarboxylate acid (9KaA) are obtained in the form of a white solid.

Mass spectrum (FAB, M + H):

Calculated for C60H79N2O16Si: 1111, 5198,

Found: 1111, 5189.

Drug N 61:

13-(N-(t-butylaminoethyl is Athyn III N-t-butylacetyl (10KA)

A solution of 0.1 M HCl is prepared from 0,071 ml acetylchloride and 9,929 ml MeOH, maintaining the mixture for 30 minutes before using.

Ether 7-TES-baccatin III-13-(3S,6R)-N-(t-butylaminoethyl)- 2-(2,4-acid)-4-phenyl-5-oxazolidinecarboxylate acid (100 mg, drug 60, 9KaA) handle the above methanolic solution of HCl (0.5 ml) under stirring in nitrogen atmosphere. Data show TCX, after 45 minutes the reaction is completed. The reaction mixture is partitioned between the phases of ethyl acetate and 5% sodium bicarbonate. The layers are separated and the aqueous phase re-extracted with ethyl acetate. The organic extracts are combined dried over sodium sulfate and evaporated under vacuum.

The crude product chromatographic on silica gel (8 g), elwira successively with a mixture of 33: 67 acetone:hexane (70 ml) and 40:60 acetone:hexane (35 ml). Fractions of 2 ml are collected and analyzed by TCX. Pure product find in fractions 18 to 29, which are combined and evaporated. 13-(N-(t-butylaminoethyl) -- phenyl-azaserine)-baccatin III (10Ka) are obtained in the form of a white solid. Its physical characteristics are similar to data obtained previously for the preparation of N 46.

THE DRUG 1A

2'-[{(2,2,2-Trichloroethyl)oxy}carbonyl]2-trichloroethyl)oxy} carbonyl] Taxol (1 equivalent) in carbon disulfide. Then add sodium hydride (2.1 equivalents) and stirred the mixture, controlling the formation of methylxanthine with TCX. Upon completion of the reaction, excess of carbon disulfide and iodotope bromide is removed by evaporation. The resulting residue is distributed between water and ether, the layers separated, the organic layer dried, filtered and concentrated, obtaining the desired connection.

THE DRUG 2A

2'-[{(2,2,2-Trichloroethyl)oxy}carbonyl] Taxol, 7-Methanesulfonate

Methanesulfonanilide (1.2 equivalent) was added dropwise to a solution of 2'-[{ (2,2,2-trichloroethyl)oxy} carbonyl]Taxol (1 equivalent) and pyridine (5 equivalents) in CH2Cl2that is stirred in an ice bath. Then the reaction mixture is transferred into heat and continue to stir until until TCX data shows that the reaction is fully completed. The reaction mixture is cooled in ice water and extracted with CH2Cl2these extracts are successively washed with diluted acid, dilute aqueous NaHCO and water, and then dried, filtered and concentrated, obtaining the crude reaction product. The chromatography was carried out gross product on silica gel gives pure target product.

PREPARATION 3A
oC. Then the reaction mixture is transferred into heat and continue to stir until until TCX data shows that the reaction is fully completed. The reaction mixture is cooled in ice water and extracted with CHCl2. CH2Cl2The extracts are successively washed with cold diluted acid, dilute aqueous NaHCO and water, and then dried, filtered and concentrated, obtaining the crude reaction product. The chromatography was carried out gross product on silica gel gives pure target product.

PREPARATION 4A

2'-[{(2,2,2-Trichloroethyl)oxy}carbonyl]-7-deoxy-7-asiatica

A solution of 2'-[{ (2,2,2-trichloroethyl)oxy} carbonyl] Taxol, 7-triftormetilfullerenov (1 equivalent) and 18-crown-6 (1 equivalent) of N,N-dimethylpropanediamine stirred with potassium azide (10 equivalents). The mixture is stirred and heated to until TCX data confirm the completion of the reaction. The reaction mixture is cooled in ice water and extracted with ether. The ether extract is washed thoroughly with water, dried, filtered and concentrated, obtaining the crude reaction product. Chromatographie gross product on silica gel gives pure target product.

The product 5 is l]-7-deoxy-7 - asiaticae in ethanol is stirred with 10% palladium-on-coal as a catalyst in hydrogen atmosphere. Upon completion of the reaction, the catalyst was removed by filtration, and the filtrate is concentrated to obtain a coarse product of the reaction. The chromatography was carried out gross product on silica gel gives pure target compound.

PREPARATION 6A

Obtaining N-Desbenzoyl-N-benzyloxycarbonyl-2'-[{ (2,2,2 - trichloroethyl)oxy} carbonyl] Taxol, ((Ether (Benzyloxycarbonylamino) -- { [(2,2,2-trichlorethane)-carbonyl] oxy}benzoylpropionic acid, 6,12 b-Bis-(atomic charges)-12- (benzoyloxy)-2a,3,4,4 a, 5,6,9,10,11,12,12 a, 12b-dodecahydro - 4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-7,11-methane - 1H-cyclodina[3,4]Benz[1,2-b]-oxet-9-yl)) (12BA), and

N-Desbenzoyl-N-benzyloxycarbonyl-2', 7-bis{ [(2,2,2 - trichloroethyl)oxy] carbonyl}-Taxol, ((ether {2R-[2a,4,4 a, 6,9,(R*S*),11,12,12 a,12ba]}-- (benzyloxycarbonylamino) -- { [(2,2,2-trichlorethane)- carbonyl} oxy]benzoylpropionic acid, 6, 12-b-Bis(atomic charges)-12-(benzoyloxy)-4-{ [(trichlorethane)carbonyl] oxy} - 2a, 3,4,4 a, 5,6,9,10,11,12,12 a, 12b-dodecahydro-11-hydroxy - 4a,8,13,13-tetramethyl-5-oxo-7,11-methane-1H-cyclodina[3,4]Benz[1,2-b]- oxet-9-yl)).

The procedure is carried out according to the method described for obtaining 2'-Troc-Taxol [Magri et al., J. Org. Chem., 1986, 51, 797], using N-desbenzoyl-N-benzyloxycarbonyloxy (0,290 g 0,328 mm) and 2,2,2-trichlorethylphosphate (59 the product (0,340 g), which chromatographic on silica gel (40-63 μm, column Merck, size B) using CH2Cl2solution for application to the column and mixtures 40% EtOAc:hexane (90 fractions), 60% EtOAc:hexane (30 fractions) and EtOAc for elution from the column (collect fractions with a volume of 8 ml). N-Desbenzoyl-N-benzyloxycarbonyl-2', 7-botroctacoc (0,053 g, 13%) eluted in fractions 14-23. Source material (0,014 g, 5%) comes in the fractions 139-143. The desired N-Desbenzoyl-N-benzyloxycarbonyl-2'-Troc-Taxol 12BA (0,248 g 0,234 mm, 71%) eluted in fractions 49-80 and is characterized by the following spectroscopic data:

1H NMR (CDCl3TMS): 8,15 (D., 2H, aromatic), a 7.62 (t, 1H, aromatic), 7,52 (t , 2H, aromatic), 7,30-to 7.50 (m, 5H, aromatic), 7,17 (m , 2H, aromatic), of 6.26 (m, 1H, H13), and 6.25 (C., 1H, H10), 5,71 (m, 1H, -NH-), 5,67 (D., 1H, H2), to 5.58 (m, 1H, H3), 5,41 (D., 1H, H2), 5,08 (D. , 1H, PhCHaHO-); 4,96 (D., 1H, PhCHHbO-), 4,94 (m, 1H, H5), 4,79 (D., 1H, -OCHaHCCl3), 4,68 (D., 1H, J = 11.8 Hz, -OCHHbCCl3), was 4.42 (m , 1H, H7), or 4.31 (D., 1H, H20a), 4,18 (D., 1H, H20b), 3,78 (D., 1H, H3), to 2.55 (m, 1H, H6a), 2,47 (m, 1H, H14a), 2,45 (C., 3H, -CH3), 2,31 (m, 1H, H14), 2,24 (C., 3H, -CH3), with 1.92(m, 1H, H6b), 1,86 (C., 3H, -CH3), 1,68 (C., 3H, -CH3), 1,23 (C., 3H, -CH3), 1,14 (FMR Taxol (0,026 g, 0,030 mm) and 98% hydrazine (0.035 g, 1.1 mm) in 95% ethanol (1.0 ml) was stirred at room temperature for 2 hours. This solution is poured into a mixture of water and ether, mixed well and separated layers. The aqueous phase is extracted with an additional portion of ether. The combined ether extracts are dried over Na2SO4filter and concentrate, receiving 0,021 g of target compound:

1H NMR spectrum in CDCl3identical to the spectrum obtained for the 10-deacetyltaxol (Ringel, I.; Horwitz, S. B. J. Pharmacol. Exp. Ther., 1987, 242, 692) and is identical to the spectrum of an authentic sample.

The drug 8A

10-Deacetylbaccatin III

The solution baccatin III (0,024 g 0,041 mm) in 95% ethanol (1.0 ml) is prepared by heating the mixture. Then the solution is cooled to room temperature, add 98% hydrazine (0.035 g, 1.1 mm) and stirred the mixture at room temperature for 24 hours. The solution is poured into a mixture of water/ether, mixed well and separated layers. The ether layer is washed with water, dried (Na2SO4) filtered and concentrated, obtaining 0,010 g of target compound:

1H NMR spectrum in CDCl3(moderately soluble) is identical to the spectrum of the authentic sample 10-deacetylbaccatin III.

The drug 10A

N-Desbenzoyl-N-[{(2,2,2-trial,2-trichlorocyanuric) -- phenylisopropyl] -baccatin III, 10DA, preparation 28)) is subjected to selective introduction of silyl groups by reaction with triethylsilane in pyridine containing 4-dimethylaminopyridine in the quantity necessary for catalysis. The reaction mixture is poured into cold water and extracted with CH2Cl2. The extract was dried, filtered, concentrated and cleaned crude product chromatographytandem on silica gel, receiving pure target compound.

The drug 13A

N-Desbenzoyl-N-(t-butyl)oxycarbonyl-2'-{ [(2,2,2 - trichloroethyl)oxy]carbonyl}Taxol A (Compound 12DA), ((Ester { [(2,2,2-trichloroethane)carbonyl] oxy} benzoylpropionic acid, 6,12 b-Bis(atomic charges)-12-(benzoyloxy)-2a, 3,4,4 a, 5,6,9,10,11,12,12 a,12b - dodecahydro-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-7,11-methane-1H - cyclodina[3,4]Benz[1,2-b]-oxet-9-yl)), and N-Desbenzoyl-N-(t - butyl)oxycarbonyl-2', 7-bis{ [(2,2,2-trichloro-ethyl)oxy]carbonyl}-Taxol ((Ether [{ (2,2,2-trichloroethane)carbonyl} -oxy] benzoylpropionic acid, 6,12 b-Bis(atomic charges)-12-(benzoyloxy)-4-{[(trichlorethane) carbonyl]oxy}-2a,3,4,4 a, 5,6,9,10,11,12,12 a, 12b-dodecahydro-11-hydroxy - 4a, 8,13,13-tetramethyl-5-oxo-7,11-methane-1H-cyclodina[3,4]Benz[1,2-b]- oxet-9-yl)).

Trying the procedure for obtaining the preparation of 2'-Troc-Taxol (Magri et. al., J. Org. Chem., 1986, 51, 797), but starting with N-is 94 mm) in CH2Cl2(80 ml), get the product 12DA. Following the technique, get a rough product that chromatographic on silica gel 40-63 μm, 37 x 350 mm, 190 g) using CH2Cl2-solution for application to the column and 40% EtOAc:hexane (63 faction), and then 75% EtOAc: hexane for elution of product from the column (collected fraction volume 45 ml). N-Desbenzoyl-N-(t-butyl)oxycarbonyl-2', 7-bistro-Taxol (0,140 g) eluted in fractions 6. Source material (0,192 g) found in the fractions 70-78. The desired N-Desbenzoyl-N-(t-butyl)oxycarbonyl-2'-Troc-Taxol (Compound 12DA) eluted in fractions 18-38 and is characterized by the following spectroscopic data:

1H NMR (CDCl3TMS): 8,12 (D., 2H, J = 8.1 Hz), a 7.62 (t, 1H, J = 7,2 Hz), 7,51 (t, 2H, J = 7,7 Hz), 7,30-7,44 (m, 5H), 6.30-in (C., 1H, H10), 6,30 (t , 1H, H13), 5,68 (D., 1H, J = 7,1 Hz, H2), 5,48 (D., 1H, -NH - or H3), 5,44 (D., 1H, H3or-NH-), are 5.36 (D., 1H,J = 2.2 Hz, H2), to 4.98 (D., 1H, J = 9,3 Hz, H5), 4,79 (D., 2H, J = 11,9 Hz, 2'-Troc-Ha), 4,70 (D., 2H, J = 11.8 Hz, 2'-Troc-Hb), of 4.44 (m, 1H, H7), 4,32 (D., 1H, J = 8,4 Hz, H20a), 4,18 (D., 1H, J = 8,4 Hz, H20b), 3,82 (D., 1H, J = 6,8 Hz, H3).

