Method for synthesis of epothilone derivatives, novel epothilone derivatives, as well as novel intermediate compounds for realising said method and synthesis methods thereof

FIELD: chemistry.

SUBSTANCE: invention relates to novel epothilone derivatives of formula (8) , to synthesis method thereof and use thereof to obtain compounds of formula (9) , as well as to novel intermediate compounds for realising said method and synthesis methods thereof. The abbreviation P in said general structural formulae denotes a protective group of a functional hydroxyl selected from silyl protective groups, R₂ denotes a 5-member heteroaryl containing N and S as heteroatoms, optionally substituted with C₁-C₆ alkyl, and R₁ denotes methyl.

EFFECT: method of obtaining novel epothilone derivatives is simpler and better, can be well implemented on an industrial scale owing to a shorter synthesis path, and provides high reproducibility of synthesis of highly pure key intermediate compounds and end products.

21 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 C the problems.

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 the use of what Finance 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_{2 preferably 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(the) 2), 2-methylpyrimidin-4-yl, oxazol-5-yl, 2-methyl-1,3-dioxolane-2-yl, lH-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, e.g. a radical, selected from the following structures:

where R_xmeans acyl.

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

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 sultam-derived formula 2, for example,

where R means IT is a protective group, preferably a silyl protective is tnou 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°C to -100°C, and then at an elevated temperature from -20°C to +20°C, with the formation of the compounds 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 temperatures from -70°C to +25°C in the presence of 2,6-lutidine with the formation of compounds of formula 4

where R₂and R have the values specified above.

Connection formula 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 R₂and 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 HP•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 n the 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, etc., Bull. Chem. Soc. Jpn., 52, 1989 (1979), you get a fully protected derivative epothilone 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 from 0°C to 30°C and otscheplaut silyl protective groups, with a gain derived epothilone formula 9

where R₁means methyl, a 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 is Etat, 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), L1A1H4 (sociallyengaged), linitiative 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 is the Rupp choose from a number of TMS (trimethylsilyl), TES (triethylsilyl), TPS (tri-n-propulsion), TBDS (tert-butyldimethylsilyl), DEIPS (diethylenediamine), IPDMS (dimethylazobenzene), TDS (taxidermically), TIPS (triisopropylsilyl), TPR (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, first of all, citric acid, etc. First of all it should be noted HF•pyridine in THF or HF•pyridine in pyridine.

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,

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 -78°C and then at a temperature of 0°C with the 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 from -20°C to 25°C, first at a temperature of -10°C in dichloromethane as the inert solvent, with the formation of compounds of formula 4.

C) In the resulting compound of formula 4 otscheplaut auxiliary Sultanova group when processing TWON/N₂About₂in DME or LiO₂H in THF/Meon/N₂Oh, with the formation of carboxylic acids, i.e. the unity of formula 5.

g) the compound Obtained of formula 5 is treated using as reducing agent LiBHET3 in 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 HP•pyridine in an inert solvent, for example 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°C, and then the reaction mixture was added to a solution of 4-DMAP in toluene and the temperature was raised to about 75°C, while getting 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 transform in metal salts of a hundred the standard methods.

Used in the specified way of starting compound of formula 1 (where R₂means 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 RN at a temperature of from 50°to 150°C., more specifically at a temperature of 100°C, and then with KHMDS in an inert solvent, especially in THF at 0°C, and then after cooling the mixture to a temperature from -50°C to -100°C product treatment reagent CH₃CO₂CL, more specifically at a temperature of -78°C., to form 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 temperature the round from 20°C to 60°C, more specifically at a temperature of 40°C, with the formation of compounds of formula XIII

C) recovering the compound of formula (XIII) regenerating agent, primarily DIBALH, in an inert solvent, for example toluene, at temperatures from -50°C to -100°C., more specifically at a temperature of -78°C and then at an elevated temperature to 0°C, with the 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) epoxydodecane the 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 meanings is shown above.

