EP0599973A1 - Process for the preparation of beta-phenylisoserine derivatives and use thereof - Google Patents

Abstract

Process for preparing novel beta-phenylisoserine derivatives of general formula (I) and their use for preparing biologically active taxane derivatives.

Description

 PROCESS FOR THE PREPARATION OF DERIVATIVES OF β-PHENYLISOSERTNE AND T F.TTR TrTTT.TSATION

The present invention relates to a process for the preparation of new derivatives of β-phenylisoserine of general formula:

in which R represents a t-butoxy or phenyl radical and Ar represents an aryl radical chosen from phenyl or α- or β-naphthyl radicals optionally substituted by one or more atoms or radicals, identical or different, chosen from atoms '' halogen and the alkyl, alkenyl, alkynyl, alkyloxy, alkylthio, hydroxy, mercapto, amino, monoalkoylamino, dialcoylamino, acylamino, alkoxycarbonylamino, carboxy, carbamoyl, N, N-dialkoyluoremethyl, or cyanoometro-racemic, cyanoometric, or nitrofluorochemical radicals pure or in the form of their mixtures, optionally in the form of a salt or an ester.

The products of general formula (I) are particularly useful for preparing the taxane derivatives of general formula:

in which R and Ar are defined as above and Rj represents a hydrogen atom or an acetyl radical, which have remarkable antileukemic and antitumor properties. According to American patents US 4,924,011 and US 4,924,012, it is known to prepare the taxane derivatives of formula (II), in which Ar represents a phenyl radical by condensation of a β-phenylisoserine derivative of general formula : in which R is defined as above and G represents a protecting group for the hydroxy function, which is in particular the 1-ethoxy-ethyl radical, on a derivative of baccatin read or of 10-deacetyl baccatin read of general formula:

in which R'i represents an acetyl radical or a protective group for the hydroxy function and G2 represents a protective group for the hydroxy function, followed by the replacement of the protective groups, which are preferably chosen from 2,2,2-trichloro radicals ethoxycarbonyl and trialkylsilyl, each alkyl part of which contains 1 to 4 carbon atoms, through hydrogen atoms.

However, the product of general formula (lu), in particular when G represents a 1-ethoxy-ethyl radical, is not very stable, which requires special precautions for its synthesis and storage.

It should be considered that the use of a product of general formula (E1) which is not fully protected may cause considerable reductions during its condensation with the 10-deacetyl-10 baccatin derivative of general formula (IV). yield.

Furthermore, the use as a protective group of the 1-ethoxy ethyl radical introduces, on the one hand, a methyl radical which can have a steric influence on re-esterification and, on the other hand, an unsolved asymmetric carbon atom which results in the presence of two stereoisomers making the purification processes difficult.

It has now been found that the 2,2,2-trichloroethoxymethyl protective group of the product of general formula (I) has the following advantages: it is very stable under the usual conditions of basicity and acidity, - it does not have an asymmetric carbon atom causing stereoisomerism problems or grouping inducing steric effects,

- it is easily introduced in mild, non-epimerizing conditions,

- It is easily eliminated under the conditions which allow the replacement of the 2,2,2-trichloro-ethoxycarbonyl protecting groups of the taxane ring with hydrogen atoms.

The present invention therefore relates to the preparation of the new product of general formula (I) optionally in the form of a salt or ester and its use for preparing the taxane derivatives of general formula (II). According to the invention, the product of general formula (I) can be obtained by the action of a halide, preferably bromide, of 2,2,2-trichloroethoxymethyl on a product of general formula which can be in racemic form or enaπtiomerically pure or in the form of their mixtures:

in which Z represents an ester function (-COOR2) or a vinyl double bond (-CH = CH2), followed depending on the case of saponification or oxidation of the product obtained.

Generally, the action of 2,2,2-trichloroethoxymethyl halide on the product of general formula (V) is carried out by operating in an anhydrous organic solvent such as acetonitrile at a temperature between 0 and 50 °. C, and preferably around 20 ° C. It is particularly advantageous to operate in the presence of a proton acceptor such as 1,8-bis- (dimethylamino) naphthalene (or "proton sponge"), 2-methyl-butene-2 and a desiccant such as 3  or  molecular sieve. When Z represents an ester-COOR2 function, R2 being an alkyl radical containing 1 to 4 carbon atoms optionally substituted by a phenyl radical, the product obtained is saponified to the acid of general formula (I).

Generally the saponification is carried out using a mineral base under conditions which do not affect the rest of the molecule. The saponification can be carried out by means of an alkaline carbonate such as potassium carbonate in a hydroalcoholic medium such as a water-methanol mixture. When Z represents a vinyl bond -CH = CH2, the product obtained is oxidized to the acid of general formula (I).

Generally the oxidation is carried out using a periodate such as sodium periodate in the presence of a catalytic amount of a ruthenium salt such as ruthenium chloride RUCI3. The reaction is carried out in a homogeneous or heterogeneous hydroorganic medium. As solvent can be used acé¬ tonitrile and carbon tetrachloride. The reaction can be carried out in a basic medium, for example in the presence of sodium hydrogencarbonate.

The oxidation can also be carried out by means of potassium permanganate, for example in the presence of adogen in a pentane-water mixture or in the presence of aliquat or of dicyclohexyl-18 crown-6 in dichloromethane or in a mixture pyridine-water.

Can also be used triethylbenzylammonium permanganate in the presence of pyridine in dichloromethane. The product of general formula (V) in which Z represents an ester function (-COOR2) can be prepared according to known methods.

The product of general formula (V) in which Z represents a vinyl double bond (-CH = CH2)) can be obtained:

- by the action of acrolein on a benzylamine derivative of general formula:

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

The double anionization of the product of general formula (VI) is generally carried out using 2 equivalents of an organolithium derivative such as s-butyllithium, operating in an anhydrous organic solvent such as tetrahydrofuran at a lower temperature. at -50 ° C.

The reaction of acrolein with the dianion of the product of formula (VI) is generally carried out by adding acrolein, preferably freshly distilled to the solution of the dianion previously cooled to a temperature between -50 to -100 ° C, preferably around -100 ° C. After hydrolysis, the product of formula (V) is obtained in the form of a mixture of syn and anti diastereoisomers from which the syn form is optionally separated by chromatography,

- by the action of a vinyl magnesium halide on the aldehyde obtained by oxidation of an alcohol of general formula: NHCO-R

(VII)

Ar ^' S "CH ₉ OH in which R and Ar are defined as above, which is itself obtained by treating with a reducing agent and with a reagent making it possible to introduce a t-butoxycarbonyl or benzoyl group, an amino acid of general formula : H ₂

Ar ^ COOH (VIII) in which Ar is defined as above.

Generally, the alcohol of general formula (V) is obtained by adding the aldehyde to a solution of a vinyl magnesium halide, preferably vinyl magnesium bromide, in an inert organic solvent such as tetrahydrofuran, possibly in a mixture. with methylene chloride.

Generally, the oxidation of the alcohol of formula (VII) is carried out by means of the oxalyl chloride-dimethyl sulfoxide mixture 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.

It is not necessary to isolate the aldehyde to react the vinyl magnesium halide.

The alcohol of formula (VII) can be obtained:

either by the action of an agent allowing the introduction of a tbutoxycarbonyl or benzoyl group on the amino alcohol obtained by reduction of the amino acid of general formula (VIE),

- Either by the action of a reducing agent on the acid obtained by the action of an agent which allows both to introduce a t-butoxycarbonyl or benzoyl group on the amino acid of general formula (VIII). As reducing agent, lithium aluminum hydride or borane (BH3) is preferably used, preferably in the form of a complex with dimethylsulfide in the presence of boron trifluoride etherate. Generally the reaction is carried out in an organic solvent such as for example an ether such as tetrahydrofuran or dimethoxvethane. Generally the reduction is carried out at a temperature between 50 and 100 ° C. As agent for introducing a t-butoxycarbonyl or benzoyl group, use is preferably made, depending on the case, of di-t-butyl dicarbonate or benzoyl chloride. Generally one operates 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 or bicarbonate or sodium car¬ bonate or a base organic such as triethylamine or 4-dimethylamino pyridine. Generally the reaction is carried out between 0 ^β C and the reflux temperature of the reaction mixture.

The acid of general formula (I), optionally in the form of a salt or an ester, obtained according to the process of the present invention can be purified by physical methods such as crystallization or chromatography. The product of general formula (I) (syn or syn-anti form, racemic mixture) can also be split into its syn enantiomers, for example by formation of a salt with an optically active base such as ephedrine or pseudo- ephedrine then hydrolysis of the salt obtained.

The acid of general formula (I) is useful, in particular, for preparing the taxane derivatives of general formula (II).

The products of general formula (II) are obtained by esterification of the alcohol of general formula (IV), followed by the replacement of the protecting groups for the hydroxy functions by hydrogen atoms and optionally by the separation of the 2R.3S enantiomers .

