FI113641B - Process for the preparation of (2R, 3S) -beta-phenyl-isoserine, its use and its salts - 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

113641

The present invention relates to the preparation of (2R, 3S) -β-phenylisoserine of the formula h2n cooh ») —L ™

C6H5 OH

10 as well as its alkali metal and alkaline earth metal salts and salts with nitrogenous bases. The invention also relates to its salts and its use in the manufacture of therapeutically active products.

Although the (2R, 3R), 15 (2S, 3S) and (2S, 3R) isomers of β-phenylisoserine are known in the scientific literature, for example, E. Kamandi et al. Arch. Pharmaz., 307, 871-878 (1974), Kamandi, E. et al., Arch. Pharmaz., 308, 135-141 (1975) or K. Harada and Y. Nakajima, Bull. Chem. Soc. Japan 47, 2911-2912 (1974), 20 (2R, 3S) -β-phenylisoserine does not yet appear to be described other than in the ester form [H. König et al., Tetrahedron 46 V ': (11) 3841-3850 (1990)].

The present invention relates to a process for the preparation of (2R, 3S) -β-phenyl- for the preparation of isoserine, optionally in the form of a salt, which process comprises reacting an aqueous solution of ammonia with a salt of (2R, 3R) -β-phenylglycidic acid, wherein 10-100 moles of ammonia are used per mole of (2R, 3R) -p- • · · 'phenylglycidic acid and the process is carried out at a temperature of 0-100 ° C. The process is characterized by the use of ammonium salt of (2R, 3R) -β-phenylglycidic acid and the isolation of (2R, 3S) -β-phenylisoserine, possibly in the form of a salt. The salt of (2R, 3R) -β-phenylglycidic acid, ···, is preferably in the form of an alkali or alkaline earth metal salt (sodium, potassium, calcium), an ammonium salt> 35 or a nitrogenous base (α-methylbenzylamine, pyr dine) in the form of a salt.

2 113641

Generally, the process is carried out in water, optionally in admixture with an organic solvent such as methanol. Preferably, water is employed.

In carrying out the process, it is necessary to use 5 excess ammonia in relation to (2R, 3R) -β-phenylglycidic acid. 10 to 100 moles of ammonia, and preferably 50 to 80 moles, per mole of (2R, 3R) -β-phenylglycidic acid are used.

It is preferable to use ammonia in the form of a concentrated aqueous solution of ve-10, such as a solution having a concentration between 20 and 32% (w / w) at a temperature of about 25 ° C.

The process is carried out at a temperature between 0 and 100 ° C, preferably between 40 and 60 ° C. Generally, an autogenous pressure of about 2.5 bar at 60 ° C is employed at atmospheric pressure or well below.

In order to accelerate the reaction, it is particularly useful to act in the presence of an ammonium salt such as ammonium chloride or ammonium hydrogen carbonate. It is preferable to use ammonium bicarbonate 20 which allows the reaction rate to be increased while maintaining full selectivity. Generally, the stoichiometric amount of the ammonium salt is used relative to the β-phenylglycidic acid used.

lii ·

In general, the process is carried out using a salt of (2R, 3R) - 25-phenylglycidic acid with α-methylbenzylamine.

• I »» *

However, the alkali metal salt '(sodium, potassium) obtained by reacting the base (sodium hydroxide, potassium hydroxide) with a stoichiometric amount of (2R, 3R) -β-phenylglycidic acid and α-methylbenzylamine may also be used with, or the ammonium salt of · '· *; obtained by displacing (2R, 3R) -β-phenylglycidic acid and α-. salt of methylbenzylamine with excess ammonia. In the latter case, it is possible to favor displacement of "· 35 α-methylbenzylamine by continuous or semi-continuous extraction with a suitable organic solvent such as toluene.

Of particular interest is the use of the ammonium salt of (2R, 3R) -β-phenylglycidic acid, which allows for the initiation of both the regioselectively and stereoselectively with the am-5 mono.

