SK19094A3 - Process for preparing of beta-phenylisoserine derivatives and use thereof - Google Patents

Abstract

Process for the preparation of new ss-phenylisoserine derivatives of general formula (I) and their use for preparing biologically active taxane derivatives. <IMAGE>

Description

FIELD OF THE INVENTION The present invention relates to a process for the preparation of novel derivatives of ^: beta-phenylenediamine of formula I

in which

R is tert-butoxy or phenyl, and Ar is aryl selected from phenyl, and 1-naphthyl and beta-naphthyl, which may optionally be substituted by one or more atoms or groups which are the same or different and are selected from the group consisting of halogen atoms and alkyl groups, alkenyl groups, alkynyl groups, alkyloxy groups, alkylthio groups, hydroxyl groups, mercapto groups, amino groups, monoalkylamino groups, dialkylamino groups, acylamino groups, acylamino groups, acylamino groups, acylamino groups, acylamino groups, carboxy groups, Ν, Ν-dialkylcarbamoyl, cyano, nitro and trifluoromethyl groups, in the form of racemic or enantiomerically pure or in the form of a mixture thereof, optionally in the form of a salt or an ester.

The compounds of formula (I) are particularly suitable for the preparation of taxane derivatives of formula (II) in which:

(II)

R and Ar are as defined above and represents a hydrogen or acetyl atom having a high anti-leukemic and anti-tumor activity.

BACKGROUND OF THE INVENTION

According to U.S. Pat. Nos. 4,924,011 and 4,924,012, it is known to prepare taxane derivatives of formula (II) in which Ar is a phenyl group by condensation of a beta-phenyl derivative and a compound of formula (III).

OH (III) in which

R is as defined above and

G 1 represents a hydroxyl protecting group, in particular a 1-ethoxyethyl group, to a baccatin III or 10-desacetylbaccatin III derivative of the general formula IV

(IV) in which

R 1 represents an acetyl group or a hydroxyl protecting group a

Ga is a hydroxyl protecting group, followed by a substitution of protecting groups, which are preferably selected from 2,2,2-trifluoroethoxycarbonyl and trialkylsilyl, each of which contains 1-4 carbon atoms, hydrogen atoms.

However, the compound of formula III, especially when G 1 is a 1-ethoxyethyl group, is not very stable, so care must be taken in its synthesis and storage.

It will be appreciated that the use of a compound of formula III which is not fully protected may result in a significant reduction in yield when condensed with the 10-desacetylbaccatin III derivative of formula IV.

In addition, the use of a 1-ethoxyethyl group as a protecting group introduces both a methyl group which may have a steric effect on the esterification of the fusion and an asymmetric carbon atom that is not split, resulting in the presence of two stereoisomers, which make cleaning procedures more difficult.

The essence of the invention Now it was found that protecting group 2,2,2-trichloroethoxymethyl compound general v zorca I has the following advantages: - is very stable at the usual conditions a 1 k a 1 i t y a

and children,

- it does not contain an asymmetric carbon atom with which stereoisomeric problems e or a steric effect group would be associated,

- easy to introduce under mild and non-epimerizing conditions,

it is readily eliminated under conditions allowing the replacement of the 2,2,2-trichloroethoxycarbonyl protecting groups of the taxane ring with hydrogen atoms.

Accordingly, it is an object of the present invention to provide a novel compound of formula (I), optionally in the form of a salt or ester, and its use for the preparation of taxane derivatives of formula (11).

According to the invention, a compound of the formula I can be obtained by treating a compound of the formula V with 2,2,2-trichloroethoxymethyl halide, preferably bromide, which can be in racemic or enantiomerically pure form or in the form of mixtures thereof,

R-CONH

A-z ⁽ⁱⁿ '

Ar

OH wherein Z represents an ester group (-COORs) or a double vinyl bond, followed, if appropriate, by saponification or oxidation of the product obtained.

Usually, the treatment of the compound of formula V with 2,2,2-trichloroethoxymethyl halide is carried out by operating in an anhydrous organic solvent, for example acetonitrile, at a temperature in the range of 0 to 50 ° C and preferably at a temperature close to 20 ° C. . It is especially preferred to work in the presence of a proton acceptor such as 1, S-bis (dimethylamino) naphthalene (proton sponge, or), 2-butene-mety1-2 a dehydrating agent such as molecular sieves ^{5 O} 3.10 ~ 4.10 m and ¹⁰ m.

When Z represents an ester group -COOFL · wherein R = is a C 1 -C 4 alkyl group optionally substituted by a phenyl group, the obtained compound is saponified to the acid of formula (I).

The saponification is usually carried out using a mineral base under conditions that do not affect the rest of the molecule. The saponification can be carried out using an alkali carbonate such as potassium carbonate in a water-alcoholic medium, for example in a mixture of water and methanol.

When Z represents a vinyl bond -CH = CH's, the product obtained is oxidized to the acid of formula I.

Typically, the oxidation is carried out with a periodate, such as sodium periodate, in the presence of a catalytic amount of a ruthenium salt such as chlorine and ruthenium R at Cle. The reaction is carried out in an aqueous-organic, homogeneous or heterogeneous environment. Acetonitrile and carbon tetrachloride may be used as the solvent. The reaction may be carried out in an alkaline medium, for example in the presence of sodium hydrogen carbonate.

The oxidation can also be carried out with potassium permanganate, for example in the presence of adogen in pentane / water or in the presence of an aliquot or 18-dicyclo-1-6-crown in dichloromethane or pyridine / water.

Triethylbenzylammonium manganese can also be used in the presence of pyridine in dichloromethane.

A compound of formula V wherein Z is an ester group (-COOR 2) can be prepared by known methods.

A compound of formula V wherein Z is a double vinyl bond (-CH = C =.) Can be prepared by:

by treating a benzylamine derivative of the general formula VI with acrolein

NHCO-R (VI) in which R and Ar are as defined above, after double anion.

The double anionization of a compound of formula (VI) is usually carried out using 2 equivalents of an organo derivative, for example sec-butyl, working in an anhydrous organic solvent, for example tetrahydrofuran, at a temperature below -50 ° C.

The reaction of the roll nusdianione in the compound of formula (vi) is usually carried out by adding a roll of n, preferably freshly distilled, a solution of dianione pre-cooled to a temperature in the range of -50 to -100. C. After hydrolysis, the compound of formula V is obtained in the form of a mixture of the syn and anti diastereoisomers, from which the syn form is optionally separated by chromatography,

- treatment of the aldehyde obtained by oxidation of the alcohol of the general formula VII with the action of vinylmagnesium halide

NHCO-R:

Ar ^S ^-CHgOH in which R and Ar are as defined above, which is itself obtained by the action of a reducing agent and a reagent allowing the introduction of a tert-butoxycarbonyl group or a benzoyl group on the amino acid of formula VIII nh ₂

COOH (VIII) wherein Ar is as defined above.

The alcohol of formula V is usually obtained by adding an aldehyde to a solution of vinyl magnesium halide, preferably vinyl magnesium bromide, in an inert organic solvent such as tetrahydrofuran, optionally in admixture with methylene chloride.

The oxidation of the alcohol of formula VII is usually carried out with a mixture of oxalyl chloride and dimethylsulfoxide at a temperature below 0 ° C in an organic solvent such as methylene chloride or tetrahydrofuran in the presence of an organic base such as triethylamine or diisopropylethylamine.

Aldehyde does not need to be isolated for reaction with vinylmagnesium halidoin.

The alcohol of formula VII may be obtained by:

- either by the action of a tert-butoxycarbonyl or benzoyl group introducing agent on the amino alcohol obtained by reduction of the amino acid of formula VIII,

or by treating the amino acid of formula VIII with a tert-butoxycarbonyl group or a benzoyl group with a reducing agent.

The reducing agent used is preferably lithium lithium hydride or borane (BH ₃ ), preferably in the form of a complex with dimethylsulfide, in the presence of boron trifluoride etherate. Usually, the reaction is carried out in an organic solvent such as an ether such as tetrahydrofuran or dimethoxyethane. Usually, the reduction is carried out at a temperature in the range of 50 to 100 C.

Di-tert-butyl hydrogen carbonate or benzoyl chloride is preferably used as a tert-butoxycarbonyl or benzoyl group introducing agent. Generally, the reaction is carried out in an organic solvent such as methylene chloride or an ether such as tetrahydrofuran or dimethoxyethane in the presence of a mineral base such as sodium hydroxide, sodium hydrogen carbonate or sodium carbonate or an organic base such as triethylamine or 4-di-diene. methyl 1 am inopyrrolidine. Typically, the reaction is carried out between 0 ° C and the reflux temperature of the reaction mixture.

The acid of formula (a) or ester can be purified by physical chromatography. or syn-anti, enantiomers syn with a base such as ephedrine or pseudoephedrine and then recovered salts. ~

I, if appropriate in the form according to the invention, is like. crystallization of the salt obtained by the methods

A compound of formula I (form syn into its active racemic mixture) can also be resolved, for example, by forming a salt with an

The acid of the formula I is particularly suitable for the taxane derivatives of the formula II. ' for preparation

The compounds are esterified by substitution of groups optionally by partitioning of the general formula

II sa

IV, the following alcohols of the general formula protecting hydroxyl groups of the hydrogen atoms and the enantiomers of 2R, 3S.