Generally the esterification is carried out in an aromatic hydrocarbon

(benzene, toluene, xylene) at a temperature between 20 and 80 ° C in the presence of a condensing agent such as dicyclohexylcarbodiimide or 2-dipyridylcarbonate and an activating agent such as 4-dimethylamino pyridine.

Generally an excess of acid of general formula (I) is used relative to the alcohol of general formula (TV).

The replacement by hydrogen atoms of the protective groups R ′ _j , G _j and G2, when they represent a 2,2-trichloro-2,2,2 ethoxycarbonyl or 2,2-trichloro-2,2,2 ethoxymethyl radical is generally carried out by means of zinc or a zinc-copper couple in the presence of acetic acid and optionally an alcohol containing 1 to 3 carbon atoms at a temperature in the region of 60 ^β C. In the case where G2 is a trialkylsilyl radical each part of which contains 1 to 4 carbon atoms, the replacement of this radical by a hydrogen atom is carried out by an acidic subsequent treatment (for example hydroalcoholic HC1). The following examples illustrate the present invention. EXAMPLE 1

100 mg (0.339 mmol) of methyl t-butoxycarbonylamino-3-hydroxy-2-phenyl-3-phenyl-propionate- (2R, 3S) are introduced into a 10 cm 3 flask fitted with magnetic stirring under an argon atmosphere. 1.2 cm3 of anhydrous acetonitrile. Next, 214.3 mg (1 mmol) of "proton sponge", 718 μl (475.5 mg; 6.78 mmol) of 2-methyl-2-butene and 5 grains of 4 A molecular sieve are successively added. The mixture is stirred for 10 minutes at a temperature in the region of 20 ° C. and then 164.3 mg (0.678 mmol) of 2,2,2-trichloroethoxymethyl bromide are added. It is left to react for 24 hours at a temperature in the region of 20 ^β C. The mixture becomes heterogeneous as the reaction progresses. Another 214.3 mg (1 mmol) of "proton sponge" and 164.3 mg (0.678 mmol) of 2,2,2-ethoxymethyl bromide are successively added. It is left to react for 24 hours at a temperature in the region of 20 ° C. 3 cm 3 of a saturated aqueous sodium bicarbonate solution are then added. After 10 minutes of stirring, 40 cm3 of methylene chloride and 5 cm3 of water are then added. After decantation, the aqueous phase is washed twice with 10 cm 3 of methylene chloride. The combined organic phases are washed with 2 times 5 cm 3 of a 2M aqueous hydrochloric acid solution, 4 times with 5 cm 3 of water and 2 times with 5 cm 3 of a saturated aqueous solution of sodium chloride. After drying over anhydrous sodium sulfate, filtration and concentration to dryness under reduced pressure, 290 mg of product is obtained which is purified by chromatography on silica eluting with a hexane-ether mixture (8-2 by volume). There is thus obtained, with a yield of 86.133 mg (0.291 mmol) of t-butoxycarbonylamino-3-phenyl-3 (2,2,2-trichloroethoxymethoxy) -2 methyl propionate- (2R, 3S), the characteristics of which are the following :

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

- rotary power: [α] 25d) "+ 41.8 ° (c = 1.33; chloroform)

- infrared spectrum (film): main absorption bands characteristic at 3450, 3000, 2925, 1760. 1720, 1500, 1460, 1440, 1370, 1175, 1130, 1090, 1020, 950 and

810 cm " ¹

- proton nuclear magnetic resonance spectrum (deuterated chloroform; 200 MHz): 1.41 (s, 9H); 3.42 (AB _q , JAB = 11.5 Hz, δ _A -δ _B = 91.3 Hz, 2H); 3.80 (s,

3H); 4.54 (s distorted, 1H); 4.79 (AB _q , JAB = 7.3 Hz, Ô _A -δ _B = 26 Hz, 2H); 5.36 (br s, 1H); 5.46 (br s, 1H); 7.23-7.41 (m, 5H). - ^ C nuclear magnetic resonance spectrum (deuterated chloroform, 75.47 MHz): 28.25 (CH ₃ ); 52.47 (OCH ₃ ); 55.89 (CH); 77.44 (CH); 79.40

(CH ₂ ); 80.02 (C); 94.75 (CH2); 96.21 (C); 126.43 (CH); 127.82 (CH); 128.63

(CH); 139.01 (C); 155.04 (C); 169.98 (C) - mass spectrum (ic; NH3 + isobutane: molecular ion (solid): M ⁺ (456.5);

M ++ 2 (458.5); M ⁺⁺ 4 (460.5); M ⁺⁺ 6 (462.5): 4 peaks in the ratio 100-97.5-

31.7 and 3.4

- elementary analysis (C18H24O6NCI3) calculated C% 47.33 H% 5.30 N% 3.07 found 47.45 5.15 3.19

EMPLE 2

196 mg (0.43 mmol) of the ester obtained in Example 1 and 24 cm3 of methanol are introduced into a 100 cm3 flask fitted with magnetic stirring. Then added to the solution obtained, 12 cm3 of distilled water and 178 mg (1.29 mmol) of potassium carbonate. The mixture is stirred for 24 hours at a temperature in the region of 20 ° C. and then the methanol and water are evaporated off under reduced pressure. The residue obtained is dissolved in the minimum amount of water (12 cm3) with slight heating. The basic aqueous phase is washed 3 times with 10 cm3 of ether. The aqueous phase is cooled to 0 ^β C and then is acidified with 4 cm3 of 2M hydrochloric acid, with vigorous stirring, in the presence of 30 cm3 of methylene chloride. After decantation, it is then extracted 8 times with 20-25 cm3 of methylene chloride. The combined organic phases are washed 4 times with 10 cm3 of water and then with 10 cm3 of a saturated aqueous solution of sodium chloride. After drying over anhydrous magnesium sulphate, filtration and concentration to dryness under reduced pressure, a yield of 89.170 mg (0.384 mmol) of t-butoxycarbonylamino-3-phenyl-3 (2,2-trichloro-2,2) acid is obtained. 2 ethoxymethoxy) -2 propionic- (2R, 3S) pure in the form of a white solid with the following characteristics:

- rotary power: [α] 20d) = + 62.2 ° (c = 1, chloroform)

- infrared spectrum (film): main absorption bands characteristic at 3500-2300, 3000, 2940, 1760, 1730, 1500, 1460, 1400, 1375, 1260, 1180, 1135, 1090.

1020 and 810 cm " ¹

- proton nuclear magnetic resonance spectrum (deuterated chloroform; 200 MHz): 1.43 (s, 9H); 2.73 (broad s, 1H + H ₂ O); 3.44 (AB _q , JAB = 11.7 Hz, δ _A -δβ = 91 Hz, 2H); 4.60 (s, 1H); 4.83 (AB _q , JB = 7.3 Hz, Ô _A -δB = 30 Hz, 2H); 5.43 (distorted d, J ≈ 9.5 Hz, 1H); 5.59 (distorted d, J = 9 Hz, 1H); 7.29-7.38 (m, 5H)

- nuclear magnetic resonance spectrum of ^ C (deuterated chloroform 75.47 MHz): 28.25 (CH ₃ ); 55.78 (CH); 57.88 (CH); 79.43 (CH ^; 80.84 (C) 94.81 (CH ₂ ); 96.22 (C); 126.39 (CH); 127.89 (CH); 128.66 (CH); 138.92 (VS)

155.69 (C) and 171.91 (C)

- mass spectrum (ic; NH3 + isobutane): molecular ion (solid): M ⁺ (442.5);

M ++ 2 (444.5); M ++ 4 (446.5); M ++ 6 (448.5): 4 peaks with the ratio 100; 97.5; 31.7 and 3.4 - elementary analysis: (C17H22O6NCI3, IH2O) calculated C% 44.32 H% 5.25 N% 3.04 found 44.49 5.26 3.06

EXAMPLE 3

263 mg (1 mmol) of (±) phenyl-1 t-butoxycarbonylamino- 1 hydroxy-2-butene-3 syn and 3 are introduced into a 15 cm 3 flask fitted with magnetic stirring, under an argon atmosphere. , 6 cm3 of anhydrous acetonitrile. Then added successively to the resulting solution, 2.12 cm3 (1.4 g; 20 mmol) of methyl 2-butene-2, 10 molecular sieve 4Å grains and 643 mg (3 mmol) of ⁿ sponge to protons ". The mixture is stirred for 5 minutes at a temperature in the region of 20 ° C. and then 485 mg (2 mmoles) of 2,2,2-trichloroethoxymethyl bromide is added. C, then 643 mg (3 mmol) of "proton sponge" and 485 mg (2 mmol) of 2,2,2-trichloroethoxymethyl bromide are added. After 24 hours of reaction, another 242.4 mg ( 1 mmol) of 2,2,2-trichloroethoxymethyl bromide and then stirred again for 24 hours at a temperature in the region of 20 ° C. A saturated aqueous solution of sodium bicarbonate is then added and stirred for 10 minutes. 100 cm3 of methylene chloride and 5 cm3 of water After decantation, the aqueous phase is extracted twice with 20 cm3 of methylene chloride. The combined organics are washed twice with 10 cm 3 of a 2M aqueous hydrochloric acid solution, 4 times with 10 cm 3 of water, 2 times with 10 cm 3 of a saturated aqueous solution of sodium chloride, then dried over sulphate. anhydrous sodium. After filtration and concentration to dryness under reduced pressure, 868 mg of a product is obtained which is purified by chromatography on silica eluting with a hexane-ether mixture (9-1 by volume). There is thus obtained, with a yield of 70%, 298 mg (0.70 mmol) of (±) phenyl-1 t-butoxycarbonylamino-1 (2,2,2-trichloroethoxymethoxy) -2 butene-3 syn, the characteristics of which are as follows:

- melting point: 75 ^β C (hexane)

- infrared spectrum (film): characteristic absorption bands at 3460, 3380, 3080, 3050, 3020, 3000, 2950, 2910, 1720. 1500. 1400, 1370, 1290, 1255, 1170, 1130.

