Derivatives taxane

 

(57) Abstract:

The invention apply to the new derivative taxane General formula I

< / BR>
where Ar represents a phenyl, R represents a phenyl or the radical R5-O-, in which R5represents a straight or branched alkyl containing from 1 to 8 carbon atoms excluding tert-butyl, R1and R2has identical or different meanings and represent a hydrogen atom, an alkyl radical, phenylalkyl, phenyl, alkoxyphenyl or dialkoxybenzene, R3represents acetyl or a protective group of functional hydroxy-group, R4represents a protective group of functional hydroxy-group, which can be used as intermediates in obtaining Taxol, Taxotere or their analogues with anticancer or protivoanemicakimi properties. The technical result - the new derivatives taxane, allowing to obtain biologically active compounds.

The invention concerns derivatives taxane General formula (I)

< / BR>
which are of special interest as an intermediate connection when receiving Taxol, Taxotere or their analogues possessing protiva is l,

R represents phenyl or the radical R5-0-, in which R5represents a

linear or branched alkyl containing from 1 to 8 carbon atoms excluding tert-butyl, alkenyl containing from 2 to 8 carbon atoms, quinil containing from 3 to 8 carbon atoms, or cycloalkyl containing from 3 to 6 carbon atoms, cycloalkenyl containing from 4 to 6 carbon atoms, or bicycloalkyl containing from 7 to 11 carbon atoms, with the named radicals can be substituted by one or more substituents selected among halogen atoms and hydroxy groups, alkoxy, containing from 1 to 4 carbon atoms, dialkylamino, the alkyl portion of which contains from 1 to 4 carbon atoms, piperidino, morpholino, 1-piperazinil (possibly substituted in position 4 by alkyl containing from 1 to 4 carbon atoms, or phenylalkyl, the alkyl portion of which contains from 1 to 4 carbon atoms), cycloalkyl containing from 3 to 6 carbon atoms, cycloalkenyl containing from 4 to 6 carbon atoms, Feliciano, carboxy or alkoxycarbonyl, the alkyl portion of which contains from 1 to 4 carbon atoms, or

R5represents phenyl, possibly substituted by one or more atoms or R is coxi, containing from 1 to 4 carbon atoms, or

R5represents a saturated or unsaturated nitrogen-containing heterocycle, containing from 4 to 6 units, possibly substituted by one or more alkilani containing from 1 to 4 carbon atoms, with cycloalkyl, cycloalkenyl or bicycloalkyl can be substituted by one or more alkilani containing from 1 to 4 carbon atoms,

R1and R2have identical or different meanings and represent a hydrogen atom, alkyl, phenylalkyl, phenyl, alkoxyphenyl or dialkoxybenzene, or

R1and R2together form with the carbon atom to which they are linked, a cycle containing from 4 to 7 units,

R3represents acetyl or a protective group of the hydroxyl function,

R4predstavljaet a protective group of the hydroxyl function.

More specifically, AG represents phenyl or-naphthyl, possibly substituted by one or more atoms or radicals, equal or different values, selected among halogen atoms (fluorine, chlorine, bromine, iodine) and the radicals: alkyl, alkenyl, quinil, aryl, aralkyl, alkoxy, alkylthio, aryloxy, aaltio, hydroxy, oxyalkyl, mercapto, formyl, carbamoyl, dialkylamino, cyano, nitro and trifluoromethyl, with of course that alkali and the alkyl part of the other radicals contain 1 to 4 carbon atoms, and alkenyl and quinil contain from 3 to 8 carbon atoms, and aryl represents phenyl or-naphthyl, or AG is an aromatic heterocycle containing 5 parts and includes one or more atoms having the same or different is selected among nitrogen atoms, oxygen or sulfur, possibly substituted by one or more substituents, equal or different values, selected among halogen atoms (fluorine, chlorine, bromine, iodine) and the radicals: alkyl containing from 1 to 4 carbon atoms, aryl containing from 6 to 10 carbon atoms, alkoxy containing from 1 to 4 carbon atoms, aryloxy containing from 6 to 10 carbon atoms, amino, alkylamino containing from 1 to 4 carbon atoms, dialkylamino, the alkyl portion of which contains from 1 to 4 carbon atoms, acylamino, acyl portion of which contains from 1 to 4 carbon atoms, alkoxycarbonyl, containing from 1 to 4 carbon atoms, acyl containing from 1 to 4 carbon atoms, arylcarbamoyl, the aryl portion of which contains from 6 to 10 carbon atoms, cyano, carboxy, carbamate which contains from 1 to 4 carbon atoms, or alkoxycarbonyl, alkoxy containing from 1 to 4 carbon atoms.

More specifically, AG represents phenyl, 2 - or 3-thienyl or 2 - or 3-furyl, possibly substituted by one or more atoms or radicals, which have the same or different meanings selected from halogen atoms and the radicals alkyl, alkoxy, amino, dialkylamino, acylamino, alkoxycarbonyl and trifluoromethyl.

More specifically, AG represents phenyl, possibly substituted by a chlorine atom or fluorine or alkyl (methyl), alkoxy groups (methoxy), dialkylamino (dimethylamino) acylamino (acetylamino) or alkoxycarbonyl (tert-butoxycarbonylamino) or 2-thienyl or 3-thienyl, or 2-furyl or 3-furyl.

More specifically, R3represents acetyl or a protective group of functional hydroxy-group, selected from the following radicals: (2,2,2-trichloroethane)carbonyl, (2-trichlorometylperoxyl)carbonyl, trialkylsilyl, dialkylanilines, alkyldimethyl or triallelic in which alkali contain from 1 to 4 carbon atoms, and arily are mainly fenelli, and R4represents a protective group of functional hydroxy-group, selected from the following radicals: (2,2,2-t is kelsell, dialkylanilines, alkyldimethyl or triallelic in which alkali contain from 1 to 4 carbon atoms, and arily are mainly fenelli.

In the international application PCT/WO 9209589 described obtaining compounds of General formula (I) by esterification of protected baccatin 111 or protected 10-diacetylpyridine 111 General formula

< / BR>
where R3and R4have the meanings specified above,

carried out using the acid of General formula

< / BR>
where Ar, R1and R2have the meanings specified above, and

BOC represents a tert-butoxycarbonyl,

with the conversion of the compounds obtained in the Taxol, Taxotere or their derivatives of General formula

< / BR>
where AG has the values listed above,

R6represents a hydrogen atom or acetyl, and

R represents phenyl, or R5-O-, where R5matter mentioned above, by receiving at an intermediate stage of the compounds of General formula

< / BR>
where R3and R4the values listed above.

According to previously known methods, it was necessary to obtain the compounds of General formula (IV) in which absolute configuration of the lateral link defines antitumor svojstvo respectively the S configuration and the configuration of the R.

The applicant developed a method of obtaining compounds of General formula (I) at 100% stereoselectivity, namely, that atrificial protected baccatin 111 or protected 10-deacetylbaccatin 111 using the acid of General formula

< / BR>
where Ar, R, R1and R2matter,

above, and the carbon atoms of which is located in position 4 and 5, have the S configuration, or with an activated derivative of this acid.

The method allows stereoselective to obtain the compound of General formula (I), using the acid of General formula (VI), which can be used in a mixture with the acid of General formula (III).

The esterification of protected baccatin 111 or protected 10-deacetylbaccatin 111 acid of General formula (VI) is carried out in the presence of a condensing agent, such as imide, namely dicyclohexylcarbodiimide, or a reactive carbonate, namely 2-piperidinylcarbonyl, and agent activation, for example aminopyridine, namely 4 dimethylaminopyridine or 4-pyrrolidinedione using an organic solvent, selected among these ethers, like tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether or dioxalate, NITRILES, aliphatic hydrocarbons such as pentane, hexane or heptane, halogenated aliphatic hydrocarbons such as dichloromethane or 1,2-dichloromethane, aromatic hydrocarbons such as benzene, toluene, xylene, ethylbenzene, isopropylbenzene or chlorobenzene, at a temperature of from 0 to 90oC.

The etherification can be carried out using the acid of General formula (VI) in the form of an anhydride of General formula

< / BR>
where Ar, R, R1and R2have values similar to the above,

in the presence of the agent activation, for example aminopyridine, namely 4-dimethylaminopyridine or 4-pyrrolidinedione, in an organic solvent selected among these ethers, like tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether or dioxane, ketones such as methyl isobutyl ketone, such esters as ethyl acetate, isopropylacetate or n-butyl acetate, NITRILES such as acetonitrile, aliphatic hydrocarbons such as pentane, hexane, heptane, such halogenated aliphatic hydrocarbons like dichloromethane or 1,2-dichloroethane, and aromatic hydrocarbons such as benzene, toluene, xylene, ethylbenzene, isopropylbenzene or chlorobenzene, at The General formula (VI) in the form of a halide or mixed anhydride of General formula

< / BR>
where Ar, R, R1and R2have the meanings specified above, and

X represents a halogen atom or a radical of acyloxy or urologic,

possibly prepared in situ in the presence of a base, which is mostly nitrogen-containing organic base, for example an aliphatic tertiary amine, pyridine or aminopyridine, namely 4-dimethylaminopyridine or 4-pyrrolidinedione, working in an inert organic solvent selected among these ethers, like tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether or dioxane, ketones, such as methyl - tert-butylketone, esters such as ethyl acetate, isopropylacetate or n-butyl acetate, NITRILES, such as acetonitrile, aliphatic hydrocarbons such as pentane, hexane or heptane, halogenated aliphatic hydrocarbons, for example dichloromethane or 1, 2-dichloroethane, and aromatic hydrocarbons, for example benzene, toluene, xylene, ethylbenzene, isopropylbenzene or chlorobenzene, at a temperature of from 0 to 90oC.