Esterification of a hydrocarbon (benzene, 20 to 80 ° C as usually carried out in aromatic toluene, xylene) at a temperature in the presence of a condensation agent of dicyclohexylcarbide imide or 2-dipyridylcarbonate or activating agent as 4-dimethylaminopyridine. It typically uses an excess of the acid of formula I relative to the alcohol of formula IV.

Sa and Ge, when they represent or 2,2,2-trichlora, is usually carried out in the presence of an acid of 1 to 3 carbon atoms if it contains an

G = is up to 4

Replacement of the protecting groups R 1, G> 2,2,2-trichloroethoxycarbonyl with ethoxymethyl, hydrogen atoms with zinc or a zinc-copper pair with acetic acid and optionally an alcohol containing at a temperature of about 60 C. In the trialkylsilyl group, each part of the carbon atom, the substitution of this group is carried out by further treatment with an acid, for example hydrochloric acid in an aqueous-alcoholic solution.

hydrogen • i iiMrtk ». «Η .. tU.KfkkuUú.L'M i'.nAÍLkv ·.

DETAILED DESCRIPTION OF THE INVENTION

The following examples illustrate the invention.

Example 1

A 10 ml flask equipped with a magnetic stirrer was charged with 100 mg (0.339 mmol) of (2R, 3S) -methyl 1-3-tert. butoxycarbonyl-amino-2-hydroxy-3-phenylpropionate and 1.2 ml of anhydrous acetonitrile. Then, 214.3 mg (1 mmol) of proton sponge, 718 μΐ (475.5 mg; 0.678 mmol) of 2-methyl-2-butene and 5 grains of molecular sieve of 4.10 ^-10 m are gradually added. After stirring for 10 minutes at a temperature in the region of 20 DEG C., 164.3 mg (0.678 mmol) of 2,2,2-trifluoroethoxymethyl bromide are added. The mixture is allowed to react at about 20 ° C for 24 hours. During the course of the reaction, the mixture becomes heterogeneous. 214.3 mg (1 mmol) of proton sponge and 164.3 mg (0.678 mmol) of 2,2,2-trifluoroethoxymethyl bromide are added successively. The mixture is allowed to react at about 20 ° C for 24 hours. 3 ml of saturated aqueous sodium hydrogen carbonate solution are then added thereto. After stirring for 10 minutes, 40 ml of methylene chloride are then added and the mixture is washed 5 times with 10 ml. After decantation, the aqueous phase of methylene chloride. The combined organic phases were 5 ml of a 2M aqueous hydrochloric acid solution, 4 times with 5 ml of water and twice with 5 ml of saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, filtration and evaporation to dryness under reduced pressure, 290 mg of product are obtained, which is purified by chromatography on silica eluting with hexane / ether (8/2 by volume). There was thus obtained (2R, 3S) -methyl-3-tert-133 mg (0.29.1 mmol) in 86% yield. butoxycarbonylamino-3-phenyl-2- (2,2,2-trichloroethoxymethoxy) propionate having the following characteristics:

- melting point: 90-91 ° C (cyclohexane)

- rotation: [α] - ^with _D - +41.8 '(c = 1.33, chloroform)

1 and infrared absorption bands

440, 1 70, 1 75, 1 30,

proton spectrum (deuterochloroform;

spectrum (film): at 3450, 3000, 2925, 1090, 1020,

50

200 core

MHz): 1,41 and 8

11.5 Hz

Ôa-Ôb = 9 1

Hz, 2H); 3.80 character i s t i c k

1720 cm

500, UcO, resonance

4.79 (A B α, s, 1H); 5.46 (broad s, s, 1H);

(broad magnetic (S, 9H); 3.42 (s, 3H); 4.54 (deformed

Jab = 7.3 Hz, [Delta] A-ee = 26 Hz, 2H): 5.36

1H); 7.23-7.41 (m, 5H) Magnetic Nuclear Spectrum Resonance ³ C

(deuterochlo chloroformate, 75.47 MHz): 28 25 (CHs ); 52.47 (C iCH =); 55.89 (CH) ; 77.44 (CH) : 79, (CHc); 80 02 (C); 94.75 (CHc); 96.2 1 (C); 126.43 (CH) ; 1 27.82 (C H) ; 128.63 (CH); 139.01 (C); 155,04 (C); 169.98 (C) - mass sp ektrum (Chem. i o n i z ác i a ; NH ₃ + i z o b u t); m / z (%) RE1. i nt. ): M ”4 5 6, 5 (100) : [M + 2] - 458.5 (9 7.5); [M + 41 * 460.5 (31.7) and [M + 6] * 46 2,5 (3 , 4)

- chemical analysis:

calculated for C18H16O6NCl3

47,33

47.45

H% 5.30

5.15

N, £ 3.07

3.19

Example 2

Into the flask can be admixed with Example 1, with the contents

100 injects 196 mg ml per minute.

Magnetic solution obtained in ml, equipped with (0,43 mmol) of the ester solution is then added 12 ml of potassium.

distilled water

It is stirred for 24 hours and 178 mg (1.29 mmol) of carbonate at a temperature of about 20 DEG C. and methanol and water are evaporated under reduced pressure. The resulting solution dissolves under gentle heating in the minimum alkaline phase and is washed three times, after which it is acidified by stirring vigorously with a lot of water (12 ml) for 4 hours. Aqueous ml of ether. The aqueous phase is cooled to 0 C C F ml of 2M hydrochloric acid

2 in the presence of 30 ml methylene chloride. After decantation, it is extracted eight times with 20 to 25 ml of methylene chloride. The combined organic phases are washed four times with 10 ml of water and then with 10 ml of saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, filtration and evaporation to dryness under reduced pressure, (2R, 3S) -3-tert-butoxycarbonylamino-3-phenyl-2- (2,2-yield) was obtained in 89% yield. , 2-1 (chloroethoxymethoxy) propionic acid in the form of a white solid having the following properties:

- rotation: [a] ² ° D = + 62.2 (c = 1, ^chloroform);

- IR (film): main characteristic absorption bands at 3500-2300, 3000, 2940, 1760, 1730, 1500, 1460, 1400, 1375, 1260, 1180, 1135, 1090, 1020 and 810 cm ¹

- proton spectrum (deuterochloroform; 200 MHz):

singlet), 1H + H = O); 3.44 (AB _α , 2H); 4.60 (s, 1 H); 4.33 (ABa,

2H); 5.43 (distorted d, J d, J = 9 Hz, 1H); 7.29 - 7.38 nuclear magnetic resonance imaging

1.43 (s, 9H); 2.73 (broad

Jab = 11.7 Hz, ÔA-Ôe = 91 Hz, Jab = 7.3 Hz, ÔA-Ôe = 30 Hz,

9.5 Hz (1H); 5.59 (deformed (m, 5H))

Nuclear Magnetic Resonance Spectrum ¹³ C (CDCl3, 75.47 MHz): 28.25 (CH3); 55.78 (CH); 57.88 (CH);

79.43 (CH =); 80.8 * (C); 94.81 (CHc); 96.22 (C); 126.39 (CH); 127.89 (CH); 128.66 (CH); 138.92 (C); 155.69 (C) and 171.91 (C)

- mass spectrum (chemical ionization, NH 3 + isobutane); m / z rel. M +: 442.5 (100); [M + 2] + 444.5 (97.5); [M + 4]

446.5 (31.7); (M + 6) + 448.5 (3.4)

Chemical analysis for C 13 H 15 N 3 O 2 O • 1 H 2 O calculated C% 44.32 H found

44.49 <per za

5.25 N

5.26, 04

3.06

3

Example 3

A 15 ml flask equipped with a magnetic stirrer was charged with syn - (-) - 1-phenyl-1-tert-butoxycarbonylamino-2-hydroxy-3-butene and 3.6 ml under argon. anhydrous acetone it 1 µ. add gradually 2.12 ml (1.4 g; molecular sieve grains 4.10 ¹⁰ m)