The drug 14A

2'-Triethylsilyl-Taxol, 7-methylxanthine

500 mg (0,52 mm) 2'-Triethylsilyl-Taxol is dissolved in 5 ml of distilled THF. To the solution was added the sodium in oil) in distilled THF and about half of it was added to the reaction mixture, which is stirred and with TLC test education methylxanthine. After 0.5 hours the residue is partitioned between a saturated solution of NH4Cl and EtOAc, the layers separated, the organic phase is filtered through Na2SO4and concentrate to obtain the target compounds. The product is cleaned by using column chromatography using 60 g of silica gel in the system 1:4 EtOAc: hexane. The product is applied, using methylene chloride, and elute the column successively with 400 ml of 1:4, 400 ml of 1:3 and 300 ml of a 1:2 mixture of EtOAc:hexane. The fractions containing the product, was determined by TLC, combined and evaporated, obtaining 2'-Triethylsilyl-Taxol, 7-methylxanthine in the form of a white solid.

TLC: silica gel 60; 33% EtOAc: 67% hexane, Rf: 0,40.

1H NMR (CDCl3TMS): 0,44 (m, 6H), 0,81 (m), 1,19 (C., 3H), 1,22 (C. , 3H), 2,16 (C., 3H), 2,48 (C., 3H), 2,58 (C., 3H), equal to 2.94 (m, 1H), 4,03 (D., 1H), 4,25 (D., 1H), 4,37 (D., 1H), 4,70 (S., 1H), 5,00 (D., 1H), 5,73 (m, 2H), 6,28 (m, 1H), 6,32 (S., 1H), 6,40 (m, 1H), 7,11 (D., 1H), 7,30-the 7.65 (m), 7,75 (D., 2H), 8,15 (D., 2H).

The drug 15A

2'-Taxol 7-Triflate

A solution of 2'-Triethylsilanol [0.10 g, Director et al., J. Org. Chem., 1993, 58, 3798] and dry pyridine (0,29 ml) in CH2Cl2(4 ml) cooled to a temperature of -20oC and add triplify anhydride (0.17 ml). The solution is stirred and under using EtOAc. The organic extract is washed with diluted aqueous NaHSO4saturated NAHCO solution, dried over Na2SO4, filtered and concentrated at room temperature. Crude reaction product chromatographic on silica gel (flash chromatography) using 30% EtOAc in hexane for elution of the column and collecting fractions of 5 ml Fractions (4-10) containing the desired product are pooled, obtaining the target compound (0,094 year).

The drug 16A

Baccatin III 7-O-triflate (24)

The solution baccatin III (5,25 g, 8,93 mm) in CH2Cl2(21 ml) and pyridine (18,1 ml) is cooled in a bath with a temperature of -30oC. Add triftormetilfullerenov anhydride (3,76 ml of 6.31 g, 22.3 mm) and stirred the mixture, allowing it to warm to room temperature for one hour. After 4 hours the reaction is completed, after that add saturated aqueous NH4Cl (50 ml) and extracted the reaction mixture with CH2Cl2. The organic extract was successively washed with 1 M aqueous NaHSO4(50 ml), saturated aqueous NaHCO3(G ml) and saturated aqueous NaCl, dried (Na2SO4), filtered and concentrated under reduced pressure. Should take measures to prevent the heating of the solution to ( subjected to flash chromatographicaliy on silica gel (6" silica gel in 75 mm column, faction 125 ml). The material is applied to the column in a solution of CH2Cl2and elute column with 5% CH3CN : CH2Cl2. Faction 19-35 contain the desired baccatin III 7-0-triplet (4,837 g of 6.71 mm, 75%) as a white solid.

1H NMR (CDCl3TMS): 8,10 (D., 2H, J = 7,2 Hz), 7,63 (t, 1H, J = 7.4 Hz), 7,49 (t, 2H, J = 7,6 Hz), 6,63(C., 1H, H10), 5,68 (D., 1H, J = 7,0 Hz, H2), 5,52 (DD., 1H, J = 7.5 Hz, 10.1 Hz, H7, 4,94 (D., 1H, J = 8,4 Hz, H5), a 4.86 (m , 1H, H3), 4,35 (D., 1H, J = 8,4 Hz, H20a), 4,15 (D., 1H, J = 8,4 Hz, H20b), 4,01 (D., 1H, J = 7,0 Hz, H3), 2,87 (lines 5, H14a), 2,30 (C., 3H, -CH3), 2,20 (C., 3H, -CH3), 2,10 - 2,30 (m, H6aH6bH14b), 1,87 (C., 3H, -CH3), 1,59 (C., 3H, -CH3), 1,19 (C., 3H, -CH3), 1,05 (C., 3H, -CH3).

The drug 18A

7-Deoxy-7,8 - methane-baccatin III (26)

A solution of 7-trifloromethyl-baccatin III (24,87 mg, 0.12 mm) in distilled dioxane (1.5 ml) is treated with an aqueous solution of sodium azide (0.10 g, 1.5 mm NaN3of 0.30 ml of water). The reaction mixture was refluxed in nitrogen atmosphere for one hour. The mixture is then diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The resulting product is cleaned chromatographytandem on casacci-7,8 - methane-baccatin III.

NMR (CDCl3TMS): 1,10 (s, 3H), 1,22 (s, 3H), of 1.35 (m, 1H), 1,64 (m, 1H), 1,78 (s, 1H), 2,03 (C. + m, 4H), of 2.21 (s, 3H), and 2.26 (s, 3H), 2,20 - to 2.55 (m, 5H), 4.04 the (doctor, 1H, J = 8.5 Hz), 4,18 (D., 1H, J = 7.5 Hz), 4,30 (doctor , 1H, J = 8.5 Hz), 4,74 (D., 1H), a 4.83 (m, 1H), 5,63 (D., 1H, J = 7.5 Hz), 6.35mm (s, 1H), 7,49 (m, 2H), 7.62mm (m, 1H), 8,13 (m, 2H).

13C-NMR (CDCl3TMS): 15,15, 15,28, 20,43, 20,82, 21,99, 25,90, 26,35, 31,63, 35,19, 38,57, 42,20, 67,51, 75,30, 76,20, 76,49, 79,23, 79,91, 84,73, 128,50, 129,33, 129,99, 132,59, 133,54, 144,19, 167,20, 169,63, 170,00, 202,08.

The drug 19A

7-Deoxy-7 - azido-baccatin III (27)

A mixture of 7-trifloromethyl-baccatin III (24,102 mg, 0.14 mm), sodium azide (13 mg, 0.20 mm) and 18-crusadename-6 (32 mg, 0.12 mmol) in 13-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyridinone (1.0 ml) was stirred at room temperature overnight in an atmosphere of inert gas. The reaction mixture is distributed between ethyl acetate and water. The organic phase is dried over anhydrous sodium sulfate and evaporated. The coarse product is cleaned by chromatographytandem on a column of silica gel 60 in a mixture of 15% ethyl acetate : methylene chloride. Next, the product is cleaned by crystallization from a mixture of methylene chloride : hexane, receiving 37 mg of 7-deoxy - alpha - azido-baccatin III.

NMR (DMCO-d6TMS): 0,96 (C., 6H), 1,59 (C., 3H), 1.91 a (C., 3H), 2.13 in (C., 3H), 2,25 (C., 3H), of 2.10 to 2.35 (m, 4H), 2,47 (m, 1H), 3,60 (m, 2H), 4,07 (D. , 1H, J = 8.0 Hz), 4,33 (D., 1H, J = 8.0 Hz), 4,60 (C. + m, , MS): 15,40, 17,31, 20,67, 22,20, 25,93, 29,81, 39,22, 40,63, 41,73, 55,57, 64,28, 65,91, 75,33, 76,91, 77,33, 78,22, 80,44, 80,94, 128,77, 129,58, 129,98, 130,28, 133,33, 145,43, 165,30, 168,75, 169,09, 207,11.

The examples below continue to illustrate the object of the present invention.

Example 1.

Receiving: 2'{[(2,2,2-Trichloroethyl)-oxy]carbonyl}-7-deoxy-7 - portakal (compound 13AA, 111a), ((Ether {2aR[2a,alpha - {[(2,2,2 - trichloroethane)carbonyl]-oxy} benzoylpropionic acid, 6,12 b-Bis(atomic charges)-12-(benzoyloxy)-2a,3,4,4 a, 5,6,9,10,11, -12,12 a,12b-dodecahydro-4-fluoro-11-hydroxy-4a,8,13, 13-tetramethyl-5-oxo-7,11-methane-1H-cyclodina[3,4]Benz[1,2-b]-oxet-9 - yl)), and

2'{ [(2,2,2-trichloroethyl)-oxy] carbonyl}-7-deoxy-7,8 - metadatacache (compound 14AA), ((Ester { [(2,2,2 - trichloroethane)carbonyl] -oxy} benzoylpropionic acid, 6,12 b-Bis(atomic charges)-12-(benzoyloxy)-2a, 3,4,4 a, 5,6,9-, 10,11, 12,12 a,12b-dodecahydro-11-hydroxy-8,13, 13-trimethyl-5-oxo-4,4 a,7,11-biomethane-1H-cyclodina[3,4]Benz [1,2-b]-oxet-9-yl)).

Dimethylaminomethylphenol (Matildas) (250 μl, 0,340 g of 2.56 mm) with a syringe quickly injected into a well stirred and cooled (bath with a mixture of acetone-dry ice) solution of 2'-{[(2,2,2-trichlorethyl)carbonyl}Taxol 12AA [Magri, N. F.; Kingston, D. G. I. J. Org. Chem., 1986, 51, 797] (1,60 g 1,55 mm) in CH2Cl2(180 ml). The cooling bath is removed and allows the C to 70 minutes the results of the TLC show the source material is almost completely consumed. The reaction is stopped by the addition of water and transfer the reaction mixture into a separating funnel using an additional portion of CH2Cl2. The layers separated, the organic phase is once washed with water, dried (Na2SO4), filtered and concentrated, obtaining white solid (1.65 g). The remainder chromatographic on silica gel (40-63 μm, 195 g in column (3.7 x 35 cm, the fraction by volume of 40 ml), using for application to the column CH2Cl2the solution, and elution of column with 25% acetone in hexane.

Faction 32-39 contain a mixture of at least two compounds.

Faction 40-42 contain a mixture which may include some compounds 14AA.

Faction 43-49 (0,391 g) contain primarily compound 14AA (Rf= 0,22 in a mixture of 30% acetone:hexane), together with two minor components.

Faction 50-54 contain rate £ 0.162 g of a mixture of 14AA and 13AA. This mixture chromatographic on silica gel (column Merck Lobarsize 8, fraction volume 8 ml) using CH2Cl2for application to the column and a mixture of 25% acetone:hexane for elution from the column. Faction 58-70 containing 0,056 g 14AA, combine (pool A) vysheupomjanutym components of A pool is separated and obtained as pure compounds by repeated chromatographytandem on silica gel (two columns Merck Lobarsize B, fraction volume: 9 ml). The mixture is applied on the column in CH2Cl2and elute column with a solution of 25% EtOAc:hexane to fraction 72, 30% EtOAc: hexane to fraction 180 and 40% EtOAc:hexane until the end of the elution.

Faction 195-215 (0,373 g) contain 14AA and the second minor component, which is not separated until the removal of the Troc-protecting groups, despite the presence of a minor component, compound 14AA forms beautiful crystals upon slow evaporation of the solvent and plays the following spectral characteristics:

FAB mass spectrum gives peaks at 1012, 1010, 551, 533, 511, 491, 450 and 442 mass units.

1H NMR (CDCl3TMS): 8,19 (D., 2H, J = 7,1 Hz), 7,71 (D., 2H, J = 7,2 Hz), to 7.59 (t, 1H), of 7.48 (m), of 7.36 (m), 6,98 (D., 1H, -NH-), 6,57 (C., 1H, H10), 6,28 (t, 2H, J = 8.7 Hz, H13), between 6.08 (DD., 1H, J = a 9.5, 2.7 Hz, H3), 5,67 (D., 1H, J = 7,6 Hz, H2), 5,54 (D., 1H, J = 2,8 Hz, H2), of 4.77 (DD., 2H, 2'-Troc-CH2-), 4,74 (1H, H5), 4,32 (D., 1H, J = 8.6 Hz, H20a), 4.09 to (doctor, 1H, J = 8.6 Hz, H20b), 4,07 (1H, H3), 2,47 (C., 3H, -CH3), of 2.23 (DD., 1H, JH-7= 9.9 Hz, JH-19a= 5.3 Hz, H19b), 2,19 (C., 3H, -CH3), 1,90 (D., 3H, J = 1.3 Hz, -CH3), 1,67 (DD., 1H, JH-7= 7,2 Hz, JH-19a= 5.3 Hz, H19b), to 1.38 (m, 1H, H7), 1,26 (C., 3H, -CH3and 1,21 (C., 3H, -CH3)

13C NMR (CDCl

Faction 55-65 (to 0.480 g) contain a pure compound 13AA and after merging with 13AA, obtained by the above-mentioned second chromatographicaliy mixed fractions, gives 13AA in the form of a colorless crystalline solid:

Rf= 0,19 30% acetone:hexane,

FAB mass spectrum gives peaks at 1034, 1032, 1030, 571, 511, 460, 442, 210 and 105 mass units,

1H NMR (CDCl3TMS): 8,18 (DD., 2H, J = 7,0, 1.5 Hz), 7,76 (DD., 2H, J = 7,0, 1.5 Hz), a 7.62 (t, 1H), 7,50 (m), 7,43 (m), 6,95 (D., 1H, -NH-), 6,57 (C., 1H, H10), 6,27 (t, 1H, H13), between 6.08 (DD., 1H, J = a 9.5, 2.6 Hz, H3), 5,78 (D. , 1H, J = 7,3, H2), 5,55 (D., 1H, J = 2.7, and H2), of 5.05 (D., 1H, J = 7,5, H5), 4,78 (D., 1H, J = 11.8 in, H20a), 4,74 (D., 1H, J = 11.8 in, H20a), 4,48 (DD. , 1H, JF= 48 Hz, H7), and 4.40 (D., 1H, J = 8,4 Hz, H20a), or 4.31 (D., 1H, J = 8,2 Hz, H20b), Android 4.04 (D., 1H, J = 7,2 Hz, H3), 2,63 at 2.45 (m), 2.49 USD (C., 3H), 2,27 - 2,10 (m), 2,20 (C., 3H), 1.91 a (C., 3H), 1,74 (C., 3H), 1,20 (C. , 3H) and 1,17 (C., 3H).