The acid of General formula (VI) can be obtained by saponification of ester of General formula

< / BR>
where Ar, R, R1and R2have the values pointed to by the him or multiple fenelli.

Basically, the saponification is carried out in aqueous medium, possibly in the presence of an aliphatic alcohol containing from 1 to 4 carbon atoms (methanol, ethanol, isopropanol, tert-butanol) in the presence of mineral substrates, selected from hydroxides, carbonates or bicarbonates of alkali metals or alkaline earth metals at a temperature of from 0 to 50oWith, and preferably equal to approximately 20oC.

Ester of General formula (IX) can be obtained by exposure of the aldehyde or ketone of General formula

< / BR>
where R1and R2have the meanings specified above,

perhaps in the form of dialkylated or enol Olkiluoto ether, an ester of General formula

< / BR>
where Ar, R and R7have the meanings specified above,

carrying out the reaction in an inert organic solvent in the presence of a strong mineral acid, for example sulphuric acid, or organic acids such as para-toluenesulfonic acid, possibly in the form of a pyridinium salt, at a temperature of from 0oC to the boiling temperature of the reaction mixture.

Particularly suitable solvents are aromatic hydrocarbons, namely toluene.

Ester of General formula (>where R5has the values listed above, and Y represents a halogen atom or a radical-O-R5or-O-CO-R5on an ester of General formula

< / BR>
where AG and R7have the meanings specified above,

carrying out the reaction in an organic solvent such as an aliphatic ether, namely, ethyl acetate, or a halogenated aliphatic hydrocarbon, namely dichloromethane, possibly in the presence of a mineral base such as sodium bicarbonate, or in the presence of an organic base such as triethylamine. Basically, the reaction is carried out at a temperature of 0 - 50oWith, and preferably close 20oC.

Ester of General formula (XII) can be obtained in accordance with the method described in E. Kamandi et coll. , Arch. Pharmaz., 308 135-141 (1975).

The anhydride of General formula (VII) can be obtained by treating the dehydration agent, e.g., dicyclohexyltin-diimides, acids of General formula (VI) is carried out in an organic solvent chosen from ethers such as tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether or dioxane, ketones such as methyl isobutyl ketone, esters such as ethyl acetate, isopropylacetate Il is h, halogenated aliphatic hydrocarbons, such as dichloromethane or 1,2-dichloroethane, and aromatic hydrocarbons such as benzene, toluene, xylene, ethyl benzene or chlorobenzene, at temperatures from 0 to 30oC.

The activated acid of General formula (VIII) can be obtained by exposing the halide Sulfuryl, preferably chloride Sulfuryl, or compounds of General formula

R8-CO-Z (XIII),

where R8represents alkyl containing from 1 to 4 carbon atoms, or phenyl, possibly substituted by 1-5 atoms or radicals, which have the same or different meanings selected from halogen atoms and radicals, nitro, methyl or methoxy, a Z is a halogen atom, and predpochtitelnye chlorine, acid of General formula (VI) is carried out in a suitable organic solvent, such as tetrahydrofuran, in the presence of an organic base, such as tert-amine, namely triethylamine, and at a temperature of from 0 to 30oC.

The acid of General formula (VI) can also be obtained by oxidation of compounds of General formula

< / BR>
where Ar, R, R1and R2have the values specified above.

Typically the oxidation is carried out using 3) and sodium bicarbonate, acting in an aqueous-organic medium, for example in a mixture of acetonitrile-carbon tetrachloride-water. Basically, the reaction is carried out at a temperature close to 20oC.

The compound of General formula (XIV) can be obtained by exposure of the aldehyde or ketone of General formula (X) may be in the form of dialkylated or complex enol ester to the compound of General formula

< / BR>
where AG and R have the meanings stated above,

carried out in an inert organic solvent in the presence of a strong mineral acid, for example sulphuric acid or in the presence of organic acids, such as para-toluenesulfonic acid, possibly in the form of a pyridinium salt at a temperature of from 0oC to the boiling temperature of the reaction mixture. Particularly suitable solvents are aromatic hydrocarbons.

The compound of General formula (XV) can be obtained under the conditions described in EP-A-0530385.

Ester of General formula (IX) where AG and R7have values similar to the above, a R1represents a hydrogen atom, R2represents phenyl, alkoxyphenyl or dialkoxybenzene can be obtained by cyclization of compounds of General formula
carried out preferably in an anhydrous medium, in an organic solvent, selected from among ethers, esters, ketones, NITRILES, possibly halogenated aliphatic hydrocarbons, aromatic hydrocarbons, possibly containing halogen, in the presence of an oxidising agent, such as dichlorodicyanoquinone, at a temperature of from 0oC to the boiling temperature of the reaction mixture. Preferably the cyclization to implement in a halogenated aliphatic hydrocarbon, such as dichloromethane or acetonitrile, at a temperature close to 20oC.

Cyclization leads to the formation of a mixture of epimeres 2R and 2S compounds of General formula (IX), which can be divided in accordance with known techniques. Especially, it is advisable to obtain mainly epimer 2R for the preparation of Taxol, Taxotere or their derivatives of the compounds of General formula (I).

Derivatives taxane General formula (I) obtained using the method according to the invention, can be converted into Taxol, Taxotere or their analogues in accordance with the methods described in international application PCT WO 9209589, when R1and R2are each alkyl Loy environment (hydrochloric acid, sulfuric acid, acetic acid, methanesulfonate, triftoratsetata, a pair of toluensulfonate) when using an organic solvent (alcohol, simple ester, ester, aliphatic hydrocarbon, halogenated aliphatic hydrocarbon, aromatic hydrocarbon, nitrile) at a temperature of -10 to 60oWith, and when R1represents a hydrogen atom, and R2represents phenyl, alkoxyphenyl or dialkoxybenzene, receiving at the intermediate stage of the compounds of General formula

< / BR>
where Ar, R and Ph have the meanings indicated above,

and R' represents a hydrogen atom or acetyl,

after replacement of the protective groups R4and perhaps R3hydrogen atoms in accordance with known methods.

The following examples illustrate the present invention.

Example 1.

In a flask with a capacity of 10 cm3equipped with a magnetic stirring system, introducing an argon atmosphere 28 mg (0,087 mmole) of 3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-1,3-oxazolidin-5-carboxylic-(4S, 5S) acid dissolved in 1.5 cm3anhydrous toluene. Then added 18 mg (0,087 mmole) of distilled dicyclohexylcarbodiimide. The mixture is left for Saimaa) 4-N,N-dimethylaminopyridine and 26 mg (0,029 mmole) of 4-acetoxy-2-benzoyloxy-5, 20-epoxy-1,13-deoxy-9-oxo-7, 10-bis-(2,2,2-trichlorocarbanilide)-11-taxen. The mixture is left to interact for 5 minutes at a temperature close to 20oSince, then, it is heated for 16 hours at a temperature of 72oC. After cooling at a temperature close to 20oC, add 40 cm3ethyl acetate. The organic phase is washed with 5 cm3distilled water, 2 times 5 cm3saturated aqueous sodium bicarbonate solution, then 5 cm3saturated aqueous solution of sodium chloride and finally dried on anhydrous sodium sulfate. After filtration and evaporation of the solvents under reduced pressure to obtain the residue (solid), which is purified by preparative chromatography on a thin layer of silica using as eluent a mixture of ether-hexane-dichloromethane (5:20:75 by volume). Thus obtained (yield 86%) 30 mg (0,025 mmole) of 3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-1,3-oxazolidin-5-carboxylate-(4S, 5R)-4-acetoxy-2-benzoyloxy-5, 20-epoxy-1-hydroxy-9-oxo-7, 10-bis(2,2,2-trichlorocyanuric)oxy-11-taxen-13-Il, has the following characteristics.