The resulting compound of formula XVI is a new compound and is used as intermediate compounds in the next stage (e), where

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 of the 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 diversified 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 and 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 according to the present izobretetelya 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°C was 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-Ben is biloxicasino)oxazolidin-2-it (V)

The solution 87,7 g (of 0.50 mol) (8)-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 are washed twice with 250 ml of saline is astora, 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) Lil₄in 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 H₂Oh, 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/tO, 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% de (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 n. HCl and was extracted with 300 ml of heptane. The organic layer was washed with 100 ml 0,1N. HCl, 200 ml of a saturated solution of NaHCO₃200 ml saline solution is, 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[(8)-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°C, 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°C for 12h. 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

Aldehyde 1, the content DMS-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°C. 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 tO (300 ml) and water (150 ml). The layers were separated and the aqueous phase was extracted with tO (150 ml). The combined organic layers were washed with saturated NaCl solution (2×200 ml), dried over MgSO₄and concentrated in vacuum to receive neojidanni the 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 at 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 6.90 to (s, 1H, C_5"(H)6,77 (t, J 7.5 Hz, 1H, C₃-N), 6,47 (s, 1H, C₇(H)4,20 (dd, J 7,2, 5.4 Hz, 1H, C₅-N), of 3.69 (s, 3H, CO₂CH₃), 3,40 (dd. J 9,9, 5.7 Hz, 1H, C_5'-N_and), 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 2,28-2,21 (two m, 4H, C -N₂and C_1'-N₂), from 2.00 (s, 3H, C₆-CH₃), 1,30-1,15 (two m, 4H, C_2'-N₂With_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, Si₃), of 0.01 (s, 6H, two SiCH₃), -0,01 (s, 3H, Si₃).

(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 0,1N. HCl. The layers were separated and the aqueous phase washed TWO (2×50 ml). The combined organic extracts were washed with saturated solution of Panso₃(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-enyl]-2-[(8)-5-(tert-butyltin is tilelevel.exe)-4-methylpentyl]oxiranyl} methanol (XV)

Allyl alcohol (XIV) (3.00 g, 5,28 mmole) was dissolved in 51 ml of CH₂Cl₂at -30°C was added a 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 CH₃CL₂. 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°C was added to 2.74 ml (16,0 mmole) of N-ethyldiethanolamine and the resulting mixture was stirred at 0°C in those who begins 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 0,1N. HCl (40 ml), a saturated solution Panso₃(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-((5)-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.), at 0°C was added to 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) and brine (20 ml), dried over MSO ₄and 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°C 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 a saturated solution Panso₃(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

4-[(E)-(S)-3-(tert-Butyldimethylsilyl is yloxy]-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/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 1H. HCl (5 ml), a saturated solution Panso₃(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. The resulting 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 is the second 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 1N. HCl and 150 ml TWO. The layers were separated and the organic layer was sequentially washed with 100 ml of saturated solution Panso₃and 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'-H), 3,66 (d, J of 14.2 Hz, 1H, C_8'-N_b), 2,84 (dd, J 17.4 years, 4.6 Hz, 1H, C₂-H_a), 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, 6H, C_2'-H₂With_3'-H and C_5'-N₂), 1,48 is 1.20 and 1.34-1,24 (2 m, 2H, C -H₂), 1,10 (s, 3H, C_4'-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+Ca]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 f 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 was stirred at -78°C for 1 h Then the mixture was heated to 0°C and was stirred for another 15 min to complete the reaction (TLC results). The reaction was stopped at 0°C by addition of a phosphate buffer solution (the N 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 a saturated solution Panso₃(2×4 ml) and brine (4 ml), dried over MgS04 and 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 0,1N. 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 a saturated solution Panso₃(2×5 ml) and brine (5 ml), dried over MgSO₄and concentrated 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+Ca]2+).}

Carboxylic acid (5)