Regardless of the manner in which the ammonia is reacted with (2R, 3R) -β-phenylglycidic acid, any of (2R, 3S) -β-phenylisoserine can be isolated by any of the following methods: 1) excess ammonia can be removed under reduced pressure to give the (2R, 3S) -β-phenylglycidic acid ammonium salt in aqueous solution. After addition of strong mineral acid, (2R, 3S) -β-phenylisoserine precipitates and is isolated by filtration, or 2) before, during or after elimination of the ammonia under reduced pressure, it is possible to add an alkaline base (sodium hydroxide, potassium hydroxide); alkaline earth alkali (slaked or slaked lime); the resulting salt precipitates, if necessary, after the addition of an organic solvent such as acetone. The thus obtained alkali or alkaline earth salt is filtered off. In order to facilitate separation of the salt, especially '1' sodium salt, from (2R, 3S) -β-phenylisoserine, and to improve the yield, jv. It is useful to saturate the water present in the reaction mixture by addition of sodium chloride.

• (2R, 3R) -β-Phenylglycidic acid can 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 the process of the invention is particularly useful for the synthesis of therapeutically active products. as with taxane derivatives of the following general formula:> * 4 113641 R O S> oh

RjCO-NH1 / 3sl CO-O \ X> L (II)

? C6H5 /? 2R

Where OH represents a hydrogen atom or an acetyl radical and R 10 represents a phenyl radical or t-butoxy.

Through the action of a benzoyl (benzoyl chloride) or t-butoxycarbonylating agent and then a hydroxy function protecting agent, β-phenylisoserine leads to the product of the general formula: 15

RjCO-NH

, L-C 6 H 5 is (III) 0-z, 20 1 where R 1 represents a phenyl radical or t-butoxy and Z 1 'represents a hydroxy function group (ethoxy-1-ethyl).

· By condensation of an acid of general formula (III) with: * ·, · with baccatin III or desacetyl-10-baccatin III, · · in which the hydroxy functions in position -7 and possibly in position -10 are protected by protecting groups (silyl radicals, trichloro) -2,2,2-ethoxycarbonyl) followed by substitution of hydrogen atoms for protecting groups gives the product of general formula (II).

· * ·. ' 30 Condensation of the acid of general formula (III) with protected baccatin III or protected desacetyl-10-baccatin III as well as replacement of protecting groups. US hydrogen atoms may be carried out under the conditions described in EP-0 336 840 or EP-0 336 841.

5, 113641

The following example, which is presented in a non-limiting manner, illustrates how the invention may be practiced.

Example 1 3 kg of (2R, 3R) -β-phenylglycidate of α-methylbenzylamine (98%) with an enantiomeric excess of greater than 98.5% and 15 liters of 32% (w / w) ammonia are introduced into the column. Toluene is introduced into the bottom of the column by means of a metering pump in an amount of 10 3 to 5 1 / hour. The toluene solution which decantes to the top of the column is removed by overflow. After the addition of 18 liters of toluene, no α-methylbenzylamine is detected in the toluene extract.

Introduce into the 150-liter autoclave the above-obtained Ammonium 15-N, N-phenylglycidate solution and 30 liters of 32% (w / w) ammonia. The autoclave is sealed, then heated to 60 ° C for 1 hour with stirring. The pressure is about 2.5 bar. Stirring is continued at 60 ° C for 5 hours, then allowed to cool to 18 ° C. Ammonia is removed by 20 vacuum distillations (100 - 700 mmHg; 13.3 - 93 kPa) at 24 ° C after addition of 9 kg of sodium chloride t · · V and 0.42 kg of sodium hydroxide in pastes in 2.5 liters of Vatu. When the pressure in the apparatus has reached 45 mmHg (6 kPa), the reaction mixture is warmed to 48 ° C to dissolve the salts, then cooled again to -5 to -8 ° C for 3 hours.

The white crystals obtained are separated by filtration, then dried at 40 ° C under reduced pressure (1 mm Hg; 0.13 kPa). This gives 1932 g of the sodium salt of (2R, 3S) -β-phenylisoserine, which melts at 218 ° C.

