Method of obtaining epotilone derivatives

FIELD: chemistry.

SUBSTANCE: method ensures carrying out aldole condensation in presence of epoxide mesilate and tosilate, using auxiliary chiral sultamic group as carboxyl- protecting group, as a result, reduction and oxidation stages, requiring extra time, before carrying out final stage of macrolactonisation are excluded. Introduction of epoxidic group at early stages of method allows also excluding stage of epoxilation of more complex intermediate compounds at further stages of process.

EFFECT: high reproducibility of synthesis of highly-purified epothilone derivatives.

8 cl, 6 ex

The invention relates to a new method of obtaining derivatives epothilone, containing not only 2-methylthiazolyl Deputy, but, for example, other heteroaryl or aryl substituents, or a heterocyclic radical, condensed with the benzene ring cycle, and methyl as the substituent at the position 12 in the structure epothilone, as well as new derivative epothilone and intermediate compounds for the implementation of the method and to methods of their preparation. These intermediate compounds are new compounds and are included in the scope of the invention.

Epothilone (16-membered macrolides, which were first isolated from Mycobacterium Sorangium cellulosum) represent a new class of promising anti-tumor agents. It was found that epothilone show activity against different lines of tumor cells, including cell lines of breast cancer.

These agents act on the same biological mechanism as Taxol, an anticancer agent, used as the primary therapy in the treatment of breast cancer. It was found that they are more effective than Taxol.

Possible applications epothilones include the treatment of Alzheimer's disease, malaria and diseases caused by gram-negative bacteria. Epothilone primarily suitable for the treatment of proliferative for the of oleani.

The term "proliferative disease" means a disease in the form of solid tumors, liquid tumors, such as leukemia and psoriasis.

The term "disease in the form of solid tumor" refers primarily a tumor of the breast, a tumor of the colon and gastrointestinal tract, including stomach cancer, hematoma, lung cancer, especially small cell lung cancer and non-small cell lung cancer, kidney cancer, mesothelioma, glioma, squamous cell skin cancer, head and neck cancer, cancer of the urinary tract, such as cervical cancer, uterine cancer, ovarian cancer, testicular cancer, prostate cancer or bladder, Hodgkin's disease, carcinoid syndrome, or Kaposi's sarcoma.

Derivatives epothilone described, for example, in WO 97/19086. These derivatives are obtained from natural epothilones a and B.

Total synthesis epothilone As described Schinzer, etc., Chem. Eur. J., 2, 11, 1477-1482 (1996). Other methods of synthesis epothilone a and b and their derivatives described K.C.Nicolaou and others, Angew. Chem., 109, 170-172 (1997), Nature, 387, 268-272 (1997).

In article K.C.Nicolaou etc., Chem. Commun, 2343-2344 (1997)described the total synthesis of 26-hydroxyapatite and related compounds using as a key reaction stages selective referirovanija for Wittig, aldol reaction and macromechanical. In more detail, the total synthesis of 26-hydroxyapatite In and related analogues with ISOE what Itanium macrolactones described in article K.C.Nicolaou and others, Tetrahedron, 54, 7127-7166 (1998).

In addition, in WO 98/25029 K.C.Nicolaou and other described and claimed synthesis epothilone And epothilone, analogues epothilone, library of analogues epothilone using solid-phase and liquid-phase chemical methods.

The object and purpose of the present invention is to overcome all of the disadvantages of the known methods and to develop more simple and improved method of producing the above epothilones derived epothilone and their salts, which thus feasible on an industrial scale due to the shorter path synthesis, and this method provides the average high total yield and the obtaining of high purity precursors and end products.

Synthesis with the aim of obtaining derivatives epothilone formula 9

where R₁means methyl, and

R₂means unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl or unsubstituted or substituted heterocyclic radical, condensed with the benzene ring cycle,

and their salts.

The prefix "ness." means a radical containing up to and including a maximum of 6, especially up to and including a maximum of 4 carbon atoms, with the specified moiety is unbranched or branched with one or more branches.

Unsubstituted or substituted aryl R 2preferably means an aromatic radical containing from 6 to 14 carbon atoms, especially phenyl, naphthyl, fluorenyl or phenanthrene, and the specified radical unsubstituted or substituted by one or more substituents, preferably up to three, more preferably one or two substituents, especially selected from the group including an amino group; (ness.)alkanolamines, especially acetylamino; halogen, especially fluorine, chlorine or bromine; (ness.)alkyl, especially methyl or also ethyl or propyl; halogen(ness.)alkyl, especially trifluoromethyl; hydroxy; (ness.)alkoxy, especially methoxy or also ethoxy; phenyl(ness.)alkoxy, especially benzyloxy; nitro, cyano, C₈-C₁₂alkoxy, especially n-decyloxy, carbarnoyl, (ness.)allylcarbamate, such as N-methyl - or N-tert-butylcarbamoyl, (ness.)alkanoyl, such as acetyl, phenyloxy, halogen(ness.)alkoxy, such as triptoreline or 1,1,2,2-tetrafluoroethoxy, (ness.)alkoxycarbonyl, such as etoxycarbonyl, (ness.)allylmercaptan, such as methylmercapto, halogen(ness.)allylmercaptan, such as triptoreline, hydroxy(ness.)alkyl, such as hydroxymethyl or 1-hydroxymethyl, (ness.)alkanesulfonyl, such as methanesulfonyl, halogen(ness.)alkanesulfonyl, such as trifloromethyl, phenylsulfonyl, dihydroxybis-IN(OH) ₂), 2-methylpyrimidin-4-yl, oxazol-5-yl, 2-methyl-1,3-dioxolane-2-yl, 1H-pyrazole-3-yl, 1-methylpyrazole-3-yl and (ness.)alkylenedioxy, which is associated with two adjacent carbon atoms, such as methylenedioxy.

Aryl R₂first of all means phenyl.

Halogen means fluorine, chlorine, bromine or iodine, especially fluorine or chlorine.

Unsubstituted or substituted heteroaryl R₂means, for example, a radical selected from the following structures:

and

where R_xmeans acyl.

Heterocyclic radical R₂condensed with a benzene cycle, means a radical selected from radicals of the formula

and

A new synthesis includes the following stages:

a) interaction of the compounds of formula 1

where R₂matter above and methylgroup replaced by tailgroup etc. and R means IT is a protective group, preferably a silyl protective group, more preferably any of the following silyl groups, and most preferably (ness.)alkylsilane protective group, preferably selected from the range of TES, TBDS, TPS,

with sultanovici formula 2, for example,

where R means IT is a protective group, preferably a silyl protective group, more preferably any of the following silyl groups, and most preferably (ness.)alkylsilane protective group, preferably selected from the range of TES, TBDS, TPS, using the selective aldol condensation in the presence of a Lewis acid when adding a base in an inert solvent at low temperature from -50 to -100°and then at an elevated temperature from -20 to+20° With formation of the compound of formula 3

where R₂has the values listed above.

The above compound of formula 2 can be replaced by a compound of formula 2 where R means IT is a protective group, preferably a silyl protective group, more preferably any of the following silyl groups, and most preferably (ness.)alkylsilane protective group, preferably selected from the range of TES, TBDS, TPS.

The compounds of formula 3 are new compounds and are used as intermediate products in stage b) of the above method, where

b) the compounds of the above formula 3 interact with the connection, forming a simple silyl ether, at a temperature of from -70 to +25°in the presence of 2,6-lutidine with the formation of compounds of formula 4

where R₂and R have the values specified above.

The compounds of formula 4 are new compounds and are used as precursors in stage C) of the above method, where

in) from the above compounds of formula 4 after removal of the chiral auxiliary groups when processing TWON/N₂About₂in DME or LiO₂H in THF/Meon/N₂About get carboxylic acid, i.e. the compound of formula 5

where R and R have the values specified above.

The compounds of formula 5 are new compounds and are used as intermediate products in stage d) of the above method, where

g) the compound of formula 5 communicates with the regenerating agent in an inert solvent with the removal of mesyl or tailgroup or other similar groups with the formation of compounds of formula 6

where R₂and R have the values specified above.

The compounds of formula 6 are new compounds and are used as intermediate products in stage d) of the above method, where

d) tizamidine Tris-silyl ethers of the above formula 6 hydrolyzing in the presence of desilicious reagent or acid in an inert solvent or mixtures thereof, for example TASF or HF•pyridine in THF, while selectively receive disilylgermane compound of formula 7

where R₂and R have the values specified above.

The compounds of formula 7 are new compounds and are used as precursors in stage e) of the above method, where

e) the compounds of formula 7 macrolactones in the conditions described in article M.Yamaguchi and others, Bull.Chem.Soc. Jpn., 52, 1989 (1979), you get a fully protected proizvoditelna In formula 8

where R₂and R have the values specified above.

The compounds of formula 8 are new compounds and are used as precursors in stage g) of the above method, where

g) the compound obtained of the formula 8 is treated with HF•pyridine in an inert solvent at a temperature of from 0 to 30°and otscheplaut silyl protective groups, with a gain derived epothilone formula 9

where R₁means methyl, and R₂has the values listed above,

and the compounds of formula 9 are not necessarily converted into metal salts by standard methods.