Then, to the resulting solution of mmol) of 2-methyl-2-butene, 10 and 643 mg (3 mmol) of the proton fungus. Stir 5 minutes at approximately 20 ° C, then add 485 mg (2 mmol) of 2,2,2-trichloroethoxymethyl bromide. After stirring for 24 hours at approximately 20 ° C, 643 mg (3 mmol) of proton sponge and 485 mg (2 mmol) of 2,2,2-trichloroethoxymethyl bromide were added. After 24 hours of reaction, 242.4 mg (1 mmol) of 2,2,2-trichloroethoxymethyl bromide are added again and then stirred for a further 24 hours at a temperature of about 20 ° C. A saturated aqueous solution of sodium hydrogen carbonate was then added. Stir 10 minutes. Then 100 ml of methylene chloride and 5 ml of water are added. After decantation, the aqueous phase is extracted twice with 20 ml of methylene chloride. The combined organic phases are washed twice with 10 ml of a 2M aqueous hydrochloric acid solution, four times with 10 ml of water, twice with 10 ml of a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate. Filtration and evaporation to dryness under reduced pressure gave 868 mg of product which was purified by chromatography on silica eluting with hexane: ether (9: 1, v / v). Thus, in a yield of 70%, 298 mg (0.70 mmol) of syn- (s) -1-phenyl-1-tert-butoxycarbonylamino-2- (2,2,2-trichloroethoxymethoxy) -3-butene is obtained, which has the following features:

melting point: 75 ° C (h e x a n

- infrared spectrum (fi absorption bands at 3460, 3380,

1 0, 1 720, 1 500, 1 400, 1 370,

Im): main characteristics

3080, 3050, 3020, 3000, 2950

290, 1 55, 1 70, 1 30, 1 080,

1020, 940 and 810 cm ^-1

4

- proton spectrum - nuclear magnetic resonance i e (deuterochloroform; 200 MH Z): 1.43 (, s, 9H); 3 42 (A B m, J A B = 11.8 Hz, 6a-ee = 74 Hz. 2 H) ; 4.37 (deformed dd, J = 2, 5 Hz and 7 Hz, 1H); 4.74 (AB «, J A B ⁼ 7 Hz = 17, 7 Hz , 2H) ; 4. 86 (broad singlet, 1H); 5 35 (d, J = 11 Hz, 1H); 5.36 (D, J = 1 1 Hz, 1H); 5.36 (d, J = 17 H z, 1H); 5,32 - 5.41 (m , 1H) ; 5 83 (ddd, J = 7Hz, 11Hz and 1 7 Hz, 1H), 7.26 - 7.40 (M, 5H) - nuclear spectrum magnet i ckej rust onanc i e 1 ³ C (deutero-chloroform; 75.47 MHz): 28.34 (CH ); 57.64 (CH);

79.16 (CH -); 79.68 (C); 79.98 (CH); 92.76 (CH -); 96.60 (C); 119.67 (CH 2); 126.65 (CH); 127.43 (CH); 128.40 (CH); 134.25 (CH); 140.31 (C) and 155.43 (C)

- mass spectrum (chemical ionization; NHb + isobutane); m / z (% rel. int.): M + 424.5 (100); [M-2] + 426.5 (97.5); [M + 4]

428.5 (3,11); [M + 6] + 430.5 (3.4)

chemical analysis

for CisHid-CaNCla calculated C% 50.90 H% 5.69 N% 3.30 found 50.81 5.30 3,2 9

syn- (R) -1-phenyl-1-tert-butylcarbonylamino-2-hydroxy-3-butene is obtained in pure form from tert-butylbenzylcarbamate by the method described in French patent no. 2,662,440.

A 10 ml flask equipped with a magnetic stirrer was charged with 245 mg (0.577 mmol) of the product obtained above dissolved in 1.2 ml of acetonitrile under argon. 1.2 ml of carbon tetrachloride, 1.8 ml of distilled water are added sequentially, while vigorously stirring 315 mg (3.75 mmol) of solid sodium hydrogen carbonate are added. The heterogeneous reaction mixture was allowed to react until gas evolution ceased and 24.5 mg RuCla was added. With vigorous stirring, the reaction mixture is allowed to react for 29 hours at approximately 20 ° C, then diluted with water until a total volume of ml is reached. The alkaline aqueous phase is washed three times with 10 ml of ether and then cooled to 0 ° C. In the presence of 40 ml of methylene chloride, 2 ml of 2M hydrochloric acid are added with vigorous stirring. The aqueous phase is extracted eight times with 40 ml of methylene chloride. The organic phases are combined and washed three times with 10 ml of water, then with 10 ml of saturated aqueous sodium chloride solution and finally dried over a mixture of sodium sulphate and anhydrous magnesium sulphate. Filtration under reduced pressure through celite and evaporation to dryness yielded 80% yield. 204 mg (0.461 mmol) of (t) -3-tert-butoxycarbonylamino-3-phenyl-2- (2,2,2-trichloroethoxymethoxy) propionic acid. ;

Example 4

To a 10 ml flask was charged 215 mg (0.48 mmol) of syn - (-) - 3-tert-butoxycarbonylamino-3-phenyl-2- (2,2,2-trichloroethoxymethoxy) propionic acid obtained under the conditions of Example 3, and 1.2 ml of acetone. The resulting solution was heated gently until a perfectly homogeneous solution was added, and a solution of 85 mg (0.51 mmol) of (+) - ephedrine in 1.2 ml of acetone was added. The reaction mixture is stirred until a homogeneous solution is obtained, then crystallized by cooling to approximately 20 ° C. The white crystals obtained are filtered off and washed twice with ether. 130 mg of ephedrine salt of (2R, 3S) -3-tert. butoxycarbonylamino-3-phenyl-2- _(2> 2,2-trichlóretoxymetoxy) prop ionic.

The crystals thus obtained are dissolved hot in 2 ml of methanol. Add 0.5 ml of ethyl acetate, then cool to about 20 ° C. The formed white crystals are filtered off, then treated with 1N aqueous hydrochloric acid in dichloromethane at a temperature of about 20 ° C. Extraction by customary methods yielded 30.1% yield of 64 mg (0.1446 mol) of (2R, 3S) - (+) -3-tert-butoxycarbonyl-amino-3-phenyl-2- ( 2,2,2-1 (chloroethoxymethoxy) propionic acid, in which

MwíZ.

6, the enantiomeric excess is greater than 99% (as determined from

Mosher esters corresponding to 1 (racemic and optically pure) and whose infrared and proton nuclear magnetic resonance spectra are the same as those of the product of Example 2.

The mother liquors obtained in the first crystallization are evaporated to dryness. The residue is dissolved hot in 2.5 ml of methanol. 0.5 ml is added ^; ety1acetátu. After cooling to 20 ° C, 78 mg of white crystals are collected by filtration, which are combined with the evaporator obtained by evaporation to dryness of the mother liquors from crystallization of (2R, 3S) - (+) - 3-tert-butoxycarbonylamino-3-phenyl- 2- (2,2,2-trichloroethoxymethoxy) propionic i. Recrystallization of the mixture with methanol-ethyl acetate gave 33.5 mg of white crystals, which were treated with 1 N aqueous hydrochloric acid in dichloromethane at 20 ° C. Extraction under usual conditions gives 24.5 mg (0.055 mmol) of (2R, 3S) - (+) - 3-tert-butoxycarbonylamino-3-phenyl-2- (2,2,2-trichloroethoxymethoxy) propionic acid, m.p. of which the enantiomeric excess is greater than 99 S.

Together, 88.5 mg of (2R, 3S) - (+) - 3-tert-butoxycarbonylamino-3-phenyl-2- (2,2,2-trichloroethoxymethoxy) propionic acid are obtained, the rotation of which is:

( ^.alpha.) D @ ²⁰ = + 60 DEG (c = 0.92; chloroform).

The yield of resolution on the enantiomers is 83%.

Example 5

A 15 ml flask equipped with a magnetic stirrer was charged with 202 mg (0.77 mmol) of (X) 1-tert-butoxycarbonylamino-1-phenyl-2-hydroxy-3-butene under argon atmosphere at a ratio of syn / anti equals 6/1, and 2.3 ml of anhydrous acetonitrile. To the solution obtained, 1.63 ml is added gradually

7 (1.08 g: 15.4 mmol) of 2-methyl-2-butene, 8 grains of molecular sieve at 4.10 &lt; -1 &gt; m and 494 mg (2.3 mmol) of proton sponge. Stir 5 minutes at approximately 20 ° C, then add 381 mg (1.57 mmol) of 2,2,2-trifluoroethoxymethyl bromide. Stir for 24 hours at approximately 20 ° C, then add 494 mg (2.3 mmol) of the proton sponge and 381 mg (1.57 mmol) of 2,2,2-trifluoroethoxymethyl bromide. After stirring for 24 hours, 190 mg (0.785 mmol) of 2,2,2-trichloroethoxymethyl bromide are added again, followed by stirring at 20 ° C for 24 hours and then at 25 to 30 ° C for 20 hours.

The reaction mixture was treated with saturated sodium bicarbonate solution for 10 minutes, then treated with 80 mL of dichloromethane and 4 mL of water. After decantation, the aqueous phase is extracted twice with 15 ml of dichloromethane. The combined organic phases were washed twice with 8 ml of a 2M aqueous hydrochloric acid solution, four times with 8 ml of water and twice with 8 ml of saturated sodium chloride solution. After drying over anhydrous sodium sulfate, filtration and evaporation to dryness, 674 mg of a yellow oil is obtained, which is purified by chromatography on a silica gel column, eluting with a 9: 1 mixture of hexane and ether.

Thus, in 62% yield, 202 mg (0.476 mmol) of (*) -1-tert. butoxycarbonylamino-1-phenyl-2- (2,2,2-trichloroethoxymethoxy) -3-butene in which the syn / anti ratio is 6/1.