A solution of compound 4 (318 mg, 0,274 mmole) in 1,2-dimethoxyethane (4.8 ml) at 0°C was 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/CH₃SP/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 resulting 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 consequently is washed with a saturated solution Panso ₃(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)-(8)-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°C was 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 Panso₃(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). The organic extracts were combined and washed with 150 ml 0,1N. 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 6.90 to (s, 1H, C_5"(H)to 6.75 (t, 1H, J 7.5 Hz, C₃-N), 6,51 (s, 1H, C₇(H)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, 6H, C_2'-H₂With_3'-N_andWith_4'-H, C₅HE 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, C₄-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°C was 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 CH₂CL₂(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%), it 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, δ, C_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-C₂), 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 C₃-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°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 2n. HCl and diluted to 100 ml TWO. The layers were separated and the aqueous phase extragere the Ali TWO (2×100 ml). The combined organic extracts were washed with 100 ml Panso₃, 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 trend (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-OH), 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"-N_and), 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-H₂), of 1.99 (s, 3H, C₆-CH₃), 2,00-1,90 (user. m, 2H, C_1"-N₂), 1,58 of 1.46 (m, 1H, C_4"-H), 1,43-1,22 (m, 3H, C_3"-N_andand 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, 12H, 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"'-triethylenediamine]oxiranemethanol (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°C was 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°C 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-d₆, 400 MHz, 300 K): δ 7,28 (s, 1H, C_5"'-N), 6,44 (s, 1H, C₄(H)4,30 (dd, J 8,2, a 4.1 Hz, 1H, C_2'(H)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"'-N_and), 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"' -N2With2"'-N2With3"'-NandWith4"'-N,), 1,08-0,98 (m, 1H, C3"'-Nb), 0,93-0,83 (m, 18H, two Si(CH2CH3)3), of 0.82 (d, J 6,7 Hz, 3H, C4"'-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°C was 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, to 30.1 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 were washed with 0,1N. 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 updat the additional 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'-N), 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'-H_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-4'-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, about what ivali salt solution, 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 (SiO₃, eluent: heptane/AcOEt, 1:1).

¹H-NMR (DMSO-d₆, 400 MHz, 300 K): δ 7,42 (s, 1H, C_5"'(H)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"-H, partially overlaps C₁-H_a), 4,07 (d, J 11.8 Hz, 1H, C₁-H_a), 3,30 is 3.23 (m, 1H, C_5'-H_a), 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"-N_and), 1,70 is 1.58 (m, 1H, C_1"-N_b), and 1.54-1.32 to (m, 6N, C_1'-H₂With_2'-N₂With_3'-N_andWith₄-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 Hz, 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 (10, [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°C was 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 a saturated solution Panso₃(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 (SiO_a, 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"(H)of 6.52 (s, 1H, C_4'(H)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, SO₃CH₃), a 2.71 (s, 3H, C_{2"/sub> -CH3), of 2.33 (m, 1H, C4"'-N)2,02 (s, 3H, C3'-CH3), 1,99-1,32 (6 m, 8H, C1'-H2C1"'-H2C2"'-H2With3"'-N2), is 1.11 (d, J 7,1 Hz, 3H, C4"'-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 compounds of formula 3

where R₂means a 5-membered heteroaryl containing N and S as heteroatoms, optionally substituted C₁-C₆the alkyl, and the group R represents a protective group of the hydroxyl functional selected from silyl protective groups.

2. The method of obtaining compounds of formula 3, which consists in the fact that the compound of formula 1

where R₂means a 5-membered heteroaryl containing N and S as heteroatoms, optionally substituted C₁-C₆the alkyl group R represents a protective group of the hydroxyl functional selected from silyl protective groups, and mutilata group in all subsequent reactions may be replaced by Totila or similar group, the interaction is with the duty to regulate derivatives of Sultana formula 2

in particular, by selective reaction of aldol condensation in the presence of a Lewis acid and adding a base in an inert solvent at low temperature in the range from -50 to -100°C and then at a higher temperature in the range -20 to 20°C, to obtain the compounds of formula 3.