Turning epothilone In the corresponding lactam is shown in scheme 21 and described in example 3 in WO 99/02514 (p.31-32 and p.48-50, respectively). The transformation of compounds of formula 9, which differs from epothilone In the corresponding lactam carried out in the same way.

The inert solvents mentioned on any of the steps a)-f)include, without limitation, methanol, ethanol, propanol, dichloromethane, dichloroethane, DMF, tetrahydrofuran (THF), benzene, toluene, pyridine, ethyl acetate, acetone or tert-butyl methyl ether (TME), hexane or heptane and the like and mixtures thereof.

Organic bases mentioned in any of the stages a)to f), include, without limitation, organic amines, such as unsubstituted or replacement of mono-, di - or trialkylamine, especially mono-, di -, or three(ness.)the bonds alkylamines, for example methylamine, dimethylamine, di-n-Propylamine, triethylamine, tri-n-Propylamine, tri-n-butylamine and diisopropylethylamine (iPr₂NEt), nitrogen-containing heterocycles, ethylenimine, pyrrolidine, piperidine and morpholine, primarily 4-dimethylaminopyridine (DMAP), pyridine, 2,6-lutidine, 2,6-di-tert-butylpyridinium etc.

ORGANOMETALLIC bases include, for example, LDA (diisopropylaminoethyl), BuLi, sec-BuLi, KHMDS, LiHMDS or NaHMDS.

Reducing agents mean, for example, DIBAL-H (diisobutylaluminium), LiAlH₄(sociallyengaged), limitliability etc.

Group f mean HE is a protective group commonly used in organic chemistry designed to protect the functional hydroxyl groups against undesirable side reactions. Simple silyl ethers are, for example, the standard protective groups commonly used in organic synthesis, and preferably silyl protective group is a (ness.)alkylsilane, more preferably a silyl protective group selected from a number of TMS (trimethylsilyl), TES (triethylsilyl), TPS (tri-n-propulsion), TBDS (tert-butyldimethylsilyl), DEIPS (diethylenediamine), IPDMS (dimethylazobenzene), TDS (taxidermically), TIPS (Tr is ISOPROPYLCUMYL), TNR (tetrahydropyranyl) or the like, preferably of a number of TES TPS or TBDMS, most preferably a protective group means TPS. If the compound contains more than one protective group, the protective group is chosen independently from each other, and they are the same or different or they can be used in any combination, preferred protective groups are identical, most preferably a protective group means TPS.

The term "pharmaceutically acceptable metal salts" means salts of sodium, potassium, calcium, magnesium, aluminum, iron or zinc. Salts receive by standard methods.

Suitable acids for cleavage of the bis-trimethylsilyloxy in the compound of formula 4 by hydrolysis are weak organic acids, which do not disclose the epoxide cycle in the structure epothilone, and these acids include dilute acetic acid, propionic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, timelineview acid, subernova acid, azelaic acid, malic acid, tartaric acid, maleic acid, almond acid, amino acids such as glutamic acid or aspartic acid, especially citric acid, etc. First of all it should be noted HF•pyridine in THF or HF•pyridine at pyrid is not.

Chiral auxiliary group, which are used when the behavior of aldol condensation in stage a)indicate, for example, Sultanova support group or oxazolidinone group, for example

first of all

and other well-known chiral auxiliary group.

Stages a)to f) in the sequence of reactions in the method of producing compounds of formula 9 is carried out, as described in more detail below:

a) the compounds of formula 1 is introduced into reaction with the compound of the formula 2, for example, in the presence of TiCl₄and grounds Hunya (iPr₂NEt) in dichloromethane at a temperature of -78°and then at a temperature of 0°With formation of new compounds of formula 3;

b) the compound obtained of the formula 3 is introduced into reaction with the compound, forming a group of simple silyl ether, for example TPSCl, TBDMSOTf, in the presence of 2,6-lutidine at a temperature of from -20 to 25°With, especially at a temperature of -10°With, in dichloromethane as the inert solvent to form the compounds of formula 4;

C) in the resulting compound of formula 4 otscheplaut auxiliary Sultanova group when processing TWON/N₂About₂in DME or LiO₂N in THF/Meon/N₂About with the formation of carboxylic acids, i.e. compounds of formula 5;

g) the compound obtained Faure the uly 5 process using as a reducing agent LiBHEt ₃in THF in an inert solvent with the removal of mesyl or tailgroup or similar group and the formation of the compound of formula 6;

d) the compounds of formula 6 hydrolyzing when processing desilicious reagent, primarily TASF or organic acid, above all HF•pyridine in an inert solvent, such as pyridine or THF, at the same time, receive the compounds of formula 7;

e) the compounds of formula 7 are subjected to macrolactones by the method M.Yamaguchi and others, for example, when processing hydroxy acid reagent Et₃N and 2,4,6-trichlorobenzaldehyde at low temperature, for example at 0°and then the reaction mixture was added to a solution of 4-DMAP in toluene and the temperature was raised to about 75°With, by the compounds of formula 8;

W) obtained protected derivative epothilone formula 8 is treated with HF•pyridine in pyridine in an inert solvent and after removal of the two silyl protective groups (TPS, TES, TBDMS) receive derivative epothilone formula 9, where R₁means methyl, a R₂has the values listed above, and the compounds of formula 9, where R₁and R₂have the meanings indicated above in the formula 9, it is not necessarily converted into metal salts by standard methods.

Used in the specified way of starting compound forms of the crystals of 1 (where R ₂means unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl or unsubstituted or substituted heterocyclic radical, condensed with the benzene ring cycle, aryl) are used as key intermediates for obtaining derivatives epothilone formula 9, and the compounds of formula 1 are novel compounds and can be obtained by the following sequence of reactions involving the stages a)to f), as described below.

Specific values of R₂and P is specified in the definition of formula 9 and formula 1, respectively.

The proposed new synthesis includes the following stages:

a) interaction of the compounds of formula X

with PPH₃at a temperature of from 50 to 150°more specifically at a temperature of 100°and then with KHMDS in an inert solvent, especially in THF, at 0°and then after cooling the mixture to a temperature of from -50 to -100°S, product handling reagent CH₃CO₂Cl, more specifically at a temperature of -78°C, with the formation of the compounds of formula XI

and

b) interaction of the compounds of formula XI with the compound of the formula XII

in an inert solvent, for example toluene, at a temperature of from 20 to 60°more specifically, if t is mperature 40° With the formation of the compounds of formula

C) recovering the compound of formula (XIII) regenerating agent, primarily DIBALH, in an inert solvent, for example toluene, at temperatures from -50 to -100°more specifically at a temperature of -78°and then at an elevated temperature to 0°With formation of compounds of formula XIV

(formula XIV and subsequent connections are shown in simplified form), where R₂and P have the meanings mentioned above, and

d) epoxidation of compounds of formula XIV in the conditions he sang sharpless [(+)-diethyl L-tartrate, Ti(OPr)₄, t-BuOOH] with the formation of the compounds of formula XV

where R₂and R have the meanings specified in the definition of formula 9 and formula 1, respectively.

The resulting compound of formula XV is a new compound and is used as a precursor to the next stage d), where

d) in a compound of formula XV enter mesyl group's handling methylchloride (mailgroup can be replaced by the corresponding tailgroup or similar group in the presence of triethylamine (Et₃N) in an inert solvent, for example dichloromethane, with the formation of compounds of formula XVI

where R₂and R have the values specified above.

e) the resulting compound of formula XVI is treated with an organic acid in an inert solvent, more specifically para-toluensulfonate pyridinium or camphorsulfonic acid in absolute ethanol, hydrolyzing one protective group, and thus obtain the compound of formula XVII

where R₂has the values listed above, and

g) carry out the oxidation in Turn, for example, oxidation of the alcohol group in the presence of a promoter, oxalicacid, and activator, dimethyl sulfoxide, are salt alkoxysilane and after adding the base and intramolecular rearrangements get catasetinae formula 1, which is used in the above method according to the invention as the source of the connection.

The method of obtaining derivatives epothilone formula 9 according to the invention has many advantages compared with other known and published methods of synthesis.

- Unexpectedly found that the introduction of epoxy groups in the early stages eliminates stage epoxysilane more complex intermediates for subsequent stages of the synthesis.

- There is a noticeable stabilization of nelfinavir and is silata epoxides. In the presence of these functional groups can take a number of other stages.

- Achieved high yield and high diastereoselectivity passing aldol condensation of the key fragments, α-branched aldehyde in the form of enolate titanium with ethylketone.

- Unexpectedly found that aldorino condensation can be carried out in the presence of nelfinavir and tosilata epoxide.

- Alcalina condensation ensures high reproducibility of the synthesis of derivatives of epothilone.

- Unexpectedly found that andolina condensation allows the use of chiral auxiliary Sultanova group as carboxyl-protective group and, therefore, exclude requiring additional time recovering and oxidation before conducting the final stage of macrolactones.

