SK74693A3 - Beta-phenylisoserine-(2r, 3s), salts, preparation and use thereof - 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

Technical field

The present invention relates to (2R, 3S) -beta-phenyl and to the compounds of formula I:

COOH

(I) its alkali metal, alkaline earth metal and nitrogen base salts, process for its preparation and its use for the preparation of therapeutic active substances.

BACKGROUND OF THE INVENTION

While the (2R, 3R), (2S, 3S) and (2S, 3R) beta-phenylisoserine isomers are known in the scientific literature, for example, the articles of E. Kamandi et al. in Arch.Pharmaz., 307, 871-878 (1974), E. Kamandi et al. in Pharm. Pharm., 308, 135-141 (1975) or K. Harada and Y. Nakajima in Bull.Chem.Soc.Japan, 47, 2911-2912 (1974), or (2R, 3S) -beta. Phenylisoserine to date described so far other than in the form of the ester (H.H. iga et al., Tetrahedron, 46 (11) 3841-3850 (1990)).

SUMMARY OF THE INVENTION

According to the invention, (2R, 3S) -beta-phenylisoserine, optionally in the form of a salt, can be obtained by treating ammonia with (2R, 3R) -beta-phenyl 1 g of 1-acid, preferably in the form of an alkali metal or alkaline earth metal salt. , potassium or calcium salt), ammonium or nitrogen base salts (alpha-methylbenzylamine, pyridine).

Typically, this reaction is carried out in water, optionally in admixture with an organic solvent such as methanol. Preferably, said reaction is carried out in water.

In the process according to the invention, it is necessary to use an excess of ammonia with respect to (2R, 3R) -beta-phenyl 1 g of 1-ylic acid. Usually 10 to 100 moles of ammonia, preferably 50 to 80 moles of ammonia, are used per mole of (2R, 3R) -beta-phenylglycidic acid.

The ammonia is preferably used in the form of a concentrated aqueous solution, such as a solution having a concentration in the range of 20 to 32% by weight i.

The process according to the invention is carried out at a temperature of 0 to 100 ° C, preferably at a temperature of 40 to 60 ° C. Usually, the process is carried out at atmospheric pressure or else at an autogenous pressure, which at 60 [deg.] C. equals about 5 bar.

In order to accelerate the reaction, it is particularly advantageous to work in the presence of an ammonium salt such as ammonium chloride or ammonium bicarbonate. It is preferred to use ammonium bicarbonate which allows to increase the reaction rate while maintaining the selectivity of the reaction. Usually, a stoichiometric amount of said ammonium salt relative to the amount of beta-phenyl acid used is used.

The process according to the invention is usually carried out using (2R, 3R) -beta-phenylglycidic acid salt and 1-methylbenzylamine.

However, it is also possible to use an alkali metal salt (sodium salt, potassium salt) which is obtained by treating the (2R, 3R) -beta-phenylglycidic acid salt with alpha-methylbenzylamine by stoichiometric treatment with a base (sodium hydroxide, potassium hydroxide), or ammonium salt, which is obtained by treating excess (2R, 3R) -beta-phenylglycidic acid with alpha-methylbenzylamine with an excess of ammonia. In the latter case, the course of the reaction can be favorably influenced by continuous or semi-continuous extraction of alpha-methylbenzylamine with a suitable organic solvent, such as toluene.

Of particular interest is the use of the ammonium salt of (2R, 3R) -beta-phenylglycidic acid, which allows ring opening by ammonia, which is regioselective and stereoselective.

Regardless of how (2R, 3R) -beta-phenylglycidic acid is treated with ammonia, (2R, 3S) -betaphenyl may be isolated by one of the following methods:

1) Excess ammonia can be removed under reduced pressure to obtain an aqueous ammonium salt of (2R, 3S) -beta-phenylglycidic acid. Upon addition of a strong mineral acid, (2R, 3S) -beta-phenylisoserine precipitates which is separated by filtration, or

2) alkali metal (sodium hydroxide or potassium hydroxide) or alkaline earth metal (calcium oxide, calcium hydroxide) may be added before, during or after removal of ammonia under reduced pressure; the salt formed precipitates upon optional addition of an organic solvent such as acetone. The alkali metal or alkaline earth metal salt thus obtained is separated by filtration. In order to facilitate the salting out of the salt, especially the sodium salt of (2R, 3S) -beta-phenylcarboline, and to improve the yield, it is advantageous to saturate the water present in the reaction mixture by adding sodium chloride.

Said (2R, 3R) -beta-phenyl-1-gacidic acid may be prepared under the conditions described by J-N.Deriis et al. Chem., 51, 46-50 (1986).

The (2R, 3S) -beta-phenylisoserine obtained by the process according to the invention is particularly suitable as active compounds.

CO-O-are derivatives for the synthesis of a therapeutically taxane of formula

wherein R represents an atom represents a phenyl group of hydrogen or an acetyl group and R => or a tert-butoxy group.

By treatment with a benzoylating agent (benzoyl chloride) or a tert-butoxycarbonylating agent (tert-butyl dicarbonate) and then a hydroxy-protecting agent, a compound of formula III is obtained from beta-phenyl and serine:

RJCO-NH

COOH (III) wherein R 1 represents a phenyl group or a tert-butoxy group and Z 1 represents a hydroxyl function protecting group (1-ethoxyethyl).

Condensation of an acid of formula III with saccharin III or 10-deacetylbaccatin III, whose hydroxyfunction at position 7 and optionally at position 10 are protected by protecting groups (silylated groups, 2,2,2, -trichloroethoxycarbonyl group) and subsequent replacement of said protecting groups hydrogen atoms to give the product of formula II.

