IL95436A - Method for the preparation of phenzlisoserine derivatives - Google Patents

Abstract

Process for the preparation of enantioselective preparation of phenylisoserine derivatives of general formula (I) in which R denotes a phenyl or tert-butoxy radical and R1 denotes a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms and R2 denotes a hydrogen atom or a group for protecting the alcohol functional group. <IMAGE>

Description

1 · no 1 τ ·> a1? ■> J D nninn nioni? -p^nn METHOD FOR THE PREPARATION OF PHENYLISOSERINE DERIVATIVES The present invention relates to the enantioselective preparation of phenylisoserine derivatives of formula: in which R represents phenyl or tert-butoxy, R^ represents hydrogen or alkyl of 1 to 4 carbon atoms and R2 represents hydrogen or an alcohol-protecting group.

In formula (I) , R2 as an alcohol-protecting group may represent, more especially , hydrogen , methoxymethyl , l-ethoxyethyl , benzyloxymethyl , (β-trimethyl-silylethoxy) methyl , tetrahydropyrannyl or 2,2, 2-tri-chloroethoxycarbonyl. Preferably, R2 is l-ethoxyethyl.

The products of. general formula (I) are useful for preparing derivatives of baccatine III and of 10-deacetylbaccatine III of formula: in which R3 represents hydrogen or acetyl and R represents phenyl or tert-butoxy.

The products of formula (II) in which R represents phenyl correspond to taxol and 10-deacetyltaxol, and the products of formula (II) in which R represents tert-butoxy correspond to compounds described in European Patent EP 253,738.

The products of general formula (II) , and especially those which occur in the 2^,3*8 form, possess especially advantageous antitumour and antileukemic properties .

The products of general formula (II) may be obtained by the action of a compound of formula (I) in which represents hydrogen on a taxane derivative of general formula : 0-CO-C6H5 in which R'3 represents acetyl or a group protecting the hydroxyl function and R4 represents a group protecting the hydroxyl function, followed by replacement of the protective groups R2 and R4 and, where appropriate, R3 by hydrogen, under the conditions described by J-N. DENIS et al., J.

Amer. Chem. Soc. , 110 (17) 5917-5919 (1988) or by L. MANGATAL et al., Tetrahedron, 45, 4177-4190 (1989). - 2a - J-N. DENIS et al, J. Org. Chem. £1:46-50 (1986) describe a process for the preparation of N-benzoyl-3-phenylisoserine by acylation of the hydroxy function of an azidohydroxy compound, reduction of the resulting esterified product and subsequent transfer of the benzoyl group from the oxygen atom to the nitrogen atom. This is a multistep process, in which all intermediates are isolated and does not have the advantages of a single-step process. - 3 - According to the present invention, the products of formula (I) in which R represents phenyl or tert-butoxy, represents hydrogen or alkyl of 1 to 4 carbon atoms and R2 represents hydrogen or an alcohol-protecting group are obtained from an oxirane derivative of general formula: in which R-^ is alkyl of 1 to 4 carbon atoms, by treatment with an azide to produce an azide of formula: in which is alkyl of 1 to 4 carbon atoms; the hydroxyl function is optionally protected to convert it into a group -0R2 so as to obtain more particularly a product of formula: in which R^ is alkyl of 1 to 4 carbon atoms and R2 represents an alcohol-protecting group; the azide group is reduced to give an amine of formula: 95436/2 - 4 - in which R-^ and R2 are defined as above; the amine is treated with a reagent enabling a benzoyl or tert-butoxycarbonyl group to be introduced, to obtain a product of general formula (I) in which represents alkyl of l to A carbon atoms; and the product is then optionally saponified to give a product of formula (I) in which R-^ represents hydrogen.

The opening of the oxirane of general formula (IV) to a product of general formula (V) may be performed by the action of an azide, working in a suitable organic solvent at a temperature generally of between 40 and 80°C. It is advantageous to use trimethy lsily 1 azide in the presence of zinc chloride, or an alkali metal (sodium, potassium, lithium) azide in an aqueous-methanoi ic medium in the presence of methyl formate.

The products of general formula (VI) may be obtained from the product of general formula (V) under the usual conditions for preparing ethers and acetais, and more especially according to the processes described by J-N. DENIS et al., J. Org. Chem. , 51, 46-50 (1986) .