The method according to the invention is a shorter way of synthesis compared with other known methods of synthesis, and, in addition, it achieves high overall output.

These advantages acknowledge an inventive step sequence of reactions.

Another object of the present invention are new intermediate compounds that get described reactions and used to obtain compounds of formula 9.

Production is adnie epothilone formula 9, intended for the treatment, you can enter any known method, which is chosen from the group comprising the intravenous route, intra-arterial method, intradermal method, subcutaneous method, oral method, transbukkalno way, intramuscular way, anal way, percutaneous method, intradermal method, intrathecal way, etc.

In addition, it is possible to obtain compositions with delayed release, including biodegradable microspheres, such as microspheres polyacrylic acid, polyglycolic acid or mixtures thereof.

The compounds of formula 9 according to the invention can be used alone or in combination with other pharmaceutically active compounds, for example with other chemotherapeutic agents such as classical cytostatics. In the case of combinations with other chemotherapeutic agents fixed combination of two or more components (e.g., the set of components) is obtained by methods known to the person skilled in the art, a compound of the present invention and any other chemotherapeutic agent is administered with an interval that ensures the achievement of a common, or more preferably a synergistic effect in the treatment of tumor diseases.

A preferred method of preparing compounds of the present invention is clusterwide the following examples, not limiting its scope.

Example 1: compound X

6-Benzyloxyethanol acid (II) (Can. J.Chem., 70, 1427 (1992))

The solution to 102.2 g (about 0.90 moles) of 6-caprolactone in 1.5 l of toluene was added 250,6 g (4,48 mol) of KOH and 113,3 ml (0,98 mole) of benzylchloride and the reaction mixture is boiled under reflux with stirring for 20 hours the Reaction was stopped by the addition of 1.7 l of water at room temperature. The aqueous layer was separated, solution in toluene was extracted with 200 ml of water. To the combined aqueous phase at 12°With added 300 ml conc. HCl to pH 1.0 and the solution was extracted with two portions of isopropylacetate (1.1 l). The combined extracts were washed with 300 ml of brine, dried over MgSO₄and concentrated under reduced pressure, thus received 151,2 g (76%) acid II in the form of a yellowish oil. R_f0,35 (SiO₂, eluent: CH₂Cl₂/CH₃HE, 95:5).

The acid chloride 6-benzyloxyethanol acid (III)

The crude acid (II) (110 g, and 0.50 mole) was dissolved in 320 ml of toluene and to the solution was added 140 μl of DMF, and then of 56.7 ml of 0.66 mole) of oxalicacid. The reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum, thus received 126 g of the carboxylic acid III, which is directly used in the next stage.

(S)-4-Benzyl-3-(6-be biloxigeneral)oxazolidin-2-it (V)

The solution 87,7 g (of 0.50 mol) of (S)-4-benzyl-2-oxazolidinone IV was dissolved in 1.4 l of THF and cooled to -78°C. Then the solution was added exility (0,45 mole, 178 ml of 2.5 M solution in hexane)and then slowly added to the solution of the carboxylic acid III (126 g, and 0.50 mole) in 100 ml THF. The mixture was stirred at -78°C for 1 h, and then was heated to 0°C. the Reaction was stopped by adding a saturated solution of ammonium chloride (400 ml), the layers were separated and the organic layer was washed with 100 ml of saturated solution of ammonium chloride. The THF layer was twice washed with 200 ml of 1 M NaOH and 500 ml of brine, dried over MgSO₄and concentrated. The crude product (162,4 g) was purified Express chromatography (200 g of SiO₂, eluent: heptane/TVME, from 80:20 to 60:20), received 110,1 g (58% over two stages) amide V. R_f0,41 (SiO₂, eluent: hexane/TWO, 1:1).

(S)-4-Benzyl-3-[(S)-6-benzyloxy-2-methylhexanoic]oxazolidin-2-it (VI)

To 372 ml of 0.37 mole) of NaHMDS (1.0 M solution in THF) in 380 ml of THF at -78°C was added a solution of amide V (120,1 g of 0.32 mol) in THF (200 ml)and then added to the solution of CH₃I (78,4 ml of 1.26 mol) in 70 ml THF. The reaction mixture was stirred at -78°C for 2 h and the reaction was stopped by adding a saturated solution of ammonium chloride (670 ml). The layers were separated and the aqueous phase was extracted with 200 ml TWO. The combined organic layers twice about the Ali 250 ml of saline solution, dried over MgSO₄and concentrated in vacuum to receive the product VI (123,9 g, 87%)which was directly used in the next stage. R_f0,50 (SiO₂, eluent: heptane/TWO, 1:1).

(S)-6-Benzyloxy-2-methylhexan-1-ol (VII)

To a suspension of 13.2 g (0,35 mol) LiAlH₄in 380 ml of THF was added a solution of amide VI in 250 ml of THF at 0°C. the Mixture was stirred at 0°C for 2 h and the reaction was stopped by adding 14 ml of N₂Oh, 14 ml 15% NaOH and 25 ml of N₂O. Precipitated precipitated aluminum salts were removed by filtration, the filtrate was concentrated, the crude product was purified by filtration through a layer of silica gel (570 g SiO₂, eluent: toluene/EtOAc, 3 l 90:10 and 1 l of 80:20). The product VII was obtained as a colourless oil (54,5 g, 81% over two stages). R_f0,24 (SiO₂, eluent: heptane/TWO, 1:1). GHUR: 87% (column: Chiralcel OD, eluent: n-hexane/i-D, 95:5, 1 ml/min, 30°C), t_R10,07 minutes

[(S)-6-Benzyloxy-2-methylhexanoic]-tert-butyldimethylsilyl (VIII)

Alcohol VII (of 54.4 g of 0.25 mole) was dissolved in 100 ml DMF, was added 33.3 g (0,49 mole) of imidazole, and then at 0°C was slowly added a solution of 55.4 g (of 0.37 mole) of tert-butyldimethylsilyloxy in 100 ml of DMF. The mixture was stirred at 20°C for 2 h, poured into 240 ml of ice-cold 0.1 G. of HCl and was extracted with 300 ml of heptane. The organic layer was washed with 100 ml of 0.1 N. HCl, 200 ml of a saturated solution of NaHCO₃200 ml Sol is the first solution, dried over MgSO₄and concentrated in vacuum. The crude product (81,5 g) was purified by filtration through a layer of silica gel (670 g of SiO₂, eluent: toluene), to receive 64,8 g (79%) of colorless oil. R_f0,64 (SiO₂, eluent: heptane/TWO, 1:1).

(S)-6-(tert-Butyldimethylsilyloxy)-5-methylhexan-1-ol (IX)

The solution 64,0 g (to 0.19 mol) of benzyl ester VIII in 500 ml of THF was first made (3.5 bar) in the presence of 7.0 g of 20% Pd(OH)₂/C at room temperature for 30 minutes, the Catalyst was removed by filtration and the filtrate was concentrated, to receive the alcohol IX in the form of a colorless oil (46,9 g, 100%). R_f0,33 (SiO₂, eluent: heptane/TWO, 1:1).

tert-Butyl[(S)-6-iodine-2-methylhexanoic]dimethylsilane (X)

To a solution of 15 g (60,9 mmole) of the alcohol IX in 390 ml of acetonitrile/toluene (1:5) at room temperature was added triphenylphosphine (23,91 g, 91,16 mmol) and imidazole (12,45 g, 182,9 mmole). The mixture was cooled to 0°With four portions over 10 min was added 23,13 g (91,13 mmole) of iodine is added and the heterogeneous solution was stirred for 90 minutes and Then was added a solution of bisulphite (4%, 300 ml) and 100 ml of toluene. The aqueous layer was separated and again extracted with toluene (100 ml). The combined layers of toluene was filtered through silica gel and concentrated in vacuum. To the residue was added heptane (225 ml), the resulting suspension was stirred for 10 min and kept at 4°t is the increase in the 12 o'clock Then the mixture was filtered and the filtrate was concentrated, it was received 21,05 g (97%) of the iodide X in the form of oil is light yellow in color. R_f0,66 (SiO₂, eluent: heptane/AcOEt, 7:3).

Example 2

The aldehyde 1 with TBDMS protective group

Methyl ester of (S)-7-(tert-butyldimethylsilyloxy)-6-methyl-2-(triphenylphosphonio)heptane acid (XI)

To 8 ml of toluene at room temperature in an argon atmosphere was added iodide X (15,46 g, 43,4 mmole) and triphenylphosphine (to 12.52 g, 45,75 mmole) and the resulting mixture was heated at 100°C for 3 hours and Then under reduced pressure to remove the toluene, the residue (29.67 per g) was added THF (400 ml), the solution was cooled to 0°and then the solution was added bis(trimethylsilyl)amide potassium in toluene (0.5 M, 174 ml, 86,8 mmole). The resulting orange suspension was stirred at 0°C for 1 h and then was cooled to -75°C. To the mixture was added methyl ether of Harborview acid (and 3.72 ml, 48,2 mmole), the mixture was stirred at -75°C for 1 h and the reaction mixture is yellowish heated to -40°C. To the mixture was added a solution of NaHCO₃(300 ml)and then added EtOAc (300 ml) and water (150 ml). The layers were separated and the aqueous phase was extracted with EtOAc (150 ml). The combined organic layers were washed with saturated NaCl solution (2×200 ml), dried over MgSO₄and concentrated in vacuum, etc which were obtained crude product XI (27,02 g) as a viscous orange oil, which is directly used in the next stage.