13C NMR (CDCl3TMS) 206,0, 169,9, 168,8, 167,2, 167,17, 153,2, 140,9, 136,4, 133,7, 133,5, 132,1, 130,3, 129,3, 129,2, 128,8, 128,7, 128,6, 127,2, 126,5, 96,2, 93,9, 81,9, 80,8, 78,8, 77,9, 77,8, 77,4, 77,2, 75,0, 72,1 56,8 (D., J = 18 Hz), 52,7, 42,7, 40,1, 35,7, 33,9, 33,6, 25,8, 22,6, 21,3, 20,8, 14,6, 14,4 ppm.

Example 3.

Receive:

N-Desbenzoyl-N-benzyloxycarbonyl-2'-{ [(2,2 is appropedia acid, 6, 12b-Bis(atomic charges)-12-(benzoyloxy)-2a, 3,4,4 a, 5,6,9,10,11,12,12 a,12b - dodecahydro-4-fluoro-11-hydroxy-4a,8,13,13-tetramethyl-5-oxo-7,11 - methane-1H-cyclodina[3,4]Benz[1,2-b] oxet-9-yl)), and

N-Desbenzoyl-N-benzyloxycarbonyl-2'-{[(2,2,2-trichloroethyl)oxy]carbonyl} -7-deoxy-7,8-/ metaethical(14BA), ((Ester,{2aR { [(2,2,2-trichloroethane)carbonyl] oxy} benzoylpropionic acid, 6,12 b-Bis(atomic charges)-12-(benzoyloxy)-2a, 3,4,4 a, 5,6,9,10,11,-12,12 a,12b - dodecahydro-11-hydroxy-8,13,13-trimethyl-5-oxo-4,4 a; 7,11-biomethane-1H-cyclodina[3,4]Benz[1,2-b]-oxet-9-yl)).

Using the procedure described for treatment of 2'-Troc-Taxol using Matildas (example 1), using N-desbenzoyl-N-benzyloxycarbonyl-2'-Troc-Taxol (12BA, preparation 6A, 0,223 g, 0.21 mm) and dimethylaminoacetonitrile (Matildas, 49 μl, of 0.066 g, 0.50 mm just added in two portions) in CH2Cl2(20 ml) in an atmosphere of N2at a temperature of -78oC. using this method get the coarse product in the reaction mixture (0,211 g, white solid), which chromatographic on silica gel (40-63 μm, two columns Merck size B) using a solution of CH2Cl2for application to the column and a mixture of 25% acetone:hexane for elution of material from the column. Collect fractions of 8 ml f is isano below.

Faction 128 - 140 contain the connection 13BA (of 0.081 g, 0.076 mm, 36%), which is characterized by the following spectroscopic data:

1H NMR (CDCl3TMS): 8,16 (D., 2H, J = 7.2 Hz, aromatic); 7,63 (t , 1H, J = 7.5 Hz, aromatic), 7,53 (t, 2H, J = 7,6 Hz, aromatic), 7,30 was 7.45 (m, 5H, aromatic), 7,24 (m, aromatic) 7,12 - 7,19 (m , 2H, aromatic), 6,56 (C., 1H, H10) 6,24 (t, 1H, H13), 5,74 (D. , 1H, J = 7,4 Hz, H2), 5,74 (1H, -NH-), 5,62 (D., 1H, H3), 5,44 (D., 1H, H2), 5,09 (D., 1H, J = 12,5 Hz, PhCHaHO-), 5,03 (D., 1H, H5), equal to 4.97 (D., 1H, PhCHHbO-), 4,77 (D. , 1H, J = 11,9 Hz, -OCHaHCCl3), 4,68 (D., 1H, J = 11,9 Hz, -OCHHbCCl3), 4,56 (DD., 1H, JF= 50 Hz, H7), 4,37 (D., 1H, H20a), 4,30 (D., 1H, H20b), 4,00 (D., 1H, J = 7,3 Hz, H3), to 2.57 (m, 1H, H6a), 2,46 (C., 3H, -CH3), is 2.40 (m, 1H, H14a), 2,21 (C., 3H, -CH3), of 2.15 (m, 1H, H14b), 1,89 (C. , 3H, -CH3), of 1.85 (m, 1H, H6b), 1,74 (C., 3H, CH3), 1,19 (C., 3H, -CH3), 1,16 (C., 3H, -CH3)

mass spectrum (FAB) 1060, 2466, C51H53Cl3FNO16+ H

requires 1060, 2492, 571, 553, 511, 472, 389, 347, 329, 105, 91 m/z.

Combined fractions 107-118 (0,065 g), obtained by elution with the previous column, subjected to repeated chromatographicaliy on silica gel (40-63 μm, one column Merck size B) using CH2Cl2for the 8 ml.

Faction 96 - 120 contain 0,043 g (0,041 mm, 20%) connection 14BA.

1H NMR (CDCl3TMS): 8,17 (D., 2H, J = 7,1 Hz, aromatic), to 7.59 (t , 1H, aromatic), 7,52 (t, 2H, aromatic), 7,31 - 7,46 (m, 5H, aromatic), 7,24 (m, aromatic), to 7.09 (m, 2H, aromatic), 6,32 (C. , 1H, H10), 6,28 (t, 1H, J = 8.6 Hz, H13), 5,75 (D., 1H, J = 10.0 Hz, -NH-), 5,64 (D. , 1H, J = 7.8 Hz, H2), 5,59 (d, 1H, H3), 5,41 (D., 1H, J = 2.6 Hz, H2), 5,00 (D., 1H, J = 12,5 Hz, ArCHaHO-), 4,91 (D., 1H, J = 12,6 Hz, ArCHHbO-), 4,76 (D., 1H, J = 9.8 Hz, -OCHaCCl3), 4,73 (D., 1H, H5), 4,68 (D., 1H, J = 9.9 Hz, -OCHHbCCl3), 4,30 (D., 1H, JF= 8.6 Hz, H20a), 4,07 (D. , 1H, H3), 4,05 (D., 1H, H20b), of 2.50 (m, 1H, H14a), 2,43 (C., 3H-CH3), a 2.36 (m , 1H, H6a), 2,24 (m, 1H, H19a), 2,20 (C., 3H, -CH3), 2,10 (D., 1H, J = 16.1 Hz, H14b), a 1.88 (C., 3H-CH3), of 1.66 (m, 1H, H19b), to 1.38 (m, 1H, H7), 1,26 (C., 3H-CH3), 1,21 (C., 3H-CH3)

mass spectrum (FAB) 1040, 2416, C51H52Cl3NO16+ H requires 1040, 2430, 980, 962, 551, 491, 369, 105, 91 m/z.

Example 10

Getting ether [2aR- [{ (2,2,2-trichloroethane)carbonyl} oxy] benzoylpropionic acid, 6,12 b-Bis(atomic charges)-12-(benzoyloxy)-2a, 3,4,4 a, 5,6,9,10,11,12,12 a,12b - dodecahydro-4-fluoro-11-hydroxy-4a, 8,13,13-tetramethyl-5-oxo-7,11-methane about-1H-cyclodina[3,4] Benz[1,2-b] -oxet-9-yl, 2'-[{(2,2,2-Trichloride is Xola [Magri, N. F.; Kingston, D. C. I. J. Org. Chem., 1986, 51, 797] (0,021 g 0,020 mm) in CH2Cl2(1.5 ml) is added via syringe over 5 minutes to a stirred and cooled (bath with a mixture of acetone : dry ice) solution of dimethylaminoacetonitrile (DUST) (2 μl, of 0.014 mm) in CH2Cl2(0.5 ml), placed in a vial of Reacti-vial (Reactivial) volume of 3 ml After 15 minutes the cooling bath is removed and allow the reaction mixture to warm to room temperature. The reaction mixture is stirred again cooled in a bath with a mixture of acetone : dry ice and add another portion will GIVE (4 μl, 0,028 mm) in CH2Cl2.After 15 minutes, remove the cooling bath, and after 90 minutes the reaction mixture is diluted by addition of CH2Cl2and washed with water. The layers separated, the organic phase is dried (Na2SO4), filtered and concentrated, obtaining the remainder of 0.017 g). The remainder chromatographic on silica gel (40 - 63 μm, 60 g), using for application to the column CH2Cl2-the solution and the mixture is 30% acetone in hexane for elution from the column with obtaining the desired target product, with Rf= 0,19 (30% acetone : hexane):

FAB mass spectrum gives peaks at 1034, 1032, 1030, 571, 511, 460, 442, 210 and 105 units of mass,

1H NMR (CDCl3TMS): ,76 (D., 2H), 4,66 (DV, 0.5 H), and 4.40 (d, 1H), or 4.31 (d, 1H), 4.04 the (doctor, 1H), 2,63 at 2.45 (m ), 2.49 USD (C., 3H), 2,27 - 2,10 (m), 2,20 (C., 3H), 1.91 a (C., 3H), 1,74 (C., 3H), 1,20 (C., 3H) and 1,17 (C., 3H),

13C NMR (CDCl3TMS) 206,0 169,9, 168,8, 167,2, 167,17, 153,2, 140,9, 136,4, 133,7, 133,5, 132,1, 130,3, 129,3, 129,2, 128,8, 128,7, 128,6, 127,2, 126,5, 96,2, 93,9, 81,9, 80,8, 78,8, 77,9, 77,8, 77,4, 77,2, 75,0, 72,1, 56,8, (D., J = 18 Hz), 52,7, 42,7, 40,1, 35,7, 33,9, 33,6, 25,8, 22,6, 21,3, 20,8, 14,6, 14,4 ppm.

Example 11

Getting Ether [2aR - hydroxybenzophenone acid, 6,12 b-Bis(atomic charges)-12(benzoyloxy)-2a, 3,4,4 a, 5,6,9,10,11,12,12 a, 12b - dodecahydro-4-fluoro-11-hydroxy-4a,8,13,13-tetramethyl-5-oxo-7,11 - methane-1H-cyclodina[3,4]Benz[1,2-b]oxet-9-yl;

7-deoxy-7-portakal (compound IIIb)

A solution of 2'-[{ (2,2,2-Trichloroethyl)oxy}carbonyl]-7-deoxy-7-portakal (compound 13AA, IIIa, 0,010 g, 0,0097 mm) in a mixture of 9:1 methanol/acetic acid (1 ml) is stirred with activated metal zinc (0,012 g) at room temperature. After 90 minutes the reaction is complete by removal of the zinc by filtration, followed by concentration of the filtrate under reduced pressure. The residue is dissolved in CH2Cl2sequentially and the resulting solution was washed with 0.1 N HCl, 5% aqueous NaHCO3and water. The aqueous layers are re-extracted with CH2Cl2, then the organic extracts are dried (Na2SO4), filtered and it is using to apply the solution in CH2Cl2. Column elute first with 60 ml of 20% ethyl acetate in hexane, and then 40% ethyl acetate in hexane. The desired product (compound IIIb) are obtained in the form of solids:

FAB mass spectrum 856, 571, 511, 286, 268, 240, 210, 105 units of mass,

1H NMR (CDCl3TMS): 8,15 (DD, 2H), of 7.75 (DD, 2H), 7,63 (t, 1H), 7,50 (m), 7,38 (m), 7,06 (d, 1H), 6,53 (S., 1H), 6,18 (t, 1H), (DD), 1H), 5,76 (D. , 1H), 5,02 (D., 1H), 4,80 (t, 1H) and 4.65 (DV, 0.5 H), 4,50 (DV, 0.5 H), to 4.38 (D., 1H), 4,29 (D., 1H), 4.04 the (doctor, 1H), 3,55 (D., 1H), 2,70 - 2,40 (m ), 2.40 a (C., 3H), 2,37 was 2.25 (m), 2,21 (C., 3H), of 1.75 (3H), 1,62 (C., 3H), 1,20 (C., 3H), 1,18 (C., 3H);

13C NMR (CDCl3TMS) 205,7, 172,4, 169,5, 169,4, 167,1, 166,9, 140,4, 138,0, 133,8, 133,7, 132,4, 131,9, 130,2, 129,2, 129,0, 128,75, 128,71, 128,3, 127,02, 126,98, 81,9, 81,0, 78,6, 77,2, 74,8, 73,2, 72,1, 57,0 (J = 17 Hz), 54,7, 42,6, 39,9, 35,8, 16,0, 22,5, 21,0, 20,8, 14,7, 14,2 ppm.