(1) -1-ter c. butoxycarbonylamino-1-phenyl-2-hydroxy-3-butene in the form of a 6/1 mixture of the di-stereoisomers of syn and antia can be prepared as follows:

A 250 ml flask equipped with a magnetic stirrer was charged sequentially with 4.2 g (20.3 mmol) of tert-butylbenzyl carbamate, 40 ml of anhydrous tetrahydrofuran and 6.5 ml (5.01 g, 43.1 mmol) of tetramethylethylenediamine. (TMEDA). The solution was cooled to -70 ° C, then 60 mL (60 mmol) of a 1M solution of secondary butyl lithium in hexane was added dropwise. Allow

3 ml (2.5 g, 44.9 mmol) of freshly distilled acrolein are added, allowed to react for 3 to 4 minutes at this temperature, then 3 ml (2.5 g, 44.9 mmol). The resulting reaction mixture was hydrolyzed at -78 ° C with 20 mL of water, then extracted twice with 30 mL of ether. The organic phases are combined, then washed twice with 20 ml of water and once with 10 ml of saturated aqueous sodium chloride solution. They are then dried over anhydrous sodium sulfate. After filtration, the solvents were distilled off under reduced pressure. The residue obtained (11.6 g) was purified on a silica gel column using a 95: 5 mixture of methylene chloride and ether as the eluent. 2.606 g (9.91 mmol) of 1-tert-butoxycarbonylamino-1-phenyl-2-hydroxy-3-butene are obtained in a 49% yield as a 6: 1 mixture of the syn and anti diastereoisomers.

Example 6

A 10 ml flask equipped with a magnetic stirrer was charged with 102 mg (0.24 mmol) of (t) -1-tert-butoxycarbonylamino-1-phenyl-2- (2,2,2-trichloroethoxymethoxy) -3-butene in the form of a 6: 1 mixture of the syn and anti diastereoisomers in a solution of 0.5 ml of acetone tri-l. 0.5 ml of carbon tetrachloride, 0.75 ml of distilled water are then added successively, with vigorous stirring 132 mg (1.57 mmol) of sodium hydrogen carbonate. 282 mg (1.32 mmol) of solid sodium periodate are then added in small portions. Allow to react for 5 minutes until gas evolution ceases, then 10.2 mg RuCla is added in one portion. The reaction mixture, which turned black, was stirred at a temperature in the region of 20 DEG C. for 50 hours. 5 mg of RuCla is added again, then stirring is continued for 40 hours at a temperature close to 20 ° C. After completion of the reaction, 6 ml of water are added. The alkali aqueous phase is separated by decantation, then washed three times with 4 ml of ether. The aqueous phase is cooled to 0 ° C, then 17 ml of dichloromethane and 0.8 ml of 2M hydrochloric acid are added with vigorous stirring. The acidic aqueous phase is separated by W.W. »· 1 W Hv ^ -V ^ t! w ^. ^. ^^ ťÍÍKÍafclAc J.ťuaaVMe ^ l ^ jA · » '*:

The mixture was extracted by decantation, and extracted eight times with 17 ml of dichloromethane. The organic phases are combined and then washed four times with 4 ml of water and twice with 4 ml of saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, filtration and evaporation to dryness under reduced pressure, 75 mg (0.17 mmol) of (t) -3-tert-butoxycarbonylamino-3-phenyl-2- (2,2,2-trichloroethoxymethoxy) are obtained. ) propionic as a 6: 1 mixture of syn and anti diastereoisomers.

Yield 71%.

Example 7

A 25 mL flask was charged with 701 mg (1.584 mmol) of the product obtained in Example 6 dissolved in 4 mL of acetone. Heat gently until a homogeneous solution is obtained. A solution of 277 mg (1.69 mmol) of (+) - ephedrine in 4 ml of acetone is then added. Stir until a homogeneous solution is obtained. After cooling to a temperature in the region of 20 DEG C., the crystals obtained are filtered off and washed twice with ether. After drying, 385 mg of ephedrine salt is obtained. The crystals thus obtained are dissolved in a hot mixture of 6 ml of methanol and 2 ml of ethyl acetate. After evaporation of the 10% solvent and cooling to a temperature in the region of 20 DEG C., the crystals obtained are filtered off. 190 mg of ephedrine salt are obtained in the form of white crystals which are treated with 1N hydrochloric acid in the presence of dichloromethane at a temperature close to 20 ° C. Extraction by customary methods yielded 138 mg (0.313 mmol) of (2R, 3S) - (+) - 3-tert-butoxycarbonylamino-3-phenyl-2- (2,2,2-trichloroethoxymethoxy) propionic acid in which it is enantiomeric excess of more than 95%.

Yield 19.8%.

The mother liquors from recrystallization of the ephedrine salt from methanol / ethyl acetate were evaporated to dryness. Acquired ·> c

the residue is dissolved in a hot mixture of 3 ml of methanol and 1 ml of ethyl acetate. After evaporation of 10% solvent and cooling to a temperature in the region of 20 DEG C. for 24 hours, 92 mg of white crystals were treated with 1N hydrochloric acid in the presence of dichloromethane. Extraction by conventional methods afforded 65 mg of (2R, 3S) - (+.) - 3-tert. butoxycarbonylamino-3-feny1-2- (2,2,2-t.ríchl.óretoxymeto-

(xy) propionic in which the enantiomeric excess is greater than 99% / © · Yield 9. , 3%. Processing e mother liquors of the other crystallization ephedrine salt as described above conditions (evaporation to

Drying, recrystallization from methanol / ethyl acetate, acid hydrolysis) afforded 31.4 mg of (2R, 3S) - (+) - 3-tert. butoxycarbonylamino-3-phenyl-2- (2,2,2-trichloroethoxymethoxy) propionic acid in which the enantiomeric excess is greater than 99%.

Yield 4.5%.

The overall yield of (2R, 3S) - (+) - 3-tert-butoxycarbonylamino-3-phenyl-2- (2,2,2-dichloroethoxymethoxy) propionic acid is 33%, and the resolution yield is about 76%.

Example 8

A 10 ml flask equipped with a magnetic stirrer was charged with 119.5 mg (0.27 mmol) of the acid obtained in Example 2 dissolved in argon under argon.

2.25 ml of anhydrous toluene. Then add

55.7 mg (0.27 mmo1) N,

N-dicycloxycarbodiimide. The mixture was allowed to stand for 5 minutes after which a mixture of 11 mg (0.09 mmol) of 4-N, N-dimethylaminopyridine was added.

d 81 mg (0.09 mmol) of 4-acetoxy-2a-benzoyloxy-50,2O-epoxy-1,13a-dihydroxy-9-oxo-bis (2,2,2-trichloroethoxy) -7P, 10O-carbonyloxy- 11-taxene. Allow to react for 3 to 4 minutes at a temperature close to 20 ºC, then heat at 72 to ‘C for 24 hours. The heterogeneous reaction mixture is taken up in 60 ml of ethyl acetate. The organic phase is washed with 5 ml of water twice; 5 ml of saturated aqueous sodium bicarbonate solution, 4 times with 5 ml of water and twice with 5 ml of saturated aqueous sodium chloride solution. Finally, it is dried over anhydrous sodium sulfate. After filtration and evaporation to dryness under reduced pressure, the residue obtained (270 mg) was purified by thin-layer chromatography on silica using a 95: 5 mixture of methylene chloride and ether (2 passages) as eluent.

There was thus obtained (2R, 3S) -3-tert 112 mg (0.085 mmol) in 94% yield. 4-acetoxy-2a-benzoyloxy-50,2O-epoxy-1-hydroxy-9-oxo-bis (2,2,2-trichloroethoxy) butoxycarbonylamino-3-phenyl-2- (2,2,2-trichloroethoxymethoxy) propionate -70,100-carbonyloxy-11-taxen-13a-yl, the properties of which are as follows:

Infrared (film): characteristic absorption bands at 3450, 3000, 2950, 2910, 1760, 1720, 1500, 1455, 1440, 1380, 1250, 1175, 1090, 1070, 1020, 380, 910, 820, 780 and 720 cm @ -1 magnetic resonance magnetic resonance spectra of the proton

(CDCl ; 300 MHz): 1.21 (S, 3H); 1.30 (s, 3H); 1.34 (s, 9H); 1, 79 - 1,84 (m, 1 H); 1.86 (s 3H); 2.04 (s, 3H); 2.0 - 2.08 (m, 1H); 2, 14 - 2.46 (m, 2H); 2.51 (s, 3H); 2 , 55 - 2.71 (m, IH); 3.53 (A B α, Brightness = 11.7 Hz, ÔA-δβ = 109 HZ, 2H); 3.95 (d, J = 7 Hz, 1H); 4.2 / (Aΰ * and Jab - 8.6 Hz, 6a-δe = 45 Hz, 2H); 4.65 (wide ng (et, 1H); 4.75 (AB a, Jab ⁼ 1 2 HZ, 6a-Ôb = 90 Hz , 2H) ; 4.77 (pseudotr i p 1et, J = 5Hz, 2H); 4.95 (d, J = 55.6) Hz, 2 H); and, 98 (d, J = 8.3 H) z, 1H); 5.44 (broad s (ng, 1 H); 5, 58 (dd, J 7 Hz and 10.6 Hz, 1H); 5.72 (d , J =

t r i p 1 e t,

Hz and 1H);

J = 8.3

6.26 (s, 1 H); 6.31 (deformed

Hz and 9.2 Hz, 1H); 7.31 - 7.64 (m, 8H); S, 05 - S, 13 (m. 2H)

A 10 ml flask equipped with a magnetic stirrer was charged with SO mg (0.0606 mmol) of the above product dissolved in 3.2 ml of methanol under argon. 3.2 ml of glacial acetic acid and 320 mg of zinc-copper pair (prepared from 20 g of zinc powder and 3 g of hydrated copper sulphate) are added successively. Heat at 60 ° C for 30 minutes. After cooling, 50 ml of ethyl 1-acetate are added. The mixture was filtered through celite under reduced pressure. The solid product was washed five times with 10 mL of ethyl acetate. The combined organic phases are washed three times with 5 ml of water and twice with 5 ml of saturated aqueous sodium chloride solution and finally dried over anhydrous sodium sulphate. After filtration and evaporation to dryness under reduced pressure, the obtained residue (50 mg) was purified by preparative TLC on silica eluting with methylene chloride / methanol (94: 6, v / v) (2 passages).