1080, 1020, 940 and 810 cm " ¹

• proton nuclear magnetic resonance spectrum (deuterated chloroform; 200 MHz): 1.43 (s, 9H); 3.42 (AB _q , JAB = H. 8 Hz, δ _A -δβ - 74 Hz, 2H); 4.37 (dd distorted, J = 2.5 Hz and 7 Hz, 1 H); 4.74 (AB _q , JAB ≈ 7 Hz, δ _A -δβ = ¹⁷ - ⁷ H ² ' ^2H >: 4.86 (broad s, 1 H); 5.35 (d. J _* 11 Hz. 1 H); 5.36 (d, J = 17 Hz, IH); 5.32-5.41 (m, IH); 5.83 (ddd, J = 7 Hz. 11 Hz and 17 Hz. IH); 7.26 -7.40 (m, 5H)

- 1 ^ C nuclear magnetic resonance spectrum (deuterated chloroform; 75.47 MHz): 28.34 (CH ₃ ); 57.64 (CH); 79.16 (CH ₂ ); 79.68 (C); 79.98 (CH); 92.76 (CH ₂ ); 96.60 (C); 119.67 (CH ₂ ); 126.65 (CH); 127.43 (CH); 128.40 (CH); 134.25 (CH); 140.31 (C) and 155.48 (C)

- mass spectrum (ic; NH3 + isobutane): molecular ion (solid): M ⁺ (424.5);

M ⁺⁺ 2 (426.5); M ⁺⁺ 4 (428.5); M ⁺⁺ 6 (430.5): 4 peaks with ratio 100; 97.5; 31.7 and 3.4

- elementary analysis: (C18H24O4NCI3) calculated C% 50.90 H% 5.69 N 3.30 found 50.81 5.80 3.29

(±) -phenyl-l t-butylcarbonylamu o-1 hydroxy-2 butene-3 syn is obtained pure from t-butyl benzylcarbamate according to the procedure described in French patent application FR 2 662440.

245 mg (0.577 mmol) of the product obtained above dissolved in 1.2 cm3 of acetonitrile are introduced into a 10 cm3 flask fitted with magnetic stirring, under an argon atmosphere. 1.2 cm3 of carbon tetrachloride, 1.8 cm3 of distilled water and, with vigorous stirring, 315 mg (3.75 mmol) of solid sodium bicarbonate are successively added. Then added, in small portions, 680 mg (3.18 mmol) of sodium periodate. The heterogeneous reaction mixture is left to react until gas evolution ceases, then 24.5 mg of RUCI3 is added. The reaction medium is left to react with vigorous stirring for 29 hours at a temperature in the region of 20 ° C., then the reaction mixture is diluted with water until a total volume of 20 cm 3 is obtained. The basic aqueous phase is washed 3 times with 10 cm3 ether and then cooled to 0 ° C. In the presence of 40 cm3 of methylene chloride, 2 cm3 of 2M hydrochloric acid are added, with vigorous stirring. The aqueous phase is extracted 8 times with 40 cm3 of methylene chloride. The organic phases are combined and washed 3 times with 10 cm 3 of water then with 10 cm 3 of a saturated aqueous solution of sodium chloride and finally dried over a sodium sulfate-anhydrous magnesium sulfate mixture. After filtration under reduced pressure on celite and concentration to dryness, a yield of 80.204 mg (0.461 mmol) of (±) t-butoxycarbonylamino-3-phenyl-3 (2,2,2-trichloroethoxymethoxy) acid is obtained. ) -2 propionic.

EXAMPLE 4

215 mg (0.48 mmol) of (±) -t-butoxycarbonylamino-3-phenyl-3 (2,2,2-trichloro-2,2,2 ethoxymethoxy) -2 propionic acid (syn) are introduced into a 10 cm 3 flask under the conditions of Example 3) and 1.2 cm3 of acetone. The solution obtained is slightly heated until a perfect homogeneous solution is obtained, then a solution of 85 mg (0.51 mmol) of (+) - ephedrine in 1.2 cm3 of acetone is added. The reaction mixture is stirred until a homogeneous solution is obtained, then it is left to crystallize while cooling to a temperature in the region of 20 ° C. The white crystals obtained are separated by filtration and washed 2 times with ether. 130 mg of ephedrine salt of tbutoxycarbonylamino-3-phenyl-3 (2,2-trichloro-2,2,2 ethoxymethoxy) -2 propionic acid (2R, 3S) are thus obtained.

The crystals thus obtained are dissolved hot in 2 cm3 of methanol. 0.5 cm3 of ethyl acetate are added and then the mixture is cooled to a temperature in the region of 20 ° C. The white crystals formed are separated by filtration and then treated with aqueous IN hydrochloric acid in dichloromethane at a temperature in the region of 20 ° C. After extraction according to the usual methods, 64 mg (0.1446 mol) of (+) - tbutoxycarbonylamino-3-phenyl-3 (2,2,2-trichloro-2,2,2-ethoxymethoxy) acid is obtained in a yield of 30.1% -2 propionic- (2R.3S) for which the enantiomeric excess is greater than 99% (determination from the Mosher esters of the racemic and optically pure alcohol-esters corresponding) and whose infrared and of the nuclear magnetic resonance of the proton are identical to those of the product of Example 2.

The mother liquors obtained during the first crystallization are concentrated to dryness. The residue is dissolved hot in 2.5 cm3 of methanol. 0.5 cm3 of ethyl acetate are added. After cooling to 20 ° C., 78 mg of white crystals are obtained, after separation by filtration, which are mixed with the residue obtained by dry concentration of the crystallization mother liquors of (+) - tbutoxycarbonylamino-3-phenyl-3 (2,2,2-trichloroethoxymethoxy) -2 propionic- (2R.3S). After recrystallization of the mixture from a methanol-ethyl acetate mixture, 33.5 mg of white crystals are obtained which are treated with 1N aqueous hydrochloric acid in dichloromethane at 20 ° C. After extraction under the usual conditions, 24.5 mg (0.055 mmol) of (+) - tbutoxycarbonylamino-3-phenyl-3 (2,2,2-trichloro-2,2,2 ethoxymethoxy) -2 propionic acid (2R.3S) are obtained. which the enantiomeric excess is greater than 99%.

In total, we obtain 88.5 mg of acid (+) - t.butoxycarbonylamino-3-phenyl-3 (2,2,2-trichloroethoxymethoxy) -2 propionic- (2R.3S) whose rotary power is: [ α] ²⁰ o = + 60 ° (c ≈ 0.92; chloroform).

The resolution yield is 83.

EXAMPLE !?

202 mg (0.77 mmol) of (±) -tbutoxycarbonylamino-1 phenyl-1-hydroxy-2-butene-3, for which 15 cm3 flask, fitted with magnetic stirring, is introduced under an argon atmosphere. the syn / anti ratio is equal to 6/1 and 2.8 cm3 of anhydrous acetonitrile. To the solution obtained, 1.63 cm3 (1.08 g; 15.4 mmol) of 2-methyl-2-butene are added successively, 8 grains of molecular sieve 4A and 494 mg (2.3 mmol) of ^{, π} sponge to protons ". Stir for 5 minutes at a temperature in the region of 20 ° C., then add 381 mg (1.57 mmol) of 2,2,2-trichloroethoxymethyl bromide. Stir for 24 hours at a temperature of around at 20 ° C and then 494 mg (2.3 mmol) of proton sponge "and 381 mg (1.57 mmol) of 2,2-ethoxymethyl trichloro bromide are added. After 24 hours of stirring, 190 mg (0.785 mmol) of 2,2,2-trichloroethoxymethyl bromide are added again, followed by stirring for 24 hours at 20 ° C. and then for 20 hours at 25-30 ° C. .

The reaction mixture is treated with a saturated solution of sodium hydrogen carbonate for 10 minutes. 80 cm3 of dichloromethane and 4 cm3 of water are then added to the resulting mixture. After decantation, the aqueous phase is extracted twice with 15 cm3 of dichloromethane. The combined organic phases are washed twice with 8 cm 3 of a 2M aqueous hydrochloric acid solution, 4 times with 8 cm 3 of water and 2 times with 8 cm 3 of a saturated solution of sodium chloride. After drying over anhydrous sodium sulfate, filtration and concentration to dryness, 674 mg of a yellow oil are obtained which is purified by chromatography on a column of silica gel, eluting with a hexane-ether mixture (9-1 by volume) . There is thus obtained, with a yield of 62%, 202 mg (0.476 mmol) of (±) - tbutoxycarbonylamino-1 phenyl-1 (2,2,2-trichloroethoxymethoxy) -2 butene- 3 for which the syn / anti ratio is equal to 6/1.