Said condensation of an acid of formula III with baccatin III or with 10-deacetylbaccatin III protected as described above, as well as the replacement of the protecting groups with hydrogen atoms can be carried out under the conditions described in European patents EP-0 336 840 or EP-0 336 841.

In the following, the invention will be further elucidated by means of examples of specific embodiments thereof, which, however, are provided by way of illustration only and are not intended to limit the scope of the invention as defined by the claims.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

3 kg of alpha-methylbenzylamine (2R, 3R) beta-phenylglycidate having a purity of 98% and having an enantiomeric excess of greater than 98.5% and 15 liters of 32% (w / w) are loaded onto the column. ammonia. Toluene at a rate of 3-5 liters per hour is fed to the bottom of the column. The toluene solution is removed at the top of the column by flow. After the introduction of 18 liters of toluene, the presence of α 1 -methylbenzylamine can no longer be detected in this toluene extract.

A solution of beta-phenyl 1 g of ammonium nitrate and 30 liters of 32% (w / w) ammonia was introduced into the 150-liter autoclave as described above. The autoclave is sealed and heated to 60 ° C with stirring for one hour. The pressure in the autoclave is about 0.25 MPa. Stirring was then continued at 60 ° C for 5 hours and then allowed to cool to 18 ° C. The ammonia is removed by distillation under reduced pressure (13.3 to 93 kPa) at 24 ° C after the previous addition of 9 kg of sodium chloride and 0.42 kg of lime sodium hydroxide in 2.5 liters of water. When the pressure in the autoclave reaches 6 kPa, the reaction mixture is heated to 48 ° C to dissolve the salts, and then cooled to -5 to -8 ° C for 3 hours.

White crystal obtained e. The mixture is separated by filtration and then dried at 40 ° C under reduced pressure (0.13 kPa). In this way, 1932 g of (2R, 3S) -beta-phenyl-iso-serine sodium salt melting at 218 ° C is obtained.

^{13 The} C-Nuclear Magnetic Resonance Spectrum of (2R, 3S) -beta-phenylene iodine sodium, determined in heavy water at 90 MHz, is characterized by the following delta chemical shifts:

60.2 ( ¹ JCH = 140 Hz);

80.0 ( ¹ JCH = 147Hz; ² J = 2.6Hz);

129.6; 131.5; 144.4 and 181.6 ppm.

Example 1 a d 2

10 kg of alpha-methylbenzylamine- (2R, 3R) -beta-phenyl 1 g of cyanate (35.08 mol), 15 liters of water and 20 liters of toluene are introduced into a 250-liter reactor and then 10 liters are added over 10 minutes. 4N sodium hydroxide at a temperature close to 20 ° C. The mixture was stirred for one hour. The aqueous phase is separated by decantation. The toluene phase containing alpha-methylbenzylamine is retained for further processing. The aqueous phase is washed twice with 10 liters of toluene to completely remove the alpha-methylbenzylamine. The α-methylbenzylamine can then be isolated from the combined toluene phases.

1.860 kg of ammonium chloride and 162 liters of 20% (w / v) ammonia are added to the aqueous phase introduced into the 250-liter reactor. The mixture was heated to 50 ° C and maintained at this temperature for 17 hours with stirring. After cooling to 35 ° C, 35 kg of sodium chloride are added and the mixture is maintained at this temperature for 30 minutes. The reaction mixture is then slowly (over 2 hours) allowed to cool to 0-5 ° C and maintained at this temperature for one hour. The precipitate formed is collected by filtration and then dried under reduced pressure at 50 ° C. In this way, 7 kg of dry product are obtained which contains about 25% sodium chloride and about

5.300 kg of pure (2R, 3S) -beta-phenyl isosine sodium.

Yield 72%.

The compound thus obtained can be used as such in the reaction steps of the following syntheses.

Claims (6)

PATENT CLAIMS (2R, 3S) -Beta-phenylsulfine and its salts with alkali metals, alkaline earth metals or nitrogen bases. 2. Method of preparation (2R, 3S) -beta-phenyliin, optionally in the form of a salt, characterized in that (2R, 3R) -beta-phenyl 1 g of 1-acetic acid or one of its salts is treated with ammonia and then isolated (2R, 3S-beta-phenylene from serine, optionally in the form of a salt. The process according to claim 1, wherein 10 to 100 moles of ammonia are used per mole of (2R, 3R) -beta-phenylglycidic acid. Process according to either of Claims 1 and 2, characterized in that the process is carried out in water or in an organic solvent. 5. process by Claim 4, wherein n and no e n ý t ý m that sa like organic solvent used aliphatic alcohol h u j u c 1 to 4 carbon atoms. 6th process by any of the claims 1 to 5, y z n a - č e n ý t ý m, that in addition to working in presence ammonium salt. 7. process by of claim 6; and no e n ý t ý m that ammonium salt is a ammonium chloride or bicarbonate ammonium • 8. process by any of the claims 6 or 7, v y z - n and no e n ý team that it will be used one ammonium mol salts to one mole of (2R, 3R) -beta-phenylglycidic acid used. Process according to one of Claims 1 to 8, characterized in that the process is carried out at a temperature of 0 to 100 ° C. Use of (2R, 3S) -beta-phenylisoserine according to claim 1 for the preparation of a taxane derivative of the formula wherein R represents a hydrogen atom or an acetyl group and R 1 represents a phenyl group or a tert-butoxy group, (2R, 3S) -beta-phenylisoserine is treated with a benzoylating or tert-butoxycarbonylating agent and then a hydroxy-protecting agent and subsequently the product obtained is condensed with baccatin III or 10-deacetylbaccatin III, whose hydroxy function is in the 7-position and optionally in the 10-position, they are protected, and after replacement of the hydroxyl function protecting groups with hydrogen atoms, the product obtained is isolated.