Using the procedure described Magri and Kingston to obtain 2'-[{ (2,2,2-Trichloroethyl)oxy} carbonyl] Taxol, get 2'-[{(2,2,2-Trichloroethyl)oxy}carbonyl]-derivatives of 7-epitaxial (ref.: Rengel, I.; Horwitz, S. B. J. Pharmacol. Exp. Ther., 1987, 242, 692: Director Preferably et al., J. Org. Chem., 1993, 58, 3798).

Example 12.

2'-[{(2,2,2-Trichloroethyl)oxy}carbonyl]-7-deoxy-7-epicortical

Using the procedure of example 10, but replacing 2'-[{(2,2,2-trichloroethyl)oxy} carbonyl] -7-Taxol 2'-[{(2,2,2-trichloroethyl)oxy}carbonyl]-7-epitaxy, get the target connection. The term 7-Dee fluorine-Deputy ephemera relative configuration of 2'-[{ (2,2,2-Trichloroethyl)oxy} carbonyl]-7-deoxy-7-portakal (compound 13AA, IIIa, example 1) and does not include a configuration similar to the configuration 7-epitaxial.

Example 13.

7-Deoxy-7-epicortical

Using the procedure of example 11, but replacing 2'-[{(2,2,2 - trichloroethyl)oxy} carbonyl]-7-deoxy-7-portakal 2'-[{(2,2,2 - trichloroethyl)oxy} carbonyl] -7-deoxy-7-epitaxy, get the target connection. The term 7-deoxy-7-epicortical used in the name of the target compounds only means that the configuration of the fluorine-Deputy ephemera relatively configuration 7-deoxy-7-portakal (compound IIIb, example II) and does not include a configuration similar to the configuration 7-epitaxial.

Example 14.

2'-[{(2,2,2-Trichloroethyl)oxy}carbonyl]Taxol, 7-Methanesulfonate

Methanesulfonyl chloride (1.2 equivalents) is added dropwise to a solution of 2'-[{ (2,2,2-Trichloroethyl)oxy} carbonyl]Taxol (1 equivalent) and pyridine (5 equivalents) in CH2Cl2that stirred at the temperature of the ice bath. Then the reaction mixture was allowed to warm up, continuing the mixing until until the TLC results confirm the completion of the reaction. The reaction mixture is cooled with ice water, extracted with CH2Cl2obtained extract is washed so it dried, filtered and concentrated, obtaining the coarse reaction product, chromatography was carried out gross product on silica gel gives pure target product.

Example 15.

2'-[{(2,2,2-Trichloroethyl)oxy}carbonyl]-7-deoxy-alpha - chlorthal

A solution of 2'-[{(2,2,2-Trichloroethyl)oxy}carbonyl]Taxol, 7-Methansulfonate (1 equivalent) in N,N-dimethylformamide (DMF) is stirred with potassium chloride (10 equivalents). Add the catalyst phase transition and heat the reaction mixture to increase the reaction rate. The progress of the reaction is followed by TLC. The reaction mixture is diluted by addition of water and extracted with CH2Cl2. The organic extract is dried, filtered and concentrated, and the crude reaction product chromatographic on silica gel, which results in pure target product.

Example 16.

7-Detox-7 - chlorthal

Using the procedure of example 11, but substituting 2'-[{(2,2,2-trichloroethyl)oxy} carbonyl] -7-deoxy-alpha of portixol 2'-[{(2,2,2-trichloroethyl)oxy}carbonyl]-7-deoxy-7-hortical get the target connection.

Example 17.

7-Deoxy-7 - chlorthal

Using the procedures of examples 14 and 15, but starting the reaction with 2'-[{ (2,2,2-trichloroethyl)oxy}carbonyl]-7-Epica is rocedure example 15 the corresponding metal salts, such as sodium bromide or potassium iodide, sodium or potassium, receive the following connections:

7-Deoxy-7 - brataccas,

7-Deoxy-7 - brataccas,

7-Deoxy-7 - iodoxy,

7-Deoxy-7 - iodoxy.

The compounds of formula III<where X = chlorine, bromine or iodine, can also be obtained by reaction of the corresponding precursor (i.e., 1 if R1= -C6H5, R2= -NHC(O)C6H5, R3= H, R4= -OTROC, R5= H, R10= -COCH3and X = (OH) C (C6H5)3P/X2; (C6H5)3P/CX4or (C6H5O)3P/X2in the following, for example, numerous examples, and experimental conditions described Castro (Castro, B. R., Organic Reactions, 1983, 29, pp. 1-162).

Derivatives of 7-deoxy-7-galatical, in which the 2'-hydroxyl group etherification, obtained directly from the desired 7-deoxy-7-galatical using the methods described in: Mathew, A. E.; et al., J. Med. Chem. , 1992, 35, 145, U.S. Patent 4942184, U.S. Patent 5059699.

In accordance with the General procedure, Matthew co-authors (see also U.S. patent 4960790, 4924184 and 5059699) using the corresponding change in the analog 7-deoxy-7-galatical receive the following connections:

2'-succin-7-deoxy-7-portixol,

2'-[-C(O)(CH2)3C(O)NH(CH2)3N(CH3)2]-7-deoxy-7-portixol,

2-(- sulfopropyl)-7-deoxy-7-portixol,

2'-(2-sulfonamide)succinyl-7-deoxy-7-portixol,

2'-(3-sulfopropyl)succinyl-7-deoxy-7-portixol,

2'-(triethylsilyl)-7-deoxy-7-portixol,

2'-(t-butyldimethylsilyl)-7-deoxy-7-portixol,

2'-(N,N-diethylaminopropyl)-7-deoxy-7-portixol,

2'-(N,N-dimethylglycine)-7-deoxy-7-portixol,

2'-(glycyl)-7-deoxy-7-portixol,

2'-(L-alanyl)-7-deoxy-7-portixol,

2'-(L-leucyl)-7-deoxy-7-portixol,

2'-(L-isoleucyl)-7-deoxy-7-portixol,

2'-(L-felled)-7-deoxy-7-portixol,

2'-(L-i.e. phenylalanyl)-7-deoxy-7-portixol,

2'-(L-prolyl)-7-deoxy-7-portixol,

2'-(L-lysyl)-7-deoxy-7-portixol,

2'(L-glutamyl)-7-deoxy-7-portixol,

2'-(L-arginyl)-7-deoxy-7-portixol,

7-deoxy-7-portixol,

2'-succinyl-7-deoxy-7-hortexa,

2-(- alanyl)-7-deoxy-7-harmacology ester of formic acid,

2'-glutaryl-7-deoxy-7-hortexa,

2'-[-C(O)(CH2)3C(O)NH(CH2)3N(CH3)2]-7-deoxy-7-hortexa,

2-(- sulfopropyl)-7-deoxy-7-hortexa,

2'-(2-sulfonamide)females who)-7-deoxy-7-hortexa,

2'-(t-butyldimethylsilyl)-7-deoxy-7-hortexa,

2'-(N,N-diethylaminopropyl)-7-deoxy-7-hortexa,

2'-(N,N-dimethylglycine)-7-deoxy-7-hortexa,

2'-(glycyl)-7-deoxy-7-hortexa,

2'-(L-alanyl)-7-deoxy-7-hortexa,

2'-(L-leucyl)-7-deoxy-7-hortexa,

2'-(L-isoleucyl)-7-deoxy-7-hortexa,

2'-(L-felled)-7-deoxy-7-hortexa,

2'-(L-i.e. phenylalanyl)-7-deoxy-7-hortexa,

2'-(L-prolyl)-7-deoxy-7-hortexa,

2'-(L-lysyl)-7-deoxy-7-hortexa,

2'-(L-glutamyl)-7-deoxy-7-hortexa,

2'-(L-arginyl)-7-deoxy-7-hortexa,

7-deoxy-7-chartacter,

2'-succinyl-7-deoxy-7-brataccas,

2-(- alanyl)-7-deoxy-7-postaxotomy ester of formic acid,

2'-glutaryl-7-deoxy-7-brataccas,

2' -[-C(O)(CH2)3C(O)NH(CH2)3N(CH3)2]-7-deoxy-7-brataccas,

2-(- sulfopropyl)-7-deoxy-7-brataccas,

2'-(2-sulfonamide)succinyl-7-deoxy-7-brataccas,

2'-(3-sulfopropyl)succinyl-7-deoxy-7-brataccas,

2'-(triethylsilyl)-7-deoxy-7-brataccas,

2'-(t-butyldimethylsilyl)-7-deoxy-7-brataccas,

2'-(N,N-diethylaminopropyl)-7-deoxy-7-brataccas,

2'-(N,N-dimethylglycine)-7-deoxy-7-brataccas,

2'-(R>2'-(L-isoleucyl)-7-deoxy-7-brataccas,

2'-(L-felled)-7-deoxy-7-brataccas,

2'-(L-i.e. phenylalanyl)-7-deoxy-7-brataccas,

2'-(L-prolyl)-7-deoxy-7-brataccas,

2'-(L-lysyl)-7-deoxy-7-brataccas,

2'-(L-glutamyl)-7-deoxy-7-brataccas,

2'-(L-arginyl)-7-deoxy-7-brataccas,

7-deoxy-7-bromaxefed,

2'-succinyl-7-deoxy-7-iodoxy,

2-(- alanyl)-7-deoxy-7-Itacolomi ester of formic acid,

2'-glutaryl-7-deoxy-7-iodoxy,

2-[-C(O)(CH2)3C(O)NH(CH2)3N(CH3)2]-7-deoxy-7-iodoxy,

2-(- sulfopropyl)-7-deoxy-7-iodoxy,

2'-(2-sulfonamide)succinyl-7-deoxy-7-iodoxy,

2'-(3-sulfopropyl)succinyl-7-deoxy-7-iodoxy,

2'-(triethylsilyl)-7-deoxy-7-iodoxy,

2'(t-butyldimethylsilyl)-7-deoxy-7-iodoxy,

2'-(N,N-diethylaminopropyl)-7-deoxy-7-iodoxy,

2'-(N,N-dimethylglycine)-7-deoxy-7-iodoxy,

2'-(glycyl)-7-deoxy-7-iodoxy,

2'-(L-alanyl)-7-deoxy-7-iodoxy,

2'-(L-leucyl)-7-deoxy-7-iodoxy,

2'-(L-isoleucyl)-7-deoxy-7-iodoxy,

2'-(L-felled)-7-deoxy-7-iodoxy,

2'-(L-i.e. phenylalanyl)-7-deoxy-7-iodoxy,

2'-(L-prolyl)-7-deoxy-7-iodoxy,

2'-(L-lysyl)-7-deoxy-7-taxoter and

their pharmaceutically acceptable salts, when the compound contains either an acidic or basic functional group.

Example 18.

Preparation of ester { [(2,2,2-trichloroethane)carbonyl] oxy} benzoylpropionate acid, 6,12 b-bis(atomic charges)-12-(benzoyloxy)-2a, 3,4,4 a,5,6,9,10,11,12,12 a,12b-dodecahydro-11-hydroxy-8,13,13-trimethyl-5-oxo-4,4 a, 7,11-biomethane-1H-cyclodina[3,4] Benz[1,2-b]oxet-9-yl, 2'-{[(2,2,2-Trichloroethyl)oxy]carbonyl}-7-deoxy-7,8 - metadatacache (compound 14AA, 11a)

A solution of 2'-{[(2,2,2-Trichloroethyl)oxy]carbonyl}Taxol [Magri, N. E.; Kingston, D. G. I. J. Org.Chem., 1986, 51, 797] (0,021 g 0,020 mm) in CH2Cl2(1.5 ml) is added via syringe over 5 minutes to a stirred and cooled (bath with a mixture of acetone:dry ice) solution of dimethylaminoacetonitrile (will GIVE) (2 μl, of 0.014 M) in CH2Cl2(0.5 ml), placed in a vial of Reacti-vial (Reactivial) volume of 3 ml After 15 minutes the cooling bath is removed and allow the reaction mixture to warm to room temperature. The reaction mixture is stirred again cooled in a bath with a mixture of acetone:dry ice and add another portion will GIVE (4 μl, 0,028 mm) in CH2Cl2. After 15 minutes, remove the cooling bath, and after 90 minutes the reaction mixture is diluted by adding trout and condense, getting the balance (of 0.017 g). The remainder chromatographic on silica gel (40-63 μm, 60 g), using for application to the column CH2Cl2-the solution and the mixture is 30% acetone in hexane for elution from the column. The desired target compound has an Rf= 0,22 (30% acetone: hexane) and crystallized from a mixture of acetone:hexane as colorless needle-like crystals:

FAB mass spectrum gives peaks at 1020, 1010, 551, 533, 511, 491, 460 and 442 mass units.