Infrared spectrum (film): the main characteristic absorption bands at 3450, 2970, 2910, 1760, 1720, 1700, 1600,the mission of the proton (300 MHz, CDCl3, chemical shift in ppm, constants combination J in Hz): 1,18 (s, N); of 1.27 (s, 3H); 1,6-2,0 (m, 1H); to 1.76 (s, 3H); is 1.81 (s, 3H); to 1.83 (s, 3H); 1,95 (s, 3H); is 2.05 (s, 3H),2,20 (d, J=9, 2H); 2,55-to 2.65 (m, 1H); 3,90 (d, J=7, 1H); 4,20 (ABq,AB= 8,5A-B= 47,2, 2H); 4,47 (d, J=6,4, 1H); at 4.75 (ABq, JAB=12A-B= 92,2, 2H); 4,78 (s, 2H); 4,91 (d, J = 12, 1H); 5,12 (s, broad, 1H); to 5.58 (DD, J=7,1 and 10.6, 1H); 5,67 (d, J=7, 1H); and 6.25(s, 1H); 6,28 (t, J= 9, 1H); of 7.2 to 7.4 (m, 5H, aromatic); 7,47-7,52 (m, 2H, aromatic); to 7.61-7,66 (m, 1H, aromatic); 8,03-with 8.05 (m, 2H, aromatic).

Mass spectrum (FAB(+)-matrix PVA) of molecular ion (array): M+(1198).

3-tert-Butoxycarbonyl-2,2-dimethyl-4-phenyl-1,3-oxazolidin-5-carboxylic-(4S,5S) acid can be obtained as follows.

In a flask with a capacity of 25 cm3equipped with a magnetic stirring system, consistently give 40 mg (0.12 mmole) of 3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-methoxycarbonyl-1,3-oxazolidine (4S, 5S), 5 cm3methanol, 2 cm3distilled water and 50 mg (or 0.36 mmole) of solid potassium carbonate. The reaction mixture is stirred for 40 hours at a temperature close to 20oWith, then methanol is evaporated under reduced pressure. Add 13 cm3water, then the aqueous phase is washed three times 20 cm3loretana with vigorous stirring by addition of 2M aqueous solution of hydrochloric acid. The organic phase is separated by decantation, after which the aqueous phase is extracted 6 times with 30 cm3dichloromethane. The collected organic phases are washed with 3 times 5 cm3distilled water, then 1 every 5 cm3saturated aqueous solution of sodium chloride, and then, finally, dried on anhydrous magnesium sulfate. After filtration and concentration dry under reduced pressure to obtain (yield 99%) 38 mg (0.12 mmole) of 3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-1,3-oxazolidin-5-carboxylic-(4S, 5R) acid having the following characteristics:

Infrared spectrum (film): the main characteristic absorption bands at 3650-2200, 2970, 2920, 1760, 1740, 1700, 1470, 1450, 1370, 1250, 1215, 1165, 1135, 1110, 1065, 875 and 690 cm-1.

Spectrum of nuclear magnetic resonance of the proton (200 MHz, Dl3, chemical shift in ppm, constants combination J in Hz): 1,20 (est.) and 1.43 (neon.) (2s, broad, N), of 1.64 (s, 3H); of 1.94 (s, 3H); 3,0 (s, very broad, 1H); equal to 4.97 (d, distorted, J=7, 1H); 5.0 to a 5.25 (m, 1H); of 7.2 to 7.4 (m, 5H, aromatic).

Mass spectrum (i. c. NH3+ isobutane): 339 (MN+), 322 (MN+HE), 283, 266, 222, 206, 158, 124, 110.

3-tert-Butoxycarbonyl-2,2-dimethyl-4-phenyl-5-methoxycarbonyl-1,3-oxazolidin (4S, 5S) can be obtained as follows.

3anhydrous toluene. Then to the resulting suspension was added 10 granules of zeolite size 188,5 ál (144,2 mg, 2.0 mmole) of 2-methoxypropene and 12.5 mg (0.05 mmole) para-toluensulfonate pyridinium. The reaction mixture is left for 1 hour at a temperature close to 20oC, then heated to 120oWith and left to interact for 2 hours. The reaction mixture, which acquires a dark brown color, is cooled at a temperature close to 20oC. was Added 60 cm3dichloromethane. The organic phase is washed with 5 cm3saturated aqueous sodium bicarbonate solution, 3 times with 5 cm3water, and then 1 every 5 cm3aqueous saturated solution of sodium chloride. The organic phase is dried on anhydrous sodium sulfate. After filtration and concentration dry under reduced pressure to obtain a residue, which was subjected to chromatography on a column of silica gel, using as eluent a mixture of ethyl ether-hexane (15:85 by volume). Get (yield 36%) 60 mg (of 0.18 mmole) of 3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-methoxycarbonyl-1,3-oxazolidine-(4S,5S) that has the following characteristics.

Infrared spectrum (film): the main characteristic absorption bands at 30 magnetic resonance of the proton (200 MHz, DCl3, chemical shift in ppm, constants combination J in Hz): 1,20 (max) and 1.43 (minutes) (2s, broad, N); and 1.63 (s, 3H); 1,90 (min) and 1.95 (max) (2s, broad, 3H); of 3.32 (s, 3H); 4,95-5,20 (m, 1H); equal to 4.97 (d, distorted, J=7, 1H); 7,15-7,40 (m, 5H, aromatic).

Mass spectrum (i. c. , NH3+ isobutane): 353 (M+NH4+); 336 (MN+); 320 (M+-CH3); 297; 280; 239; 236; 222; 220.

Methyl-3-tert-butoxycarbonylamino-3-phenyl-2-oxopropionate-(2S, 3S) can be obtained as follows.

To a suspension of 6.5 g of phenylglycidate-(2S,3R)--methylbenzylamine 20 cm3toluene and 10 cm3water is added within 5 minutes of aqueous 4 n sodium hydroxide solution. After 2 hours stirring at a temperature close to 20oWith the separated aqueous phase is extracted with 2 times 7 cm3of toluene. The aqueous phase is injected into the autoclave. After adding 97,5 cm332% aqueous ammonium hydroxide solution and 1.22 g of ammonium chloride, the autoclave is closed and then heated under stirring for 6 hours at a temperature of 60o(Autogenous pressure 3 bar). After cooling to a temperature close to 20oC, add 6 cm3aqueous 4 n sodium hydroxide solution. Within 30 minutes exercise stirring, then remove ammonia under reduced C. The resulting residue is dissolved in 75 cm3of methanol. To the formed suspension was added during 35 minutes at a temperature of 20oWith a methanol solution of sulfuric acid formed 4.83 g of concentrated sulfuric acid in 20 cm3of methanol. The reaction mixture is heated at a temperature of 50oC for 3 hours and 30 minutes. After cooling to 0oTo add a solution of 27 g of sodium carbonate in 20 cm3water. After stopping the release of carbon dioxide, the reaction mixture was cooled to 23oC for 30 minutes. Then within 30 minutes, add a solution of 6.1 g of di-tert-BUTYLCARBAMATE 7 cm3of methanol. Within 4 hours of stir, and then, after evaporation of 50 cm3methanol was added 60 cm3water, then the whole is evaporated methanol. The connection drawn in the precipitate is separated by filtration, then washed with 2 times 25 cm3water and dried to constant weight. Thus obtained (30% yield) of 2 g of methyl 3-tert - butoxycarbonylamino-3-phenyl-2-oxopropionate-(2S,3S) that has the following characteristics: melting point 135,5-136oC; torque capacity: []D25 = +29,6o(C = 0,5, chloroform).

Infrared spectrum (film): the main characteristic bands my absorption is p nuclear magnetic resonance of the proton (200 MHz, D13, chemical shift in ppm, constants combination J in Hz): USD 1.43 (s, N); 2,84 (d, J=7, 1H); 3,71 (s, 3H); 4,60 (DD, J=3.5 and 7, 1H); 5,10 (d distorted., J=8, 1H); 7,20-7,37 (m, 5H aroma.).

Spectrum of nuclear magnetic resonance of the proton (360 MHz, D-d6, 298oTo, chemical shift in ppm, constants combination J in Hz): 1,31 (with a wide, N); 3,55 (s, 3H), 4,14 (d, J=7,7, 1H); 4,71 (DD, 1H); 5,65 (broad, 1H); to 7.18 (d, J=7, 1H); 7,15-to 7.3 (m, 5H).

Example 2.