Methyl ester of (2E,6E)-(S)-5-(tert-butyldimethylsilyloxy)-2-[(S)-5-(tert-butyldimethylsilyloxy)-4-methylpentyl]-6-methyl-7-(2-methylthiazole-4-yl)hepta-2,6-diene acid (XIII)

The solution ilide (XI) (27 g) in toluene (200 ml) at room temperature in an argon atmosphere was added to a solution of the aldehyde (XII) (12.7 g, 39.0 mmole) in toluene (80 ml) and the resulting mixture was stirred at 70°C for 5 h the Solvent was removed under reduced pressure, the obtained residue in the form of a solid substance (of 37.8 g) was transferred in 370 ml of heptane and consistently stirred at 40°C for 30 min, at room temperature for 2.5 h and finally, when 0°C for 30 minutes the resulting suspension was filtered and the filter residue was washed with heptane (2×60 ml). The filtrates were combined and concentrated in vacuum to receive 24,85 g of the reaction product of the Wittig XIII in the form of a yellowish oil, which was used in the next stage without additional purification. R_f0,59 (SiO₂, eluent: heptane/AcOEt, 1:1).

¹H-NMR (DMSO-d₆, 300 MHz, 300 K): δ make 6.90 (s, 1H, C_5"-N), 6,77 (t, J 7.5 Hz, 1H, C₃-N), 6,47 (s, 1H, C₇-N), 4,20 (dd, J 7,2, 5.4 Hz, 1H, C₅(H)of 3.69 (s, 3H, CO₂CH₃), 3,40 (dd, J 9,9, 5.7 Hz, 1H, C_5'-H_a), and 3.31 (dd, J of 9.9, 6.6 Hz, 1H, C_5'-N_b), 2,68 (s, 3H, C_2"-CH₃), 2,44-2,36 and 2,2-2,21 (two m, 4H, C₄-H₂and C_1'-H₂), from 2.00 (s, 3H, C₆-CH₃), 1,30-1,15 (two m, 4H, C_2'-H₂With_3'-N_andand C_4'-H), 1.06 a is 0.99 (m, 1H, C_3'-N_b), 0,86 (s, S, SiC(CH₃)₃)to 0.85 (s, 9H, SiC(CH₃)₃), or 0.83 (d, J 6,6, 3H, C_5'-CH₃), of 0.05 (s, 3H, SiCH₃), of 0.01 (s, 6H, two SiCH₃), -0,01 (s, 3H, SiCH₃).

(2E,6E)-(S)-5-(tert-Butyldimethylsilyloxy)-2-[(S)-5-(tert-butyldimethylsilyloxy)-4-methylpentyl]-6-methyl-7-(2-methylthiazole-4-yl)hepta-2,6-Dien-1-ol (XIV)

To a 13.9 g (23 mmole) allyl ether XIII in 500 ml THF at -78°C for 10 min was added 47 ml (70 mmol) of DIBALH (1.5 M solution in toluene). The reaction mixture was successively stirred at -78°C for 3 h, warmed up to 0°C for 30 min, and then stirred at 0°C for 30 min and the reaction was stopped by adding 50 ml of 0.1 G. of HCl. The layers were separated and the aqueous phase washed TWO (2×50 ml). The combined organic extracts were washed with saturated solution of NaHCO₃(2×50 ml) and brine (50 ml), dried over MgSO₄and concentrated in vacuum. The crude product was purified Express chromatography (SiO₂, eluent: heptane/EtOAc, 5:1), was obtained 10.0 g (76%) of allyl alcohol XIV in the form of oil is light yellow in color. R_f0,16 (SiO₂, eluent: heptane/AcOEt, 3:1).

{(2S,3S)-3-[(E)-(S)-2-(tert-Butyldimethylsilyloxy)-3-methyl-4-(2-methylthiazole-4-yl)but-3-EN is l]-2-[(S)-5-(tert-butyldimethylsilyloxy)-4-methylpentyl]oxiranyl) methanol (XV)

Allyl alcohol (XIV) (3.00 g, 5,28 mmole) was dissolved in 51 ml of CH₂Cl₂at -30°With added 0,59 M solution of (+)-diethyl L-tartrate (4,48 ml of 2.64 mmole) in CH₂Cl₂and then added a 0.34 M solution of isopropoxide titanium (IV) (6,21 ml, 2,11 mmole) in CH₂Cl₂. The mixture was stirred at -30°C for 30 min, and then for 5 min was added 2,11 ml (16,6 mmole) of tert-butylhydroperoxide (5.5 M solution in decane) and the reaction mixture was stirred at -30°C for 24 h and Then to the mixture was added a solution of NaHSO₃(4%, 50 ml), the layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with 50 ml of brine, dried over MgSO₄and concentrated in vacuum to receive 3.11 g of the crude apocopate XV in the form of oil is light yellow in color, which is used in the next stage without additional purification. R_f0,22 (SiO₂, eluent: heptane/AcOEt, 2:1). MS (ES+): m/z (%) 606 (100, [M+Na]⁺), 584 (13, [M+H]⁺).

(2S,3S)-3-[(E)-(S)-2-(tert-Butyldimethylsilyloxy)-3-methyl-4-(2-methylthiazole-4-yl)but-3-enyl]-2-[(S)-5-(tert-butyldimethylsilyloxy)-4-methylpentyl]oxiranylmethyl ether methanesulfonate acid (XVI)

To a solution of the crude apocopate (XV) (3.11 g, 5.3 mmole) in CH₂Cl₂(40 ml) at 0°added to 2.74 ml (16,0 mmole) of N-ethyldiethanolamine and the resulting mixture per Merivale at 0° C for 15 minutes Then to the mixture was added dropwise methanesulfonate (0.75 ml, 8.0 mmole) and the mixture was stirred at 0°C for 1 h the Reaction was stopped by adding 40 ml of H₂O and 40 ml TWO. The layers were separated and the aqueous layer was extracted with TWO (40 ml). The organic extracts were washed with 0.1 N. HCl (40 ml), a saturated solution of NaHCO₃(2×40 ml), brine (40 ml) and dried over MgSO₄. After concentration in vacuo was received with 3.79 g of the crude nelfinavir XVI, which was used in the next stage without additional purification. R_f0,27 (SiO₂, eluent: heptane/AcOEt, 2:1). MS-BP: m/z 684,3222 ([M+Na]⁺C₃₁H₅₉NO₆S₂Si₂, Rasch. 684,3220).

(2S,3S)-3-[(E)-(S)-2-(tert-Butyldimethylsilyloxy)-3-methyl-4-(2-methylthiazole-4-yl)but-3-enyl]-2-((S)-5-hydroxy-4-methylpentyl)oxiranylmethyl ether methanesulfonate acid (XVII)

The crude TBDMS ether XVI (3,79 g, 5.7 mmole) was dissolved in CH₂Cl₂/CH₃HE (140 ml, 1:1 vol./vol.), when 0°With added 1,33 g (5,73 mmole) of 10-camphorsulfonic acid and the reaction mixture was stirred at 0°C for 1 h After completion of the reaction, the removal of the protective group was added 20 ml of a saturated solution of NaHCO₃and 20 ml TWO. The layers were separated and the aqueous layer was extracted with TWO (2×20 ml). The combined organic layers were washed with saturated solution of NaHCO₃(2×20 ml) of the salt solution (20 ml), dried over MgSO₄and concentrated under reduced pressure. The crude product XVII (3.11 g) was obtained as yellowish oil and used in the next stage without additional purification. R_f0,28 (SiO₂, eluent: heptane/AcOEt, 1:1).

(2S,3S)-3-[(E)-(S)-2-(tert-Butyldimethylsilyloxy)-3-methyl-4-(2-methylthiazole-4-yl)but-3-enyl]-2-((S)-4-methyl-5-oxopent)oxiranylmethyl ether methanesulfonate acid (1)

To a solution of alcohol XVII (3.11 g, 5.7 mmole) in CH₂Cl₂(15 ml) at 0°consistently for 5 min was added triethylamine (10 ml), DMSO (6 ml) and the solution SO₃·pyridine (3,61 g, an increase of 22.7 mmole) in DMSO (40 ml). The mixture was stirred at 0°C for 1 h, the reaction was stopped by adding a solution of NaHSO₄(10%, 20 ml) and the mixture was diluted TWO (20 ml). The layers were separated and the aqueous layer was extracted with TWO (2×20 ml). The combined organic layers were washed with saturated solution of NaHCO₃(2×20 ml) and brine (20 ml), dried over MgSO₄and concentrated under reduced pressure. The residue was purified Express chromatography (SiO₂, eluent: heptane/AcOEt, 3:1). The aldehyde 1 was obtained in the form of oil is light yellow in color (2.20 g, yield 76% (based on four stages and the product (XIV). R_f0,39 (SiO₂, eluent: heptane/AcOEt, 1:1).

