IE920127A1 - (2R,3S)-ß-PHENYLISOSERINE AND ITS SALTS AND THEIR¹PREPARATION AND USE - Google Patents

Abstract

(2R,3S)- beta -Phenylisoserine, its salts and its preparation by the action of ammonia on (2R,3R)- beta -phenylglycidic acid, and its use for the preparation of taxane derivatives of general formula: <IMAGE> (R = H, COCH3; R1 = C6H5, (CH3)3C-O-).t

Description

The present invention relates to β-phenylisoserines, their preparation and their use in the preparation of therapeutically useful products.

The (2R,3R), (2S,3S) and (2S,3R) isomers of Bphenylisoserine are known, see, e.g., the papers by E. Kamandi et al.. Arch. Pharmaz., 307. 871-878 (1974), E. Kamandi et al.. Arch. Pharmaz., 308. 135-141 (1975), and K. Harada and Y. Nakajima, Bull. Chem. Soc. Japan, 47. 2911-2912 (1974). (2R,3S)-B-phenylisoserine has not yet been described other than in ester form [H. Honig et al., Tetrahedron, 16, (11) 3841-3850 (1990)].

The present invention provides (2R,3S)B-phenylisoserine, of formula: h2n COOH 3S ) - -< 2R / \ (I) C6«5 OH and its salts with alkali metals, alkaline earth metals and nitrogenous bases, which may be obtained by the action of ammonia on (2R,3R)-B-phenylglycidic acid, preferably in the form of an alkali metal or alkaline earth metal (sodium, potassium, calcium) salt, of an ammonium salt or of a salt with a nitrogenous base (α-methylbenzylamine, pyridine). - 3 Generally, the process is carried out in water, optionally mixed with an organic solvent such as methanol, or in an organic solvent by itself. It is preferable to work in water.

An excess of ammonia relative to (2R,3R)β-phenylglycidic acid should be used. Generally, from 10 to 100 moles of ammonia, and preferably from 50 to 80 moles, are used per mole of (2R,3R)-β-phenylglycidic acid.

The ammonia is preferably used in the form of a 10 concentrated aqueous solution such as a solution whose concentration is between 20 and 32% (w/w) at a temperature in the region of 25°C.

The process is ordinarily carried out at a temperature of between 0 and 100°C, and preferably between 40 and 60°C. Generally, it is performed at atmospheric pressure or alternatively under an autogenous pressure which may be in the region of 2.5 bars at 60°C.

In order to speed up the reaction, it is especially advantageous to work in the presence of an ammonium salt such as ammonium chloride or ammonium hydrogen carbonate.

It is preferable to use ammonium hydrogen carbonate which enables the reaction rate to be increased while retaining its selectivity. Generally, a stoichiometric amount of ammonium salt is used relative to the β-phenylglycidic acid employed.

Generally, the process is carried out using the - 4 salt of (2R,3R)-β-phenylglycidic acid with amethylbenzylamine. However, it is also possible to use an alkali metal (sodium, potassium) salt which is obtained by the action of a base (sodium hydroxide, potassium hydroxide) in stoichiometric amount on the salt of (2R,3R)-β-phenylglycidic acid with α-methylbenzylamine, or the ammonium salt which is obtained by displacement of the salt of (2R,3R)-β-phenylglycidic acid with α-methylbenzylamine by an excess of ammonia solution. In 10 the latter case, it is possible to favour the displacement by continuous or semi-continuous extraction of the amethylbenzylamine with a suitable organic solvent such as toluene.

It is especially advantageous to use the ammonium 15 salt of (2R,3R)-β-phenylglycidic acid, which enables the ring-opening with ammonia to be rendered both regioselective and stereoselective.