The product of general formula (VII) may be obtained by reduction of the product of general formula (v.i ) by means of hydrogen in the presence of a hydrogenat i on catalyst such as 'palladium on charcoal, working in an alcohol such as methanol.

The product of general formula (I) in which R represents an alkyl radical containing 1 to 4 carbon atoms may be obtained by the action of di-tert-butyl dicarbonate or benzoyl chloride on the product of general formula (VII) .

In general, the reaction is performed in an organic solvent such as methylene chloride in the presence of an inorganic base such as sodium bicarbonate or an organic base such as a tertiary amine, for example triethyla ine. It is not necessary to isolate the product of general formula (VII) in order to react it with di-tert-butyl dicarbonate or benzoyl chloride.

The oxirane derivative of general formula (IV) may be obtained under the conditions described by J-N. DENIS et al., J. Org. Chem. , 51, 46-50 (1986).

The products of formula (I) in which R^. represents alkyl of 1 to 4 carbon atoms and R2 represents hydrogen may be obtained by the acylation/hydrogenation of a hydroxy azide of formula (V) in which R^ is defined as above .

The acylation and hydrogenation may be carried out simultaneously or successively without isolation of the intermediate reaction products.

When R represents phenyl or tert-butoxy, the reaction may be carried out using benzoic anhydride or di-tert-butyl dicarbonate in the presence of hydrogen and a hydrogenation catalyst such as palladium on charcoal, working in an inert organic solvent such as an ester, for example methyl acetate or ethyl acetate, at a temperature of between 0 and 40°C, and preferably in the region of 20 °C.

When R represents phenyl, the reaction may be carried out using benzoyl chloride in the presence of an organic base such as triethylamine and an activating agent such as 4-dimethylaminopyridine, then adding methanol and thereafter placing the reaction mixture under a hydrogen atmosphere in the presence of a hydrogenation catalyst such as palladium on charcoal, working in an inert organic solvent such as an ester, for example methyl acetate or ethyl acetate, at a temperature of between 0 and 40°C, and preferably in the region of 20°C.

The products of general formula (I) in which R^ represents an alkyl radical containing 1 to 4 carbon atoms and R2 represents a group protecting the hydroxyl function may be obtained from a product of general formula (I) in which R± represents an alkyl radical containing 1 to 4 carbon atoms and R2 represents a hydrogen atom, under the usual conditions for preparing the ethers and acetals mentioned above.

The products of general formula (I) in which Rl represents a hydrogen atom may be obtained by the saponification of a product of formula (I) in which R^ represents alkyl, by means of an inorganic base such as an alkali metal (lithium, sodium) hydroxide, an alkali metal carbonate or bicarbonate (sodium bicarbonate, potassium carbonate or bicarbonate) in an aqueous-alcoholic medium such as a methanol/water mixture at a temperature of between 10 and 40°C, and preferably in the region of 25°C.

The present invention also provides a process for the preparation of a product of formula (II) , by the condensation of a phenylisoserine derivative of formula (I) in which R-^ represents hydrogen and R2 represents an alcohol protecting group obtained by the process of the invention, with a product of formula (III) in which the protective groups represented by R'3 and R4 are generally 2,2,2-trichloroethoxycarbonyl or trialkylsilyl in which each alkyl portion contains 1 to 3 carbon atoms, followed by the replacement of the protective groups by hydrogen.

In general, the esterification is performed in the presence of a condensing agent such as a carbodiimide, for example dicyclohexylcarbodiimide, or a reactive carbonate, for example 2-dipyridyl carbonate, and an activating agent such as a dialkylaminopyridine, for example 4-dimethylaminopyridine , working in an aromatic organic solvent such as benzene, toluene, xylenes, ethylbenzene, isopropylbenzene or chlorobenzene at a temperature of between 60 and 90°C.

It is especially advantageous to use a molar excess of acid of formula (I) relative to the taxane derivative of formula (III) , the condensing agent being used in a stoichiometric amount relative to the acid of formula (I) and 4-dimethylaminopyridine being used in a stoichiometric amount relative to the taxane derivative of formula (III) .