(±) -t.butoxycarbonylarnino-1 phenyl-1 hydroxy-2 butene-3 in the form of the mixture of syn and anti diastereoisomers in the ratio 6/1 can be prepared as follows:

4.2 g (20.3 mmol) of t.butyl benzylcarbamate, 40 cm3 of anhydrous tetrahydrofuran and 6.5 cm3 are successively introduced into a 250 cm3 flask placed under argon and fitted with a magnetic stirring system. (5.01 g, 43.1 mmol) of tetramethylethylenediamine (TMEDA). The solution obtained is cooled to -78 ^β C and then added thereto, drop by drop, 60 cm3 (60 mmol) of a 1M solution of secondary butyllithium in hexane. It is left to react for 3 hours at this temperature and then cooled to -100 ° C. 3 cm3 is then added (2.5 g, 44.9 mmol) of freshly distilled acrolein was allowed to react for 3 to 4 minutes at this temperature then for 3 hours at -78 ^β C. The resulting reaction mixture is hydrolyzed to -78 ^β C with 20 cm3 of water, then it is extracted with 2 times 30 cm3 of ether. The organic phases are combined and then they are washed twice with 20 cm3 of water and once with 10 cm3 of a saturated aqueous solution of sodium chloride. They are then dried over anhydrous sodium sulfate. After filtration, the solvents are removed under reduced pressure. The residue obtained (11.6 g) is purified on a column of silica gel, eluting with a methylene chloride-ether mixture (95-5 by volume). 2.606 g (9.91 mmol) of t.butoxycarbonylamino-1 phenyl-1 hydroxy-2 butene-3 are obtained with a yield of 49%, in the form of the mixture of syn and anti diastereoisomers in the ratio 6/1.

EXAMPLE 6

102 mg (0.24 mmol) of (±) -t.butoxycarbonylamino-l phenyl-1 (trichloro-2,2,2 ethoxymethoxy) are introduced into a 10 cm 3 flask fitted with a magnetic stirring system. 2 butene-3, in the form of the mixture of syn and anti diastereoisomers in the ratio 6/1, in solution in 0.5 cm3 of acetonitrile. Then added successively 0.5 cm3 of carbon tetrachloride, 0.75 cm3 of distilled water and, with vigorous stirring, 132 mg (1.57 mmol) of sodium hydrogen carbonate. Then 282 mg (1.32 mmol) of solid sodium periodate is added in small portions. It is left to react for 5 minutes until gas evolution ceases and then 10.2 mg of RUCI3 are added all at once. The reaction mixture which has turned black is stirred vigorously for 50 hours at a temperature in the region of 20 ° C. We add to again 5 mg of RUCI3 then continue stirring for 40 hours at a temperature in the region of 20 ° C. When the reaction is complete, 6 cm 3 of water are added. The basic aqueous phase is separated by decantation and is then washed 3 times with 4 cm3 of ether. The aqueous phase is cooled to 0 ° C. and then 17 cm3 of dichloromethane and 0.8 cm3 of 2M hydrochloric acid are added with vigorous stirring. The acidic aqueous phase is separated by decantation and is then extracted 8 times with 17 cm3 of dichloromethane. The organic phases are combined and then washed 4 times with 4 cm3 of water and 2 times with 4 cm3 of an aqueous solution saturated with sodium chloride. After drying over anhydrous sodium sulphate, filtration and concentration to dryness under reduced pressure, 75 mg (0.17 mmol) of (±) -tbutoxycarbonylamino-3-phenyl-3 (2,2,2-trichloroethoxymethoxy) acid are obtained. -2 propionic in the form of the mixture of syn and anti diastereoisomers in the 6/1 ratio.

The yield is 71%.

EXAMPLE 7 701 mg (1.584 mmol) of the product obtained in Example 6 is dissolved in 4 cm3 of acetone in a 25 cm3 flask. It is slightly heated until a homogeneous solution is obtained. A solution of 277 mg (1.69 mmol) of (+) - ephedrine in 4 cm3 of acetone is then added. Stir until a homogeneous solution is obtained. After cooling to a temperature in the region of 20 ° C., the crystals obtained are separated by filtration and washed twice with ether. After drying, 385 mg of ephedrine salt is obtained. The crystals thus obtained are dissolved in hot in a mixture of 6 cm3 of methanol and 2 cm3 of ethyl acetate. After evaporation of 10% of the solvent and cooling to a temperature of 20 ^C C, the crystals obtained are separated by filtration. 190 mg of ephedrine salt are thus obtained in the form of white crystals which are treated with IN hydrochloric acid in the presence of dichloromethane at a temperature in the region of 20 ° C. After extraction according to the usual methods, 138 mg (0.313 mmol) of (+) - t.butoxycarbonylamino-3-phenyl-3 (2,2,2-ethoxymethoxy) -2 propionic acid - (2R.3S) are obtained. ) for which the enantiomeric excess is greater than 99%.

The yield is 19.8%.

The mother liquors for recrystallizing the ephedrine salt from the methanol-ethyl acetate mixture are concentrated to dryness. The residue obtained is dissolved hot in a mixture of 3 cm3 of methanol and 1 cm3 of ethyl acetate. After evaporation of 10% of the solvent and cooling to a temperature in the region of 20 ° C. for 24 hours, 92 mg of white crystals are obtained, after filtration, which are treated with IN hydrochloric acid in the presence of dichloromethane. After extraction according to the usual methods, 65 mg (0.147 mmol) of (+) - t.butoxycarbonylamino-3-phenyl-3 (2,2,2-ethichymethoxy) -2 propionic acid (2R, 3S) are obtained. which the enantiomeric excess is greater than 99%. The yield is 9.3%.

The treatment of the mother liquors of crystallization of the second jet of the ephedrine salt under the conditions described above (dry concentration, recrystallization from a methanol-ethyl acetate mixture, acid hydrolysis) makes it possible to obtain 31, 4 mg of (+) - t.butoxycarbonylamino-3 phenyl-3 (2,2,2-trichloroethoxymethoxy) -2 propionic acid (2R, 3S) for which the enantiomeric excess is greater than 99%. The yield is 4.5%.

The overall yield of (+) - tbutoxycarbonylamino-3-phenyl-3 (2,2,2-trichloroethoxymethoxy) -2 propionic acid (2R, 3S) is 33%. The resolution yield is close to 76%.

EXAMPLE S

119.5 mg (0.27 mmol) of the acid obtained in Example 2 dissolved in 2.25 cm3 are introduced into a 10 cm3 flask fitted with magnetic stirring, under an argon atmosphere. anhydrous toluene. 55.7 mg (0.27 mmol) of N, N-dicyclohexylcarbodiimide are then added. The mixture is left for 5 minutes and then a mixture of 11 mg (0.09 mmol) of N, N-dimethylamino-4 pyridine and 81 mg (0.09 mmol) of 4-acetoxy-2-benzoyloxy-2α-epoxy-5β is added, 20 dihydroxy-1,13σ oxo-9 bis- (2,2,2-trichloro ethoxy) carbonyloxy-7β, 10β taxene-11. It is left to react for 3-4 minutes at a temperature in the region of 20 ° C and then heated for 24 hours at a temperature of 72-75 ° C. The heterogeneous reaction mixture is taken up in 60 cm3 of ethyl acetate. The organic phase is washed with 5 cm 3 of water, 2 times 5 cm 3 of a saturated aqueous solution of sodium bicarbonate, 4 times 5 cm 3 of water and 2 times 5 cm 3 of a saturated aqueous solution of sodium chloride, then finally dried over anhydrous sodium sulfate. After filtration and concentration to dryness under reduced pressure, the residue obtained (270 mg) is purified by chromatography on a thin layer of silica, eluting with a methylene chloride-ether mixture (95-5 by volume; 2 passages).