1H NMR (CDCl3TMS) 8,19 (D., 2H), 7,71 (D., 2H), to 7.59 (t, 1H), of 7.48 (m), of 7.36 (m), 6,98 (D., 1H) 6,57 (S., 1H), 6,28 (t, 1H), between 6.08 (DD., 1H), 5,67 (D., 1H), 5,54 (D., 1H), 4,77 (DD., 2H), 4,74, 4,32 (D., 1H), 4.09 to (doctor, 1H), 4,07, 2,47 (C., 3H), 2,19 (C., 3H), 1,90 (C., 3H), 1,67 (DD., 1H), 1,38 (m, 1H), 1.26 in (C., 3H) and 1,21 (C., 3H).

13C NMR (CDCl3TMS) 201,88, 169,64, 169,59, 167,45, 167,03, 166,96, 153,24, 140,41, 136,43, 133,89, 133,61, 133,36, 132,05, 130,31, 129,25, 129,15, 129,07, 120,95, 128,75, 128,68, 128,59, 127,17, 126,49, 93,82, 84,83, 80,11, 79,56, 79,47, 77,78, 77,23, 75,66, 75,41, 72,17, 52,58, 42,85, 38,57, 35,93, 33,04, 32,26, 26,05, 22,30, 21,60, 20,83, 15,82, 14,56 ppm.

Example 19.

Receiving Broadcast hydroxybenzophenone acid, 6, 12b-bis(atomic charges)-12-(benzoyloxy)-2a, 3,4,4 a, 5,6,9,10,11,12,12 a,12b - dodecahydro-11-hydroxy 8,13,13-trimethyl-5-oxo-4,4 a,7,11-biomethane-1H-cyclodina[3,4]- benzo[1,2-b]-oxet-9-Il,

7-Deoxy-7,8 - metadatacache (compound 11b)

A solution of 2'-{ [(2,2,2-trichloroethyl)oxy]carbonyl}-7-de active metal zinc (0,010 g) at room temperature. After 60 minutes add a new portion of zinc (0,010 g) and continued stirring for another 30 minutes. Solids are removed from the reaction mixture by filtration, and the filtrate concentrated under reduced pressure. The resulting residue was dissolved in CH2Cl2and washed successively with 0.1 N aqueous HCl solution, 5% aqueous solution of NaHCO3and water. The organic layer is dried (Na2SO4), filtered and concentrated, and the residue chromatographic on silica gel (40-63 μm, column 8 x 250 mm, applying the material in a solution of CH2Cl2, elution with a mixture of 40% ethyl acetate in hexane). The target compound is a colorless solid:

FAB mass spectrum gives peaks at 836, 776, 758, 551, 533, 491, 286, 240 and 105 units of mass.

1H NMR (CDCl3TMS) 8,19 (D., 2H), 7,69 (D., 2H), 7,60 (t, 1H), 7,60-7,35 (m), 6,95 (D., 1H), of 6.31 (SD, 1H), and 6.25 (t, 1H), of 5.82 (D., 1H), 5,66 (D., 1H), 4,78 (DD., 1H), 4.72 in (D., 1H), or 4.31 (D., 1H), 4,07 (D., 1H), 4,06 (m , 1H), 2.40 a (C., 3H), 2,20 (C., 3H), 1,60 (C., 3H), 1,38 (m, 1H), 1.26 in (C., 3H) and 1.22 (C., 3H),

13C NMR (CDCl3TMS) 204,45, 201,81, 172,74, 169,87, 169,56, 167,41, 166,96, 140,12, 138,04, 134,07, 133,53, 131,93, 130,33, 129,28, 129,04, 128,74, 128,55, 128,32, 127,04, 126,86, 84,86, 80,08, 79,57, 79,40, 77,21, 75,66, 75,46, 73,22, 72,28, 54,79, 42,86, 38,54, 36,07, 35,09, 32,15, 26,11, 22,27, 21,49, 20,88, 15,77 and 14,59 ppm.

Use oratel)-oxy}carbonyl]-7-deoxy-7-aminocyclo

Chilled in ice, a solution of sodium nitrite (1.5 equivalent) was added in portions to a vigorously stir cooled in ice two-phase mixture solution of 2'-[{ (2,2,2-Trichloroethyl)oxy} carbonyl] -7-deoxy-7-aminocyclo (1 equivalent) in ether and a solution of sulfuric acid in water. The mixture is stirred at the temperature of the ice bath for several hours after the components are added. Then the excess nitric acid is associated with the addition of an aqueous solution of urea. By careful addition of sodium carbonate bring the pH of the aqueous phase of the mixture to around neutral values, the layers separated and the aqueous phase is extracted with additional ether. The combined ether extracts are dried, filtered and concentrated, obtaining the coarse reaction product. The chromatography was carried out gross product on silica gel gives pure compound 14AA.

Example 21.

Obtaining 2'-[{ (2,2,2-trichloroethyl)oxy}carbonyl]-7-deoxy-7,8 - methane-Taxol (14AA, 11a) of 2'-[{(2,2,2-Trichloroethyl)oxy}carbonyl]Taxol 7-Trifluoromethyl-sulfonate

A solution of 2'-[{ (2,2,2-Trichloroethyl)-oxy} carbonyl] Taxol 7-Triftormetilfullerenov in a mixture of 80% ethanol:water is heated and analyzing the reaction mixture by TLC. Upon completion regixtration with methylene chloride. The extracts are dried, filtered and concentrated to obtain a rough reaction product. The coarse product chromatographic on silica gel, receiving a pure compound 14AA.

Example 22.

N-Desbenzoyl-N-benzyloxycarbonyl-7-deoxy-7-vertical (compound 18);

((Ether hydroxybenzophenone acid, 6, 12b-Bis(atomic charges)-12-(benzoyloxy)-2a, 3,4,4 a, 5,6,9,10,11,12,12 a, 12b-dodecahydro-4-fluoro-11-hydroxy - 4a,8,13,13-tetramethyl-5-oxo-7,11-methane-1H-cyclodina[3,4]Benz [1,2-b]-oxet-9-yl))

Applying, in General, the procedure of example No. 11 (reaction 2'-Troc-7-deoxy-7-portixol with activated zinc), but using N-desbenzoyl-N-benzyloxycarbonyl-2'-{ [(2,2,2-trichloroethyl)oxy] carbonyl} -7-deoxy-7-portakal (example 3, the connection 13BA, 0,079 g 0,074 mm) and activated zinc metal (0,153 g) in a mixture of CH3HE:HOAc (9:1,16 ml) and EtOAc (8 ml), get your desired product 18. Using the following method (reaction time 2 hours) and after the chromatography was carried out (silica gel, 40% EtOA:hexane, fraction 8 ml) coarse obtain the desired product 18, which eluted in the fractions 59-76, in the form of solids, characterized by the following main analytical parameters:

1H NMR (CDCl3TMS) to 8.14 (D., 2H, J = 7.4 Hz), a 7.62 (t, J = 7.2 Hz, H2), 5,38 (D., 1H, H3), 5,09 (D., 1H, J = 12,5 Hz, -OCHaHPh), 4,99 (D. , 1H, H5), 4,96 (D., 1H, J = 12.3 Hz, -OCHHbPh), 4,66 (D., 1H, H2), of 4.57 (DD. , 1H, JF= 54 Hz, H7), 4,36 (D., 1H, J = 8,4 Hz, H20a), 4,29 (D., 1H, H20b), 3,41 (D., 1H, J = 7,3 Hz, H3), 2,63-2,46 (lines 7, 1H), 2,38 (c, 3H, -CH3), 2,43-of 2.30 (m, 1H), 2,28 is 2.10 (m, 1H), 2,22 (C., 3H, -CH3), a 2.01 (m , 1H), 1.77 in (C., 3H, -CH3), 1,73 (C., 3H, -CH3), 1,19 (C., 3H, -CH3), 1,16 (C., 3H, -CH3).

13C NMR (CDCl3TMS) 206, 172, 169,5, 169,3, 166,9, 156, 140,5, 138, 137, 133,7, 132, 130,2, 129,3, 128,8, 128,7, 128,4, 128,0, 127,6, 126,7, 96, 93, 81,9, 80,9, 78,6, 78, 74,8, 73,6, 71,8, 66,8, 57, 56, 42,5, 39,9, 35,9, 34, 34, 25,9, 22,4, 21,0, 20,8, 14,5, 14 ppm,

mass spectrum 886, 571, 511, 371, 347, 329, 316, 298, 105, 91 m/z.

Example 23.

N-Desbenzoyl-N-benzyloxycarbonyl-7-deoxy-7,8 - mechanotaxis (compound 21),

((Ether hydroxymethylpropane acid, 6,12 b-Bis(atomic charges)-12-(benzoyloxy)-2a, 3,4,4 a, 5,6,9,10,11,12,12 a, 12b-dodecahydro-11-hydroxy-8,13,13 - trimethyl-5-oxo-4,4 a; 7,11-biomethane-1H-cyclodina[3,4]Benz[1,2-b]-oxet-9-yl))

Applying, in General, the procedure of example 11 [reaction of 2'-Troc-7-deoxy-7-portixol with activated zinc], but using N-desbenzoyl-N-benzyloxycarbonyl-2'-{[(2,2,2 - trichloroethyl)oxy]carbonyl}-7-deoxy-7,8 - metadatacache (VA, 0,040 g, 0.038 mm and activated zinc metal (0,072 g is according to the above method, after 3 hours of the completion of the reaction, and after chromatography was carried out (silica gel, 40% EtOAc:hexane, fraction 8 ml) coarse product, get the source material (0,007 g) in fractions 30-37, and the desired product (21, 0,020 g 0,023 mm, 61%), which eluted in the fractions 75-100, in the form of solids, characterized by the following main analytical parameters:

1H NMR (CDCl3TMS) 8,17 (d, 2H, J=7,3 Hz), 7,58 (m, 1H), 7,50 (t, 2H), 7,30 - 7,42 (m, 5H), 7,24 (m), was 7.08 (m, 2H), of 6.31 (C., 1H, H10), of 6.26 (t, 1H, J=8.6 Hz, H13), 5,70(D., 1H, J=9.6 Hz, -NH-), 5,64 (D., 1H, J= 7.7 Hz, H2), 5,38 (D. , 1H, J=8.6 Hz, H3), to 4.98 (D., 1H, J=12,5 Hz, -OCHaHPh), 4,88 (D., 1H, J=12,5 Hz, -OCHHbPh), 4,71 (D., 1H, J=3,7 Hz, H5) and 4.65 (C., 1H, H2), 4,28 (D., 1H, J=8.6 Hz, H20a), 4,07 (D., 1H, H3) 4,05 (D. , 1H, H20b), 2,49-of 2.34 (m, 1H), 2,38 (C., 3H, -CH3), of 2.23 (m), 2,21 (C., 3H, -CH3), 2,08 (m ), of 1.94 (m), 1,82 (C., 3H, -CH3), to 1.37 (m, 1H, H7), 1,25 (C., 3H, -CH3), 1,21 (C., 3H, -CH3)

13C NMR (CDCl3TMS) 202, 172,5, 169,2, 169,1, 167, 155,5, 149,5, 138, 136, 133,5, 133, 130,0 128,6, 128,4, 128,1, 127,7, 127,2, 126,3, 84,5, 79,9, 79,2, 79,0 75,3, 75,2, 73,0, 71,7, 66,5, 56,0, 42,5, 38,2, 36,0, 34,7, 32,0, 25,7, 21,5, 21,0, 20,5, 15,5, 14,2 ppm,

mass spectrum 886,3423, C48H51NO14+ H requires 866, 3388, 848, 806, 788, 511, 533, 491, 105, 91 m/z.

Example 24.

N-Desbenzoyl-N-(t-butyl)oxycarbonyl-2'-{ [(2,2,2-trichloroethyl)oxy] the Wai acid, 6,12 b - Bis(acetoxy)-12-(benzoyloxy)-2a, 3, 4, 4a, 5, 6, 9, 10, 11, 12, 12a, 12b, dodecahydro-4-fluoro-11-hydroxy-4a, 8, 13, 13-tetramethyl-5-oxo-7,11-methane-1H-cyclodina [3,4]Benz[1,2-b]-oxet-9-yl)), and

N-Desbenzoyl-N-(t-butyl)oxycarbonyl-2'-{[(2,2,2-trichloroethyl)oxy]carbonyl} -7-deoxy- -7,8 - mechanotaxis (connection 14DA),

((Ester { [2,2,2-trichloroethane)carbonyl] oxy}benzoylpropionic acid, 6,12 b-Bis(atomic charges)-12-)benzoyloxy)-2a, 3,4,4 a, 5,6,9,10,11,12,12 a,12b-dodecahydro-11-hydroxy-8,13,13-trimethyl-5-oxo - 4,4 a,7,11-biomethane-1H-cyclodina [3,4]-benzo[1,2-b] -oxet-9-yl)).

Using the General procedure of example 10 (reaction 2'-Troc-Taxol with Matildas) using N-desbenzoyl-N-(t-butyl)oxycarbonyl-2'-Troc-Taxol (compound 12 DA, 1,800 g of 1.75 mm) and dimethylaminoacetonitrile (Matildas, 286 μl, 0,390 g of 2.93 mm) in CH2Cl2(120 ml) in an atmosphere of N2at a temperature of -78oC. using the Following method, the mixture of coarse product (1.77 g) chromatographic on silica gel (40-63 μm, 191 g in column 37 x 350 mm, fraction volume 45 ml) using a solution in CH2Cl2for application to the column and a mixture of 20% acetone:hexane (1.5 l) and then a mixture of 25% acetone-hexane for elution of product from the column. A mixture containing 14DA (0,511 g) eluted in fractions 41-46. the E. combined fractions 47-48 gives an additional amount of the mixture, containing 14DA and clean 13DA.