In odnogolosy flask with a capacity of 5 cm3equipped with a magnetic stirring system, administered 9 mg (0,028 mmole) of 3-benzoyl-2,2-dimethyl-4-phenyl-1,3-oxazolidin-5-carboxylic-(4S, 5S) acid dissolved in 0,46 cm3anhydrous toluene. Then add to 5.7 mg (0,028 mmole) dicyclohexylcarbodiimide. The reaction mixture became turbid, leave to react for 5 minutes at a temperature close to 20oWith, then add a mixture of 6.4 mg (0,009 mmole) 4,10-diacetoxy-2-benzoyloxy-5,20-epoxy-1,13-deoxy-9-oxo-7-triethylsilyl-11-taxen and 1.1 mg (0,009 mmole) 4-N,N-dimethylaminopyridine. The reaction mixture is left to react for 5 minutes at a temperature close to 20oC, then heated for 16 hours at 72oC. After cooling to a temperature close to 20oC, the reaction mixture Tasbulat, is astora sodium bicarbonate, 3 times 5 cm3water, and then 1 every 5 cm3aqueous saturated solution of sodium chloride and finally dried on anhydrous sodium sulfate. After filtration and removal of solvents under reduced pressure the resulting residue (21 mg) purified by chromatography on thin layer silica using as eluent a mixture of ethyl ether-dichloromethane (8: 92 by volume). Chromatography is carried out twice. Thus obtained (yield 91%) of 8.4 mg (0,008 mmole) of 3-benzoyl-2,2-dimethyl-4-phenyl-1,3-oxazolidin-5-carboxylate-(4S, 5R)-4,10-diacetoxy-2-benzoyloxy-5,20-epoxy-1-hydroxy-9-oxo-7-triethylsilyl-11-taxen-13-Il, has the following characteristics.

Infrared spectrum (film): the main characteristic absorption bands at 3400, 2930, 2850, 1730, 1720, 1630, 1590, 1570, 1440, 1360, 1340, 1230, 1195, 1065, 1015, 1005, 980 and 810 cm-1.

Spectrum of nuclear magnetic resonance of the proton (400 MHz, D13, chemical shift in ppm, constants combination J in Hz): 0,54-0,61 (m, 6N), to 0.92 (t, J=8, N); of 1.20 (s, 3H); 1,22 (s, 3H), of 1.65 (s, 3H), of 1.86 (s, 3H); 1.93 and (s, broad, 3H); 2,00 (s, 3H); of 2.08 (s, 3H); 2,19 (s, 3H); 1,82-of 2.15 (m, 3H); 2,46-of 2.54 (m, 1H); of 3.77 (d, J=7,2, 1H); 4.16 the (ABqJAB=8,4,A-B= 59,4, 2H); to 4.46(DD, J= 6.6 and a 10.5, 1H); 4,56 (d, J=6,8, 1H); 4,88 (d, J= 8, 1H); at 5.27 (d, J= 6, 1H); 5,64 (d, J=7,2, 1H); 6,24 (t, J= 9, 1H); 6,45 (s, 2H); 6,94 (WHO CLASS="ptx2">

Spectrum of magnetic resonance13(100 MHz, DC13): 5,20, 6,69, 9,99, 14,26, 20,82, 21,07, 21,62, 26,42, 35,27, 37,04, 43,18, 46,69, 58,28, 65,97, 71,68, 72,06, 74,79, 74,85, 76,32, 78,93, 80,74, 84,09, 93,43, 102,65, 126,11, 126,86, 127,83, 128,02, 128,50, 128,69, 129,14, 129,43, 130,00, 133,67, 133,82, 138,81, 139,90, 166,93, 169,13, 169,85, 201,60.

Mass spectrum (FAB (+)-matrix NBA+KC1): 1046, 1008 (MN+), 948, 930.

3-Benzoyl-2,2-dimethyl-4-phenyl-1,3-oxazolidin-5-carboxylic-(4S, 5S) acid can be obtained as follows.

In odnogolosy flask with a capacity of 2 cm3equipped with a magnetic stirring system, enter 12.5 mg (0.04 mmole) of 5-vinyl-3-benzoyl-2,2-dimethyl-4-phenyl-1,3-oxazolidine-(4S, 5R) dissolved in 80 μl of acetonitrile. Then add 80 μl of carbon tetrachloride, 120 μl of water and 22 mg (0,26 mmole) of pure sodium bicarbonate. Then, with vigorous stirring, the reaction mixture is injected in small doses 47 mg (0.22 mmole) of periodate sodium. The reaction mass is left to interact for 5 minutes at a temperature close to 20oWith, then add one dose of 2.4 mg trichloride ruthenium. The resulting heterogeneous mixture of black color intensively stirred at a temperature of 20oWith within 72 hours.

The reaction mixture is diluted with 10 cm3water. Received VI is then acidified with vigorous stirring and in the presence of 20 cm3dichloromethane using aqueous 2M hydrochloric acid to pH=1. After decanting acidic aqueous phase is extracted 6 times 15 cm3dichloromethane. The collected organic phase is washed with 3 times 5 cm3water, then 1 every 5 cm3aqueous saturated solution of sodium chloride. After drying on anhydrous sodium sulfate and filtering, the organic phase is concentrated to dryness under reduced pressure. Thus obtained (yield 77%) 10.0 mg (0,031 mmole) of 3-benzoyl-2,2-dimethyl-4-phenyl-1,3-oxazolidin-5-carboxylic-(4S,5S) acid having the following characteristics:

Infrared spectrum (film): the main characteristic absorption bands at 3700-2300, 2970, 2940, 2930, 2900, 2825, 1740, 1600, 1590, 1570, 1420-1400, 1370, 1360, 1190, 1180, 1150, 1120, 1090 and 855 cm-1.

Spectrum of nuclear magnetic resonance of the proton (200 MHz, D13, chemical shift in ppm): is 1.81 (s, 3H); 2,11 (s, 3H); 4,90-of 5.06 (m, 2H); 6,78-6,93 (m, 4H aromatic.); 7,07-7,30 (m, 6N aromatic.).

5-Vinyl-3-benzoyl-2,2-dimethyl-4-phenyl-1,3-oxazolidin-(4S,5R) can be obtained as follows.

In odnogolosy flask with a capacity of 10 cm3equipped with a magnetic stirring system and refrigerator, introducing argon atmosphere 32 mg (0.12 mmole) of 1-phenyl-1-benzoylamine-2-hydroxy-3-butene is Elena, 6.0 mg (0,024 mmole) para-toluensulfonate pyridinium and 8 pellets of zeolite size of the Resulting reaction mixture is left to interact at a temperature close 15oWith over 2.5 hours, then have it heated to 100oC for 2 hours. After cooling to a temperature close 15oC, the reaction mixture is diluted with 40 cm3dichloromethane. The organic phase is washed with 1 in every 5 cm3saturated sodium bicarbonate solution, 3 times with 5 cm3water water and 1 time with saturated sodium chloride solution, then dried on anhydrous sodium sulfate. After filtration and concentration dry under reduced pressure, the obtained residue is purified by chromatography on silica gel, using as eluent the first time a mixture of ethyl ether-dichloromethane (2: 98 by volume), and then a mixture of ethyl acetate-hexane (10: 90 by volume). Thus obtained (yield 38%) 14 mg (0,0456 mmole) of 5-vinyl-3-benzoyl-2,2-dimethyl-4-phenyl-1,3-oxazolidine-(4S, 5R) having the following characteristics:

Infrared spectrum (film): the main characteristic absorption bands at 3050, 3010, 2980, 2920, 1635, 1595, 1570, 1490, 1385, 1370, 1355, 1245, 1215, 1145, 1065, 1030, 1020, 935, 850 and 690 cm-1.

Spectrum of nuclear magnetic resonance ,4, 1H); 4,79 (pst, J=6,4, 1H); equal to 4.97-5,10 (m, 2H); to 5.21-of 5.26 (m, 1H); 6,78-6,94 (m, 4H aromatic.); ? 7.04 baby mortality-7,30 (m, 6N aromatic.).

Example 3.

In odnogolosy flask with a capacity of 5 cm3equipped with a magnetic stirring system, introducing an argon atmosphere 23 mg (0,058 mmole) of 3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidin-5-carboxylic-(2R, 4S, 5S) acid in 1 cm3anhydrous toluene, then added to 11.9 mg (0,058 mmole) dicyclohexylcarbodiimide. The reaction mass is left to interact for 5 minutes at a temperature near 25oWith, then add a mixture of 2.3 mg is 0.019 mmole) 4-N, N-dimethylaminopyridine and 17 mg is 0.019 mmole) of 4-acetoxy-2-benzyloxy-5, 20-epoxy-1,13-deoxy-9-oxo-7,10-bis-(2,2,2-trichlorocarbanilide)-11-taxen. The reaction mass is left to react for 5 minutes at a temperature of 25oWith, and then heated for 24 hours at a temperature of 74oC. After evaporation of the toluene under reduced pressure, the obtained residue (74 mg) purified by chromatography on thin layer silica gel, using as eluent a mixture of ethyl ether-dichloromethane (5: 95 by volume). So get to 23.4 mg (0,012 mmole) of 3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidin-5-carboxylate-(2R, 4S, 5R)-4-acetoxy-2 is t-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxa-solidin-5-carboxylate-(2R, 4S, 5S)-4-acetoxy-2-benzoyloxy-5, 20-epoxy-1-hydroxy-9-oxo-7, 10-bis-(2,2,2-trichlorocarbanilide)-11-taxen-13-Il.