The replacement of the protective groups by a hydrogen atom may be performed by means of zinc in the presence of acetic acid at a temperature of between 30 and 60°C, or by treatment with an inorganic or organic acid such as hydrochloric acid or acetic acid, in solution in an aliphatic alcohol containing 1 to 3 carbon atoms, in the presence of zinc.

The examples which follow show how the invention may be put into practice.

EXAMPLE 1 530 mg of (+)- (methyl 3-azido-2-hydroxy-3-phenylpropionate) (2.4 mmol), 12 cm3 of dry dichloromethane , 60.2 mg of pyridinium p-toluenesulphonate (0.24 mmol) and 2.3 cm3 of ethyl vinyl ether (24 mmol) are introduced successively under an argon atmosphere into a 25-cm3 round-bottomed flask equipped with a magnetic stirrer. The mixture is stirred for 4 hours at a temperature in the region of 20°C. When the reaction is complete, one drop of pyridine is added and 50 cm3 of dichloromethane are then added. The reaction mixture is washed twice with 5 cm3 of water and twice with 5 cm3 of saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulphate. After filtration and evaporation of the solvent, 706 mg of methyl 3-azido-2- (1-ethoxyethoxy) -3-phenylpropionate are obtained in the form of an equimolecular mixture of the 2 epimers. 0.6 g of methyl 3-azido-2- ( 1-ethoxyethoxy) -3-phenylpropionate (2.05 mmol), 16.4 cm3 of methanol, 0.714 cm3 of triethylamine (5.12 mmol) and 107 mg of palladium on charcoal containing 10 % by weight of palladium are introduced successively under an argon atmosphere into a 25-cm3 round-bottomed flask equipped with a magnetic stirrer. The mixture obtained is placed under a hydrogen atmosphere and then stirred vigorously for 4 hours at a temperature in the region of 20°C. When the reaction is complete, the reaction mixture is placed under an argon atmosphere. The catalyst is separated by filtration through Celite. The catalyst is washed three times with 15 cm3 of methylene chloride. The combined organic phases are concentrated to dryness under reduced pressure. A colourless liquid residue is obtained.

The residue obtained above and 10.3 cm3 of dichloromethane are introduced under an argon atmosphere into a 25-cm3 round-bottomed flask equipped with a magnetic stirrer. 1.43 cm3 of triethylamine (10.25 mmol) and 536.9 mg of di-t-butyl dicarbonate (2.46 mmol) are added to the solution obtained. The reaction mixture is stirred for 43 hours at a temperature in the region of 20°C and 100 cm3 of ethyl acetate are then added. The reaction mixture is washed twice with 10 cm3 of saturated aqueous sodium bicarbonate solution, 3 times with 5 cm3 of water and once with 5 cm3 of saturated aqueous sodium chloride solution, then dried over - 10 -anhydrous sodium sulphate. After filtration and evaporation of the solvents, a residue (720 g) is obtained, which is purified by filtration on a column of silica gel, eluting with an ethyl ether/methylene chloride mixture (1:99 by volume) . 413 mg of pure methyl (2R, 3S) -3-t-butoxy-carbonylamino-2- ( 1-ethoxyethoxy) -3-phenylpropionate are thereby obtained in the form of an equimolecular mixture of the 2 epimers.

The overall yield is 55 % from the (+)- (methyl 3-azido-2-hydroxy-3-phenylpropionate) .

The characteristics are as follows: 24 - Optical rotation: [Q]D = +6.0° (c = 1.52; chloroform) .

- Melting point: 105-109°C.

- Infrared spectrum (film): 3350, 3000, 2950, 2900, 2875, 1722, 1665, 1515, 1420, 1380, 1355, 1320, 1305, 1280, 1250, 1240, 1160, 1130, 1100, 1070, 1035, 1020, 995, 945, 890, 860, 840, 760, 745 and 698 cm-1.

- Proton nuclear magnetic resonance spectrum (300 MHz, CDC13, chemical shifts in ppm, coupling constants J in Hz) : 0.79 and 0.96 (2t, J = 7.0, 3H) ; 1.08 and 1.16 (2d, J = 5.4, 3H) ; 1.41 (s broad, 9H) ; 2.69-2.75 and 3.14-3.34 (m, 2H) ; 3.757 and 3.762 (2s, 3H); 4.34 and 4.46 (2s broad, 1H) ; 4.39 and 4.73 (2q, J = 5.4, 1H) ; 5.22 and 5.54 (2s broad, 1H) ; 7.23-7.33 (m, 5H aromatic).