There is thus obtained, with a yield of 94%, 112 mg (0.085 mmol) of t-butoxycarbonylamino-3-phenyl-3 (2,2,2-trichloroethoxymethoxy) -2 propionate- (2R.3S) of acetoxy-4 benzoyloxy-2α epoxy-5β, 20 hydroxy- 1 oxo-9 bis- (trichloro- 2,2,2 ethoxy) carbonyloxy-7β, 10β taxene-11 yle-13, the characteristics of which are as follows:

- infrared spectrum (film): characteristic absorption bands at 3450, 3000, 2950, 2910, 1760, 1720, 1500, 1455, 1440, 1380, 1250, 1175. 1090, 1070, 1020, 980, 910, 820 , 780 and 720 cm ^{* 1}

- proton nuclear magnetic resonance spectrum (deuterated chloroform; 300 MHz): 1.21 (s, 3H); 1.30 (s, 3H); 1.34 (s, 9H); 1.79-1.84 (m, 1H); 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, 1H); 3.53 (AB _q , JAB = H. 7 Hz. Δ _A -δβ = ¹⁰⁹ Hz. 2H); 3.95 (d, J = 7 Hz, 1 H); 4.27 (AB _q , JAB = 8.6 Hz, δ _A -δ _B = 45 Hz, 2H); 4.65 (br s, 1H); 4.75 (AB _q , JAB = 12 Hz, δ _A -ÔB = 90 Hz, 2H); 4.77 (pseudo t. J = 5 Hz, 2H); 4.95 (d, J = 55.6 Hz, 2H); 4.98 (d, J = 8.3 Hz. 1H); 5.44 (br s. 1H); 5.58 (dd, J = 7 Hz and 10.6 Hz, 1 H); 5.72 (d, J = 7 Hz, 1H); 6.26 (s. 1H); 6.31 (t distorted, J = 8.3 Hz and 9.2 Hz, 1 H); 7.31-7.64 (m. 8H); 8.05-8.13 (m. 2H). 80 mg (0.0606 mmol) of the product obtained above in solution in 3.2 cm3 of methanol are introduced into a 10 cm3 flask fitted with magnetic stirring, under an argon atmosphere. 3.2 cm3 of glacial acetic acid and 320 mg of the zinc-copper couple are successively added (prepared from 20 g of powdered zinc and 3 g of hydrated copper sulphate). The mixture is heated at 60 ° C for 30 minutes. After cooling, 50 cm 3 of ethyl acetate are added. The mixture is filtered through celite under reduced pressure. The solids are washed with 5 times 10 cm 3 of ethyl acetate. The combined organic phases are washed 3 times with 5 cm3 of water and 2 times with 5 cm3 of a saturated aqueous solution of sodium chloride and finally dried over anhydrous sodium sulfate. After filtration and concentration to dryness under reduced pressure, the residue obtained (50 mg) is purified by preparative chromatography on a thin layer of silica, eluting with a methylene chloride-methanol mixture (94-6 by volume; 2 passages).

There is thus obtained, with a yield of 78%, 38 mg (0.0471 mmol) of t-butoxycarbonylamino-3 phenyl-3-hydroxy-2-propionate- (2R, 3S) acetoxy-4-benzoyloxy-2α epoxy- 5β, 20 trihydroxy-l, 7β, 10β oxo-9 taxene-11 yle-13α, the characteristics of which, which are identical to those given in the literature, are as follows: - infrared spectrum (film): 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 - proton nuclear magnetic resonance spectrum (deuterated chloroform; 300 MHz): 1.13 (s, 3H); 1.24 (s, 3H); 1.34 (s, 9H); 1.76 (s, 3H); 1.85 (s, 3H); 1.74-1.85 (m, 1H); 2.26-2.29 (m, 2H); 2.37 (s, 3H); 234-2.66 (m, 1H); 3.32 (ps s, 1H); 3.92 (d, J = 7 Hz, 1H); 4.18-4.30 (m, 1H); 4.24 (AB, J ^ ≈ 8.25 Hz, δ _A -δβ = 36.5 Hz, 2H); 4.62 (ps s, 1H); 4.94 (d, J = 7.4 Hz, 1H); 5.20 (s, 1H); 5.25 (ps d, 1H); 5.42 (ps d, 1H); 5.68 (d, J ≈ 7 Hz, 1H); 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. 1H); 8.09-8.12 (m, 2H).

EXAMPLE?

200 mg (0.67 mmol) of methyl benzoylamino-3-hydroxy-3-phenyl-3-propionate- (2R,) are introduced into a 15 cm 3 monocol, provided with a magnetic stirring system. 3S) and 2.4 cm3 of acetonitrile. Then added to the resulting suspension, 431 mg (2.01 mmol) of "proton sponge", 1.42 cm3 (940 mg, 13.4 mmol) of 2-methyl-2-butene and 7 grains of sieve molecular 3 Â. The resulting reaction mixture is stirred for 5 minutes at a temperature in the region of 20 ° C. and then 325 mg (1.34 mmol) of 2,2,2-trichloroethoxymethyl bromide is added. It is left to react for 30 hours at a temperature in the region of 20 ° C. The reaction mixture is highly heterogeneous. Another 431 mg (2.01 mmol) of "proton sponge" and 585 mg (2.41 mmol) of 2,2,2-trichloroethoxymethyl bromide are successively added. After 24 hours of reaction at a temperature in the region of 20 ° C, the reaction not having been completed, 215.4 mg (1.05 mol) of "proton sponge" and 162.4 mg (0 , 67 mmol) of 2,2,2-trichloroethoxymethyl bromide. Allowed to react for another 42 hours at a temperature of 20 ^β C. After 96 hours of reaction in total, although the reaction is not yet complete, it is stopped. The reaction mixture is then treated with 5 cm 3 of a saturated aqueous solution of sodium bicarbonate for 10 minutes. Then added 100 cm3 of methylene chloride and 10 cm3 of water. After decantation, the aqueous phase is extracted twice with 15 cm3 of methylene chloride. The combined organic phases are washed with 2 times 5 cm 3 of an aqueous solution of 2N hydrochloric acid, 4 times with 10 cm 3 of water and 2 times with 10 cm 3 of a saturated aqueous solution of sodium chloride. After drying over anhydrous sodium sulfate, filtration and concentration to dryness under reduced pressure, 950 mg of crude product is obtained which is purified by chromatography on silica eluting a hexane-ether mixture (85-15 by volume). 222 mg (0.482 mmol) of 3-benzoylamino-phenyl-3 (2,2,2,2-ethoxy trichloro) are thus obtained, with a yield of 72%. methoxy) -2 methyl propionate- (2R3S) whose characteristics are as follows:

- melting point: 70-71 ^β C

- rotary power: [α] 25d _≈ + 7.2 ° (c = 1.16; chloroform) - infrared spectrum (film): main characteristic absorption bands at 3450, 3340, 3070, 3040, 2950, 2920 . 1750, 1660, 1602, 1580, 1518. 1485, 1435, 1355, 1315, 1290. 1270. 1210, 1170, 1125, 1080, 1018, 805 cm ' ¹

- proton nuclear magnetic resonance spectrum (deuterated chloroform; 300 MHz): 3.49 (AB _q . JAB = 11.3 Hz. δ _A -δ _B ≈ 126.5 Hz, 2H); 3.79 (s, 3H); 4.69 (d, J = 1.8Hz, 1H); 4.86 (AB _q , JAB = 7.1 Hz, δ _A -δ _B = 32.2 Hz, 2H); 5.81 (dd, J = 1.8

Hz and 9 Hz, 1H); 7.05 (d, J≈9 Hz, 1H); 7.26-7.56 (m, 8H); 7.80-7.83 (m, 2H).

- nuclear magnetic resonance spectrum of ^ C (75.41 Hz; deu¬ tered chloroform): 52.49 (CH ₃ ); 54.76 (CH); 77.19 (CH); 79.39 (CH ₂ ); 94.68 (CH ₂ ); 96.09

(VS) ; 126.43 (CH); 127.02 (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 (ic; NH3 + isobutane): molecular ion (solid): M ⁺ (460.5);

M + +2 (462.5); M ⁺ (464.5); M + + € (466.5): peaks in the ratio 100-97.5-31.7 and 3.4.

- elementary analysis (C20H20O5NCI3) calculated C% 52.14 H% 4.38 N% 3.04 found 52.11 4.49 3.04

EXAMPLE 10

107 mg (0.232 mmol) of the ester obtained in Example 9 and 14 cm3 of methanol are introduced into a 50 cm3 flask fitted with a magnetic stirring system. 7 cm 3 of distilled water and 98 mg (0.71 mmol) of potassium carbonate are then added to the solution obtained. The mixture is stirred for 20 hours at a temperature in the region of 20 ° C. and then the methanol and water are evaporated off under reduced pressure. The residue obtained is dissolved in 10 cm3 of water. The resulting basic aqueous phase is washed 3 times with 10 cm 3 of ether. The aqueous phase is cooled to 0 ° C. and then is acidified with 2 cm 3 of 2M hydrochloric acid (aqueous), with vigorous stirring, in the presence of 20 cm 3 of methylene chloride. After decantation, it is extracted 8 times with 20 cm3 of methylene chloride. The combined organic phases are washed 3 times with 10 cm3 of water and then 1 time with 10 cm3 of a saturated aqueous solution of sodium chloride. After drying over anhydrous magnesium sulfate, filtration and dry concentration under reduced pressure, 91 mg (0.204 mmol) of 3-benzoylamino-3-phenyl (2,2,2-ethoxymethoxy) -2-propionic acid (2R, 3S) is obtained, with a yield of 88% the characteristics are as follows:

- rotary power: [afàj) = + 22.8 ° (c ≈ 1.02; chloroform) - infrared spectrum (film): main characteristic absorption bands at 3440, 3700-2300. 3070, 3040. 2975. 2925. 1745. 1640. 1602. 1580, 1520, 1485. 1295, 1265, 1205, 1175, 1135, 1080. 1020, 810 cπr *