3-tert-Butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidin-5-carboxylate-(2R, 4S, 5R)-4-acetoxy-2-benzoyloxy-5,20-epoxy-1-hydroxy-9-oxo-7, 10-bis-(2,2,2-trichlorocarbanilide)-11-taxen-13-Il has the following characteristics: melting point 164-167oC.

Infrared spectrum (film): the main characteristic absorption bands at 3500, 2950, 2900, 1760, 1730, 1720, 1700, 1605, 1580, 1505, 1380, 1375, 1360, 1240, 1140, 1060, 815, 760 and 710 cm-1.

Spectrum of nuclear magnetic resonance of the proton (500 MHz, D13, chemical shift in ppm, constants combination J in Hz): 1,05 (s, N); to 1.16 (s, 3H); 1,24 (s, 3H); of 1.64 (s, 3H); of 1.80 (s, 3H); 1.85 to (s, W, 3H); 1,98-2,05 (m, 1H), 2,07 with 2.14 (m, 1H); 2,18-of 2.26 (m, 1H); 2,53-of 2.64 (m, 1H); 3,81 (d, J=7,0, 1H); is 3.82 (s, 3H); 4,18 (ABqI , JAB=8,5,A-B= 80,7, 2H); 4,58 (s, 1H); 4,74 (ABqI , JAB= 11,8, A-B= TO 150.6, 2H); 4,77 (ABqI , JAB=11,8A-B= 7,7, 2H); 4,88 (l OSD, J=9,3, 1H); 5,41 (s, W, 1H), 5,50 (DD, J=7.2 and 10,7, 1H); 5,64 (d, J=7,0, 1H); 6,10 (t, J=8,8, 1H); 6,14 (s, 1H); 6,40 (s, W, 1H); 6,93 (d, J=8,8, 2N aromatic.); 7,26-7,44 (m, 7H, aromatic.); of 7.48-7,52 (m, 2H aromatic.); a 7.62-of 7.65 (m, 1H aromatic.); 8,01-8,03 (m, 2H aromatic.).

In odnogolosy flask with a capacity of 5 cm3equipped with the in), in the solution of 0.75 cm3methanol, then add 0.75 cm3ice

of acetic acid. The contents of the flask are heated at a temperature of 65oC for 5 minutes, then added 65 mg of the Association of zinc-copper (obtained from 20 g of zinc and 3 g monohydrate copper sulfate). A heterogeneous mixture of black stirred at 65oC for 30 minutes. After cooling to a temperature close to 25oC, the reaction mixture is diluted with 30 cm3dichloromethane. Perform filtering on celite, then washing the solids 3 times 10 cm3dichloromethane. The solvents are removed under reduced pressure. The resulting residue is purified by chromatography on thin layer silica gel, using as eluent a mixture of methanol-dichloromethane (5:95 by volume). Thus obtained (yield 60%) of 5.6 mg (0.006 mmole)of 3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidin-5-carboxylate-(2R, 4S, 5R)-4-acetoxy-2-benzoyloxy-5, 20-epoxy-9-oxo-1,7, 10 - trioxi-11-taxen-13-sludge, contaminated 15-20% of 3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidin-5-carboxylate-(2R, 4S, 5S)-4-acetoxy-2-benzoyloxy-5,20-epoxy-9-oxo-1,7, 10-trioxi-11-taxen-13-Il.

3-tert-Butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazol the tion.

Infrared spectrum (film): characteristic absorption bands at 3430, 2960, 2880, 2840, 1730, 1720, 1700, 1685, 1605, 1580, 1505, 1440, 1380, 1360, 1340, 1265, 1240, 1170, 1130, 1060, 1015, 975, 905, 720 and 695 cm-1.

Spectrum of nuclear magnetic resonance of the proton (400 MHz, D13, chemical shift in ppm, constants combination J in Hz): 1,05 (s, N), of 1.09 (s, 3H); of 1.20 (s, 3H); 1.57 in (s, 3H); to 1.70 (s, 3H); 1,73-1,90 (m, 1H); 1,85 (Shir., 3H); 2,02-2,19 (m, 2H); 2,47-2,60 (m, 1H); 3,81 (d, J=7, 1H); is 3.82 (s, 3H); 4,15 (d, J=1,5, 1H); 4,18 (ABqI , JAB=8,5,A-B= 55,6, 2H); 4,56 (d, J=5,0, 1H); 4,87 (DD distorted. , J=8, 1H); 5,10 (d, J=1,5, 1H); 5,42 (Shir., 1H); 5,62 (d, J=4, 1H); 6,13 (t, J=8, 1H); 6,39 (Shir., 1H); 6,92 (m, 2H aromatic.), 7,30-7,44 (m, 7H, aromatic.); 7,47-7,51 (m, 2H aromatic.); to 7.59-to 7.64 (m, 1H aromatic.); 8,01-with 8.05 (m, 2H aromatic.).

Mass spectrum (FAB (+)-matrix PVA + KS1): 1276 (M+).

Elemental analysis (C57H61O19NCl6):

Calculated, %: C 53,62, N To 4.81, N 1,10.

Found, %: C 53,22, N 4,82, N 1,16.

In odnogolosy flask with a capacity of 5 cm3equipped with magnetic stirrer, injected 4.4 mg (0,0047 mmole) of the compound obtained above. The contents of the flask cooled to 0oWith, then add 64 μl of a solution of ethyl acetate containing 0,28 µl of 33% hydrochloric acid. The resulting homogeneous mixture is left to react in teuu mixture is diluted with 20 cm3ethyl acetate, after which process the organic phase is 5 cm3aqueous saturated solution of sodium bicarbonate. The organic phase is separated by decantation, washed with 3 times 5 cm3water and 1 in every 5 cm3aqueous saturated solution of sodium chloride, then dried on anhydrous sodium sulfate. After filtration and concentration to dryness under reduced pressure, the obtained residue is purified by chromatography on thin layer silica gel, using as eluent a mixture of methanol-dichloromethane (5:95 by volume). Thus obtained (yield 78%) 3.0 mg (0,0037 mmole) of pure 3-tert-butoxycarbonylamino-3-phenyl-2-oxopropionate-(2R, 3S)-4-acetoxy-2-benzoyloxy-5, 20-epoxy-9-oxo-1,7,10-trioxi-11-taxen-13-Il (or Taxotere), which contains no trace of 3-tert-butoxycarbonylamino-3-phenyl-2-oxopropionate-(2S,3S)-4-acetoxy-2-benzoyloxy-5,20-epoxy-9-oxo-1,7, 10-trioxi-12-taxen-13-Il.

Recuperat 0.8 mg (0,0009 mmole) of 3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidin-5-carboxylate-(2R, 4S, 5S)-4-acetoxy-2-benzoyloxy-5, 20-epoxy-9-oxo-1,7, 10-trioxi-11-taxen-13-Il,

has not removed the protective group used in conditions.

Thus obtained Taxotere has comprehension at 3450, 3100, 3050, 2950, 2920, 2890, 2850, 1730, 1710, 1600, 1580, 1490, 1450, 1390, 1370, 1315, 1270, 1245, 1160, 1105, 1095, 1070, 1020, 980, 910, 730 and 710 cm-1.

Spectrum of nuclear magnetic resonance of the proton (300 MHz, D13, chemical shift in ppm, constants combination J in Hz): of 1.13 (s, 3H); 1,24 (s, 3H); of 1.34 (s, N); to 1.76 (s, 3H); of 1.85 (s, 3H); 1,74-of 1.85 (m, 1H); 2.26 and-to 2.29 (m, 2H); is 2.37 (s, 3H); 2,54-of 2.66 (m, 1H); 3,31 (d distorted., J=4,4, 1H); to 3.92 (d, J=7, 1H), 4,18-4,30 (m, 1H), 4,18 (s, 1H), 4,25 (ABqI , JAB=8,3,A-B= 35,3, 2H), 4,62 (Shir., 1H), 4,94 (d, J= 8,5, 1H), 5,20 (s, 1H), 5,26 (s, W, garbled., 1H), 5,41 (d, distorted., J=9,4, 1H), of 5.68 (d, J=7, 1H), 6,21 (t, J=8.0 and 8.8, 1H), 7,31-7,40 (m, 5H aromatic.), 7,47-7,52 (m, 2H aromatic.), to 7.59-to 7.64 (m, 1H aromatic.), 8,09-to 8.12 (m, 2H aromatic.).

3-tert-Butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidin-5-carboxylic-(2R, 4S, 5S) acid can be obtained as follows.