.. · 13C- (2R, 3S) -β-Phenylisoserine Sodium Salt: *; the nuclear magnetic resonance spectrum determined in deuterated water at 90 MHz is characterized by the following chemical shifts (δ): 60.2 (1 JCH = 140 Hz); 80.0 7 35 (1 JCH = 147 Hz; 2 J = 2.6 Hz); 129.6; 130.2; 131.5; 144.4 and, 181.6 ppm.

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Example 2

Introduce 10 kg of α-methylbenzylamine (35.08 moles) (2R, 3R) -β-phenylglycidate, 15 liters of water and 20 liters of toluene into a 250 liter reactor, then add 10 liters of 4 N in 10 minutes. sodium hydroxide at a temperature of about 20 ° C. Stir for 1 hour. The aqueous phase is separated by decantation. The toluene phase containing α-methylbenzylamine is retained. The aqueous phase is washed 2 times with 10 liters of toluene to give alpha-10 all methyl a-methylbenzylamine. Α-methylbenzylamine can be isolated from the combined toluene phases.

Add 1 860 kg of ammonium chloride and 162 liters of 20% (w / v) ammonia to the aqueous phase charged to the 250 liter reactor. Warm to 50 ° C, then keep stirring for 17 hours.

! After cooling to 35 ° C, 35 kg of sodium chloride are added, then kept at this temperature for 30 minutes. Allow to cool slowly (2 hours) to 0-5 ° C, then hold for 1 hour at this temperature. The precipitate is filtered off, then dried under reduced pressure at 50 ° C. This gives 7 kg of dry product containing about 24% sodium chloride and about 5,300 kg of pure (2R, 3S) -β-phenylisoserine sodium salt.

1: 25 The yield is 72%.

The product thus obtained can be used as such for subsequent synthesis operations.

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Claims (7)

113641 A process for the preparation of (2R, 3S) -β-phenylisoserine, optionally in the form of a salt, which comprises reacting an aqueous solution of ammonia with a salt of (2R, 3R) -p-phenylglycidic acid using 10-100 moles of ammonia (2R). , 3R) -β-phenylglycidic acid per mole and the process is carried out at a temperature of 0 to 100 ° C, characterized in that an ammonium salt of (2R, 3R) - 10-phenylglycidic acid is used and (2R, 3S) -β-phenylisoserine is isolated, optionally in salt form . Process according to Claim 1, characterized in that the ammonium salt of (2R, 3R) -β-phenylglycidic acid is obtained by displacement of an alkali metal salt, an alkaline earth metal salt or a salt of nitrogenous bases of (2R, 3R) -β-phenylglycidic acid. Process according to claim 2, characterized in that the displacement is effected by contacting an alkali metal salt or an alkaline earth metal salt of (2R, 3R) -β-phenylglycidic acid with an ammonium salt selected from ammonium chloride and ammonium hydrogen carbonate. . The process according to claim 2, characterized in that the displacement is carried out by contacting the salt of (2R, 3R) -β-phenylglycidic acid with nitrogenous bases in the presence of excess ammonia and a nitrogenous base. -li continuous extraction with an organic solvent. The process according to claim 2 or 4, characterized in that the nitrogenous base is α-methylbenzylamine. 6. A process for the preparation of the taxane derivatives of formula (II) 113641 R 10 - & OH R 10 CO-NH- (R 3 S 5 CO-O - X (II) In which R is a hydrogen atom or an acetyl radical, and Rx is a phenyl or t-butoxy radical, in which (2R, 3S) -β-phenylisoserine is reacted with a benzoylating agent or t-butoxycarbonyl and thereafter the compound thus obtained is reacted with a hydroxy function protecting agent, and then the product obtained is condensed with baccatin III or 10-desacetyl baccatin III having hydroxy groups at the 7-position and optionally at the 10-position the hydroxy groups of 20 are protected and the protecting groups of the hydroxy groups are replaced by hydrogen atoms followed by isolation of the product, *; · characterized in that the (2R, 3S) -β-phenylisoserine used as starting material is obtained according to 1. 7. Salts of (2R, 3S) -β-phenylisoserine with alkali metals, alkaline earth metals or nitrogenous bases. ♦ »♦» »» 113641