- Mass spectrum (c.i., NH3 + isobutane) : m/e = 385 (MH + NH3)+, 368 (MH)+, 339, 322, 296, 283, 257, 240, 222, 206.

- Elemental analysis: C % calculated 62.10 found 62.01 H % calculated 7.96 found 7.97.

(+) - (Methyl 3-azido-2-hydroxy-3-phenyl-propionate) may be prepared according to one of the following methods: a) 84 mg of methyl (2R, 3R) -3-phenyloxiranecarboxylate (0.472 mmol) , 65.1 mg of trimethylsilyl azide (0.57 mmol) and 2-3 mg of zinc chloride are introduced under an argon atmosphere into a 5-cm3 round-bottomed flask equipped with a magnetic stirrer and surmounted by a condenser. The reaction mixture is heated for 20 hours to 72 °C. 0.47 cm3 of a solution prepared from 2 cm3 of tetrahydrofuran, 0.2 cm3 of acetic acid and two drops of concentrated hydrochloric acid is added. Hydrolysis is complete after one hours' reaction at a temperature in the region of 20°C. 20 cm3 of dichloromethane and 3 cm3 of water are added to the reaction mixture. The two phases are separated after settling has taken place.

The aqueous phase is extracted twice with 5 cm3 of dichloromethane. The combined organic phases are washed twice with 5 cm3 of saturated aqueous sodium bicarbonate solution, three times with 5 cm3 of water and once with 5 cm3 of saturated aqueous sodium chloride solution, and are then dried over anhydrous sodium sulphate. After filtration and evaporation of the solvents under reduced pressure, a residue (97 mg) is obtained, which is purified by filtration on a column of silica gel, eluting - 12 -with an ether/hexane mixture (2:8 by volume). 91 mg of (+)-(methyl 3-azido-2-hydroxy-3-phenylpropionate) are thereby obtained in an 87 % yield. b) 430 mg of methyl (2R, 3R) -3-phenyloxiranecarboxylate (2.4 mmol) , 12 cm3 of a methanol/water mixture (8:1 by volume), 800 mg of sodium azide (12.3 mmol) and then 2 cm3 of methyl formate (3.3 mmol) are introduced successively under an argon atmosphere into a 50-cm3 round-bottomed flask equipped with a magnetic stirrer and surmounted by a condenser. The reaction mixture is heated to 50 °C and then stirred for 24 hours. After cooling to a temperature in the region of 20°C, the reaction mixture is diluted by adding 50 cm3 of ether, and 5 cm3 of water are then added. The two phases are separated after settling has taken place. The aqueous phase is extracted twice with 10 cm3 of ethyl ether. The combined organic phases are washed with 5 cm3 of saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulphate. After filtration and concentration under reduced pressure, a residue is obtained, which is purified by filtration on silica gel, eluting with an ethyl acetate/hexane mixture (2:8 by volume). 475 mg of pure (+)- (methyl 3-azido-2-hydroxy-3-phenylpropionate) are obtained in a 90 % yield.

The product obtained possesses characteristics (infrared spectrum, proton nuclear magnetic resonance spectrum) identical to those described by J-N. DENIS et al., J. Org. Chem. , 51, 46-50 (1986) . - 13 - Melting point = 56-57°C (pentane); [a^ = +142° (c = 1.1; chloroform) .

EXAMPLE 2 146.8 mg of methyl (2R,3S)-3-t-butoxycarbonylamino-2- (1-ethoxyethoxy) -3-phenylpropionate (0.4 mmol), 14 cm3 of distilled methanol, 7 cm3 of water and 166 mg of solid potassium carbonate (1.2 mmol) are introduced successively into a 50-cm3 round-bottomed flask equipped with a magnetic stirrer. The mixture is stirred for 40 hours at a temperature in the region of 20°C and the methanol is then evaporated off under reduced pressure. The residual basic aqueous phase is washed several times with ether, then acidified with 2.5 % (weight/volume) aqueous hydrochloric acid solution in the presence of methylene chloride and then extracted four times with 20 cm3 of methylene chloride. The combined organic phases are washed 4 times with 5 cm3 of water and then once with 5 cm3 of saturated sodium chloride solution, and then dried over anhydrous magnesium sulphate. After filtration and evaporation of the solvents under reduced pressure, 108 mg of pure (2R, 3S) -3-t-butoxycarbonylamino-2- ( 1-ethoxyethoxy) - 3-phenylpropionic acid are obtained in a 76 % yield.