3. The compounds of formula 4

where R₂means a 5-membered heteroaryl containing N and S as heteroatoms, optionally substituted C₁-C₆the alkyl, and the group R represents a protective group of the hydroxyl functional selected from silyl protective groups.

4. The method of obtaining compounds of formula 4, which consists in the fact that the compound of formula 3

where R₂means a 5-membered heteroaryl containing N and S as heteroatoms, optionally substituted C₁-C₆the alkyl group R represents a protective group of the hydroxyl functional selected from silyl protective group, is reacted at a temperature in the range from -70 to 25°C with forming simple silloway ether compound in an inert solvent in the presence of 2,6-lutidine with the formation of compounds of formula 4.

5. The compounds of formula 5

where R₂means a 5-membered heteroaryl containing N S as heteroatoms, optionally substituted C₁-C₆the alkyl, and the group R represents a protective group of the hydroxyl functional selected from silyl protective groups.

6. The method of obtaining compounds of formula 5, which consists in the fact that the compound of formula 4

where R₂and P defined in claim 3, converted into carboxylic acids by cleavage of the chiral auxiliary groups using TWAIN/N₂About₂in DME or LiO₂H in THF-Meon/N₂About obtaining the compounds of formula 5.

7. The compounds of formula 6

where R₂means a 5-membered heteroaryl containing N and S as heteroatoms, optionally substituted C₁-C₆the alkyl, and the group R represents a protective group of the hydroxyl functional selected from silyl protective groups.

8. The method of obtaining compounds of formula 6, which consists in the fact that the compound of formula 5

where R₂and P defined in claim 5, interacting with regenerating agent in an inert solvent with the removal mesilate or tosylate, or similar groups, and obtaining the compounds of formula 6.

9. The compounds of formula 7

where R₂means a 5-membered heteroaryl containing N and S as heteroatoms, not necessarily for ewenny C ₁-C₆the alkyl, and the group R represents a protective group of the hydroxyl functional selected from silyl protective groups.

10. The method of obtaining compounds of formula 7, which includes the hydrolysis of three protected trisilicate ethers of the compounds of formula 6 by desilicious reagent, in particular TASF or organic acids, in particular HF/pyridine in an inert solvent, such as pyridine or THF, to obtain the compounds of formula 7.

11. The method of obtaining compounds of formula 8

where R₂means a 5-membered heteroaryl containing N and S as heteroatoms, optionally substituted C₁-C₆the alkyl, and the group R represents a protective group of the hydroxyl functional selected from silyl protective groups, including macrolactones compounds of formula 7 by treatment of the hydroxy acid by Et₃N and 2,4,6-trichlorobenzaldehyde at low temperature, after which the reaction mixture is added to a solution of 4-DMAP, the temperature of the reaction mixture rises to get fully protected derivative epothilone formula 8.

12. The compounds of formula 1

where R₂means a 5-membered heteroaryl containing N and S as heteroatoms, optionally substituted C₁-C₆the alkyl, and the group R about who appoints the protective group of the hydroxyl functional, selected from silyl protective groups.

13. The method of obtaining compounds of formula 1, including
a) interaction of the compounds of formula X

where the group R represents a protective group of the hydroxyl functional selected from silyl protective groups,
with PPH₃at a temperature in the range from 50 to 150°C, more precisely at 100°C, and then with KHMDS in an inert solvent, especially in THF at 0°C followed by cooling the reaction mixture to a temperature in the range from -50 to -100°C and processing of CH₃CO₂CL, preferably at a temperature of -78°C., to obtain compounds of formula XI

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

in an inert solvent, such as toluene, at a temperature in the range from 20 to 60°C., preferably at a temperature of 40°C, to obtain the compounds of formula XIII