Example 3

Aldehyde XVI' containing TBDMS protective group

/p>

4-[(E)-(S)-3-(tert-Butyldimethylsilyloxy)-4-{(2S,3R)-3-[(S)-5-(tert-butyldimethylsilyloxy)-4-methylpentyl]-3-iodotyrosine}-2-methylbut-1-enyl]-2-methylthiazole (XVI')

To a solution of apocopate XV' (50 mg, 86 mcmole), triphenylphosphine (34 mg, of 0.13 mmole) and imidazole (18 mg, 0.26 per mmole) in toluene/acetonitrile (2.4 ml, 5:1, vol/about.) at room temperature in an argon atmosphere to one portion was added iodine (33 mg, of 0.13 mmole) and the mixture was stirred for 30 minutes After completion of the reaction (according to the results of TLC), the reaction mixture was poured into a saturated solution of NaHSO₄(5 ml), the layers were separated and the aqueous layer was extracted with toluene (2×2 ml). The combined organic layers were washed 1 N. HCl (5 ml), a saturated solution of NaHCO₃(5 ml) and brine (5 ml), dried over MgSO₄and concentrated in vacuum. The residue is suspended in heptane and insoluble triphenylphosphine was separated by filtration, it was obtained the crude iodide XVI' in the form of oil is light yellow in color (65 mg)which was used without further purification.

Example 4

Connection 2

1-(10,10-Dimethyl-3,3-dioxo-6-thia-4-azatricyclo[5.2.1.0]Dec-4-yl)-3-hydroxy-4,4-dimethylheptan-1,5-dione (11)

The TBDMS ether (10) (of 9.21 g, 18,43 mmole) were mixed in a Teflon vessel in an argon atmosphere with a complex of HF·pyridine (26,3 ml, 921 mmol) at room temperature. Recip is nnow the reaction mixture was stirred for 2 h, and then the reaction was stopped by adding a solution of NaHCO₃(78 g in 500 ml of water and 200 ml TWO. The layers were separated, the organic layer washed with brine (2×200 ml), dried over MgSO₄and concentrated in vacuum, when it got to 6.80 g of the crude product, which was used without further purification.

1-(10,10-Dimethyl-3,3-dioxo-6-thia-4-azatricyclo[5.2.1.0]Dec-4-yl)-4,4-dimethyl-3-triethylchlorosilane-1,5-dione (2)

To a solution of the crude alcohol (11) (6,80 g and 17.6 mmole) in CH₂Cl₂(90 ml) at 0°C was added 2,6-lutidine (6,14 ml, 52,9 mmole), and then criticalinformation (7,98 ml, was 35.3 mmole) and the resulting solution was stirred at 0°C for 30 minutes the Reaction was stopped by the careful addition of 140 ml of 1 N. HCl and 150 ml TWO. The layers were separated and the organic layer was sequentially washed with 100 ml of a saturated solution of NaHCO₃and 100 ml of brine, dried over MgSO₄and concentrated in vacuum. The crude product was purified by chromatography (SiO₂, eluent: hexane/AcOEt, 4:6), when it got to 8.3 g of peeled TES-ether 2 (yield 90% over two stages). R_f0,62 (SiO₂, eluent: heptane/AcOEt, 1:1).

¹H-NMR (DMSO-d₆, 400 MHz, 300 K): δ 4,55 (t, J 5.2 Hz, 1H, C₃-N), 3,86 (d, J and 14.3 Hz, 1H, C_8'-H_a), 3,83 (t, J 6,1 Hz, 1H, C_1'-N), 3,66 (d, J of 14.2 Hz, 1H, C_8'-H_b), 2,84 (dd, J 17.4 years, 4.6 Hz, 1H, C₂-N and), to 2.54 (m, 3H, C₂-N_band C₇-N₂partially overlapped with DMSO), from 2.00-1.92 and 1,87-1,73 (2 m, 6N,_2'-N₂With_3'-H and C_5'-N₂), 1,48 is 1.20 and 1.34-1,24 (2 m, 2H, C_4'-N₂), 1,10 (s, 3H, C₄-CH₃), with 1.07 (s, 3H, C₄-CH₃), and 0.98 (s, 3H, C_9'-CH₃), of 0.95 (s, 3H, C_9'-CH₃), 0,94-of 0.87 (m, 12H, Si(CH₂CH₃)₃and C₇-N₃), 0.60 and 0.45 in (m, 6H, Si(CH₂CH₃)₃).

¹³C-NMR (DMSO-d₆, 100 MHz, 300 K): δ 215,3, 169,7, 73,1, 65,1, 52,9, 52,7, 49,2, 48,1, 45,1, 40, 38,8, 32,8, 32,1, 26,7, 21,5, 20,9, 21,0, 20,4, 8,5, 7,6, 7,5, 5,4.

IR (KBr): ν_max2958s, 2913m, 2878s, 1702s, 1391m, 1333s, 1312m, 1267m, 1237m, 1219m, 1166m, 1136s, 1087s, 743m, 539m cm^-1.

MC (ES+): m/z (%) 769 (3, [3M+Sa]²⁺), 538 (6, [M+K]⁺), 522 (100, [M+Na]⁺), 519 (17, [2M+Sa]²⁺), 500 (5, [M+H]⁺).

Example 5.

Compound 6 containing TBDMS protective group

Alderny product (3)

A solution of compound 2 (750 mg, 1.50 mmol) in CH₂Cl₂(5.6 ml) at -78°C in an atmosphere of argon was sequentially treated with a 0.5 m solution of TiCl₄in CH₂Cl₂(to 3.00 ml, 1.50 mmole) and N-ethyldiethanolamine (2.57 m) ál, 1.50 mmole), and the solution was immediately acquired an intense dark red color. The mixture was stirred at -78°C for 10 min, then was added dropwise a solution of compound 1 (900 mg, 1.65 mmole) in CH₂Cl₂(1.9 ml) and the solution per Merivale at -78° C for 1 h Then the mixture was heated to 0°and was stirred for another 15 min to complete the reaction (TLC results). The reaction was stopped at 0°With the addition of a phosphate buffer solution (pH 7, 4 ml) and diluted TWO (5 ml). The aqueous layer was extracted with TWO (2×5 ml). The combined organic layers were washed with saturated solution of NaHCO₃(2×4 ml) and brine (4 ml), dried over MgSO₄and concentrated in vacuum. The residue was purified Express chromatography (50 g of SiO₂, eluent: heptane/AcOEt, 2:1), to receive alderny product 3 (1200 mg, yield 70% (based on product 1) in the form of oil is light yellow in color. R_f0,42 (SiO₂, eluent: heptane/AcOEt, 1:2).

MS (ES+): m/z (%) 1084 (5, [M+K]⁺), 1067 (100, [M+Na]⁺), 1045 (26, [M+H]⁺).

The TBDMS ether (4)

A solution of compound 3 (1.20 g, 1.15 mmole) in CH₂Cl₂(15 ml) at 0°C in an atmosphere of argon was sequentially treated with 2,6-lutidine (of 0.87 ml, 7,49 mmole) and tert-butyldimethylchlorosilane (1,32 ml, 5,74 mmole). The mixture was stirred at 0°C for 14 h, and then was added 0.1 G. of HCl (5 ml) and CH₂Cl₂(5 ml). The layers were separated and the aqueous layer was extracted with CH₂Cl₂(2×5 ml). The combined organic extracts are then washed with saturated solution of NaHCO₃(2×5 ml) and brine (5 ml), dried over MgSO₄he concentrically in vacuum. The residue was purified Express chromatography (50 g of SiO₂, eluent: heptane/AcOEt, 2:1), to receive the connection 16 (893 mg, 67%) as oil is light yellow in color. R_f0,70 (SiO₂, eluent: heptane/AcOEt, 1:2).

MS (ES+): m/z (%) 1197 (12, [M+K]⁺), 1081 (100, [M+Na]⁺), 1059 (31, [M+H]⁺), 599 (75, [M+Sa]²⁺).

Carboxylic acid (5)

A solution of compound 4 (318 mg, 0,274 mmole) in 1,2-dimethoxyethane (4.8 ml) at 0°sequentially processed TWAIN (730 μl, was 2.76 mmole) and 30% H₂About₂(280 μl, to 2.74 mmole) and the resulting mixture was stirred at 0°C for 5 hours Then to the mixture was added a saturated solution of NH₄Cl (2 ml) and TWO (2 ml). The layers were separated and the aqueous layer was extracted with TWO (2×2 ml). The organic extracts are then washed with saturated solution of NaHCO₃(2×2 ml) and brine (2 ml), combined, dried over MgSO₄and concentrated in vacuum. The residue was purified Express chromatography (15 g of SiO₂, eluent: heptane/AcOEt, 1:1 containing 1% Asón), when it received the connection 5 (103 mg, 39%) as oil is light yellow in color. R_f0,41 (SiO₂, eluent: CH₂Cl₂/CH₃CN/hexane, 3:3:4). MS (ES+): m/z (%) 984 (100, [M+Na]⁺), 962 (12, [M+H]⁺).