There was thus obtained 4-acetoxy-2a-benzoyloxy-53,20-epoxy (2β, 3S) -3-tert-butoxycarbonylaminium-3-phenyl-2-hydroxypropionate (38 mg, 0.047 mmol) in 78% yield. -1,7β, 10β-trihyclroxy-9-oxo-11-taxen-13a-yl, the properties of which are identical to those described in the literature as follows:

Infrared spectrum (film):

3450,

2890,

15, and 710

2850,

270 cm ^{- 1}

1730, 1710, 1600

1105

1245 1160

580

095.

3100 3050

1490 1450

2950 2920

1390 1370

1070, 1020, 980, 910, 730 proton nuclear magnetic resonance spectrum

(deuterochloroform; 3G0 MHz) : 1,13 (S, 3H) ; 1 24 (s. 3H); 1.34 (with , 9H); First 76 (S, 3 H); 1, 85 (S, 3H) ; 1.74 - 1, 85 (m, 1 H); 2.26 - 2, 2 9 m 2H) ; 2.37 (s , 3H) ; 2.54 - 2,66 (m, 1H); 3.32 (ps s, 1H); 3.92 (D, J = 7Hz, 1H) : 4,18 - 4,30 (M, 1 H); 4.24 (ABc, J A B = 8.25 HZ, 6a ~ 6e - 36.5 Hz, 2H) ; 4.62 (ps S, 1H); 4.94 (d,

C '

J Σ 7.4 Hz, 1H); 5.20 (s, 1 H); 5.25 (p d, 1H); 5.42 (ps d, 1H); 5.68 (d, J = 7Hz, 1 H); 6.21 t, J = 8, 3 HZ, 1H); 7.31 - 7.40 (m, 5H); ; 7.43 - 7, 52 (m, 2H); 7,59 - 7, 64 (m, 1 H); 8,09 -

8.12 (m. 2H)

Example 9

A 15 ml flask equipped with a magnetic stirrer was charged with 200 mg (0.67 mmol) of (2R, 3S) -methyl-3-benzoylamino-2-hydroxy-3-phenylpropionate and 2.4 ml of acetone under argon. itri 1 u. To the resulting suspension was then added 431 mg (2.01 mmol) of a proton sponge, 1.42 mL (940 mg, 13.4 mmol).

2-methyl-2-butene and 7 grains of molecular sieve ^3.10-100 m. The resulting reaction mixture was stirred at about 20 ° C for 5 minutes, after which 325 mg (1.34 mmol), 2,2,2-trichloro-6-methoxybutyl bromide were added. Allow to react for 30 hours at approximately 20 ° C. The reaction mixture is substantially heterogeneous. 431 mg (2.01 mmol) of proton sponge and 585 mg (2.41 mmol) of 2,2,2-chloro-ethoxymethyl bromide were added in succession. After a reaction time of 24 hours at a temperature in the region of 20 DEG C. when the reaction is not complete, 215.4 mg (1.05 mmol) of proton sponge and 162.4 mg (0.67 mmol) of 2,2,2 are added successively. -trichlóretoxymetylbromidu. The mixture is allowed to react for 42 hours at a temperature in the region of 20 DEG C. After a total of 96 hours of reaction, although the reaction is not complete, it is stopped. The reaction mixture was then treated with a saturated aqueous solution of sodium hydrogen carbonate for 10 minutes, then 100 ml of methylene chloride and 10 ml of water were added. After decantation, the aqueous phase is extracted twice with methylene chloride (2 ml). The combined organic phases are washed twice with 5 ml of 2N aqueous hydrochloric acid solution, four times with 10 ml of water and twice with 10 ml of saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, filtration and evaporation to dryness under reduced pressure, 950 mg of crude product is obtained, which is purified by chromatography on silica, eluting with hexane / ether (35/15). 72 ^? ° yield 222 mg (0.482 mmol) of (2R, 2S) -methyl-3-benzoyl-amino-3-phenyl-2- (2,2,2-trichloroethoxymethoxy) -propionate, the properties of which are as follows:

- melting point: 70 to 71 ° C

- rotation: [α] ²⁵ _ρ = + 7,2 * (c = 1,16; chloroform) and infrared absorption bands

1580

1660 1602

1210, 1170, spectrum at 3450,, 1518,

1125, 1080, (movie):

3340, 3070

1485, 1435

1018, y

805 cm ^- * main characteristics

3040, 2950

1355 1315

2920, 1750,

1290 1270

proton nuclear magnetic resonance spectrum (deuterochromoform; 300 MHz): 3.49 (AB _q , J a = 11.3 Hz, 6a-6b = 126.5 Hz, 2H); 3.79 (s, 3H); 4.69 (d, J = 1.8Hz, 1H); 4.86 (ABa, Jab = 7.1 Hz, 6a-β = 32.2 Hz, 2H); 5.81 (dd, J = 1.8 Hz and 9 Hz, 1H); 7.05 (d, J = 9Hz, 1 H); 7.26 - 7.56 (m, 8H);

7.80 - 7.83 (m, 2H)

¹³ C nuclear magnetic resonance spectrum (75.47 Hz; deuterochloroform); 52.49 (CH ₃ ); 54.76 (CH); 77.19 (CH) -; 79.39 (CH =); 94.68 (CH =); 96.09 (C); 1 26.43 (CH); 1 27.02 (CH); 127.89 (CH); 128.38 (CH); 128.58 (CH); 131.70 (CH); 134.00 (C); 138.34 (C); 166.75 (C); 169.88 (C) mass spectrum (chem. On; NH ₃ + isobutane); m / z (% re 1.

i nt.): M *

460.5 (100); [M + 2] (97.5); [M + 4] * 464.5 (31.7); [M + 6] * 466.5 (3.4)

- chemical analysis:

calculated for CcoHcoO5NCl3

Λ 0 /

Ό / o

52.14 H

52,11

4.38 N% 3.04

4.49 3.04

Example 10

A 50 ml flask equipped with a magnetic stirrer was charged with 107 mg (0.232 mmol) of the ester obtained in Example 9 and 14 ml of methanol. 7 ml of distilled water and 98 mg (0.71 mmol) of potassium carbonate are then added to the obtained solution. Stir for 20 hours at about 20 ° C, after which the methanol and water were evaporated under reduced pressure. The residue obtained is dissolved in 10 ml of water. The resulting alkaline aqueous phase was washed three times with 10 ml of ether. The aqueous phase is cooled to 0 ° C, then acidified with 2 ml of 2M aqueous hydrochloric acid with vigorous stirring in the presence of 20 ml of methylene chloride. After decantation, it is extracted eight times with 20 ml of methylene chloride. The combined organic phases are washed three times with 10 ml of water, then once with 10 ml of saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, filtration and evaporation to dryness under reduced pressure, 91 mg (0.204 mmol) of (2R, 3S) -3-benzoylamino-3-phenyl-2- (2,2,2-trichloroethoxymethoxy) is obtained in 88% yield. ) propionic, the properties of which are as follows:

- rotation: [α] ² γ = + 22.8 '(C = 1.02; chloroform) infrared (film): main characteristic absorption bands at 3440, 3700-2300, 3070, 3040, 2975, 2925,

1645, 1745,

1602, 1580, 1520, 1485, 1295, 1265,

205, 1 7 7,

35, 1,080,

1020, 8 10 cm ¹

proton nuclear magnetic resonance spectrum (deuterochloroform; 300 MHz): 2.80 (broad singlet, 1H + H2O);

3.50 (ABa, Ia _B = 12 Hz, 6a-6b = 121.4 Hz, 2H); 4.73 (d, J =

1.7 Hz, 1 H); 4.88 (ABa, Brightness -7.3 Hz, ÔA-δe-34.7 Hz, 2H);

5.93 (dd, J = 1.7 Hz and 9 Hz, 1H); 7.19 (d, J = 9 Hz, 1H); 7.25 - 7.54 (m, 3H); 7.7 9 - 7.82 (m, 2H) @ ³ C nuclear magnetic resonance spectrum (75.47 Hz;