Irrespective of the manner in which the action of ammonia on (2R,3R)-β-phenylglycidic acid is carried out, the (2R,3S)-β-phenylisoserine may be isolated according to one of the following methods: 1) the excess ammonia may be removed under reduced pressure so as to obtain the ammonium salt of (2R,3S)β-phenylglycidic acid in aqueous solution. After the addition of a strong mineral acid, the (2R,3S)β-phenylisoserine precipitates and is separated by - 5 filtration; or alternatively 2) before, during or after the removal of the ammonia under reduced pressure, it is possible to add an alkali metal base (sodium hydroxide, potassium hydroxide) or alkaline earth metal base (quicklime or slaked lime), the salt formed precipitates after the addition, where appropriate, of an organic solvent such as acetone. The alkali metal or alkaline earth metal salt thereby obtained is separated by filtration. In order to facilitate salting-out of the salt, especially the sodium salt, of (2R,3S)-β-phenylisoserine, and to improve the yield, it may be advantageous to saturate the water present in the reaction mixture by adding sodium chloride. (2R,3R)-β-Phenylglycidic acid may be prepared under the conditions described by J-N. Denis et al., J. Org. Chem., 51, 46-50 (1986).

The (2R,3S)-β-phenylisoserine obtained by carrying out the process according to the invention is especially useful for performing the synthesis of therapeutically useful products such as the taxane derivatives of general formula: in which R represents a hydrogen atom or an acetyl radical and R^ represents a phenyl or t-butoxy radical.

By the action of a benzoylating agent (benzoyl 5 chloride) or of a t-butoxycarbonylating agent (t-butyl dicarbonate) and then of an agent for protection of the hydroxyl function, (2R,3S)-β-phenylisoserine yields the product of general formula: (HI) and Zj in which Rj represents a phenyl or t-butoxy radical represents a group protecting the hydroxyl function (1-ethoxyethyl).

By condensation of the acid of general formula (III) with baccatine III or 10-deacetylbaccatine III in 15 which the hydroxyl functions at the 7-position and, where appropriate, at the 10-position are protected by protective groups (silyl, 2,2,2-trichloroethoxycarbonyl radicals), - 7 followed by replacement of the protective groups with hydrogen atoms, a product of general formula (II) is obtained.

The condensation of the acid of general formula 5 (III) with protected baccatine III or protected -deacetylbaccatine III, as well as the replacement of the protective groups with hydrogen atoms, may be carried out under the conditions described in European Patent EP-0,336,840 or EP-0,336,841.

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

EXAMPLE 1 α-Methylbenzylamine (2R,3R)-B-phenylglycidate (3 kg), assaying at 98% and the enantiomeric excess of which is greater than 98.5%, and 32% (w/w) ammonia solution (15 litres) are introduced into a column. At the bottom of the column, toluene is introduced by a metering pump at a flow rate of 3 to 5 litres/hour. The toluene solution which separates out at the column head is removed by overflowing.

After 18 litres of toluene have been introduced, α-methylbenzylamine is no longer detected in the toluene extract.

The ammonium β-phenylglycidate solution obtained above and 32% (w/w) ammonia solution (30 litres) are introduced into a 150-litre autoclave. The autoclave is closed and then heated in the course of 1 hour to 60°C with - 8 stirring. The pressure is in the region of 2.5 bars. Stirring is continued at 60°C for 5 hours and the autoclave is then allowed to cool to 18°C. The ammonia is removed by distillation under reduced pressure (100-700 mm Hg; 13.3-93 kPa) at 24 °C after the addition of sodium chloride (9 kg) and sodium hydroxide pellets (0.42 kg) in water (2.5 litres). When the pressure in the apparatus reaches 45 mm Hg (6 kPa), the reaction mixture is heated to 48°C in order to dissolve the salts and is then cooled to a temperature of between -5 and -8°C for 3 hours.

The white crystals obtained are separated by filtration and then dried at 40°C under reduced pressure (1 mm Hg; 0.13 kPa). (2R,3S)-β-Phenylisoserine sodium salt (1932 g) , m.p. 218°C, is thereby obtained.