Metalepoxi (6)

To a solution of compound 5 (78 mg, of 0.081 mmole) in THF (1.6 ml) at room temperature was added dropwise a 1 M solution LiBHEt₃in THF (970 μl, 0.97 mmole) and the scientists and the mixture was stirred at room temperature for 1 h The reaction was stopped by adding a saturated solution of NH₄Cl (2 ml) and TWO (2 ml). The layers were separated and the aqueous layer was extracted with TWO (2×2 ml). The combined organic extracts are then washed with saturated solution of NaHCO₃(2×2 ml) and brine (2 ml), dried over MgSO₄and concentrated in vacuum. The residue was purified Express chromatography (6 g SiO₂, eluent: heptane/AcOEt, 1:1 containing 1% Asón), when it received the connection 6 (60 mg, 85%) as oil is light yellow in color. R_f0,56 (SiO₂, eluent: heptane/AcOEt, 1:1 containing 1% Asón). MS (ES+): m/z (%) 890 (100, [M+Na]⁺), 868 (50, [M+H]⁺).

Example 6

The aldehyde 1 with a single TES - and one TBDMS protective group

Methyl ester of (2E,6E)-(S)-5-hydroxy-2-[(S)-5'-hydroxy-4'-methylpentyl)-6-methyl-7-(2"-methylthiazole-4"-yl]hepta-2,6-diene acid (12)

In a Teflon vessel containing 24 ml of complex HF·pyridine (839 mol)at -10°With added allyl ether (XIII) (10.0 g, a 16.8 mmole) and the resulting mixture was stirred at -10°C for 10 min, after which the reaction was immediately stopped because the results of TLC indicated complete consumption of starting material. The mixture was poured into a stirred suspension of NaHCO₃(70 g) in water (100 ml) and TWO (100 ml). The layers were separated and the aqueous phase was extracted with TWO (3×80 ml). Organic is the cue extracts were combined and washed with 150 ml of 0.1 N. HCl, dried over MgSO₄and concentrated in vacuum to receive the crude diol (2) (6,34 g)which was directly used in the next stage. R_f0,06 (SiO₂, eluent: heptane/AcOEt, 1:1).

¹H-NMR (DMSO-d₆, 300 MHz, 300 K): δ make 6.90 (s, 1H, C_5"(H)to 6.75 (t, 1H, J 7.5 Hz, C₃-N), 6,51 (s, 1H, C₇-N)to 4.23 (t, J 6.3 Hz, 1H, C₃-N), the 3.65 (s, 3H, CO₂CH₃), to 3.41 (dd, J of 10.5, 6.0 Hz, 1H, C_5'-N_and), to 3.34 (dd, J of 10.5, 6.3 Hz, 1H, C_5'-N_b), of 2.64 (s, 3H, C_2"-CH₃), the 2.46 (t, J 6.9 Hz, 2H, C₄-N₂in ), 2.25 (t, J 7.2 Hz, 2H, C_1'-H₂), from 2.00 (s, 3H, C₆-CH₃), 1,70-of 1.55 and 1.53-1,25 (2 user. m, 6N,_2'-N₂With_3'-N_aWith₄-H, C₅-OH and C_5'-HE), of 1.15 to 1.00 (m, 1 H, C_3'-N_b)to 0.85 (d, J 6.6 Hz, 3H, C_4'-CH₃).

Methyl ester of (2E,6E)-(S)-6-methyl-7-(2'-methylthiazole-4'-yl)-2-[(S)-4"-methyl-5"-triethylchlorosilane]-5-triethylchlorosilane-2,6-diene acid (XIII')

A solution of the crude diol (12) (6,33 g, 14 mmol) in CH₂Cl₂(150 ml) at 0°sequentially treated with N-ethyldiethanolamine (23,6 ml, 138 mmol), 4-(N,N-dimethylamino)pyridine (70 mg, 0.57 mmole) and triethylchlorosilane (10.9 ml, 86,1 mmole)and the resulting solution was stirred at room temperature overnight. The reaction was stopped by adding a saturated solution of NaHCO₃(150 ml) and the aqueous layer was extracted with CH₂ 2(3×200 ml). The organic extracts were combined, washed with 200 ml of brine, dried over MgSO₄and concentrated in vacuum. The residue was purified by chromatography (SiO₂, eluent: gradient of hexane/AcOEt 20 to 30%), was obtained 8.6 g (86% over two stages) TES-protected diol (XIII'). R_f0,63 (SiO₂, eluent: heptane/AcOEt, 1:1).

¹H-NMR (DMSO-d₆, 400 MHz, 300 K): δ 7,26 (s, δWith_5'-H), 6.73 x (t, J 7,3 Hz, 1H, C₃-H), 6.48 in (s, 1H, C₇(H)4,30 (t, J 6,7 Hz, 1H, C₅-N), the 3.65 (s, 3H, CO₂CH₃), to 3.41 (dd, J of 9.8 and 5.9 Hz, 1H, C_5"-N_and), to 3.36 (dd, J of 9.8, 6.3 Hz, 1H, C_5"-N_b), to 2.66 (s, 3H, C_2'-CH₃), a 2.45 (t, J 6,7 Hz, 2H, C₄-N₂), 2,30-2,20 (user. m, 2H, C_1"-H₂), 2,04 (s, 3H, C₆-CH₃), 1,59-1,47 (user. m, 1H, C_4"-N), 1,45-1,23 (user. m, 3H, C_2"-N₂and C_3"-N_and), 1,01 of 1.00 (user. m, 1H, C_3"-N_b), 0,98-to 0.88 (m, 18H, two Si(CH₂CH₃)₃), or 0.83 (d, J 6.9 Hz, 3H, C_4"-CH₃), and 0.62-0.52 in (m, 12H, two Si(CH₂CH₃)₃).

IR (film) ν_max2953s, 2934s, 2913s, 2875s, 1713s, 1644w, 1505w, 1459m, 1437m, 1414w, 1376w, 1285m, 1269m, 1241m, 1185m, 1120m, 1072m, 1006m, 744m, 723s cm^-1.

MC (ES+): m/z (%) 618 (100, [M+Na]⁺), 596 (72, [M+H]⁺).

(2E,6E)-(S)-6-Methyl-7-(2'-methylthiazole-4'-yl)-2-[(S)-4"-methyl-5"-triethylchlorosilane]-5-triethylchlorosilane-2,6-Dien-1-ol (XIV)

To a solution of allyl ester (XIII') (45,54 g, 76,4 mmole) in THF (250 ml) at -78�B0; C was added a 1.5 M solution of DIBAL-H in toluene (153 ml, 229 mmole) and the resulting mixture was stirred at -78°C for 3 hours the Reaction was stopped by slow addition of 115 ml of 2 N. HCl and diluted to 100 ml TWO. The layers were separated and the aqueous phase was extracted with TWO (2×100 ml). The combined organic extracts were washed with 100 ml NaHCO₃, 100 ml of brine, dried over MgSO₄and concentrated in vacuum to receive 51,53 g of the crude allyl alcohol, which was purified by chromatography (SiO₂, eluent: gradient of hexane/AcOEt, 20 to 40%), it was received with 32.5 g (75%) of the purified allyl alcohol (XIV). R_f0,47 (SiO₂, eluent: heptane/AcOEt, 1:1).

¹H-NMR (DMSO-d₆, 500 MHz, 300 K): δ 7,29 (s, 1H, C_5'-N)6,38 (s, 1H, C₇(H)of 5.29 (t, J 7,1 Hz, 1H, C₃-N), 4,60 (t, J 5.4 Hz, 1H, C₁-HE), 4,10 (t, J 6.4 Hz, 1H, C₅-N), with 3.79 (d, J 5.1 Hz, 2H, C₁-H₂), 3,40 (dd, J of 9.8 and 5.9 Hz, 1H, C_5"-H_a), to 3.33 (dd, J of 9.8 and 6.5 Hz, 1H, C_5"-N_b), of 2.64 (s, 3H, C_2'-CH₃in ), 2.25 (t, J 6.8 Hz, 2H, C₄-N₂), of 1.99 (s, 3H, C₆-CH₃), 2,00-1,90 (user. m, 2H, C_1"-H₂), 1,58 of 1.46 (m, 1H, C_4"-H), 1,43-1,22 (m, 3H, C_3"-H_aand C_2"-N₂), 1,08 is-0.97 (m, 1H, C_3"-N_b), 0,95-of 0.85 (m, 18H, two Si(CH₂CH₃)₃), of 0.82 (d, J 6,7 Hz, 3H, C_4'-CH₃), is 0.58-0.50 in (m, N, two Si(CH₂CH₃)₃).