Net connection 13DA receive in the form of a solid substance, which is characterized by the following main analytical parameters:

1H NMR (CDCl3TMS) / 8,15 (D., 2H, J=7,2 Hz), a 7.62 (t, 1H, J=7,2 Hz), 7,51 (t, 2H, J=7,7 Hz), 7,25 - 7,44 (m, 5H), 6,58 (C., 1H, H10), 6,28 (t , 1H, J= 7 Hz, H13), 5,77 (D., 1H, J=7,2 Hz, H2), 5,51 (D., 1H, -NH-), 5,48 (D., 1H, J=10.0 Hz, H3), of 5.40 (D., 1H, J=2.0 Hz, H2), of 5.05 (D., 1H, J= 8,1 Hz, H5), 4,77 (D., 1H, J=11.8 Hz, Troc-Ha), 4,68 (D., 1H, J= 11.8 Hz, Troc-Hb), 4,58 (DD. 1H, J=4,6, 46,9 Hz, H7), 4,39 (D., 1H, J=8,4 Hz, H20a), 4,27 (D. , 1H, J=8,4 Hz, H20b), Android 4.04 (D., 1H, J=7,1 Hz, H3), to 2.57 (m, 1H, H6a), 2,48 (C. , 3H, -CH3), 2,21 (C., 3H, -CH3), 1,91 (C., 3H, -CH3), 1,73 (C. , 3H, -CH3), 1,34 (C., 9H, Me3C-), 1,23 (C., 3H, -CH3), 1,17 (C., 3H, -CH3)

mass spectrum 1026, 2660, C48H55Cl3FNO16+ H requires 1026, 2648, 970, 571, 511, 407, 389, 347, 329, 105, 57 m/z.

All fractions containing the mixture, which includes 14 DA, combine and re-chromatographic on silica gel (two columns Merck Lobar size B, fraction volume: 9 ml), causing the material to the column in a solution of CH2Cl2and using for elution of the column sequentially mixture of 10% CH3CN: CH2Cl2(68 fractions) and 15% of CH3CN:CH2Clesta, which is characterized by the following main analytical parameters:

1H NMR (CDCl3TMS) 8,15 (D., 2H, J=7,1 Hz), to 7.61 (t, 1H, J=7,3 Hz), 7,51 (t , 2H, J=7.5 Hz), 7,30-7,44 (m, 5H), 6,34 (C., 1H, H10), 6,30 (t, 1H, J= 8.6 Hz, H13), 5,67 (D., 1H, J=7,6 Hz, H2), 5,54 (D., 1H, -NH-), the 5.45 (D. , 1H, J=10.1 Hz, H3), 5,38 (D., 1H, J=2.3 Hz, H2) 4,76 (D., 1H, J=11.8 Hz, Troc-Ha), WAS 4.76 (1H, H5), 4,69 (D., 1H, J=11.8 Hz), Troc-Hb), 4,33 (D., 1H, J= 8.6 Hz, H20a), 4.09 to (doctor, 1H, J=7.5 Hz, H3) 4,04 (D., 1H, J=8.7 Hz, H20b), 2,48 (m , 1H, H14a), 2,44 (C., 3H, -CH3), is 2.37 (m, 1H, H6a), 2,24 (m, 1H, H19a), 2,20 (c. 3H, -CH3) 2,11 (D., 1H, J=16.0 Hz, H14b), 1,90 (C. , 3H, -CH3), of 1.66 (m, 1H, H19b), to 1.37 (m, 1H, H7); 1,28 (C., 9H, Me3C-), 1.27mm (C., 3H, -CH3), 1,25 (c. 3H, -CH3)

mass spectrum, found: 1006, 2560, C48H54Cl3NO16+ H requires 1006, 2486; 950, 551, 533, 491, 369, 327, 105, 57 m/z.

Example 25.

N-Desbenzoyl-N-(t-butyl)oxycarbonyl-7-deoxy-7-fluoro Taxol (compound 20),

((Ether hydroxybenzoyl-prapanova acid, 6,12 b-Bis(atomic charges)-12-(benzoyloxy)-2a, 3,4,4 a, 5,6,9,10,11,12,12 a, 12b-dodecahydro-4-fluoro-11-hydroxy-4a,8,13,13-tetramethyl-5-oxo-7,11 - methane-1H-cyclodina[3,4]Benz[1,2-b]-oxet-9-yl))

Apply the General procedure of example 11 [reaction of 2'-Troc-7-deoxy-7-portixol activated qi is Sola (13DA, 0,100 g, 0,097 mm) and activated zinc metal (0,183 g, followed by addition of 0.50 g) in a mixture of CH3OH: OHAc (9:1, 10 ml). After 1 hour after start of the reaction, the reaction mixture was left overnight at a temperature of -33oC, then the reaction is stopped and chromatographic crude product (silica gel, 40% EtOAc: hexane, fraction volume 8 ml), to obtain the desired compound 20 of fractions 53-76 in the form of solids, characterized by the following main analytical parameters:

1H NMR (CDCl3TMS) 8,13 (D., 2H, J = 7,2 Hz), a 7.62 (t, 1H, J=7.4 Hz), 7,51 (t, 2H, J=7.5 Hz), 7,30 - 7,42 (m, 5H), 6,56 (C., 1H, H10), 6,21 (t , 1H, H13), 5,76 (D., 1H, J=7,2 Hz, H2), 5,42 (D., 1H, J=9.7 Hz, -NH-), from 5.29 (D., 1H, H3), 5,01 (D., 1H, J=7.5 Hz, H5), 4,63 (m, 1H, H2), of 4.57 (DD. , 1H, J=4,3 and 46.8 Hz, H7), 4,37 (DD., 1H, J= 8,4 Hz, H20a), 4,27 (D., 1H, J= 8,4 Hz, H20b), Android 4.04 (D., 1H, J= 7,1 Hz, H3), 2,56 (lines 7, 1H, H6a), 2,39 (C., 3H, -CH3), 2,31 (m, 1H, in), 2.25 (m, 1H), 2,22 (C., 3H, -CH3), and 2.14 (DD. , 1H), 1,81 (C., 3H, -CH3), 1,73 (C., 3H, -CH3), 1,34 (C., 9H, Me3C-), 1,23 (c. 3H, -CH3), 1,18 (C., 3H, -CH3).

Example 26.

N-Desbenzoyl-N-(t-butyl)oxycarbonyl-7-deoxy-7,8 - mechanotaxis (compound 23)

((Ether hydroxybenzophenone acid, 6, 12b-Bis(atomic charges)-12-(benzoyloxy)-2a, 3,4,4 a, 5,6,9,BR> Apply the General procedure of example 11 [reaction of 2'-Troc-7-deoxy-7-portixol with activated zinc] using N-desbenzoyl-N-(t-butyl)oxycarbonyl-2'-{ [(2,2,2-trichloroethyl)oxy] carbonyl} -7-deoxy-7,8 - metadatacache (14DA, 0,100 g 0,099 mm) and activated zinc metal (0,200 g and then adding another 0,050 g) in a mixture of CH3OH: OHAc (9: 1, 10 ml). Using this method, after 3 hours the reaction and chromatography was carried out gross product (silica gel, 40% EtOAc: hexane, fraction volume 8 ml), get your desired product 23, which eluted in the fractions 58-86, in the form of solids, characterized by the following main analytical parameters:

1H NMR (CDCl3, TMS) of 8.15 (d, 2H, J = 7,2 Hz), to 7.61 (t, 1H, J = 7,3 Hz), 7,51 (t, 2H, J = 7,7 Hz), 7,28 was 7.45 (m, 5H), 6,33 (C., 1H, H10), 6,27 (t, 1H, H13), 5,67 (d, 1H, J = 7,6 Hz), are 5.36 (d, 1H, J = 9.6 Hz, H3), and 5.30 (m, 1H, -NH-), to 4.73 (d, 1H, J = 3,7 Hz, H2), to 4.62 (m, 1H, H5), or 4.31 (d, 1H, J = 8.6 Hz, H20a), 4.09 to (d, 1H, J = 7.5 Hz, H3), Android 4.04 (d, 1H, J = 8.7 Hz, H20b) 2,46 (d,, 1H, J = 4,3, 16.1 Hz, H6a), of 2.38(s, 3H, -CH3), 2,24 (m, 1H), of 2.21 (s, 3H, -CH3), 2,10 (d, 1H, J = 16.0 Hz), of 1.85 (s, 3H, -CH3), 1,67 (DD. , 1H, J = 7,1, 5,2 Hz) of 1.36 (m, 1H, H7), of 1.28 (s, 12H, Me3C - CH3-), 1,25 (s, 3H, -CH3)

Example 29.

2'-TES-7-deoxy-7 - Horta potassium chloride (10 equivalents). Add the catalyst phase transition and heat the reaction mixture to increase the reaction rate. The progress of the reaction is followed by TLC. To stop the reaction mixture was added water and the extraction is carried out with the use of CH2Cl2. The organic extracts dried, filtered and concentrated, and the obtained crude product chromatographic on silica gel, resulting in total net target connection.

Example 30.

7-Deoxy-7 - chlorthal

Using the procedure of obtaining the drug 12A, but starting with 2'-TES-7-deoxy-7 - horticola, get the target connection.

Using General procedure of example 29 and 30, but using the appropriate metal salts, such as sodium bromide or potassium and the iodide of potassium, according to the procedure of example 29 to obtain the following compounds:

7-Deoxy-7 - brataccas,

7-Deoxy-7 - brataccas,

7-Deoxy-7 - iodoxy,

7-Deoxy-7 - iodoxy.

Example 31.

Obtaining N-desbenzoyl-N-(t-butyl)aminocarbonyl-7-deoxy - 7-fluoro-Taxol (compound 28)

N-Desbenzoyl-N-CbZ-7-deoxy-7-fluoro-Taxol 18 (60 mg, 0.07 mmol, preparation 39) dissolved in 3 ml of absolute ethanol and added 20 mg of 10% palladium-on-charcoal grill. The mixture hydrogenizing the initial material, therefore, the reaction mixture was filtered through Celite and concentrated in vacuo. The remainder, representing 13-(- phenyl-azaserine)-7-fluoro-baccatin III (19,52 mg, 0.07 mmol, preparation 40), dissolved in 700 μl of THF, cooled to 0oC and add 7 ál (0,061 mm) t-utilizationof. As TLC after this still shows a certain amount of residual amine, add 7 µl. After 20 hours the reaction mixture was concentrated in vacuo and chromatographic on the column with 6 g of silica gel in a mixture of 1:2 EtOAc:hexane. Column elute sequentially D 30 ml of a mixture of 1:2 EtOAc: hexane, 60 ml of a mixture of 2:3 EtOAc: hexane, 50 ml of a mixture 1:1 EtOAc:hexane and 20 ml of a mixture of 2:1 EtOAc:hexane, collecting fractions of 3 ml of the Desired N-desbenzoyl-N-(t-butyl)aminocarbonyl-7-deoxy-7-fluoro-Taxol is in fractions 35 to 52.

Mass spectrum (FAB - High resolution)

The calculated value 851,3766

Found: 851,3792.

1H NMR (CDCl3TMS) 1,16 (C., 3H), 1,20 (C.), 1,72 (C., 3H), of 1.80 (s, 3H), 2,15-2,60 (m), 2,19 (C., 3H), 2,52 (C., 3H), was 4.02 (D., 1H), 4,28 (D., 1H), 4,35 (D., 1H), 4,55 (DD., 1H), 4,59 (D., 1H), 4,88 (CL., 1H), 4,99 (D., 1H), of 5.34 (m, 2H), 5,76 (D., 1H), 6,13 (m, 1H), 6,55 (S., 1H), 7,32 (m), 7,49 (m, 2H), to 7.61 (m, 1H), 8,11 (D., 2H).

Example 32.

Obtaining N-desbenzoyl-N-(t-butyl)aminocarbonyl-7-deoxy-7,8 - methane-Taxol, the Connection 29

N-Dibenzoyl-Nd coal. The resulting mixture was subjected to hydrogenation at atmospheric pressure for 5.5 hours. Data TLC shows the absence of starting material so the reaction mixture was filtered through Celite and concentrated in vacuo.

The remainder, which represents 13(-phenyl-azaserine)-7-deoxy-7,8 - methane-baccatin III (22,52 mg, 0.07 mmol, preparation 43), dissolved in 1 ml of THF and add 8 ml (0.07 mmol) t-butyl isocyanate. TLC shows the presence of some quantity of the amine, so the reaction mixture was cooled to 0oC and add 7 ml of t-butyl isocyanate. Amin is still, so add 7 ml and 3 to 5 ml and each time before adding control the composition of the reaction mixture by TLC. To stop the reaction, add water to the mixture and distribute the solution between the acidified salt solution and EtOAc. The layers separated, and the organic layer filtered through Na2SO4, concentrated in vacuo and chromatographic on 6 g of silica gel deposited on a column in a mixture of 1:2 EtOAc-hexane. The elution carried out with a column of 30 ml of 1:2 EtOAc:hexane, 50 ml of 2:3 EtOAc:hexane and 80 ml of 1:1 EtOAc:hexane to obtain 3 ml fractions. The desired N-desbenzoyl-N-(t-butyl)- aminocarbonyl-7-deoxy-7,8 - methane-Taxol is found in fractions 29-48.