The characteristics are as follows: - Deliquescent product.

- Optical rotation: [a]^4 = +17° (c = 1.28; chloroform) .

- Infrared spectrum (film) : main characteristic absorption bands at: 3700-2200, 3060, 2980, 2930, 1720, 1660, 1602, (-) - (2R, 3S) -N-benzoyl-3-phenylisoserine methyl ester are thereby obtained, the characteristics of which are as follows : - Melting point: 184-185°C (methylene chloride/cyclohexane) - Optical rotation: [a]^4= -48° (c = 1; methanol).

The yield is 92 %.

(+) -[Methyl ( 2R, 3S) -3-az ido-2-hydroxy-3-phenylpropionate ] may be prepared in the following manner: 1.35 g (7.58 mmol) of (+)-[methyl (2R,3R)-3-phenyloxiranecarboxylate ] , dissolved in 40 cm3 of a methanol/water mixture (8:1 by volume), is treated with 6.3 cm3 of methyl formate and 2.46 g (37.8 mmol) of sodium azide. The mixture is stirred for 46 hours at 50°C under an argon atmosphere. The product obtained is extracted with ether under the usual conditions. The crude product obtained is purified by chromatography on silica gel, eluting with hexane containing 10 % of ethyl acetate. 1.59 g of (+)- [methyl (2R, 3S-3) -azido-2-hydroxy-3-phenylpropionate] are thereby obtained, the characteristics of which are as follows: - Melting point: 56-57°C (pentane) 24 - Optical rotation: [ ]Q = +142° (c = 1.1; chloroform).

The yield is 95 %.

EXAMPLE 4 A suspension of 148 mg of palladium on charcoal containing 10 % (w/w) of palladium in 3 cm3 of ethyl acetate is stirred for 10 minutes under a hydrogen atmosphere at 20°C, and a solution of 1.75 g (8.02 mmol) of di-tert-butyl dicarbonate and 1.48 g (6.70 mmol) of (+)-[methyl ( 2R, 3S) -3-azido-2-hydroxy-3-phenylpropionate ] in 12 cm3 of ethyl acetate is then added.

The mixture is stirred for 56 hours. The hydrogen is replaced by argon, the mixture is diluted in 100 cm3 of ethyl acetate and the palladium on charcoal is removed by filtration under vacuum through Celite. The solids are washed 3 times with 30 to 40 cm3 of ethyl acetate and the solvent is removed under vacuum. The crude product is obtained, which is purified by chromatography on silica gel, eluting with an ether/dichloromethane mixture (5:95 by volume). 1.81 g of (-) - (2R, 3S) -N- (tert-butoxycarbony1 ) -3-phenylisoserine methyl ester are thereby obtained, the characteristics of which are as follows: - Melting point: 130.5-131.5°C (methylene chloride/ cyclohexane) - Optional rotation: [ ]^4= -7° (c = 1.2; chloroform) .

- Infrared spectrum: main characteristic absorption bands at 3500, 3380, 3110, 3060, 3000, 2975, 2930, 1735, 1690, 1518, 1500, 1442, 1390, 1360, 1300, 1250, 1170, 1100, 1050, 1030, 980, 940, 930, 900 and 705 cm"1.

- Proton nuclear magnetic resonance spectrum (chemical shifts in ppm, coupling constants J in Hz): 1.42 (s broad, 9H) ; 3.11 (s broad, 1H) ; 3.84 (s, 3H) ; 4.47 (s broad, 1H) ; 5.21 (distorted d, J = 9.4, 1H) ; 5.36 (distorted d, J = 8.5, 1H) ; 7.26-7.37 (m, 5H) .

- Mass spectrum (c.i., NH3 + isobutane) : m/e = 313 (MH + NH3)+, 296 (MH)+, 257, 240, 206, 196.