- proton nuclear magnetic resonance spectrum (deuterated chloroform; 300 MHz): 2.80 (broad s, IH + H26); 3.50 (AB _q , JAB = 12 Hz, Ô -ÔB ≈ 121.4 Hz, 2H); 4.73 (d, J = 1.7 Hz, 1 H); 4.88 (AB _q , JAB ^S 7.3 Hz, δ _A -ÔB - 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. 8H); 7.79- 7.82 (m, 2H)

- nuclear magnetic resonance spectrum of ^ c (75.47 Hz; deuterated chloroform): 54.87 (CH); 76.84 (CH); 79.58 (CH2); 94.86 (CH ₂ ); 96.18 (C); 126.52 (CH); 127.33 (CH); 128.14 (CH); 128.73 (CH); 128.82 (CH); 132.12 (CH); 133.58 (C); 138.18 (C); 168.06 (C); 170.91 (C)

- mass spectrum (ic; NH3 + isobutane): molecular ion (solid): M ⁺ (446.5);

M ++ 2 (448.5); M + +4 (450.5); M + +6 (452.5): 4 peaks in the ratio 100-97.5-

31.7-3.4 - elementary analysis (C19H18O5NCI3, IH2O) calculated C% 49.11 H% 4.34 N% 3.01 found 49.05 4.33 3.09

EXAMPLE 31

267 mg (1 mmol) of (+) - phenyl-1-hydroxy-2-butene-3 syn and 3.5 cm3 of anhydrous acetonitrile are introduced into a 50 cm 3 single-necked flask fitted with a magnetic stirring system. 2.12 cm3 (1.4 g, 20 mmol) of 2-methyl-2-butene, 14 grains of 3A molecular sieve and 614 mg (2.86 mmol) of "proton sponges" are successively added to the suspension obtained ". The reaction mixture is stirred for 5 minutes at a temperature in the region of 20 ° C. and then 481 mg (1.98 mmol) of 2,2,2-trichloroethoxymethyl bromide is added. The reaction medium is left to react for 23 hours at a temperature in the region of 20 ° C., followed by addition of 643 mg (3 mmol) of "proton sponge" and 485 mg (2 mmol) of 2,2,2-trichloroethoxymethyl bromide and then shake for 24 hours. A further 242 mg (1 mmol) of 2,2,2-trichloroethoxymethyl bromide is added and the mixture is left to react for 20 hours. When the reaction is complete, 10 cm 3 of a saturated aqueous sodium hydrogencarbonate solution are added and the mixture is stirred for 15 minutes. 100 cm3 of dichloromethane are added. The separated aqueous phase is extracted twice with 10 cm 3 of dichloromethane. The combined organic phases are washed twice with 10 cm 3 of a 2M aqueous hydrochloric acid solution, then 4 times with 15 cm 3 of water and 2 times with 15 cm 3 of a saturated aqueous solution of sodium chloride. After drying over anhydrous sodium sulfate, filtration and concentration to dryness under reduced pressure, the yellow residue obtained is purified by chromatography on a column of silica gel, eluting with a dichloromethane-ether mixture (98-2 by volume). There is thus obtained, with a yield of 63%, 270 mg of (+) - phenyl-1 benzoylamino-1 (2,2,2-trichloroethoxymethoxy) -2 butene- 3 syn whose physical characteristics are the following:

- melting point: 91-92 ° C

- rotary power: [α] 25p = + 31 ° (c = 0.8, chloroform) The infrared and nuclear magnetic resonance spectra of the proton of the product obtained are identical to those of the product described in Example 14.

EXAMPLE 12

202 mg (0.47 mmol) of (+) - phenyl-1-benzoylamino-1 (2,2-trichloro) are introduced into a 10 cm 3 monocolour flask equipped with a magnetic stirring system. 2 ethoxymethoxy) -2 butene3 syn and 1.2 cm3 anhydrous acetonitrile. To the mixture obtained, 1.2 cm3 of carbon tetrachloride, 1.8 cm3 of water are successively added and, with vigorous stirring, 317 mg (3.77 mmol) of solid sodium hydrogen carbonate. Then 683 mg (3.19 mmol) of sodium periodate are added in small portions. The highly heterogeneous reaction mixture is then stirred for 5 minutes (gassing) and then 24.8 mg of RUCI3 is added all at once. Is left to react the reaction mixture went dark for 40 hours at a temperature of 15 ^β C. the reaction is complete, is added 15 cm3 of water. The basic aqueous phase is washed 3 times with 20 cm 3 of ether. The aqueous phase is cooled to 0 ° C. and then, with vigorous stirring, is treated, in the presence of 50 cm3 of dichloromethane, with 2.5 cm3 of a 2M aqueous hydrochloric acid solution. The acidic aqueous phase thus obtained is extracted 7 times with 70 cm3 of dichloromethane. The combined organic phases are washed 4 times with 10 cm 3 of water and 1 time with 10 cm 3 of a saturated aqueous solution of sodium chloride. After drying the organic phase over sodium sulfate anhydrous, filtration and concentration to dryness under reduced pressure, 160 mg of (+) - 3-benzoylamino-phenyl-3 (2,2,2-trichloroethoxymethoxy) -2 propionic acid (76% yield is obtained) 2R.3S) in the form of white crystals whose physical and spectroscopic characteristics are identical to those of the same acid obtained in Example 10.

EXAMPLE 13

5.4 cm3 of tetramethylpiperidine (32 mmol) and 6.5 cm3 of anhydrous tetrahydrofuran are introduced into a 250 cm3 monocolor, equipped with a magnetic stirring system. The solution obtained is cooled to -60 ° C. and then 20 cm3 of a solution of 1.6M n.butyllithium in hexane are added dropwise. The temperature of the heterogeneous solution is allowed to rise to -10 ° C in 1 hour. The lithium tetramethyl piperide solution is cooled to -60 ° C. and then a solution of 2.16 g of N-benzylbenzamide (10.25 mmol) and 3.4 cm 3 of NNN 'is added over 20 minutes. '-tetramethylethylenediamine (22.5 mmol) in 8.5 cm3 of tetrahydrofuran. After 1 hour of stirring at -60 ° C., 2.4 cm 3 of acrolein (36 mmol), freshly distilled, are added all at once. It is left to react for 15 minutes at -60 ° C. and then hydrolyzed by the addition of 20 cm 3 of water. The reaction mixture is extracted 3 times with 30 cm3 of dichloromethane. The combined organic phases are washed with 10 cm3 of an IN hydrochloric acid solution, twice with 20 cm3 of water and then once with 10 cm3 of a saturated aqueous solution of sodium chloride, then dried over sulphate anhydrous sodium. After filtration and concentration under reduced pressure, a residue (4.3 g) is obtained which is purified by chromatography on silica gel, eluting with a dichloromethane-ethyl acetate mixture (9-1 by volume). There is thus obtained, with a yield of 23, 630 mg of (±) -phenyl-1 benzoylamino-1 hydroxy-2 butene-3 syn and, with a yield of 15%, 409 mg of (±) -phenyl-1 benzoylamino -1 anti-2-hydroxy-3-butene.

The characteristics of (±) -phenyl-1 benzoylamino-1 hydroxy-2 butene-3 syn are as follows:

- melting point: 137-139 ° C (dichloromethane-cyclohexane) - infrared spectrum (film): main characteristic absorption bands at 3300, 1620, 1525, 1510, 1335, 1295, 1120, 1080, 995, 920 and 700 cm " ¹

- proton nuclear magnetic resonance spectrum (deuterated chloroform; 200 MHz): 2.40 (d, J ≈ 3.9 Hz, 1H); 4.55 (dd, J ≈ 3.5 Hz. 3.5 Hz and 5 Hz, 1 H); 5.23 (dt, J = 1.5 Hz and 10.5 Hz, 1 H); 5.26 (dd, J ≈ 3.5 Hz and 7.6 Hz, 1 H); 5.40 (dt. J = 1.5 Hz and 17.1 Hz, 1H); 5.94 (ddd, J = 5 Hz, 10.5 Hz and 17.1 Hz, 1 H); 6.98 (d, J = 7.6 Hz, 1H); 7.24-7.54 (m. 8H); 7.80-7.83 (m, 2H)

- nuclear magnetic resonance spectrum of ^ C (deuterated chloroform; 75.47 MHz): 57.71 (CH); 75.31 (CH); 116.58 (CH2); 126.89 (CH); 127.04 (CH); 127.68 (CH); 12836 (CH); 128.72 (CH); 131.60 (CH); 134.31 (C); 137.41 (CH); 139.60 (C); 167.54 (C).