¹³C-NMR (DMSO-d₆, 125 MHz, 300 K): δ 164,1, 152,5, 141,1, 140,7, 119,9, 118,4, 116,6, 78,0, 67,3, 64,6, 35,2, 34,4, 32,9, 28,0, 25,4, 18,9, 16,6, 13,7, 6,74, 6,72, 4,3, 4,0.

IR (film): ν_max3341s (OSiR.), 2952s, 2932s, 2874s, 1508m, 1458m, 1414m, 1378w, 1238w, 1190m, 1071s, 1016s, 883w, 829w, 743m, 728m cm^-1.

MC (ES+): m/z (%) 590 (28, [M+Na]⁺), 568 (100, [M+H]⁺).

{(2S,3S)^-3-[(E)-(S)-3'-Methyl-4'-(2"-methylthiazole-4"-yl)-2-triethylenemelamine-3-enyl]-2-[(S)-4'"-methyl-5'"-triethylchlorosilane]oxiranyl)methanol (XV)

to 5.00 g (8,80 mmole) allyl alcohol (4) was dissolved in 100 ml of CH₂Cl₂in a dried flask in an argon atmosphere, was added molecular sieves 4Å (4 g), the mixture was cooled to -30°and added (+)-diethyl L-tartrate (7,46 ml, and 4.40 mmole) and isopropoxide titanium (IV) (10,35 ml, to 3.52 mmole). The resulting mixture was stirred at -30°C for 1 h, the solution became yellow-green color. Then added to 3.52 ml of tert-butylhydroperoxide (19,36 mmole), the reaction mixture was stirred at -25°With during the night. The reaction was stopped by adding 100 ml of NaHSO₃and the mixture was stirred. The filtrate was extracted with TWO (2×80 ml). The combined organic layers were washed with 80 ml of brine, dried over MgSO₄and concentrated in vacuum, thus received of 7.24 g of the crude product. After purification by chromatography (eluent: hexane/AcOEt, 1:1) was obtained 5.2 g (100%) apocopate (XV). R_f0,38 (SiO₂, eluent: heptane/AcOEt, 1:1).

¹H-NMR (DMSO-d sub> 6, 400 MHz, 300 K): δ 7,28 (s, 1H, C_5"(H)6,44 (s, 1H, C₄-N), 4,30 (dd, J 8,2, a 4.1 Hz, 1H, C_2'-N), of 3.46 (d, J and 12.2 Hz, 1H, C₁-H_a), 3,39 (dd, J of 10.2, 6.0 Hz, 1H, C_5'"-H_a), to 3.34 (dd, J 10,2, 6.2 Hz, 1H, C_5"-N_b), with 3.27 (d, J and 12.2 Hz, 1H, C₁-N_b), 2,90 (dd, J 7,3, 4.6 Hz, 1H, C₃-H), 2.63 in (s, 3H, C_2"-CH₃), to 1.98 (s, 3H, C_3'-CH₃), is 1.81 (ddd, J 12,3, and 8.2, 4.6 Hz, 1H, C_1'-H_a), 1,68-1,20 (4 m, 7H, C_1'-N_bC_1"'-N₂With_2'"-N₂With_3"'-N_andWith_4"'-N), 1,08-0,98 (m, 1H, C_3"'-N_b), 0,93-0,83 (m, 18H, two Si(CH₂CH₃)₃), of 0.82 (d, J 6,7 Hz, 3H, C_4"'-CH₃), 0,59-0,50 (m, 12H, two Si(CH₂CH₃)₃).

¹³C-NMR (DMSO-d₆, 125 MHz, 300 K): δ 164,7, 152,6, 141,2, 118,7, 117,1, 76,3, 67,6, 63,6, 63,6, 60,2, 57,5, 35,5, 35,4, 33,3, 28,7, 22,3, 19,1, 16,8, 14,4, 13,9, 7,1, 7,0, 4,6, 4,3.

IR (film) ν_max3403s (OSiR.), 2954s, 2876s, 1507m, 1459m, 1414m, 1377m, 1239m, 1185m, 1084s, 1007s, 976w, 802w, 744s, 676w cm^-1.

MC (ES): m/z (%) 606 (52, [M+Na]⁺), 584 (100, [M+H]⁺).

(2S,3S)-3-[(E)-(S)-3'-Methyl-4'-(2"-methylthiazole-4"-yl)-2-triethylenemelamine-3-enyl]-2-[(S)-4"'-methyl-5"'-triethylenediamine]oxiranylmethyl ether methanesulfonate acid (XVI)

To a solution of apocopate (XV) (11,71 g, 20.0 mmol) in CH₂Cl₂(148 ml) at 0°With added 10.3 ml (60,1 mmole) of N-ethyldiethanolamine and the resulting mixture was stirred at 0°C for 15 minutes Then added methanesulfonamide (2,33 ml, 3.1 mmole) and the mixture was stirred at 0° C for 1 h the Reaction was stopped by adding 50 ml of N₂O and 50 ml TWO. The layers were separated and the aqueous layer washed TWO (50 ml). The combined organic extracts washed with 0.1 G. of HCl (40 ml), a saturated solution of NaHCO₃(2×40 ml), brine (50 ml) and dried over MgSO₄. After concentration in vacuo was received of 13.7 g of apoximately (XVI), which was used without further purification. R_f0,55 (SiO₂, eluent: heptane/AcOEt, 1:1).

¹H-NMR (DMSO-d₆, 400 MHz, 300 K): δ 7,34 (s, 1H, C_5"-N), of 6.49 (s, 1H, C_4'(H)to 4.38 (d, J to 11.4 Hz, 1H, C₁-H_a), 4,34 (dd, J 8,2, and 3.7 Hz, 1H, C_2'-N)4,07 (d, J to 11.4 Hz, 1H, C₁-N_b), of 3.43 (dd, J of 9.8 and 5.9 Hz, 1H, C_5"'-H_a), 3,37 (dd, J of 9.8, 6.3 Hz, 1H, C_5"'-N_b), to 3.33 (s, 3H, SO₂CH₃), 3,06 (dd, J 7,0, 4.6 Hz, 1H, C₃-N)to 2.66 (s, 3H, C_2"-CH₃), 2,03 (s, 3H, C_3'-CH₃), 1,89 (ddd, J 15,2, 7,0, and 3.7 Hz, 1H, C_1'-H_a), 1,77-1,20 (5 m, 7H, C_1'-N_bC_1"'-H₂With_2"'-N₂With_3"'-N_andWith_4"'-N), 1,12-of 1.03 (m, 1H, C_3"'-N_b), 0,97-to 0.88 (m, 18H, two Si(CH₂CH₃)₃)to 0.85 (d, J 6.6 Hz, 3H, C_4"'-CH₃), 0,63-0,50 (m, 12H, two Si(CH₂CH₃)₃).

¹³C-NMR (DMSO-d₆, 125 MHz, 300 K): δ 164,2, 152,3, 140,5, 118,6, 117,0, 75,8, 72,1, 67,2, 60,4, 57,8, 36,6, 35,1, 34,6, 32,8, 28,1, 21,7, 18,9, 16,5, 13,6, 6,8, 6,7, 4,3, 4,0.

MC (ES+): m/z (%) 684 (100, [M+Na]⁺), 662 (54, [M+H]⁺).

(2S,3S)-2-[(S)-5'-Hydroxy'-methylpentyl]-3-[(E)-(S)-3"-methyl-4"-(2"'-methylthiazole-4'"-yl)-2-triethylenemelamine-3-enyl]oxiranylmethyl ether methanesulfonate acid (XVII)

A solution of bis-TES ether (XVI) (4,89 g, 7,38 mmole) in THF/Asón/N₂About (10:2:1 vol./about./about., 115 ml) was heated at 50°C for 15 h the Reaction was stopped by adding 460 ml of a saturated solution of NaHCO₃and the mixture was extracted with TWO (2×250 ml). The organic layers were combined, washed with brine, dried over MgSO₄and concentrated in vacuum, when it got to 4.73 g of the crude product. The product was purified Express chromatography (SiO₂, eluent: gradient AcOEt/hexane 30%to 60%), while received 3,10 g of alcohol (XVII) (79% over two stages and the product XV). R_f0,15 (SiO₂, eluent: heptane/AcOEt, 1:1).