- Elemental analysis: C % calculated 61.00 found 60.85 H % calculated 7.17 found 7.17.

The yield is 92 %.

Claims (17)

WE CLAIM

1. Process for the enantioselective preparation of a phenylisoserine derivative of formula: in which R represents phenyl or tert-butoxy, R^ represents hydrogen or alkyl of 1 to 4 carbon atoms, and R2 represents hydrogen or an alcohol-protecting group, which comprises: reacting an oxirane derivative of formula: in which R-^ is alkyl of 1 to 4 carbon atoms, with an alkali metal azide or trimethylsilyl azide to produce an azide of formula : in which R^ is alkyl of 1 to 4 carbon atoms; optionally protecting the hydroxyl group -OH to convert it into a group - OR2 where R2 is an alcohol protecting group; reducing the azide group to produce an amine of formula: 95436/2 - 19 - in which R1 is alkyl of 1 to 4 carbon atoms and R2 represents hydrogen or an alcohol-protectirtg group; treating the amine obtained with a reagent to convert the amino group into a benzoylamino or t-butoxycarbony laiiv.i no group; and optionally hydrolysing the product to produce a phenylisoserine derivative of formula I in which represents hydrogen.

2. Process according to Claim 1 in which represents hydrogen, methoxymethy1 , 1-ethoxyethy 1 , benzyloxymethyl , (β-trimethy lsilylethoxy ) methyl , tetrahydropyranny1 or 2 , 2 , 2-trichloroethoxycarbony 1 radicals .

3. Process according to Claim 1 or 2 in which the azide group is reduced to amino with hydrogen in the presence of a hydrogenation catalyst, working in a lower alcohol .

4. Process according to Claim 3, in which the catalyst is palladium on charcoal and the solvent is methanol .

5. Process according to any one of Claims 1 to 4 in which the benzoylamino or t-butoxycarbonylamino group of formula R-CO-NH- is formed by reacting a corresponding amine with benzoyl chloride or di-tert-butyl dicarbonate respectively, working in an inert organic solvent in the presence of a base.

6. Process according to Claim 5, in which the solvent is a halogenated hydrocarbon such as methylene chloride and the base is triethylamine.

7. Process according to Claim 1 or 2 for the preparation of a phenyl isoserine derivative of formula (I) in which R-^ represents alkyl of 1 to 4 carbon atoms and R2 represents hydrogen, which comprises reacting an azide of formula V with benzoic anhydride or di-tert-butyl dicarbonate in the presence of hydrogen and a hydrogenation catalyst, working in an inert organic solvent at a temperature of between 0 and 40°C.

8. Process according to Claim 7, in which the catalyst is palladium on charcoal.

9. Process according to Claim 7 or 8 , in which the solvent is methyl acetate or ethyl acetate.

10. Process according to Claim 1 or 2 for the preparation of a phenyl isoserine derivative of formula (I) in which R represents phenyl, R represents alkyl of 1 to 4 carbon atoms and R2 represents hydrogen, which comprises reacting an azide of formula V with benzoyl chloride in the presence of an organic base and an activating agent, adding methanol, and hydrogenating the reaction mixture in a hydrogen atmosphere in the presence of a hydrogenation 95436/2 - 21 - catalyst, working in an inert organic solvent at a temperature of between 0 and 40°C.

11. Process according to Claim 10, in which the organic base is triethyla ine.

12. Process according to Claim 10 or 11, in which the activating agent is 4-dimethylaminopyridine.

13. Process according to Claim 10, 11 or 12, in which the hydrogenation catalyst is palladium on charcoal.

14. Process according to Claim 10, 11, 12 or 13 in which the solvent is methyl acetate or ethyl acetate.

15. Process according to any one of Claims 1 to 14 in which a product in which represents alkyl of 1 to 4 carbon atoms is hydrolysed with an alkali metal hydroxide, carbonate or bicarbonate in an aqueous-alcoholic medium at a temperature of between 0 and 40°C.

16. · Process according to claim 1 substantially as described in any of the foregoing Examples.

17. A phenylisoserine derivative of formula (I) as defined in claim 1 when produced by the process of any of claims 1 to 15 or 16.