Mass spec is.), 1,23 (C., 3H), 1.26 in (C., 3H), of 1.66 (m ), 1,82 (C. , 3H), 1,98-2,48 (m), 2,20 (C., 3H), of 2.38 (SD, 3H), of 4.05 (m, 2H), 4,30 (D., 1H), 4,50 (m, 1H), 4,60 (D., 1H), 4,73 (M, 1H), 5,33 (m, 1H), 5,66 (D., 1H), to 6.19 (m, 1H), of 6.31 (SD, 1H), 7,32 (m), 7,51 (m, 2H), to 7.61 (m, 1H), 8,13 (D., 2H).

Derivatives of 7-deoxy-7,8 - methane-tokalov, in which the 2'-hydroxyl group etherification receive directly from the desired 7-deoxy-7,8 - methane-Taxol using the methods described in: Mathew, A. E., et al., J. Med. Chem., 1992, 35, 145, U.S. patent 4942184, U.S. patent 4059699.

In accordance with the General method of Matthew with co-authors (see also U.S. patent 4960790, 4924184 and 5059699) implement appropriate replacement for analogue 7-deoxy-7,8 - methane-Taxol receive the following connections:

2'-succinyl-7-deoxy-7,8 - methane-Taxol,

2-(-alanyl)-7-deoxy-7,8 - methane-taxonomy ester of formic acid,

2'-glutaryl-7-deoxy-7,8 - methane-Taxol,

2'-[C(O)(CH2)3C(O)NH(CH2)3N(CH3)2]-7-deoxy-7,8 - methane-Taxol,

2-(-sulfopropyl)-7-deoxy-7,8 - methane-Taxol,

2'-(2-sulfonylamino)succinyl-7-deoxy-7,8 - methane-Taxol,

2'-(3-sulfonylamino)succinyl-7-deoxy-7,8 - methane-Taxol,

2'-(triethylsilyl)7-deoxy-7,8 - methane-Taxol,

2'-(t-butyldimethylsilyl)-7-deoxy-7,8 - methane-Taxol,

2'-(N,N-diethylamino is soxi-7,8 - methane-Taxol,

2'-(L-alanyl)-7-deoxy-7,8 - methane-Taxol,

2'-(L-leucyl)-7-deoxy-7,8 - methane-Taxol,

2'-(L-isoleucyl)-7-deoxy-7,8 - methane-Taxol,

2'-(L-felled)-7-deoxy-7,8 - amino-Taxol,

2'-(L-phenylalanine)-7-deoxy-7,8 - methane-Taxol,

2'-(L-prolyl)-7-deoxy-7,8 - methane-Taxol,

2'-(L-lysyl)-7-deoxy-7,8 - methane-Taxol,

2'-(L-glutamyl)-7-deoxy-7,8 - methane-Taxol,

2'-(L-arginyl)-7-deoxy-7,8 - methane-Taxol,

7-deoxy-7,8 - methane-Taxotere, and

their pharmaceutically acceptable salts, when the compound contains either an acidic or basic functional group.

Taxol and other derivatives of Taxol is known or can be obtained by known methods.

(See The Chemistry of Taxol, Pharmal. Ther., Vol. 52, pp. 1-34, 1991, and U.S. patent N 4181470, 4857638, 4942184, 4924011 4924012, 4960790, 5015744, 5059699, 5136060, 5157049, 4876399, 5227400, as well as PCT publication N WO 92/09589, the Application for the European patent 90305845.1 (publication N A2 0400971), 89400935.6 (publication N .A1 0366841) and 90 402333.0 (publication N A1 0414610), 87401669.4 (A1 0253739), 92308608.6 (A1 0534708), 92308609.4 (A1 534709) and PCT publication N WO 91/17977, WO 91/17976, WO 91/13066, WO 91/13053, all of which are listed here as a reference).

Compounds of the present invention can be introduced into pharmaceutical compositions or presented in the form of their pharmacist is or pharmaceutically acceptable salts joining the Foundation. These salts can be obtained using traditional chemical methods of those compounds of the present invention, which contain acidic or basic groups.

In the normal case, get salt by reaction of the free base or acid, taken in stoichiometric amount or in excess, with an inorganic or organic acid, forming the desired salt in a suitable solvent or various combinations of solvents. For example, the free base can be dissolved in an aqueous solution of the appropriate acid, with the resulting salt can be isolated using standard techniques, for example by evaporation of the solution. Alternatively, the free base can be dissolved in an organic solvent such as a lower alkanol, ether, alkyl ether or their mixtures, for example in methanol, ethanol, ether, a mixture of ethyl acetate: ether and so on, after which it is treated with the appropriate acid to obtain the corresponding salt. Salt distinguish using standard technologies, for example, by filtering to separate the desired salt from solution or, alternatively, it may be precipitated by adding a solvent in which the salt is insoluble and in the end, the La cancer treatment due to their cytotoxic, antitumor activity. The new compounds can be administered in the form of tablets, pills, powder mixtures, capsules, injections, solutions, suppositories, emulsions, dispersions, food additives and other suitable forms. Pharmaceutical composition, which contains compounds of the present invention, usually mixed with non-toxic pharmaceutical organic carrier, or a non-toxic pharmaceutical inorganic carrier, usually in the range from 0.01 mg to 2500 mg or higher per unit dose, preferably from 50 to 500 mg. of a Typical pharmaceutically acceptable carriers are, for example, mannitol, urea, dextran, lactose, potato and maize starch, magnesium stearate, vegetable oils, polyalkylene glycols, ethylcellulose, poly(vinyl pyrrolidone), calcium carbonate, etiloleat, isopropylmyristate, benzyl benzoate, sodium carbonate, gelatin, potassium carbonate, silicic acid and other acceptable traditionally used media. The pharmaceutical composition may also contain additional non-toxic substances, such as emulsifiers, preservatives, moisturizing agents and others, such as sorbitanoleat, triethanolamine, polyoxyethylenated, glyceryltrinitrate active agents, includes, first, mixing the agent with a non-toxic binding substance, such as gelatin, ointment-based Arabian gum, ethylcellulose etc. Mixing is usually carried out in a standard V-shaped blender and usually in anhydrous conditions. Then only that the resulting mixture can be slowly filtered through a conventional tablet machine and the resulting viscous mass was formed into tablets. Fresh tablets may contain or not contain a floor. Examples of suitable types of coating can be non-toxic coating that includes shellac, methylcellulose, Carnauba wax, copolymers of styrene-maleic acid, etc. For oral administration compressed tablets containing 0.01 mg, 5 mg, 25 mg, 50 mg, 500 mg, and so on up to 2500 mg, manufactured based on the above disclosure and use known in the art production methods, widely applicable and set forth in Remington with pharmaceutical. Science (Remington''s Pharmaceutical Science, Chapter 39, Mack Publishing Co. 1965).

To obtain tablets active connection, corn starch, lactose, dicalcium phosphate and carbamate calcium uniformly mixed under dry conditions in a conventional V-shaped blender until until all ingred is more with a freshly prepared mixture until until a homogeneous mass is formed. The resulting mixture was passed through a sieve with fine holes, dried in anhydrous atmosphere, and then stirred with calcium stearate, pressed into tablets and, if necessary, create the floor. Other tablets containing 10, 50, 100, 150 mg, and so on, get a similar manner.

The following composition 1 is a polymer of obtaining tablets containing compounds of the present invention.

Composition 1

Ingredients: - Quantity per tablet, mg

Active connection - 50,0

Corn starch - 15,0

A paste of corn starch - 4,5

Calcium carbonate - 15,0

Lactose - 67,0

Calcium stearate - 2,0

The dicalcium phosphate - 50,0

Receipt for oral administration of capsules containing from 10 mg to 2500 mg, includes, first of all, mixing the active compounds with non-toxic carrier and incorporating the mixture into a polymer capsule, usually gelatin or similar. Capsules can be represented as known in the art soft forms, or they can be created by adding connections thoroughly mixed dispersion on the basis of the food compatible carrier, in another case, the capsule may the smoke substance, such as talc, calcium stearate, calcium carbonate, etc., Capsules containing 25 mg, 75 mg, 125 mg, etc. of the new compounds, singly or in the form of mixtures of two or more new compounds are prepared, for example, as follows:

Composition 2

Ingredients: - Quantity per capsule, mg

Active connection - 50,0

Calcium carbonate - 100,0

Lactose, USP - 200,0

Starch - 130,0

Magnesium stearate - 4,5

The above ingredients are mixed with each other in a standard blender, which is then discharged into commercially applicable capsules. In the case of using higher concentrations of the active substance accordingly reduce the amount of lactose.

Compounds of the present invention can be dried by freezing and, if necessary, combined with other pharmaceutically acceptable excipients for preparation of compositions suitable for parenteral administration or for injection. For such an introduction of the compositions can be created with the use of water (plain, salt) or a mixture of water and an organic solvent, such as propylene glycol, ethanol, etc.

For each connection-specific input dose, single dose, brannam by way of introduction, weight of the recipient and the patient. There is no specific framework to limit the input dose, however, in the usual case, this should be an effective amount, or representing a molar equivalent of a pharmacologically active free form obtained on the basis dosing of the composition under conditions of metabolic release of the active drug substance required to achieve the desired pharmacological and physiological effects.

In a typical case, the compounds of the present invention can be administered by intravenous injection at doses of 1 to 500 mg per patient per course of treatment, preferably in doses of 2 to 100 mg, the exact dose depends on age, weight and condition of the patient. One example suitable for injection composition includes a solution of the compound of the present invention in a mixture of ether, alcohol and polycarbonates acid and dehydrated alcohol (i.e. 1:1), which in the future, just before infusion or injection, diluted with 5% dextrose in water.

The compounds of formula I (including II and III are used to treat certain types of cancer, for which it was shown that the activity of Taxol, including ovarian cancer man, has swelled the neck and leukemia). On clinical pharmacology of Taxol see also overview made Eric K. Rowinsky & Ross C. Donehower, The Clinical Pharmacology and USE of Antimicrotubule Agents in Canser Chemotherapeutics, Pharmac. Ther. vol. 52, pp. 35 - 84, 1991. Review of clinical and preclinical studies of Taxol made in the work of William J. Slichenmyer & Daniel D. Von Hoff, Taxol: A New and Effective Anticancer Drugs, vol. 2, pp. 519 - 530, 1991.

The biological activity of the compounds 7-deoxy-7,8 - methane-Taxol (formula II) of the present invention was confirmed using well known techniques. For example, the comparison of the cytotoxicity of 7-deoxy-7,8 - methane-Taxol (Compound IIb, the product of example 19) with the Taxol in the culture of murine leukemic cell line L 1210 shows that IR90(90% of the concentration causing inhibition of growth) for 7-deoxy-7,8 - methane-Taxol is 0.025 μg/ml, and for Taxol she is 0.06 ág/ml In the in vitro text on tubulin polymerization method Gaskin with co-authors (F. Gaskin et al., J. Mol. Biol. 89, 737, 1974), 7-deoxy-7,8 - methane-Taxol showed very similar to Taxol ability to induce the polymerization of tubulin in vitro at 20oC.

The biological activity of the compounds 7-deoxy-7-galatical (formula III) of the present invention was confirmed using the compound IIIb, the product of example II) and the Taxol in cell culture A2780 (ovarian cancer cells human) shows that IR90(the concentration that causes 90% inhibition of growth) for 7-deoxy-7-portixol is to 0.016 μg/ml, and for Taxol equal to 0.007 μg/ml In the text in vitro by induction of tubulin polymerization carried out according to the method of F. Gaskin et al. (F. Gaskin et al., J. Mol. Biol., 89; 737, 1974) 7-deoxy-7-portakal-demonstrated the ability to induce the polymerization of tubulin in vitro at 20oC similar to Taxol. In this test, 7-deoxy-7-portixol had half compared with Taxol activity.

The biological activity of the compounds of the present invention was further confirmed by using well-known procedures conducted using leukemia cells L 1210, the results of this study are presented in the table. It was used a well-known technique (Li, L. H., Kuentzel, S. L. Murch, L. L., Pschigoga, L. M., and Krueger, "Comparative biological and biochemical effects of nogalamycin and its analogs on L 1210 Leukemia", Canser Res., 39:4816 - 4822 (1979)).