¹H-NMR (DMSO-d₆, 400 MHz, 300 K): δ 7,42 (s, 1H, C_5"'-N), of 6.50 (s, 1H, C_4"(H)to 4.38 (d, J 11.3 Hz, 1H, C₁-H_a), 4,36 (dd, J of 8.3, 4.6 Hz, 1H, C_2"-N, overlaps C₁-H_a), 4,07 (d, J 11.8 Hz, 1H, C₁-H_a), 3,30 is 3.23 (m, 1H, C_5'-N_and), 3,20 (s, 3H, SO₂CH₃), 3,22-3,14 (m, 1H, C_5'-N_bpartially overlaps SO₂CH₃), 3,06 (dd, J 7,1, 4,4 Hz, 1H, C₃-N)to 2.67 (s, 3H, C_2"'-CH₃), 2,04 (s, 3H, C_3"-CH₃), 1,90 (ddd, J 14,2, 8,3, 4,4 Hz, 1H, C_1"-H_a), 1,70 is 1.58 (m, 1H, C_1"-N_b), and 1.54-1.32 to (m, 6N, C_1'-H₂C_2'-H₂With_3'-N_andWith_4'-N), 1,10-0,98 (m, 1H, C_3'-N_b), of 0.93 (t, J 8.0 Hz, N, Si(CH₂CH₃)₃), is 0.84 (d, J 6.6 Hz, 3H, C_4'-CH₃), of 0.60 (q, J 8.0 for the C, 6N, Si(CH₂CH₃)₃).

¹³C-NMR (DMSO-d₆, 100 MHz, 300 K): δ 165,1, 153,2, 141,5, 119,4, 117,9,76,6, 73,3, 67,0, 61,2, 58,6, 37,6, 36,0, 35,5, 33,9, 29,0, 22,6, 19,7, 17,5, 14,9, 14,5, 7,63, 7,58, 5,1.

IR (film): ν_max3410s (OSiR.), 2955s, 2876s, 1655w, 1505w, 1459m, 1414m, 1359s, 1270w, 1239w, 1177s, 1081m, 1006m, 958m, 833m, 745m, 529m cm^-1.

MC (ES+): m/z (%) 586 (5, [M+K]⁺), 570 (100, [M+Na]⁺), 548 (8, [M+H]⁺).

(2S,3S)-3-[(E)-(S)-3'-Methyl-4'-(2"-methylthiazole-4"-yl)-2-triethylenemelamine-3-enyl]-2-[(S)-4"'-methyl-5'"-oxobutyl]oxiranylmethyl ether methanesulfonate acid (1)

To a solution of alcohol (XVII) (2.00 g, 3.65 mmole) in CH₂Cl₂(10 ml) at 0°sequentially added triethylamine (3,86 ml of 27.7 mmole), DMSO (6,48 ml of 91.3 mmole) and the complex pyridine·SO₃(2,32 g of 14.6 mmole) in DMSO (26 ml) and the resulting solution was stirred at 0°C for 1 h the Reaction was stopped by adding a solution of NaHSO₄(40%, 120 ml) and TWO (150 ml). The layers were separated and the organic layer was washed with saturated solution of NaHCO₃(2×100 ml). The aqueous layers are re-extracted with TWO (2×100 ml). The organic extracts were combined, washed with brine (100 ml), dried over MgSO₄and concentrated in vacuum to receive 1,94 g of the crude product. After cleaning, Express chromatography (SiO₂, eluent: gradient AcOEt/hexane, 50 to 70%) received 1.63 g (82%) of the pure aldehyde (1). R_f0,30 (SiO₂that is eluent: heptane/AcOEt, 1:1).

¹H-NMR (CDCl₃, 500 MHz, 300 K): δ being 9.61 (d, J 1.7 Hz, 1H, CHO), to 6.95 (s, 1H, C_5"-N), of 6.52 (s, 1H, C_4'-N)to 4.33 (dd, J 4.4 Hz, 1H, C_2'-N, overlaps C₁-N_and), 4,34 (d, J to 11.4 Hz, 1H, C₁-H_a), 4,08 (d, J to 11.4 Hz, 1H, C₁-N_b), the 3.11 (dd, J 7,8, 3,9 Hz, 1H, C₃-N), was 3.05 (s, 3H, SO₂CH₃), a 2.71 (s, 3H, C_2"-CH₃), of 2.33 (m, 1H, C_4"'-N)2,02 (s, 3H, C_3'-CH₃), 1,99-1,32 (6 m, 8H, C_1'-N₂C_1"'-H₂With_2"'-N₂With_3"'-N₂), is 1.11 (d, J 7,1 Hz, 3H, C_4"'-CH₃), were 0.94 (t, J 8.0 Hz, N, Si(CH₂CH₃)₃), and 0.61 (q, J 8.0 Hz, 6N, Si(CH₂CH₃)₃).

¹³C-NMR (CDCl₃, 125 MHz, 300 K): δ 204,7, 164,8, 152,8, 141,8, 119,2, 115,8, 76,0, 72,0, 60,7, 59,0, 46,3, 37,8, 35,3, 30,5, 28,3, 22,5, 19,4, 14,1, 13.5, 7,0, 4,9.

IR (film): ν 2956s, 2876s, 2720w, 1724s, 1658w, 1508m, 1459m, 1414w, 1358s, 1240w, 1177s, 1079m, 1006m, 957m, 883w, 828m, 745m, 529m cm^-1.

MC (ES+): m/z 546 (100, [M+H]⁺).

MS (ES+) m/z 546 (100, [M+H]⁺).

1. The method of obtaining derivatives epothilone formula 9

where

R₁means methyl, a R₂means thiazole, substituted alkyl, and their salts with metal cations, including

a) interaction of the compounds of formula 1

where R₂matter above and methylgroup replaced by tailgroup or similar group, and R o is mean HE is a protective group, with sultam-derived formula 2, for example,

the reaction of selective aldol condensation in the presence of a Lewis acid and adding a base in an inert solvent at low temperature from -50 to -100°and then at an elevated temperature from -20 to +20°With formation of the compound of formula 3

where R₂and P have the meanings mentioned above, and

b) interaction of the compounds of the above formula 3 with a compound, forming a simple silloway ester, in an inert solvent at a temperature of from -70 to 25°in the presence of 2,6-lutidine with the formation of compounds of formula 4

where R₂and P have the meanings mentioned above, and

C) convert the above compounds of formula 4 in the carboxylic acid with the elimination of the chiral auxiliary group processing TWON/N₂O₂in DME or LiO₂H in THF/Meon/N₂About with the formation of the compounds of formula 5

where R₂and P have the meanings mentioned above, and

g) the interaction of the compounds of formula 5 with a regenerating agent in an inert solvent with the removal of mesyl or tailgroup or similar groups, with education is the use of the compounds of formula 6

where R₂have the meanings specified above, and

d) hydrolysis of compounds of formula 6 in the presence of desilicious reagent or acid in an inert solvent or mixtures thereof, for example TASF or HF·pyridine in THF, with the formation of selectively desilusionado the compounds of formula 7

where R₂and P have the meanings mentioned above, and

e) macrolactones hydroxyacids of formula 7 by treatment with a reagent Et₃N and 2,4,6-trichlorobenzaldehyde at low temperature with the formation of the fully protected derivative epothilone formula 8

where R₂and P have the meanings mentioned above, and

g) the interaction of the compounds of formula 8 with HF·pyridine in an inert solvent at a temperature of from 0 to 30°and the removal of both silyl protective groups with the formation of derivatives epothilone formula 9

where R₁means methyl, a R₂matter listed above, not necessarily obtaining salts of compounds of formula 9, where R₁and R₂have the meanings specified in the definition of formula 9, with metal cations by standard methods.

2. The method according to claim 1 (stage a, characterized in that compounds of the formula 1 interact with the compound of the formula 2, for example, in the presence of TiCl₄and grounds Hunya (iPr₂NEt) in dichloromethane at a temperature of -78°and then at 0°With formation of new compounds of formula 3.

3. The method according to claim 1 (stage b), characterized in that the compounds of the formula 3 is introduced into reaction with the compound forming silloway simple ether, in the presence of 2,6-lutidine at a temperature of from -20°to 20°first of all, at a temperature of -10°With, in dichloromethane as the inert solvent, with the formation of compounds of formula 4.

4. The method according to claim 1 (stage b), characterized in that the compounds of the formula 4 is converted into the carboxylic acid with the elimination of the chiral auxiliary groups using TBAOH/H₂O₂in DME or LiO₂H in THF/Meon/N₂About with the formation of the compounds of formula 5.

5. The method according to claim 1 (stage d), characterized in that the compounds of formula 5 interact with LiBHEt₃as a reducing agent in THF in an inert solvent with the removal of mesyl or tailgroup or similar groups, with the formation of compounds of formula 6.

6. The method according to claim 1 (stage d), characterized in that the compounds of formula 6 hydrolyzing desilicious reagent, first of all, TASF or organic is Oh acid, first of all, HF·pyridine in an inert solvent, such as pyridine or THF, to form compounds of formula 7.

7. The method according to claim 1 (stage e), characterized in that macrolactones carried out at 0°C, then the reaction mixture was added to a solution of 4-DMAP in toluene and increase the temperature to approximately 75°With formation of compounds of formula 8.

8. The method according to claim 1 (stage f), characterized in that the resulting protected derivatives epothilone formula 8 is treated with HF·pyridine in pyridine in an inert solvent and after removal of both silyl protective groups R receive derivative epothilone formulas 9 and optionally the compounds of formula 9, where R₁and R₂have the meanings specified in the definition of formula 9, which turn into salt with cations of metals by standard methods.