In a flask with a capacity of 50 cm3equipped with a magnetic stirring system, introducing an argon atmosphere 33 mg (0.08 mmole) of 3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-5-methoxycarbonyl-1,3-oxazolidine-(2R, 4S, 5S) in suspension in 15 cm3of methanol. Then add 5 cm3water and 33 mg (0.24 mmole) of potassium carbonate. The contents of the flask is left for reaction for 96 hours at a temperature close to 25oC. the Reaction mixture becomes homage Giroud 3 times 15 cm3the ether. The aqueous phase is cooled to 0oC, then acidified in the mode of intensive mixing in the presence of 20 cm3dichloromethane using water 4M solution of hydrochloric acid to a pH below 1. An acidic aqueous phase is extracted with 8 times 20 cm3dichloromethane. The collected organic phase is washed with 3 times 5 cm3water, then 1 every 5 cm3aqueous saturated solution of sodium chloride. The organic phase is dried on anhydrous sodium sulfate. After filtration and concentration dry under reduced pressure to obtain (yield 94%) 30.0 mg (of 0.075 mmole) of 3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidin-5-carboxylic-(2R, 4S, 5S) acid having the following characteristics: melting point 148,5-150,5oC; torque capacity []D25 = +46,4o(C=1.0, chloroform).

Infrared spectrum (film): the main characteristic absorption bands at 3700-2300, 2950, 2900, 2820, 1755, 1700, 1605, 1580, 1505, 1385, 1360, 1300, 1285, 1240, 1215, 1165, 1130, 1075, 1065, 1020, 930, 850, 820 and 685 cm-1.

Spectrum of nuclear magnetic resonance of the proton in the form of 2 rotamers (200 MHz, Dl3), chemical shift in ppm, constants combination J in Hz): 1,11 (s, N); is 3.82 (s, 3H); 4,2 (with very wide., 1H); 4,99 (d, J=6,4, 1H); 5,18 (est. D. distorted., J=6.4) and are 5.36 (neon. with Shir., 1H); 6,46 (Nene): 417 (MH++NH3), 400 (MN+), 361, 344, 300, 264, 225, 192, 177, 137.

3-tert-Butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-5-methoxycarbonyl-1,3-oxazolidin-(2R, 4S, 5S) can be obtained according to one of the following methods.

1) In odnogolosy flask with a capacity of 2 cm3equipped with a magnetic stirring system, introducing an argon atmosphere, 10 mg (0,034 mmole) of methyl-3-tert-butoxycarbonyl-3-phenyl-2-oxopropionate-(2S,3S) in the form of a suspension in 0.5 cm3anhydrous toluene. Then add 1 mg (0,004 mmole) pair toluensulfonate. The resulting reaction mixture is heated at a temperature of 115oC. After 5 minutes of incubation at this temperature, add 13 ál (13.9 mg, 0,076 mmole) para-methoxybenzaldehyde. The reaction mixture became homogeneous, heated under reflux of the solvent for 5 minutes. After cooling to a temperature close to 20oC, the reaction mixture is diluted with 30 cm3dichloromethane. The organic phase is treated with 1 in every 5 cm3aqueous saturated sodium bicarbonate solution, then washed with 2 times 5 cm3water and 1 in every 5 cm3aqueous saturated solution of sodium chloride. After drying on anhydrous sodium sulfate, filtration and concentration of the but using as eluent a mixture of ethyl ether-hexane (6: 4 by volume). So get 13.9 mg (0,0336 mmole) of a mixture of 3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-5-methoxycarbonyl-1,3-oxazolidine-(2R, 4S,5S) and 3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-5-methoxycarbonyl-1,3-oxazolidine-(2S, 4S, 5S) at a ratio of 40/60. The total yield is 99%.

These esters can be separated by chromatography on a column of silica gel, using as eluent a mixture of ethyl ether-hexane (2:8 by volume).

3-tert-Butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-5-methoxycarbonyl-1,3-oxazolidin-(2R, 4S, 5S) has the following characteristics:

the melting point 208-208,5oC;

torque capacity []D25=+53o(C=1,1, chloroform).

Infrared spectrum (film): 2950, 1725, 1680, 1600, 1575, 1500, 1380, 1350, 1280, 1260, 1240, 1200, 1160, 1120, 1065, 1050, 1030 and 1010 cm-1.

Spectrum of nuclear magnetic resonance of the proton in the form of 2 rotamers (200 MHz, D13, chemical shift in ppm, constants combination J in Hz): 1,12 (s, N) ; of 3.32 (s, 3H), 3,82 (s, 3H); 5,00 (d, J=6,5, 1H); 5,16 (est., D. distorted., J= 5,6) and 5,34 (neon., with broad, 1H); 6.48 in (neon.) and 6.68 (est.) (2s, 1H); 6,93 (d, J=8,4, 2N aromatic.); 7,20-to 7.50 (m, 7H, aromatic.).

Mass spectrum (D/IC, NH3+ isobutane): 414 (MN+), 356, 314, 312, 250, 222, 206, 179, 177, 162, 151, 134, 119.

3-tert-IKI.

Infrared spectrum (film): the main characteristic absorption bands at 2950, 2900, 1760, 1730, 1695, 1600, 1580. 1505, 1450, 1430, 1380, 1360, 1335, 1290, 1240, 1210, 1160, 1150, 1080, 1030, 1020, 920, 810 and 680 cm-1.

Spectrum of nuclear magnetic resonance of the proton (200 MHz, DC13, chemical shift in ppm, constants combination J in Hz): 1,26 (s, N); 3,37 (s, 3H); is 3.82 (s, 3H); free 5.01 (d, J=7,1, 1H); at 5.27 (d, J=7,1, 1H); 6,05 (s, 1H); 6,91 (d, J= 8 4, 2N aromatic.); 7,26-7,56 (m, 5H aromatic.); 7,49 (d, J=8,4 2N aromatic. ).

Mass spectrum (D/IC NH3+ isobutane): 414 (MN+), 356, 339, 314, 312, 296, 250, 224, 222, 206, 177, 162, 151, 135, 121.

2) In a flask with a capacity of 2 cm3equipped with a magnetic stirring system, enter in the atmosphere of argon 5.0 mg (0,017 mmole) of methyl-3-tert-butoxycarbonylamino-3-phenyl-2-oxopropionate-(2S, 3S) in suspension in 0.25 cm3anhydrous toluene. Then add 10,0 ál (10,7 mg, 0,059 mmole) para-methoxybenzaldehyde. The resulting reaction mixture is heated at a temperature of 95oWith, then add 1 mg of para-toluensulfonate polymer. Heating continued for 24 hours at a temperature of 95oC. After cooling to a temperature close to 20oC, the reaction mixture is diluted with 30 cm3dichloromethane. The organic phase is treated with 1 to 5 times the3aqueous saturated solution of sodium chloride. After drying on anhydrous sodium sulfate, filtration and concentration get dry (after purification by chromatography on thin layer silica gel using as eluent a mixture of ethyl ether : hexane (1:1 by volume, 2 pass) at exit 93% to 6.5 mg (0.016 mmole) of a mixture of 3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-5-methoxycarbonyl-1,3-oxazolidine-(2R, 4S, 5S) and 3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-5-methoxycarbonyl-1,3-oxazolidine-(2S,4S,5S) in the ratio of 30/70.

3) In odnogolosy flask with a capacity of 2 cm3equipped with a magnetic stirring system, introducing an argon atmosphere 10.0 mg (0,034 mmole) of methyl-3 tert-butoxycarbonylamino-3-phenyl-2-oxopropionate-(2S,3S) in the form of a suspension in 0.5 cm3anhydrous toluene. Then add 13,0 ál (13.9 mg, 0,076 mmole) para-methoxybenzaldehyde. The resulting reaction mixture is heated at a temperature of 74oC for 5 minutes, then add 2.5 mg of para-toluenesulfonic acid (monohydrate). Heating continued at a temperature of 74oC for 17 hours. After cooling, the reaction mixture is diluted with 30 cm3dichloromethane. The organic phase is treated with 1 time cm3

4) In odnogolosy flask with a capacity of 2 cm3equipped with a magnetic stirring system, enter in the atmosphere of argon 5.0 mg (0,017 mmole) of methyl-3-tert-butoxycarbonylamino-3-phenyl-2-oxopropionate-(2S, 3S) in suspension in 0.25 cm3anhydrous toluene. Then add a 6.5 μl (695 mg, of 0.038 mmole) para-methoxybenzaldehyde. The resulting reaction mixture is heated at a temperature of 76oC for 5 minutes, then add 0.5 mg (0.002 mmole) camphorsulfonate. Continue heating at a temperature of 76oC. After 4 hours of interaction between the components of the reaction mixture in it enter to 4.0 µl (2,43 mg, 0,076 mmole) of methanol and the reaction mixture was kept at a temperature of 76ois functioning 1 times 5 cm3aqueous saturated sodium bicarbonate solution, then washed 2 times cm3water and 1 in every 5 cm3aqueous saturated solution of sodium chloride. After drying on anhydrous sodium sulfate, filtering and concentrating to dryness under reduced pressure to obtain (after cleaning carried out by chromatography on thin layer silica gel using as eluent a mixture of ethyl ether : hexane (3:2 by volume) of 3.7 mg (0,009 mmole) (yield 53%) of a mixture of 3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-5-methoxycarbonyl-1,3-oxazolidine-(2R, 4S, 5S) and 3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-5-methoxycarbonyl-1,3-oxazolidine-(2S, 4S, 5S) in the ratio of 74/26.