The 13C nuclear magnetic resonance spectrum of the (2R,3S)-β-phenylisoserine sodium salt, determined in deuterated water at 90 MHz, is characterised by the following chemical shifts (6): 60.2 (1JCH=140 Hz); 80.0 (1JCH=147 Hz; 2J=2.6 Hz); 129.6; 130.2; 131.5; 144.4 and 181.6 ppm.

EXAMPLE 2 α-Methylbenzylamine (2R,3R)-β-phenylglycidate (10 kg), water (15 litres) and toluene (20 litres) are introduced into a 250-litre reactor, and 4N sodium hydroxide (10 litres) is then added in the course of 10 minutes at a temperature in the region of 20°C. The mixture - 9 is stirred for 1 hour. The aqueous phase is separated after settling has taken place. The toluene phase, which contains α-methylbenzylamine, is retained. The aqueous phase is washed with toluene (2 x 10 litres) to remove all of the a5 methylbenzylamine. From the combined toluene phases, the amethylbenzylamine may be isolated.

Ammonium chloride (1.860 kg) and 20% (w/v) ammonia solution (162 litres) are added to the aqueous phase placed in a 250-litre reactor. The mixture is heated to 50°C and then kept stirring for 17 hours. After cooling to 35°C, sodium chloride (35 kg) is added and the mixture is then maintained at this temperature for 30 minutes. It is allowed to cool slowly (2 hours) to a temperature of between 0 and 5°C and is then maintained for 1 hour at this temperature. The precipitate is separated by filtration and then dried under reduced pressure at 50°C. A dry product (7 kg) is thereby obtained, which product contains sodium chloride (approximately 25%) and pure (2R,3S)β-phenylisoserine sodium salt (approximately 5.300 kg).

The yield is 72%.

The product thereby obtained may be used in the subsequent synthesis operations without further treatment.

Claims (12)

1. (2R,3S)-β-Phenylisoserine and its salts with alkali metals, alkaline earth metals and nitrogenous bases.

2. A process for preparing (2R,3S)5 β-phenylisoserine, optionally in salt form, which comprises reacting ammonia with (2R,3R)-β-phenylglycidic acid or one of its salts, and isolating (2R,3S)-β-phenylisoserine, optionally in salt form.

3. Process according to claim 2, wherein from 10 10 to 100 moles of ammonia are used per mole of (2R,3R)-Bphenylglycidic acid.

4. Process according to claim 2 or 3, wherein the reaction is performed in water or in an organic solvent.

5. Process according to claim 4, wherein the 15 solvent is an aliphatic alcohol of 1 to 4 carbon atoms.

6. Process according to any one of claims 2 to 5, wherein the reaction is performed in the presence of an ammonium salt.

7. Process according to claim 6, wherein the 20 ammonium salt used is ammonium chloride or ammonium hydrogen carbonate.

8. Process according to claim 6 or 7, wherein one mole of ammonium salt is used per mole of (2R,3R)-Bphenylglycidic acid employed. 25

9. Process according to any one of claims 2 to 8, wherein the reaction is performed at a temperature of - 11 between 0 and 100°C.

10. Process according to claim 2 substantially as described in Example 1 or 2.

11. (2R,3S)-β-Phenylisoseine and its salts when 5 prepared by a process as claimed in any one of claims 2 to 10.

12. Process for the preparation of a taxane derivative of formula: in which R represents a hydrogen atom or an acetyl radical 10 and Rj represents a phenyl or t-butoxy radical, which comprises reacting (2R,3S)-B-phenylisoserine with a benzoylating or t-butoxycarbonylating agent and then with an agent for protection of the hydroxyl function, condensing the product obtained with baccatine III or 1015 deacetylbaccatine III in which the hydroxyl functions at the 7- and, where appropriate, the 10-position(s) are protected, and then, after replacement of the groups protecting the hydroxyl functions with hydrogen atoms, isolating the product obtained.