The results are expressed as index IR50that means the concentration of drug required to inhibit cell proliferation to 50% level ="ptx2">

1. Derivatives tokalov General formula I

< / BR>
where R1is methyl or phenyl;

R2is a hydrogen atom, -NHC(O)H, -NHC(O) C1-C10-alkyl, -NHC(O)phenyl, -NHC(O)OCH2phenyl, -NH2, -NHC(O)-1-substituted, -NHC(O)O-3-tetrahydrofuranyl, -NHC(O)-O-4-tetrahydropyranyl, -NHC(O)CH2C(CH3)3, -NHC(O)C(CH3)3, -NHC(O)NHPh, -NHC(O)C(CH2CH3)2CH3, -NHC(O)C(CH3)2CH2Cl, -NHC(O)C(CH3)2CH2CH3phthalimidopropyl, -NHC(O)-1-phenyl-1-cyclopentyl, -NHC(O)-1-methyl-1-cyclohexyl, -NHC(S)NHC(CH3)3, -NHC(O)NHC(CH3)3or-NHC(O)NHPh;

R3is a hydrogen atom, -NHC(O)phenyl or-NHC(O)OC(CH3)3provided that one of the two substituents R2and R3represents a hydrogen atom, but both R2and R3cannot be represented by radicals - H;

R4is a hydrogen atom or is selected from the group of-OC(O)OCH2C(Cl)3or-NHC(O)phenyl;

R5is a hydrogen atom or OH group, provided that when R5- OH-group, R4- the hydrogen atom and also provided that when R5represents a hydrogen atom, R4is different from a hydrogen atom;

R6is a hydrogen atom when R7is a-R71Il is t halogen atom, and R8is methyl, or R6is a hydrogen atom, R7represents-H; R74where R74and R8together with the formation of cyclopropylamino ring;

R10is a hydrogen atom or-C(O)CH3group,

or their pharmaceutically acceptable salts, when the compound contains either an acidic or basic functional group.

2. Connection on p. 1 where the said radical R2represents NHC(O)O6H5, R4represents a hydroxy-group, R3and R5denote-H, and R1represents phenyl.

3. Connection on p. 1, where the said radical R2represents NHC(O)OC(CH3)3, R1represents phenyl, R4represents a hydroxy-group, R3and R5represent-H.

4. Connection on p. 1, where R6denotes it-H:-H, if R7is a-R71; R72when one of R71and R72is-H and the other member of the pair (R71and R72) is-X, where X denotes a halogen atom, and R8denotes-CH3.

5. Connection on p. 4, selected from the group consisting of 7-deoxy-7-portixol, 7-deoxy-7-ferta the-portixol.

6. Connection on p. 1, where R6denotes-H: -H if R7represents-H; R74while R74and R8United together, form cyclopropylamino group.

7. Connection under item 6, selected from the group consisting of 7-deoxy-7, 8-metaethical and 2'-{ [(2,2,2-trichloroethyl)oxy]carbonyl}-7-deoxy-7, 8-metaethical.

8. Connection on p. 1, selected from the group which includes:

N-desbenzoyl-N-benzyloxycarbonyl-7-deoxy-7-portixol,

N-desbenzoyl-N-benzyloxycarbonyl-7-deoxy--7, 8-metaethical,

N-desbenzoyl-N-(t-butyl)oxycarbonyl - 2'-{[(2,2,2-trichloroethyl)oxy]carbonyl}-7-deoxy-7, 8-mechanotaxis,

N-desbenzoyl-N-(t-butyl)oxycarbonyl - 2'-{[(2,2,2-trichloroethyl)oxy]carbonyl}-7-deoxy-7-portixol,

N-desbenzoyl-N-benzyloxycarbonyl - 2'-{[(2,2,2-trichloroethyl)oxy]carbonyl} -7-deoxy-7-portixol,

N-desbenzoyl-N-benzyloxycarbonyl - 2'-{[(2,2,2-trichloroethyl)oxy]carbonyl} -7-deoxy-7, 8-mechanotaxis.

9. The pharmaceutical composition exhibiting anti-tumor activity, characterized in that it comprises an effective amount of at least one of the compounds of formula I

< / BR>
where R1is methyl or phenyl;

R2- atom vodorodomobil, -NHC(O)O-4-tetrahydropyranyl, -NHC(O)CH2-C(CH3)3, -NHC(O)C(CH3)3, -NHC(O)NHPh, -NHC(O)C(CH2CH3)2CH3, -NHC(O)C(CH3)2CH2Cl, -NHC(O)C(CH3)2CH2CH3phthalimidopropyl, -NHC(O)-1-phenyl-1-cyclopentyl, -NHC(O)-1-methyl-1-cyclohexyl, -NHC(S)NHC(CH3)3, -NHC(O)NHC(CH3)3or-NHC(O)NHPh;

R3is a hydrogen atom, -NHC(O)phenyl or-NHC(O)OC(CH3)3provided that one of the two substituents R2and R3represents a hydrogen atom, but both R2and R3cannot be represented by radicals-H;

R4is a hydrogen atom or is selected from the group of-OC(O)OCH2C(Cl3or-NHC(O)phenyl;

R5is a hydrogen atom or OH group, provided that when R5- OH-group, R4- the hydrogen atom, in addition, provided that when R5represents a hydrogen atom, R4is different from a hydrogen atom,

R6is a hydrogen atom when R7is a-R71or-R72where one of R71, R72- the hydrogen atom and the other of R71and R72- X, where X represents a halogen atom, and R8is methyl, or R6is a hydrogen atom, R7represents-H; R74where R74and R< 3
group,

or their pharmaceutically acceptable salts, when the compound contains either an acidic or basic functional group, and a pharmaceutically acceptable carrier.

10. The method of receiving oxazolidine formula V

< / BR>
where R1is methyl or phenyl;

R9- C1-C6-alkyl,

R11is phenyl, substituted (OC1-C2-alkyl), where n is an integer equal to 1 to 3,

R12is selected from the group consisting of-C(O)H, -C(O)C1-C10-alkyl, -C(O)-phenyl, -C(O)OC(CH3)3, -C(O)OCH2-phenyl, -C(O)-1-adamantyl, -C(O)O-3-tetrahydrofuranyl, -C(O)O-4-tetrahydropyranyl, -C(O)CH2C(CH3)3, -C(O)C(CH3)3, -NHC(O)C(CH2CH3)2CH3, -NHC(O)C(CH3)2CH2CH3phthalimido,

-NHC(O)-1-phenyl-1-cyclopentyl, -NHC(O)-1-methyl-1-cyclohexyl, -NHC(S)NHC(CH3)3, -NHC(O)NHCC(CH3)3the interaction of hydroxylamine of formula III

< / BR>
where R1and R9have the above significance, and R2and

R3have the values listed in paragraph 1, with a benzaldehyde of the formula IV

< / BR>
or acetal of the formula Iv

< / BR>
where n is an integer equal to 1 to 3.

11. The method according to p. 10, characterized in that the said benzaldehyde of atsetoksibetulinola, 3,5-dimethoxybenzaldehyde, 2,5-dimethoxybenzaldehyde, 2,4,6-trimethoxybenzaldehyde, 4-ethoxybenzaldehyde or 4-methoxybenzaldehyde.

12. The method according to p. 10, characterized in that the said hydroxyamine formula III reacts with the dimethyl acetal of 2,4-dimethoxybenzaldehyde.

13. The method of obtaining the compounds of formula IX

< / BR>
where R1, R10, R11and R12have the above values,

R14selected from the group consisting of-C(O)C1-C6-alkyl, -C(O)OC1-C6-alkyl, -C(O)OCH2CX3where X3is a halogen atom, -C(O)OCH2SiR20where R20-C1-C6-alkyl; or Si(R20)3,

characterized in that the free acid of oxazolidine formula VII

< / BR>
where R1, R11and R12have the above meanings, is subjected to the interaction with the connection baccatin formula VIII

< / BR>
where R10and R14have the above meanings, in the presence of a dehydrating agent.

14. The method of obtaining the compounds of formula VIII

< / BR>
where Bz is benzyl, Ac is acetyl.

characterized in that connected the formula Viiic

< / BR>
where Bz and Ac have the above values,

subject entries batch is Soter or 10-acetyl-7, 8-metadatastore.

16. Connection on p. 1, in which R2represents-NHC(O)NHC(CH3)3, R4represents a hydroxy-group, R3and R4denote-H, and R1is phenyl.

17. Connection on p. 1, selected from the group consisting of

N-desbenzoyl-N-(t-butyl)aminocarbonyl-7-deoxy-7, 8-portixol, or

N-desbenzoyl-N-(t-butyl)aminocarbonyl-7-deoxy-7-portixol.

18. The compound of formula IX

< / BR>
19. Connection on p. 1, where R2represents-NHC(O)NHC(CH3)3or-NHC(O)NHPh.

Priority signs:

15.12.92 - open 7-halogenated compounds, where R2selected from the group consisting of H, -NHC(O)-phenyl, -NHC(O)C(CH3)3, -NH2and R7denotes halogen;

02.02.93 - reveals 7, 8-metanoeite, where R2selected from the group consisting of H, -NHC(O)-C1-C10-alkyl, (preferably NHC(O)-C4-C6-alkyl), -NHC(O)-phenyl, -NHC(O)C(CH3)3, -NH2and R7represents-H; R74where R74and R8together form cyclopropyl group;

11.06.93 - open 7-halo - 7, 8-metasediment, where R2selected from the group consisting of-NHC(O)-1-UB>.

Priority points related to method:

17.09.93 reveals the 7-halogen and 7, 8-metanoeite, where R2selected from the group consisting of H, -NHC(O)H, -NHC(O)-C1-C10-alkyl, -NHC(O)-phenyl, -NHC(O)OCH2-phenyl, -NH2, -NHC(O)-1-adamantyl, -NHC(O)O-3-tetrahydrofuranyl, -NHC(O)O-4-tetrahydropyranyl, -NHC(O)CH2C(CH3)3, -NHC(O)C(CH3)3, -NHC(O)C(CH3)2CH2Cl, -NHC(O)C(CH3)2CH2CH3-phthalimido,

-NHC(O)-1-phenyl-1-cyclopentyl, -NHC(O)-1-methyl-1-cyclohexyl, NHC(S)NHC(CH3)3, -NHC(O)NHC(CH3)3or-NHC(O)NHPh.

 

Same patents:

The invention relates to a derivative of oxazolidinone formula (I)

The invention relates to methods for taxan with side chain and their intermediates and to new compounds of the formula III obtained by these methods

The invention relates to new Amida 4 - oxoazetidin-2-sulphonic acids and their salts, to a process of obtaining

The invention relates to pyrazole derivative of the General formula I, where g2, g3and g6hydrogen; g4- chlorine atom or bromine, WITH1-C3-alkyl, trifluoromethyl, or phenyl; g5is hydrogen or chlorine atom; w2, w3, w5and w6is hydrogen or chlorine atom; w4is hydrogen, a chlorine atom, a C1-C3-alkyl, C1-C3-alkoxy or nitro; X is a direct bond or the group -(CH2)nN(R3)-, where R3is hydrogen or C1-C3-alkyl; n is 0 or 1; R4is hydrogen or C1-C3-alkyl and, when X is a direct bond, R is a group-NR1R2where R1is hydrogen, C1-C6-alkyl or cyclohexyl, and R2- C1-C6-alkyl, non-aromatic carbocyclic radical WITH3-C15possibly substituted by a hydroxyl group, one or more1-C5-alkilani,1-C5alkoxygroup or halogen; amino group WITH1-C4-alkyl in which the amino may dazamide1-C3-alkyl, cyclohexyl1-C3-alkyl; phenyl, unsubstituted or substituted with halogen, or WITH1-C5-alkyl; phenyl WITH1-C3-alkyl, diphenyl1-C3-Olinala, hinokitiol and oxybutylene, unsubstituted or substituted C1-C3-alkyl or benzyl; 1-adamantaneacetic; C1-C3-alkyl, substituted aromatic heterocycle selected from pyrrolyl, pyridyl or indolyl, unsubstituted or substituted C1-C5-alkyl, or R1and R2form together with the nitrogen atom to which they relate, pyrrolidinyl, piperidyl or morpholinyl; or the group R5that represents phenyl WITH1-C3-alkyl, unsubstituted or substituted C1-C5-alkyl; cyclohexyl1-C3-alkyl, or 2-norbornylene; when X represents a group -(CH2)nN(R3)-, R represents a group R2Athat represents a non-aromatic carbocyclic radical WITH3-C15; phenyl substituted by halogen; phenyl WITH1-C3-alkyl, possibly substituted with halogen; indolyl, possibly substituted C1-C5alkoxygroup; anthracene, or group with other2bin which R2b- cyclohexyl, substituted, phenyl, unsubstituted or substituted by one or two halogen atoms, WITH1-C5-alkyl or C1-C5alkoxygroup or their acid additive salts

The invention relates to a method for producing derivatives taxane General formula (I) by esterification of protected baccatin III or protected 10-desacetyl-baccatin III using the acid of General formula (II)

The invention relates to a new method of obtaining derivatives taxane General formula

< / BR>
which have valuable protivoanemicakimi and antitumor properties
The invention relates to the field of chemistry and can be used in industry as vulcanizing agents and vulcanization accelerators
The invention relates to a method of purification of 10-deacetylbaccatin III and Taxotere

The invention relates to methods for taxan with side chain and their intermediates and to new compounds of the formula III obtained by these methods

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The invention relates to a method for producing derivatives taxane General formula (I) by esterification of protected baccatin III or protected 10-desacetyl-baccatin III using the acid of General formula (II)

The invention relates to a new method of obtaining derivatives taxane General formula

< / BR>
which have valuable protivoanemicakimi and antitumor properties
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