(d) (c) f (f): 5-, 37 (CH); Δ 6.34 (CH); Δ 9.53 (CH; ··); 94.86 (CH =): 96.18 (C); 126.52 (CH); 127.33 (CH); 128.14 (CH);

128.73 (CH); 128.82 (CH); 132.12 (CH); 133.53 (C); 138.18 (C); 168.06 (C); 170.91 (C)

- mass spectrum (chemical ionization; NH ₃ + isobutane); m / z (rel. int.%): M * 446.5 (100); [M + 2] + 448.5 (97.5); [M + 4] + 45Q, 5 (31.7); [M + 6] ~ 452.5 (3.4)

- chemical analysis

for. CigHiaOsNCla, 1 H ₃ 0 calculated C% 49.11 H% 4.34 N% 3.01 found 49,05 4.33 3.09

Example 11

In a 50 ml single-necked flask equipped with a magnetic stirrer was added 27 mg (1 mmc-1) syn- (+) -1-phenyl-2-hydroxy-3-butene and 3.5 ml of anhydrous acetonitrile. The resulting suspension was added successively 2.12 ml (1.4 g, 20 mmol), 2-butene-mety1-2, 14 grains of the molecular sieve 3.10 ~ ^{10 mA} 614 mg (2.86 mmol) of proton sponge. The reaction mixture was stirred for 15 minutes at a temperature close to 20 ° C, then 481 mg (1.58 mmol) was added.

2,2,2-trichlóretoxymetylbromídu. at a temperature close to the proton sponge and bromine, followed by (2 mmol) hours.

Allow to react 23 643 mg (3 hours mmo1) was added for 2.2 hours. After the solution was added 100,2-trichloroethoxymethyl bromide to quench the reaction, sodium bicarbonate and ml of dichloromethane were added. Separated mmol), 2,2-trichloroethoxymethyl Methylamine (2) and 2 mg (1) were added and the reaction mixture was stirred for 20 minutes with saturated aqueous solution. sodium chloride solution.

phase is extracted with organic phases, washed with hydrochloric acid solution and twice with 15 ml of saturated aqueous solution. After drying over anhydrous sodium sulphate, filtration and evaporation to dryness under reduced pressure, the yellow residue obtained is purified by chromatography on a column of silica gel. CHCl3 / ether 98: 2 (v / v). There was thus obtained 63% yield of 2 70 mg with y- (+) - 1-phenyl-1-benzoylamino-2- (2,2,2-trichloroethoxymethoxy) -3-butene, the physical properties of which were as follows:

- melting point: 91-92 ° C

- rotation: [a] - ⁵ o = +31 ”(c = 0.8, chloroform)

The infrared and proton nuclear magnetic resonance spectra of the product obtained are identical to those of the product described in Example 14.

Example 12

In a 10 ml single-necked flask equipped with a magnetic stirrer was added, under argon, 202 mg (0.47 mmol) of syn - (+) -1-phenyl-1-benzoylamino-2- (2,2,2- trichloroethoxymethoxy) -3-butene and 1.2 mL of anhydrous acetonitrile. 1.2 ml of carbon tetrachloride are gradually added to the mixture obtained,

1.8 ml of water and 317 mg (3.77 mmol) of solid sodium hydrogen carbonate were stirred vigorously. 683 mg (3.19 mmol) of sodium periodate are then added in small portions. The strongly heterogeneous reaction mixture was then stirred for 5 minutes (gas evolution), to which 24.8 mg RuCls was added in one portion. The reaction mixture, which turned black, was allowed to react for 40 hours at a temperature close to 15 DEG C. After completion of the reaction, 15 ml of water were added. The alkaline aqueous phase is washed three times with 20 ml of ether. The aqueous phase is cooled to 0 ° C and 2.5 ml of a 2M aqueous hydrochloric acid solution are added thereto under vigorous stirring in the presence of 50 ml of dichloromethane. The acidic aqueous phase thus obtained is extracted seven times with 70 ml of dichloromethane. The combined organic phases are washed four times with 10 ml of water and once with 10 ml of saturated aqueous sodium chloride solution. After drying the organic phase over anhydrous sodium sulphate, filtering and evaporating to dryness under reduced pressure, in 76% yield, 160 mg of (2R, 3S) - (+) - 3-benzoylamino-3-phenyl-2- (2,2-dicarboxylic acid) is obtained. (2-trichloroethoxymethoxy) propionic acid in the form of white crystals, the physical and

spectroscopic features They are identical to properties the same acid, , obtained in Example 10. Example 13 • One-bank bank with 250 ml, equipped with

with a magnetic stirrer, 5.4 ml (32 mmol) of tetramethylpiperidine and 6.5 ml of anhydrous tetrahydrofuran are introduced under argon. The resulting solution was cooled to -60 ° C, then 20 mL of a 1.6 M solution of n-butyllithium in hexane was added dropwise. The temperature of the heterogeneous solution should not rise to -10 ° C for one hour. The solution of trifluoro-tetramethylpiperidine is cooled to -60 ° C and a solution of 2.16 g (10.25 mmol) of N-benzylbenzamide and 3.4 ml (22 ml) is added over 20 minutes. (5 mmol) of Ν, Ν, Ν ', Ν'-tetramethylethylenediamine in 8.5 ml of tetrahydrofuran. After stirring at -60 ° C for one hour, 2.4 ml (36 mmol) of freshly distilled acrolein are added in one portion. It is reacted for 15 minutes at -60 ° C, then hydrolysed by adding 20 ml of water. The reaction mixture was extracted three times with 30 ml of dichloromethane. The combined organic phases are washed with 10 ml of 1N hydrochloric acid solution, twice with 20 ml of water, then once with 10 ml of saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulphate. Filtration and evaporation to dryness under reduced pressure yielded 4.3 g of a residue which was purified by chromatography on silica gel, eluting with dichloromethane / ethyl acetate 9: 1. To obtain in 23% yield, 630 mg of N- sy ( ^'s) - 1-phenyl-1-1-benzoy1amíηο-2-hydroxy-3-butene and 15% yield of 409 mg of the anti - (+) - 1-phenyl- 1-benzoylamino-2-hydroxy-3-butene.

The properties of the syn - (*) - 1-phenyl-1-benzoylamino-2-hydroxy-3-butene are as follows:

- melting point: 1 3 7 - 1 39 C (di-chloromethane-cyclohexane) and infrared absorption bands

1080, 995, 920 spectrum at 3300, 700 cm ^-1 (film):

1620, 1525 main characteristic

1510 1335

1295 1120

proton spectrum (deuterochloroform;

nuclear

200 MHz):

magnetic

2.40 (d, J = 3.9 Hz resonance, 1H); 4.55

(Dd, J - 3, 5 Hz, 3.5 Hz and 5 Hz, 1H); 5.23 d d, J = 1, , 5 Hz 10.5 Hz, 1H); 5.26 (dd, J) = 3, 5 Hz and 7.6 Hz, 1H); 5.40 (Dt, = 1, 5 HZ a 17, 1.1 (1H, 1H); 5, 94 (ddd, J = 5Hz, 10Hz) , 5 HZ and 17 Hz, 1H); 6.98 (d, J = 7.6 Hz, 1 H); 7.2 4 - 7.54 (m, 8H); 7, 80 7.83 (M, 2H)

and

J, 1 nuclear

- spectrum (deuterochloroform; 75.47 (CH ₂ ); 126.89 (CH); 127 1 28.72 (CH); 131.60 (CH); 167.54 (C) magnetic)

MHz): 57.71 (CH);

.04 (CH); 1 27.68 (CH);

134.31 (C); 137.41 (CH) resonance (CH);

128.56 (CH);

139.60 (C);

75.31 ¹³ C

16, 58

The properties of the anti - (*) - 1-phenyl-1-benzoylamino-2-hydroxy-3-butene are as follows:

- infrared spectrum (nujo 1):

main characteristics are absorbent bands at 3300, 1620, 1600,

1520, 1520, 1300, 1115,

1080, 1060, 1035, 985, 920, 870

820, 800, 750, 700 cm- ¹

proton nuclear magnetic resonance (deuterochloroform; 200 MHz): 2.43 (broad singlet, H); 4.60 (m, IH); 5.23 (dt, J = 1.5 Hz and 10.4 Hz, 1H); 5.33 (dd, J = 4 Hz and 8 Hz, 1H); 5.34 (dt, J = 1.5 Hz and 17 Hz, 1H); 5.79 (d d d, J = 5 Hz, 10.4 Hz and 17 Hz, 1H); 6.88 (d, J = 8Hz, 1H); 7.3 - 7.54 (m, 8H); 7.78 7.82 (m, 2H)

- MS nuclear magnetic resonance ^{1 3} c (CDCl; 7 5.47 MH z): 53.23 (CH); Δ 5.23 (CH); 117.29 (CH -); 126.94 (CH); 127.52 (CH); 127.30 (CH); 128.53 (CH); 128.58 (CH); 131.64 (CH); 134.14 (C); 136.30 (CH); 137.56 (C); 167.23 (C)

Example 14

In a 1-ml 1-ml flask equipped with a magnetic stirrer was added 100 mg (0.37 mmol) of syn- (t) -1-phenyl-1-benzoylamino-2-hydroxy-3-butene and argon under argon. 3 ml of anhydrous acetone. 0.8 ml (530 mg; 7.55 mmol) of 2-methyl-2-butene, 4 grains of 3.10 &lt; ¹ &gt; molecular sieve and 230 mg (1.07 mmol) of proton fungus are added successively. The reaction mixture is stirred for 5 minutes at a temperature in the region of 20 DEG C., then 180 mg (0.74 mmol) of 2,2,2-trifluoroethoxymethyl bromide are added. Allow to react for 21 hours at a temperature close to 20 ° C, then add 115 mg (0.54 mmol) of the proton sponge and 90 mg (0.37 mmol) of 2,2,2-trifluoromethoxymethyl bromide, followed by stirring 19 hours. Add 10 mL of saturated aqueous sodium bicarbonate solution and stir for 15 minutes.