The characteristics of (±) -phenyl-1 benzoylamino-1 hydroxy-2 butene-3 anti are as follows:

- infrared spectrum (nujol): main characteristic absorption bands at 3300, 1620, 1600, 1580, 1520, 1300, 1115, 1080, 1060, 1035, 985, 920, 870, 820, 800, 750 and 700 cm ' ¹

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

- nuclear magnetic resonance spectrum of ^ C (deuterated chloroform; 75.47 MHz): 58.23 (CH); 75.28 (CH); 117.29 (CH ₂ ); 126.94 (CH); 127.52 (CH);

127.80 (CH); 12833 (CH); 128.58 (CH); 131.64 (CH); 134.14 (C); 136.30 (CH); 137.56 (C); 167.23 (C).

EXAMPLE M

In a 25 cm3 single-necked flask, fitted with a magnetic stirring system, 100 mg of (±) -phenyl-1-benzoylamino-1-hydroxy-2-butene-3 syn (Ir) are iritroduced ( 0.37 mmol) and 1.3 cm3 of anhydrous acetonitrile. To the resulting suspension were successively added 0.8 cm3 of methyl-2 butene-2 (530 mg; 7.55 mmol), 4 grains of 3Å molecular sieves and 230 mg of ⁿ proton sponge "(1.07 mmol The reaction mixture is stirred for 5 minutes at a temperature in the region of 20 ° C. and then 180 mg of trichlorc-2-2.2 ethoxymethyl bromide (0.74 mmol) is added. It is left to react for 21 hours at a temperature close to 20 ° C. and then 115 mg of ⁿ proton sponge "(0.54 mmol) and 90 mg of bromide 2,2,2-trichloro ethoxymethyl (0.37 mmol) then stirred for 19 hours. 10 cm 3 of a saturated aqueous sodium hydrogencarbonate solution are added and the mixture is stirred for 15 minutes.

40 cm3 of dichloromethane are added. The separated aqueous phase is extracted twice with 10 cm 3 of dichloromethane. The combined organic phases are washed twice with 5 cm3 of a 2M aqueous hydrochloric acid solution and then 4 times with 5 cm3 of water and finally 2 times with 5 cm3 of a saturated sodium chloride solution. After drying over anhydrous sodium sulfate, filtration and concentration under reduced pressure, the residue obtained (306 mg) is purified by chromatography on a column of silica gel, eluting with a dichloromethane-ethyl acetate mixture (98-2 by volume) . 144 mg of a solid product are thus obtained which is recrystallized from an ether-hexane mixture. There is thus obtained, with a yield of 79%, 125 mg of (±) - ρhenyl-1 benzoylamino-1 (2,2-trichloro-2,2,2 ethoxymethoxy) -2 butene-3 syn, the characteristics of which are as follows:

- melting point: 94-95 ° C (ether-hexane) - infrared spectrum (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 (deuterated chloroform; 200 MHz): 3.43 (ABq, JAB = H, 8 Hz; δ _A -ÔB "80.1 Hz, 2H); 4.56 (dd, J ≈ 2.5 Hz and 8 Hz, 1H); 4.79 (ABq, JAB - 7.0 Hz; δ _A -ÔB ≈ 17.2 Hz, 2H); 5.41 (dd, J = 2.5 Hz and

8.8 Hz, 1H); 5.42 (d, J = 17.2 Hz, 1H); 5.43 (d. J ≈ 10.2 Hz. 1 H); 5.88 (ddd, J = 6.8 Hz. 10.2 Hz and 17.2 Hz, 1 H); 6.99 (d, J = 8.8 Hz. 1H); 7.26-7.54 (m, 8H); 7.82- 7.87 (m, 2H)

- Magnetic resonance spectrum of ^ C (deuterated chloroform; 50.3 MHz): 56.24 (CH); 79.19 (CH ₂ ); 79.71 (CH); 92.86 (CH2); 96.89 (C); 119.76 (CH ₂ ); 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 (ic; NH3 + isobutane): molecular ion (solid): M ⁺ (428.5);

M + 4-2 (430.5); M + 44 (432.5); M + +6 (434.5); 4 peaks in the ratio 100-97.5- 31.7 and 3.4

- elementary analysis (C20H20O3NCI3) calculated C% 56.03 H% 4.70 N% 3.27 found 55.88 4.72 3.24

EXAMPLE 15 In a 5 cm3 single-color flask. equipped with a magnetic stirring system, 52 mg of (±) -phenyl-l benzoylamino-1 (2,2,2-trichloroethoxymethoxy) -2 butene-3 syn are introduced under an argon atmosphere obtained in Example 12 (0.12 mmol) dissolved in 0.25 cm3 of acetonitrile. 0.25 cm3 of carbon tetrachloride, 0.37 cm3 of distilled water are then added successively and, with stirring, 65.5 mg solid sodium hydrogencarbonate (0.78 mmol). Then 141 mg of sodium periodate (0.66 mmol) are added in small portions. The mixture is stirred for 5 minutes and then 5.2 mg of RUCI3 are added all at once. The reaction mixture, which has turned black, is left to react for 72 hours at a temperature of 16-17 ° C. Again 3 mg of catalyst are added and then the mixture is stirred for 44 hours at 25-30 ° C. 3 cm3 of water are then added. The basic aqueous phase is washed 3 times with 4 cm 3 of ether. The aqueous phase is cooled to 0 ° C. and then, with vigorous stirring, is treated, in the presence of 10 cm 3 of dichloromethane, with 0.5 cm 3 of an aqueous solution of 2M hydrochloric acid. The acidic aqueous phase thus obtained is extracted 8 times with 10 cm 3 of dichloromethane. The combined organic phases are washed 4 times with 2 cm3 of water and 1 time with 2 cm3 of a saturated solution of sodium chloride. After drying the organic phase over anhydrous sodium sulfate, filtration and concentration to dryness, 43 mg of a white solid is obtained which is recrystallized from an ether-hexane mixture. There is thus obtained, with a yield of 71%, 38 mg of (±) -benzoylamino-3-phenyl-3 (2,2-trichloro-2,2,2 ethoxymethoxy) -2 propionic acid syn, the characteristics of which are as follows:

- melting point: 132-133 ^β C (ether-hexane)

- infrared spectrum (film): characteristic absorption bands at 3700-2300, 3440, 3300, 3070, 3040, 2975, 2925, 1745. 1640. 1602, 1580. 1520, 1485. 1295. 1265, 1205. 1175 . 1135. 1080, 1020, 810, 720 and 700 cπr ¹

- proton nuclear magnetic resonance spectrum (deuterated chloroform; 300 MHz): 2.80 [broad s, H (+ H2O)]; 3.50 (ABq, JAB = 12 Hz; δ _A -δβ = ¹²²¹ > ⁴ ***>2H); 4.73 (d, J = 1.7 Hz, 1H); 4.88 (AB _q , JAB = 7.3 Hz, δ _A -ÔB ≈ 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, 8H); 7.79- 7.82 (m, 2H)

- nuclear magnetic resonance spectrum of ^ C (deuterated chloroform; 75.47 MHz): 54.87 (CH); 76.84 (CH); 79.58 (CH2); 94.86 (CH2); 96.18 (C); 126.52

(CH); 127.33 (CH); 128.14 (CH); 128.73 (CH); 128.82 (CH); 132.12 (CH); 133.58 (C); 138.18 (C); 168.06 (C); 170.91 (C) - mass spectrum (ic; NH3 4-isobutane): molecular ion (solid): M ⁺ (446.5);

M ⁺ 4-2 (448.5); M + 4 (450.5); M + +6 (452.5): 4 peaks in the ratio 100-97.5- 31.7-3.4

- elementary analysis (C19H18O5NCI3, IH2O) calculated C% 49.11 H% 4.34 N 3.01 found 49.05 4.33 3.09 EXAMPLE 16

115 mg of (±) -benzoylamino-3-phenyl-3 (2,2-trichloro-2,2,2 ethoxymethoxy) -2 syn propionic acid (0.26 mmol) in solution are introduced into a 10 cm3 monocolour flask. 0.5 cm3 of acetone. 43 mg of (-) - pseudoephedrine (0.26 mmol) are then added, then the reaction mixture is heated until a homogeneous solution is obtained. Then cooled to -10 ^β C for 19 hours. The white crystals obtained are isolated and dry. 80 mg of ephedrine salt are thus obtained which is dissolved in 0.5 cm3 of acetone. Cool for 15 hours at -10 ° C. After separation by filtration, 30 mg of salt is thus obtained in the form of white crystals. After hydrolysis in an acid medium (IN aqueous hydrochloric acid; dichloromethane; 20 ° C; usual extraction), the result is a yield of

19%, 22 mg of acid (4 -) - 3-benzoylamino-3-phenyl (2,2,2-trichloroethoxymethoxy) -2 propionic (2R.3S) in which the enantiomeric ratio (determined by the magnetic resonance spectrum nuclear of the proton and ⁹ F of the Mosher esters of the corresponding racemic and optically active methyl alcohol-esters) is 93-7.

The mother liquors from the second crystallization, after concentration, provide 50 mg of residue. The residue is dissolved in 03 cm3 of acetone and then cooled for 24 hours to -10 ° C. There is thus obtained, after filtration. 13 mg of salt in the form of white crystals which are hydrolyzed under the conditions described above. There is thus obtained, with a yield of 7.8 mg of (4 -) - benzoyl-3-amino-phenyl-3 (2,2-trichloro-2,2,2 ethoxymethoxy) -2 propionic acid (2R.3S) identical to that obtained above.