C) the restoration of the compounds of formula XIII regenerating agent such as DIBALH, in an inert solvent, such as toluene, at a temperature in the range from -50 to -100°C, preferably at a temperature of -78°C., followed by raising the temperature to 0°C, to obtain the compounds of formula XIV

where R₂means a 5-membered heteroaryl, soda is containing N and S as heteroatoms, optionally substituted C₁-C₆the alkyl, and the group R represents a protective group of the hydroxyl functional selected from silyl protective groups,
g) the compound of the formula XIV are epoxydecane in the conditions he sang sharpless [(+)-diethyl L-tartrate, Ti(OPr)₄, t-BuOOH] obtaining the compounds of formula XV

where R₂means a 5-membered heteroaryl containing N and S as heteroatoms, optionally substituted C₁-C₆the alkyl, and the group R represents a protective group of the hydroxyl functional selected from silyl protective groups,
d) in a compound of formula XV enter mesilate group (or, respectively, tosylate or other group) by adding methylthiourea in the presence of triethylamine in an inert solvent, such as dichloromethane, to obtain the compounds of formula XVI

where R₂means a 5-membered heteroaryl containing N and S as heteroatoms, optionally substituted C₁-C₆the alkyl, and the group R represents a protective group of the hydroxyl functional selected from silyl protective groups,
e) the resulting compound of formula XVI is treated with an organic acid in an inert solvent, in particular p-toluensulfonate pyridinium or camphor sulfonic acid in absolute ethanol and, after hydrolysis of the protective groups to obtain the compound of formula XVII

where R₂means a 5-membered heteroaryl containing N and S as heteroatoms, optionally substituted C₁-C₆the alkyl, and the group R represents a protective group of the hydroxyl functional selected from silyl protective groups,
g) carry out the oxidation by the method of oxidation Swarna, in particular the oxidation of the alcohol groups through oxalicacid and activated dimethyl sulfoxide, and through alkoxysilanes salt after adding the substrate and intermolecular rearrangement get keto-compound of formula 1

where R₂means a 5-membered heteroaryl containing N and S as heteroatoms, optionally substituted C₁-C₆the alkyl, and the group R represents a protective group of the hydroxyl functional selected from silyl protective groups.

14. The compounds of formula XV

where R₂means a 5-membered heteroaryl containing N and S as heteroatoms, optionally substituted C₁-C₆the alkyl, and the group R represents a protective group of the hydroxyl functional selected from silyl protective groups.

15. The method of obtaining compounds of formula XV, which consists in the fact that the compound of formula XIV are epoxydecane in the conditions he sang sharpless [(+)-diethyl-L-one is spending, Ti(OPr)₄, t-BuOOH] obtaining the compounds of formula XV

where R₂means a 5-membered heteroaryl containing N and S as heteroatoms, optionally substituted C₁-C₆the alkyl, and the group R represents a protective group of the hydroxyl functional selected from silyl protective groups.

16. The compounds of formula XVI

where R₂means a 5-membered heteroaryl containing N and S as heteroatoms, optionally substituted C₁-C₆the alkyl, and the group R represents a protective group of the hydroxyl functional selected from silyl protective groups.

17. The method of obtaining compounds of formula XVI, which consists in the fact that in the compound of formula XV

enter mesilate group (or, respectively, tosylate or other group) by adding methylthiourea in the presence of triethylamine in an inert solvent, such as dichloromethane, to obtain the compounds of formula XVI

where R₂means a 5-membered heteroaryl containing N and S as heteroatoms, optionally substituted C₁-C₆the alkyl, and the group R represents a protective group of the hydroxyl functional selected from silyl protective groups.

18. The compounds of formula XVII

where R₂means a 5-membered heteroaryl containing N and S as heteroatoms, optionally substituted C₁-C₆the alkyl, and the group R represents a protective group of the hydroxyl functional selected from silyl protective groups.

19. The method of obtaining compounds of formula XVII, which consists in the fact that the obtained compound of formula XVI is treated with an organic acid in an inert solvent, in particular p-toluensulfonate pyridinium or camphor sulfonic acid in absolute ethanol, and after hydrolysis of the protective groups R have the compound of formula XVII.

20. The compound of formula 2

21. The use of the compounds of formula 8 to obtain the compounds of formula 9, are used in medicine for treatment

where R₁means methyl, a R₂has the values listed above.