40 ml of dichloromethane are added. The separated aqueous phase is extracted twice with 10 ml of dichloromethane. The combined organic phases are washed twice with 5 ml of a 2M aqueous hydrochloric acid solution, then four times with 5 ml of water and finally twice with 5 ml of a saturated aqueous solution of sodium chloride. After drying over anhydrous sodium sulfate, filtration and evaporation under reduced pressure, the residue obtained (3 × 6 mg) is purified by chromatography on a column of silica gel, eluting with a dichloromethane / ethyl acetate mixture (98/2, v / v). 144 mg of a solid are obtained, which is taken up in ether / hexane. There was thus obtained in 79 [mu] l a yield of 125 mg of syn- (X) -1-phenyl-1-benzoylamino-2- (2,2,2-trichloroethoxymethoxy) -3-butene, the properties of which were as follows:

- melting point: 9 4 - 9 5 ° C (ether - hexane)

- infrared (film): main characteristic absorption bands at 3425, 3300, 3050, 3020, 2900, 1630, 1600, 1570, 1510, 1480, 1290, 1160, 1110, 1070, 1010, 930, 800 and 710 cm ^-1

- Proton nuclear magnetic resonance spectrum (CDCl, 200 MHz): 3.43 (AB ', J _and E = 11.8 Hz, _δ Α -δ' _θ = 80.1 Hz, 2H); 4.56 (dd, J = 2.5 Hz and 8 Hz, 1H); 4.79 (AB _a ; Jab = 7.0 Hz; δ _Α -δβ = 17.2 Hz, 2H); 5.41 (dd, J = 2.5 Hz and 8.8 Hz, 1H); 5.42 (d, J = 17.2 Hz, 1 H); 5.43 (d, J = 10.2 Hz, 1H); 5.88 (ddd, J = 6.8 Hz, 10.2 Hz and 17.2 Hz, 1H); 6.99 (d, J = 8.8Hz, 1H); 7.26 - 7.54 (m, 8H); 7.82 - 7.87 (m, 2H)

¹³ C NMR (CDCl 3; 50.3 MHz): 56.24- (CH); 79.19 (CH =); 79.71 (CH); 92, 86 (CH =); 96.89 (C); 119.76 (CH =); 126.66 (CH); 127.00 (CH); 127.65 (CH); 128.57 (CH); 128.65 (CH); 131.67 (CH); 134.15 (CH); 134.23 (C); 139.66 (C); 166.87 (C)

- mass spectrum (chemical ionization; NH ₃ + isobutane); m / z (rel. int.%): M * 428.5 (100); [M + 2] + 430.5 (97.5); [M + 4]

432.5 (3.1); [M + 6] * 434.5 (3.4) Chemical analysis:

for C20H20O3NCl3 calculated C% 56.03 H% 4.70 N% 3.27 found 55,88 4.72 3.24

Example 15

In a 5 ml 1-neck flask equipped with a magnetic stirrer, 52 mg (0.12 mmol) of γ- (R) -1-phenyl-1-benzoylamino-2-2,2,2 are introduced under an argon atmosphere. 2-trichloroethoxymethoxy) butene obtained in Example 12 dissolved in

0.25 ml acetonitrile. clay. 0.25 ml of carbon tetrachloride, 0.37 ml of distilled water are then added successively with stirring

65.5 mg (0.78 mmol) of solid sodium bicarbonate. 141 mg of sodium periodate (0.66 ml) are then added in slow portions

mmo1). stir is added for 5 minutes, at which time 5.2 mg of RuCla are added in one portion. Reaction mixture, which turned black, was allowed to react for 72 hours at temperature 16 to 17 ’C. Again, 3 mg of catalyst was added thereto

is stirred for 44 hours at 25-30 ° C. 3 ml of water are then added.

The alkaline aqueous phase is washed three times with 4 ml of ether. Water phase

Cool to 0 ’C, what she will leave it to with vigorous stirring

treated with 10 ml of dichloromethane with 0.5 ml of a 2M aqueous hydrochloric acid solution. The acidic aqueous phase thus obtained is extracted eight times with 10 ml of dichloromethane. The combined organic phases are washed four times with 2 ml of water and once with 2 ml of saturated sodium chloride solution. After drying the organic phase over anhydrous sodium sulfate, filtering and evaporating to dryness, 43 mg of a white solid are obtained, which is recrystallized from ether-hexane. Thus, in 71% yield, 38 mg of syn - (*) - 3-benzoylamino-3-phenyl-2- (2,2,2-trifluoroethoxymethoxy) propionic acid is obtained, the properties of which are as follows:

mp: 132-133 ° C (ether-hexane) bands

1745

1135 infrared spectrum

2300

1602 1530

1020, at 3700

1640,

080, (film): characteric tic absorption

3440, 3300, 1520, 1485,

810, 720 and 700 cm ^-1

3070, 304G

1295 1265

2975 2925

205, 1 75, \

spectrum of deuterochloroform;

proton nuclear

300 MHz.): 2.80 [broad magnetic resonance H (+ H = O) J;

3.0 (A. 3 ci , J A B - 12 Hz; --A - Ôe ~ 121.4 HZ , 2H ); 4.73 (d, J = 1,7 HZ, 1H); 4.88 (ABA Brightness - 7.3 Hz, 6a - δθ 34.7 Hz, 2H); 5.93 (dd, J = 1.7 Hz and 9 HZ, 1 H) ; 7 , 19 (d, J = 9 Hz, 1 H); 7.25 - 7.54 (m , 3H) ; 7 79-7 , 32 m 2 H)

Nuclear Magnetic Resonance Spectrum ( ³ C) (CDCl3; 75.47 MHz): 54.S7 (CH); 76.8a (CH); 79.53 (CH--); 94.86 (CH-); 96.18 (C); 126.52 (CH); 1 2 7.3 3 (CH);

128.14 (CH); 128.73 (CH); 128.82 (CH); (C); 138.18 (C); 168.06 (C); 170.91 (C) 132.12 (CH); 133.53 mass spectrum (chem. isolation; NH ₃ T i from 0 b u t n); m / z (¾ rel. M: 446.5 (100); [M + 2] + 448. , 5 (97.5) ; [M + 4] * 450.5 (31.7); [M + 6] * 452.5 (3.4) - chemical analysis: for C 10 H 16 O 5 ClCl 1 H 2 O calculated C% 49.11 U n H) • i, 34 N% 3.01 49,05 4.33 3.09

Example 16

115 mg (0.26 mmol) of syn- (Z) -3-benzoylamino-3-phenyl-2- (2,2,2-trichloroethoxymethoxy) propionic acid, dissolved in a 10 ml 1-ml flask, 0.5 ml acetone. 43 mg (0.26 mmol) of (-) - pseudoephedrine is then added and the reaction mixture is stirred until a homogeneous solution is obtained. The solution is cooled to -10 ° C for 19 hours. The white crystals obtained are isolated and dried. 80 mg of ephedrine salt are obtained, which is redissolved in 0.5 ml of acetone. Cool to 15 ° C for 15 hours. 30 mg of salt are thus obtained in the form of white crystals after filtration. After acid hydrolysis (1N aqueous hydrochloric acid, dichloromethane; 20 ° C; usual extraction), 22 mg of (2R, 3S) - (+) -3-benzoylamino-3-phenyl-2 acid is obtained in 19% yield. - (2,2,2-trichloroethoxymethoxy) propionic in which the enantiomeric ratio (determined by proton nuclear magnetic resonance spectra and 1 F Mosher esters corresponding to 1 to which the 1-methyl ester of racemic and optically active) is 93-7.

3-1

The mother liquors 1 'of the second crystallization gave 50 mg of a residue after evaporation. The residue is dissolved in 0.5 ml of acetone, then cooled at -10 ° C for 24 hours. After filtration, 13 mg of the salt is obtained in the form of white crystals which are hydrolyzed under the conditions described above. Thus, in 7% yield, 8 mg of (2R, 3S) - (+) - 3-benzoylamino-3-phenyl-2- (2,2,2-trichloro-

ethoxymethoxy) propionic acid. identical with higher z i skanou

The resolution yield is 52%.