The resolution yield is 52%.

EXAMPLE 17 62 mg of (+) - 3-benzoylamino-3-phenyl (trichloro) acid is introduced into a 5 cm 3 monocolour flask fitted with a magnetic stirring system, under an argon atmosphere. -2.2.2 ethoxymethoxy) -2 propionic (2R.3S) (0.139 mmol) dissolved in 1.16 cm3 of anhydrous toluene. 30 mg of dipyridyl-2 carbonate (0.139 mmol) are then added and the mixture is left to react for 5 minutes at a temperature in the region of 20 ° C. A mixture of 16.1 mg of triethylsilyl-7 baccatin m (0.023 mmol) and 5.6 mg of N, N-4-dimethylamino-pyridine (0.046 mmol) is then added at one time. It is left to react for 3-4 minutes at a temperature in the region of 20 ° C. and then heated to 70-72 ° C. for 48 hours. When the reaction is complete, the resulting reaction mixture is diluted with 60 cm 3 of ethyl acetate. The organic phase is washed with 3 cm3 of water, twice with 3 cm3 of a saturated aqueous hydrogen carbonate solution sodium, 4 times with 3 cm3 of water and 2 times with 3 cm3 of a saturated solution of sodium chloride and then it is dried over anhydrous sodium sulfate. After filtration and evaporation of the solvent under reduced pressure, the residue obtained (75 mg) is purified by preparative chromatography on a thin layer of silica, eluting with an ether-dichloromethane mixture (8-92 by volume) (3 passages).

There is thus obtained, with a yield of 94, 24.4 mg of (4 -) - benzoyl-3-amino-phenyl-3 (2,2,2-trichloro-ethoxymethoxy) -2 diacetoxy-4,10 benzoyloxy-2α propionate eρoxy-5β, 20 hydroxy-1 oxo-9 triethylsilyloxy-7β taxene-11 yle-13α, containing, according to the proton nuclear magnetic resonance spectrum at 300 Mz, 10% of C2 'epimer, the characteristics of which are the following :

- melting point: 137-145 ° C

- infrared spectrum (film): main absorption bands characteristic at 3400, 2960, 2870, 1740, 1650, 1600, 1580, 1508, 1480, 1445, 1365, 1265, 1235, 1140, 1105. 1095, 1080. 1015, 985. 945, 818 and 710 cm " ¹ - proton nuclear magnetic resonance spectrum (300 MHz; deuterated chloroform); 0.54-0.62 (m, 6H); 0.93 (t. J ≈ 8 Hz, 9H); 1.19 (s, 3H); 1.23 (s, 3H); 1.70 (s, 3H); 1.85-1.99 (m, IH); 2.03 (s, 3H) ); 2.10-2.20 (m, 1H); 2.17 (s. 3H); 2.33-2.60 (m, 2H); 232 (s, 3H); 3.60 (ABq, JAB = U. 7 Hz; δ _A -δβ - 101.4 Hz, 2H); 3.82 (d, J ≈ 7 Hz, IH); 4.26 (ABq, JAB "8.3 Hz; δ _A -δβ = 353 Hz. 2H); 4.48 (dd. J = 6.7 Hz and 103 Hz. IH); 4.81 (d. J = 2 Hz, IH); 4.90 (ABq. JAB = 73 Hz; δ _A -δβ = 17 Hz, 2H) ; 4.94 (d, J = 93 Hz, IH); 5.70 (d, J = 7 Hz, IH); 5.89 (dd, J = 2 Hz and 9 Hz, IH); 6.28 ( t, J = 9 Hz, 1H); 6.44 (s, 1H); 7.01 (d, J "9 Hz, 1H); 7.34-7.63 (m, 11H); 7.75- 7.78 (m, 2H); 8.12-8.16 (m, 2H).

24.8 mg of the ester obtained above, dissolved in 0.9 cm3 of methanol, are introduced, under an argon atmosphere, into a 10 cm 3 monocolour flask equipped with a magnetic stirring system. then 0.9 cm3 of glacial acetic acid and 60 mg of zinc-copper couple are successively added (prepared from 20 g of powdered zinc and 3 g of CuSO H2O). The resulting reaction mixture is heated to 55-

56 ° C for 1.5 hours. When the reaction is complete, the reaction mixture is cooled to a temperature in the region of 20 ° C. and then filtered. The solid is washed with 3 times 0.6 cm 3 of 95% ethanol. To the resulting clear solution, 70 mg of 33% (w / v) hydrochloric acid is added, then the reaction is left to react for 8 hours at a temperature in the region of 20 ° C. When the reaction is complete, the reaction mixture is diluted with 60 cm 3 of ethyl acetate. The organic phase is washed 2 times with 5 cm3 of a saturated aqueous solution of sodium hydrogencarbonate then 4 times with 5 cm3 of water and 1 time with 5 cm3 of a saturated aqueous solution of sodium chloride. The organic phase is then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue obtained (23 mg) is purified by preparative chromatography on a thin layer of silica, eluting with a methanol-dichloromethane mixture (5-95 by volume) (2 passages).

There is thus obtained, with a yield of 73%, 13.8 mg of taxol contaminated with 10% of its epimer C2 '.

The infrared and nuclear magnetic resonance spectra of the proton and of the taxol obtained are identical to those of the natural taxol described in the literature.

Claims

1 - Process for the preparation of new derivatives of β-phenylisoserine of general formula:

optionally in the form of a salt or an ester, in which R represents a t-butoxy or phenyl radical and Ar represents an aryl radical chosen from phenyl and α- or β-naphthyl radicals optionally substituted by one or more atoms or radicals, which are identical or different, chosen from halogen atoms and alkyl, alkenyl, alkynyl, alkyloyloxy, alkylthio, hydroxy, mercapto, amino, monoalkoylamino, dialcoylamino, acylamino, alkoxycarbonylamino, carboxy, carbamoyl, NN-dialkoyro-carbamoyl radicals , characterized in that a 2,2,2-ethoxymethyl trichloro halide is made to act on a product of general formula:

in which Z represents an ester function (-COOR2) or a viny¬ lique double bond (-CH≈CH2), then optionally, as the case may be, saponifies or oxidizes the product thus obtained, and isolates the β-phenylisoserine derivative which is possibly dedou¬ wheat into its enantiomers.

2 - Process according to claim 1 characterized in that the action of l ialc- 2,2,2-ethoxymethyl trichloro genide is carried out in an organic solvent such as acetonitrile in the presence of a proton acceptor at a temperature between 0 and 50 ° C.

3 - Process according to claim 2 characterized in that the proton acceptor is l, 8-bis (dimethylamino) naphthalene.

4 - Process according to claim 2 characterized in that one also operates in the presence of 2-methyl-2-butene. 5 - Process according to claim 1 characterized in that when Z represents an ester function (-COOR2), the saponification is carried out by means of a mineral base in hydroalcoholic medium.

6 - Process according to claim 1 characterized in that when Z represents a vinyl double bond (-CH≈CH2). the oxidation is carried out by means of sodium periodate in the presence of a catalytic amount of a ruthenium derivative or by means of potassium permanganate.

7 - Process according to claim 1 characterized in that the derivative of β-phenylisoserine is split into its enantiomers by formation of a salt with an optically active base followed by the hydrolysis of the salt thus obtained.

8 - New derivatives of β-phenylisoserine of general formula:

in which R and Ar are defined as in claim 1, in recurrent or enantiomerically pure form or in the form of their mixtures as well as their salts and their esters.

9 - Use of a product obtained according to the process of claim 1 for the preparation of biologically active taxane derivatives of general formula:

R

OCOC ₆ H ₅ in which R and Ar are defined as in claim 1 and Ri represents a hydrogen atom or an acetyl radical, characterized in that one esterifies a taxane derivative of general formula: in which R'i represents an acetyl radical or a protective group for the hydroxy function and G2 represents a protective group for the hydroxy function such as the trichlorc-2,2,2 ethoxycarbonyl or trialcoylsilyl group in which each alkyl part contains 1 to 4 atoms of carbon, by means of a product obtained according to the process of claim 1, then replaces the protective groups represented by R'i and G2 and the 2,2,2-trichloroethoxymethyl group by a hydrogen atom and , if necessary, carry out the resolution of the product obtained to isolate the 2R S enantiomer.

10 - Use according to claim 9 characterized in that esterification is carried out in the presence of a condensing agent such as N M-dicyclohexylcar- bodiimide or 2-dipyridylcarbonate and an activating agent such as N, N - 4-dimethylamino pyridine at a temperature between 20 and 80 ° C.

11 - Use according to claim 9 characterized in that the replacement of the protective groups is carried out by means of zinc or a zinc-copper couple in acetic acid optionally in the presence of an alcohol containing 1 to 3 atoms of carbon or, in the case of the trialkylsilyl protective group, by means of hydroalcoholic HCl.