Example 4.

To a solution of 1.6 g of 3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate acid (4S, 5S) 5 cm3anhydrous methylene chloride added with stirring at a temperature of about 20oAnd in an argon atmosphere 0,206 g dicyclohexylcarbodiimide. The reaction mixture is stirred for 35 minutes.

The resulting dicyclohexylphosphino separated by filtration and the resulting solution was added to a solution consisting of 1.5 g of 4-acetoxy-2-benzoyloxy-5, 20-epoxy-1,13-dihydroxy-9-oxo-7, 10 - bis(2,2,2-trichloro the La at the 75oC.

Stirred for further 2 hours after the addition. Cooled to a temperature of about 20oWith and dicyclohexylphosphino separated by filtration. The filtrate is concentrated to dryness and the residue absorb 10 cm3cyclohexane. After complete dissolution at 60oThe solution was poured into 25 cm3heptane, cooled to a temperature of 1-5oC. the Obtained precipitate was separated by filtration, washed with cold heptane, then dried under reduced pressure. Obtain 1.8 g of a slightly beige product, which according to HPLC analysis to contain 1.2 g of 4-acetoxy-2-benzoyloxy-5, 20-epoxy-1-hydroxy-9-oxo-7, 10 - bis(2,2,2-trichloroethane)carbonyloxy-11-taxen-13-yl (4S, 5R)-3-tert-butoxycarbonylamino-2,2-dimethyl-4-phenyl-1,3-oxazolidin-5-carboxylate, containing 15% of ephemera 4S,5S.

Example 5.

In a reactor with a capacity of 50 cm3enter in an inert atmosphere at a temperature of about 20oWith 0,321 g of 5-carboxy-2,2-dimethyl-4-phenyl-3-(tert-butoxycarbonyl)-1,3-oxazolidin (4S, 5S), 0,244 g of 2,4,6 - trichlorobenzaldehyde, 8 cm3anhydrous toluene and 0,101 g of triethylamine. The reaction mixture is left for 2 hours under stirring and at a temperature of about 20oC. Then add 0,896 g of 4-acetoxy-2-benzoyloxy-5, 20-epoxy-1, 13-Diwaniya for 20 hours at a temperature of about 20oFrom the resulting triethylamine hydrochloride is separated by filtration and washed with toluene. Toluene phase is washed with twice 10 cm3water, dried over sodium sulfate, and then concentrated to dryness under reduced pressure. Analysis by HPLC showed that the yield of 4-acetoxy-2-benzoyloxy-5, 20-epoxy-1-hydroxy-9-oxo-7, 10-bis-(2,2,2-trichlorocarbanilide)-11-taxen-13-yl-(4S, 5R)-2,2-dimethyl-4-phenyl-3-(tert-butoxycarbonyl)-1,3-oxazolidin-5-carboxylate is 77% compared to the converted alcohol and 63% in relation to the used alcohol.

Comparative example 6 illustrates the initial connection, which does not contain the Deputy Vos, and contains, for example, bentely radical, in which obtain the target compounds without an intermediate stage.

Comparative example 6.

7,10-Di(2,2,2-trichlorocyanuric)-10-deazetil-13-O-[(4S, 5R)-N-benzoyl-2, 2-dimethyl-4-phenyl-1,3-oxazolidin-5-carbonyl] -baccatin (52 mg) was triturated with 1 ml of formic acid at room temperature for 4 hours.

The acid is evaporated in vacuum and the crude reaction product is treated with methanol (1 ml), acetic acid (1 ml) and powdered zinc (40 mg) at 60oC for 1 hour. Receive 30 mg 10-deacetyltaxol phenyl;

R represents phenyl or the radical R5-O-, in which R5represents a straight or branched alkyl containing from 1 to 8 carbon atoms excluding tert-butyl;

R1and R2has identical or different meanings and represent a hydrogen atom, an alkyl radical, phenylalkyl, phenyl, alkoxyphenyl or dialkoxybenzene;

R3represents acetyl or a protective group of functional hydroxy-group;

R4represents a protective group of functional hydroxy-group.

 

Same patents:

The invention relates to a derivative of 7- (alkoxycarbonyl-substituted) -10-hydroxy-taxan following formula 3b:

< / BR>
in which R1, R2, R4, R5, R6and R14defined above

The invention relates to new derivatives of 10-deazetil-14-hydroxyacetone III of formula 1, where X represents a group >C=S, >C=NH or >S=O; OR1which can beororiented, represents hydroxy, alkylsilane (preferably triethylsilane, O-TES); R2isororiented hydroxy group or Troc group (Troc= Cl3CCH2COO-), or with the carbon atom to which it is attached, forms ketogroup; R3is izoterikoy residue of formula 2; R4is a linear or branched alkyl or alkenylphenol group having 1 to 5 carbon atoms; R5is alkyl having 1 to 5 carbon atoms or tert-butoxypropyl

The invention relates to new intermediate products for poluentes taxan and methods for their preparation

The invention relates to new taxoids General formula (I)

< / BR>
in which Rameans a hydrogen atom or a hydroxyl radical, CNS radical with 1-4 carbon atoms, acyloxy radical with 1-4 carbon atoms or alkoxyacetic-radical, the alkyl part of which contains 1-4 carbon atoms;

Rbmeans a hydrogen atom; or

Raand Rbtogether with the carbon atom to which they are bound, form a ketone function;

Z means a hydrogen atom or a radical of General formula (II)

< / BR>
in which R1means bentely radical, possibly substituted by one or more identical or different atoms or radicals selected among halogen atoms and alkyl radicals with 1-4 carbon atoms, CNS radicals with 1-4 carbon atoms or trifloromethyl; tenor or furoyl, or the radical R2-O-CO-, in which R2means:

is an alkyl radical with 1-8 carbon atoms, alkanniny radical with 2-8 carbon atoms, alkynylaryl radical with 3-8 carbon atoms, cycloalkenyl radical of 3-6 carbon atoms, cycloalkenyl radical with 4 to 6 atoms in or more substituents, selected among halogen atoms and hydroxyl radical, CNS radical with 1-4 carbon atoms, dialkylamino radical, each alkyl portion of which contains 1-4 carbon atoms, piperidino radical, morpholino radical, piperazine-1-ilen radical (possibly substituted in position 4 alkyl radical with 1-4 carbon atoms or phenylalkyl radical, the alkyl part of which contains 1-4 carbon atoms), cycloalkyl radical of 3-6 carbon atoms, cycloalkenyl radical with 4 to 6 carbon atoms, phenyl radical (possibly substituted by one or more atoms or radicals, selected among halogen atoms and alkyl radicals with 1-4 carbon atoms or CNS radicals with 1-4 carbon atoms), a cyano radical, carboxyl or alkoxycarbonyl, the alkyl portion of which contains 1-4 carbon atoms;

is phenyl or- or-nattily radical, possibly substituted by one or more atoms or radicals selected among halogen atoms and alkyl radicals with 1-4 carbon atoms or CNS radicals with 1-4 carbon atoms; or a heterocyclic aromatic patterollers radical with 4 to 6 carbon atoms, possibly substituted by one or more alkyl radicals with 1-4 carbon atoms;

R3means a linear or branched alkyl radical with 1-8 carbon atoms, a linear or branched alkanniny radical with 2-8 carbon atoms, linear or branched alkynylaryl radical with 2-8 carbon atoms, cycloalkyl radical of 3-6 carbon atoms, phenyl or- or-nattily radical, possibly substituted by one or more atoms or radicals selected among halogen atoms and alkyl, alkenyl, etkinlik, aryl, kalkilya, CNS, alkylthio, aryloxy, aaltio-, hydroxyl, hydroxyalkyl, mercapto-, formyl, acyl, acylamino, aroylamino, alkoxycarbonyl-, amino-,

alkylamino, dialkylamino-, carboxyl, alkoxycarbonyl, karamolegos, alkylcarboxylic, dialkylanilines, cyano-, nitro - and triptorelin radicals; or an aromatic five-membered a heterocycle containing one or more, identical or different heteroatoms selected among nitrogen atoms, oxygen or sulfur, and possibly substituted by one or more of the ylamino - dialkylamino-, alkoxycarbonyl-, acyl, arylcarboxylic, carboxyl, karamolegos, alkylcarboxylic, dialkylanilines or alkoxycarbonyl radicals, provided that the substituents phenyl,- or-afternova and aromatic heterocyclic radicals, the alkyl radicals and alkyl portions of other radicals contain 1-4 carbon atoms; alkeneamine and alkyline radicals contain 2 to 8 carbon atoms, and aryl radicals are phenyl or- or-raftiline radicals; and

R4means:

- linear or branched alkyl radical with 1-8 carbon atoms, a linear or branched alkanniny radical with 2-8 carbon atoms, linear or branched alkynylaryl radical with 2-8 carbon atoms, cycloalkyl radical of 3-6 carbon atoms, cycloalkenyl radical with 4 to 6 carbon atoms or bicycloalkyl radical with 7 to 11 carbon atoms, and each of these radicals may be substituted by one or more substituents selected among halogen atoms and hydroxyl radical, alkoxyl carbon piperidino radical, morpholino radical, piperazine-1-ilen radical (possibly substituted in position 4 alkyl radical with 1-4 carbon atoms or phenylalkyl radical, the alkyl part of which contains 1-4 carbon atoms), cycloalkyl radical of 3-6 carbon atoms, cycloalkenyl radical with 4 to 6 carbon atoms, possibly substituted phenyl radical, cyano radical, carboxyl or alkoxycarbonyl, the alkyl portion of which contains 1-4 carbon atoms;

- or aryl radical, possibly substituted by one or more atoms or radicals selected among halogen atoms and alkyl, alkenyl, etkinlik, aryl, kalkilya, CNS, alkylthio, aryloxy, aaltio-, hydroxyl, hydroxyalkyl, mercapto-, formyl, acyl, acylamino, aroylamino, alkoxycarbonyl-, amino-, alkylamino, dialkylamino-, carboxyl, alkoxycarbonyl, karamolegos, alkylcarboxylic, dialkylanilines, cyano-, nitro-, azido-, triptorelin or triptoreline radicals;

or saturated or unsaturated 4-6 membered heterocyclyl radical, possibly substituted by one or more alkyl radicals with 1-4 of carbon atoms is a branched alkanniny radical with 2-8 carbon atoms, linear or branched alkynylaryl radical with 2-8 carbon atoms, cycloalkyl radical of 3-6 carbon atoms, cycloalkenyl radical with 4 to 6 carbon atoms or bicycloalkyl radical with 7 to 11 carbon atoms, these radicals can be substituted by one or more substituents selected among halogen atoms and hydroxyl radical, CNS radical with 1-4 carbon atoms, dialkylamino radical, each alkyl portion of which contains 1-4 carbon atoms, piperidino radical, morpholino radical, piperazine-1-ilen radical (possibly substituted in position 4 alkyl radical with 1-4 carbon atoms or phenylalkyl radical, the alkyl portion of which contains 1-4 carbon atoms), cyanoaniline radical of 3-6 carbon atoms, cycloalkenyl radical with 4 to 6 carbon atoms, possibly substituted phenyl radical, cyano radical, carboxyl or alkoxycarbonyl, the alkyl portion of which contains 1-4 carbon atoms;

provided that cycloalkyl, cycloalkenyl or bicycloalkyl radicals can be substituted by one or more alkyl radicals with 1-4 carbon atoms

The invention relates to new taxoids General formula I, in which R denotes a linear or branched alkyl radical with 1-6 carbon atoms, Z denotes a hydrogen atom or a radical of General formula II, where R1means bentely radical or the radical R2-O-CO-, in which R2denotes an alkyl radical with 1-8 carbon atoms, R3denotes a phenyl radical

The invention relates to new derivatives of N-nitroimidazolidin-1,3 General formula I, where R represents H, CH3CH2OCH3CH2Cl, CH2N3

The invention relates to a method for producing derivatives taxane General formula (I) by esterification of protected baccatin III or protected 10-desacetyl-baccatin III using the acid of General formula (II)

FIELD: chemistry.

SUBSTANCE: proposed hydrogen sulphide and/or low-molecular mercaptan remover is in form of amino esters with general formula: (R-)nN(-CH2-O-R')m, where R is alkyl, isoalkyl C1-C14 or cyclohexyl, or benzyl, or a bivalent group with formula - CH2-O-CH2-CH2-, bonded to a nitrogen atom of an amino ester, with formation of five-member heterocyclic ring; R' - alkyl, isoalkyl or alkenyl, preferably C1-C4; n=1 or 2, m=3-n. The invention also pertains to the method of purifying oil, water-oil emulsions, oil products, hydrocarbon gases, stratal water and process liquids from hydrogen sulphide and/or low-molecular mercaptans by treating the starting material using the above described remover. The proposed remover and a composition based on it have higher reaction capacity compared to hydrogen sulphide, light mercaptans and provides for their effective neutralisation in aqueous and non-aqueous media at normal and high temperatures (10-90°C and above). The proposed remover also has bactericidal activity towards sulphate reducing bacteria and anti-corrosion activity in hydrogen sulphide-containing media, and can be used as a bactericide-inhibitor of hydrogen sulphide corrosion in oil-field media.

EFFECT: improved properties of the remover.

4 cl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of N-nitro-5-azido-methyloxazolidine-1,3 which can be used as an energetic plasticiser for polymers. The starting compounds used are potassium sulphamate and epichlorohydrin. The reaction for bonding potassium sulphamate to epichlorohydrin takes place at 50…53°C and holding time of 50…55 hours with threefold excess of potassium sulphamate. Without extraction, the formed N-(3-chloro-2-hydroxypropyl)-potassium sulphamate is condensed in form of a water-alcohol solution with formaldehyde and the water-alcohol solution of N-(5-chloro-methyloxazolidine1,3)-potassium sulphamate obtained after evaporation is suspended in acetic anhydride without extraction from the reactor and nitrated with nitric acid at 10…25°C. The formed N-nitro-5-chloromethyl-oxazolidine-1,3 is extracted with organochlorine solvents, purified by treating with aqueous sodium hydroxide solution at 70…75°C and undergoes azidation with sodium azide in dimethyl formamide medium in the presence of activated carbon at 100°C.

EFFECT: improved method.

1 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to chemistry and the technology of producing heterocyclic compounds of the oxazolidine family, specifically N-nitro-5-azidomethyloxazolidine-1,3 which is extensively studied under the name MANO-5 as an energetic polymer plasticiser. The method of producing N-nitro-5-azidomethyloxazolidine-1,3 is realised via successive reaction of a sulphamate with epichlorohydrin and formaldehyde, followed by nitration in an acetic anhydride medium and azidation in a solvent medium. The sulphamate used is triethylammonium sulphamate and the formaldehyde source used is a mixture of paraformaldehyde and acetic acid. Azidation is carried out in the presence of a phase-transfer catalysts in an aqueous medium. Triethylammonium sulphamate and epichlorohydrin react in equimolar ratios without using a solvent. The phase-transfer catalyst used is tretralkylammonium salts, e.g., tetrabutylammonium bromide or triethylbenzylammonium chloride.

EFFECT: easy implementation of the process.

5 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing N-nitro-5-chloromethyloxazolidine-1,3, which is used as a primary product in synthesis of energetic polymer plasticisers - N-nitro-5-nitroxymethyl- and N-nitro-5-azidomethyloxazolidine-1,3, and can also be used in synthesis of biologically active substances. The method of producing N-nitro-5-chloromethyloxazolidine-1,3 is realised via successive reaction of a sulphamate with epichlorohydrin and aqueous formaldehyde solution, followed by separation of N-(5-chloromethyl-oxazolidine-1,3)-sulphamate by vacuum stripping and nitration thereof with nitric acid in the presence of acetic anhydride. The sulphamate used is a triethylammonium salt. An alcohol solution of formaldehyde is used for the cyclisation reaction. The product of cylisation of the triethylammonium salt of N-(5-chloromethyloxazolidine-1,3)-sulphamic acid is treated with an alcohol solution of potassium hydroxide; the precipitated potassium N-(5-chloromethyloxazolidine-1,3)-sulphamate is separated by filtration, dissolved in glacial acetic acid and nitrated with nitric acid in the presence of acetic anhydride at temperature 20…25°C.

EFFECT: easy implementation of the process.

1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, particularly to a method of producing 3-(2-alkynyl)-1,3-oxazolidines of formula (1) where R1=R2=H; R3=n-Pr(a), n-Bu (b), Ph (c); R1=CH3, R2=H, R3=n-Pr (d), n-Bu (e), Ph (f); R1=H, R2=CH2CH3, R3=n-Pr (g), n-Bu (h), Ph (i); R1=Ph, R2=H, R3=Ph (k), which can be used as universal precursors for fine organic synthesis and biologically active compounds. The method is carried out by reacting monoethanolamine of general formula HO(R1)CHCH(R2)NH2 (where R1=R2=H; R1=CH3, R2=H; R1=H, R2=CH2CH3; R1=Ph, R2=H) with paraform while boiling in benzene for 5 hours, followed by evacuating benzene and adding alkyl(phenyl)acetylene-1 of general formula R3-C≡CH (where R3=C3H5, C4H9, Ph) in toluene and a CuCl catalyst. The reaction mass is mixed in an argon atmosphere at 80°C and atmospheric pressure for 5-7 hours. The reaction is carried out in molar ratio HO(R1)CHCH(R2)NH2: (CH2O)n: R3-C≡CH: CuCl=2:3:1:(0.03-0.07).

EFFECT: selective production of said compounds.

1 tbl, 14 ex

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