Example 17

A 1 ml magnetic acid flask (0.139 mmol) of a 5 ml flask equipped with an argon atmosphere is charged with 62 mg of (2R, 33) - (+) -3-benzoylamino-3-phenyl- 2- (2,2,2-trichloroethoxymethoxy) propionic acid, dissolved in 1.1 ml of mg (0.139 mmol) of anhydrous toluene (0.023 mmol). Thereafter, a 16.1 mg mixture was added to react for 5 minutes at a time

5.6 mg (0.046 was allowed to react) was heated 48 the resulting reaction was washed with 3 mL of sodium bicarbonate, mL of saturated aqueous sodium solution.

2-dipyridyl carbonate and close to 20 ° C. Then, 7-triethylsilylbutyropyridine is added. The mixture is at a temperature close to 20 ° C, for which it is C. After completion of the reaction, III and ethyl acetate are added. Organic saturated aqueous four times with 3 ml of water and sodium chloride, then phase out the solution

mmol) 4-N, N-d ime- 3 to 4 minutes at hours at 70 to 72 grain s Dilute 60 ml water. twice 3 ml

dried twice over anhydrous sulphate

After filtration and evaporation of the solvent under reduced pressure, the residue obtained (75 mg) is purified by preparative thin layer chromatography on silica, eluting with a mixture of ether and dichloromethane in a volume ratio.

3:92 (3 passages).

There was thus obtained, in 94 yields, 24.4 mg of 4, 10 &lt; - &gt;

-benzoyloxy-ββ, 20-epoxy-1-hydroxy-9-oxo-7β-triethylsilyloxy-1-1 -taxen-13a-yl - [(+) - 3-benzoylamino-3-phenyl-2- ( 2, 2.2 -1 rich (6-methoxy-propoxy) propionate], containing according to a proton nuclear magnetic resonance spectrum at 300 MHz of 10% epimer C 2, having the following characteristics:

- temperature Melting point: 1 3 7 to 14 5 * C - infrared spectrum (a movie): main character absorption belts at 3400, 2960 2870 1 740, 1 650, 1600 1580 1508, 1480 1445 1365 1265 1235 1140, 1105 1095 1080 1 0 1 5, 985, 945, 818 and 710 cm ^{- 1}

proton nuclear magnetic resonance spectrum (300

MHz; CDCl₃): 0.54 - 0.62 (m, 6H); 0 93 (T, J - 8 Hz, 9H); 1.19 (s, 3H); 1 , 23 (p , 3H) ; 1.70 (s, 3H); 1 , 85-1.99 (m, 1 H); 2.03 (s. 3H); 2 , 10 - 2, 20 (m, 1 H) ; 2.17 (with , 3H); 2.33 -2.60 (m, 2 H); 2.52 (s, 3H); 3.60 (AB, J A B ~ 11.7 Hz 6a-6b = 101.4 Hz, 2 H); 3.82 (d , J = 7 Hz (1H); 4.26 (AB _q , J A B - 8.3 Hz 6a-6b = 35.5Hz, 2H) ; 4.48 (Dd, J - 6, 7 Hz a 10. 3 Hz, 1H); 4.81 (d, J = 2Hz, 1 H); 4.90 (AB a, J A B - 7 .5 Hz; OA- δ e = 17 Hz 2H); 4.94 (d, J = 9.5Hz, 1H) ; 5 70 (d, J = 7 HZ, 1H); 5.89 (dd, J = 2Hz and 9Hz, 1H) ; 6.28 '(t, J = 9Hz, 1H) ; 6. 44 (p , 1H) 7.01 (d, J = 9Hz, 1 H) (m, 2H); 8.12 - 8.16 (m, J 7.34 2H) - 7, 6 3 (m, 1H); 7, 75 - 7.78 Do one day de1 nej banks with content 10 m 1, provided with

24.8 mg of the ester obtained above, dissolved in 0.9 ml of methanol, are introduced by means of a magnetic stirrer and 0.9 ml of glacial acetic acid and 60 mg of zinc-copper pair (prepared from 20 g) are added successively. zinc powder and 3 g CuSO 2, H 2 O). The resulting reaction mixture was heated at 55-56 ° C for 1.5 hours. After completion of the reaction, the reaction mixture was cooled to a temperature in the region of 20 ° C and filtered. The solid product is washed three times with 0.6 ml of 96% ethanol. To the resulting clear solution was added 70 mg of 33% hydrochloric acid, after which it was allowed to react at 20 ° C for hours. After completion of the reaction, the reaction mixture is diluted with 60 ml of ethyl acetate. The organic phase is washed twice with 5 ml of a saturated aqueous solution of sodium hydrogen carbonate, then four times with 5 ml of a saturated aqueous solution of the phase and then evaporated and evaporated to mg) with 1 ml of water and once with sodium chloride. Organic sodium sulfate. After filtration of the pressure, the obtained residue (23 on a thin layer was used a mixture (2 passages)).

dried over anhydrous dryness with reduced preparative silica chromatography, eluting with methanol / methylene chloride (5:95 by volume) to give 13.8 mg of taxicl% of its epimer C2 &apos; in 73% yield.

polluted

The infrared spectrum and the proton nuclear magnetic resonance spectrum as well as the ¹³ C spectrum of the taxel obtained are identical to those of the natural taxol described in the literature.

Claims (8)

PATENT CLAIMS A process for the preparation of novel beta-phenyllin derivatives of general formula I (I) wherein: R is ter. either a alkoxy group or a phenyl group; and Ar represents an aryl group selected from the group consisting of phenyl, alpha-naphthyl and beta-naphthyl, which groups may be optionally substituted by one or more atoms or groups which are the same or different and are selected from halogen atoms and alkyl groups, alkenyl groups, alkynyl groups, alkyloxy groups, alkylthio groups, hydroxyl groups, mercapto groups, amino groups, monoalkylamino groups, dialkylamino groups, acylamino groups, and 1-alkoxycarbonylamino groups, carboxyl groups, N-groups, carbamoyl groups, carbamoyl groups, carbamoyl groups, carbamoyl groups, nitro groups and three fluoromethyl groups, optionally in the form of a salt or an ester, characterized in that 2,2,2-trichloroethoxymethyl halide is reacted with a compound of the general formula V (V) in which Z represents a functional ester group (-COOR2) or a double vinyl bond (-CH = CH 2), pot Alternatively, the product thus obtained may be de-oxidized or oxidized and the beta-phenylene derivative derivative may be isolated and optionally separated into its enantiomers. Process according to claim 1, characterized in that the reaction of 2,2,2-tri chloroethoxymethyl halide is carried out in an organic solvent, for example acetonitrile, in the presence of a proton acceptor at a temperature ranging from 0 to 50 ° C. 3. The method of claim 2, wherein the proton acceptor is 1,8-bis (dimethylamino) naphthalene. The process according to claim 2, further operating in the presence indicated 2-butene-mety1-2. because of 5. The method of claim 1, STAMP e n ý t ý m that when Z is functional ester group (- = COOR) the saponification is carried out using a mineral base in an aqueous-alcoholic medium. The process according to claim 1, characterized in that when Z represents a double vinyl bond (-CH = CH 2), the oxidation is carried out with sodium periodate in the presence of a catalytic amount of a ruthenium derivative or with potassium permanganate. 7. A process according to claim 1, wherein the beta-phenylcaroline derivative is resolved into its enantiomers by forming a salt with an optically active base, followed by hydrolysis of the salt thus obtained. it 8. The novel beta-phenyl derivatives of the formula I it (I) R-CONH _Λ jj? T > Ατ ^ γΎοΟΗ ž wherein R and Ar are as defined in claim 1, in the form of racemic or enantiomerically pure or in the form of mixtures thereof, as well as their salts and their esters. Use of the product obtained by the process according to claim 1 for the preparation of formula II biologically active derivatives of t and x and n in general R _r ° 0 OH R-CO-NH S ----- < of 0 \ _f • \ y x y (II) ÔH Aŕ x / H of ^the HO 5 OCOCHg oococ _s h ₅ in which R and Ar are as defined in claim 1 and represents a hydrogen atom or an acetyl group, characterized in that the ester is a taxane derivative of the general formula IV (IV) in which: R 1 'represents an acetyl group or a hydroxyl protecting group; G = represents a hydroxyl protecting group such as 2,2,2-trichloroethoxycarbonyl or trialkylsilyl in which each alkyl moiety contains 1 to 4 carbon atoms, using the product obtained according to the method of claim 1, to which the protecting groups are replaced which represent R 1 and G =, and the 2,2,2-trichloroethoxymethyl group with a hydrogen atom and optionally cleaving the product obtained to isolate the enantiomer of 2R, 3S. Use according to claim 9, characterized in that the esterification is carried out in the presence of a condensing agent such as N, N-dicyclohexylcarbonyl or 2-di-pyridyl carbonate and an activating agent such as 4-N, N dimethylaminopyridine, at a temperature in the range of 20 to 80 ° C. Use according to claim 9, characterized in that the replacement of the protecting groups is carried out with zinc or a zinc-copper pair in acetic acid, optionally in the presence of an alcohol containing 1 to 3 carbon atoms or