EP0638059A1

EP0638059A1 - Process for the preparation of 3(s)-methylheptanoic acid and intermediates therefor

Info

Publication number: EP0638059A1
Application number: EP93903682A
Authority: EP
Inventors: Charles K-F Chiu
Original assignee: Pfizer Inc
Current assignee: Pfizer Inc
Priority date: 1992-05-01
Filing date: 1993-02-02
Publication date: 1995-02-15
Also published as: FI945119A0; JPH07502538A; FI945119A; WO1993022269A1; CA2134093A1

Abstract

3(S)-methylheptanoic acid is prepared by fractional crystallization of the salt of racemic 3-methylheptanoic acid with (S)-α-methylbenzyl amine followed by acidification.

Description

PROCESS FOR THE PREPARATION OF 3 (S)-METHYLHEPTANOIC ACID AND INTERMEDIATES THEREFOR ^• *

Background of the Invention The present invention is directed to a process and intermediates for the manufacture of 3(S)-methylheptanoic acid of the absolute stereochemical formula (I)

(I) which is a useful intermediate for the preparation of immunoregulatory agents of the formula (II)

(II) wherein R⁴ and R⁵ are each hydrogen or one of R⁴ and R⁵ is hydrogen and the other is (C,-C₆)alkyl or (C₆-C₈)cycloalkylmethyl as described in copending, commonly owned United States Patent Applications Serial Nos. 07/346,118, filed February 21 , 1989 and 07/341 ,350 filed February 21 , 1989, which are herein incorporated by reference.

A procedure used to prepare 3(S)-methylheptanoic acid is described by U.S. Serial No. 07/341 ,350 as shown below. TBDΠS

TBDMS

U. S. Serial No. 07/346,118 describes the synthesis of S-3-alkylheptanoic acids from a trans-4-alken-3-ol of the formula (III)

(I") wherein R is methyl or ethyl which is converted to a compound of the formula (IV)

(IV) by the action of t-butyl hydroperoxide, in a reaction inert solvent in the presence of titanium tetraisopropoxide and L-(+)-diisopropyl tartrate, in an amount sufficient to oxidize the S-enantiomer and in a second step, the product of the above reaction is stereospecifically condensed with a trif^^J-alkyljorthoacetate and, without isolation, the intermediate allyl-enol ether rearranged, in the presence of an acid in a reaction inert solvent, to yield a (C_T-CaJalkyl 3(R)-alkyl-4-hepenoate of the absolute stereochemical formula (V)

0H

(V) which may be hydrogenated to the desired S-3-alkylheptanoic acid.

Optically pure 3(S)-methylheptanoic acid (I) has been prepared from the corresponding racemate in unspecified yield by multiple (eight) crystallizations of the quinine salt at an inconveniently low temperature of -15°C. [Levene et al., J. Biol. Chem. 95, pp. 1-24, 1932, at page 18, there called 2-n-butylbutyric acid-4]. Optically active 3-methylheptanoic acid has subsequently been produced by a number of other methods (Soai et al., J. Chem. Soc, Chem. Commun. 1985, pp. 496-470; Oppolzer et al., Helv. Chim. Acta. 68, pp. 212-215 (1985); Ohno et al., U.S. Patent 4,564,620 (1986); Mori et al., Synthesis 1982, pp. 752-753; Oppolzer et al., Helva. Chim. Acta. 64, pp. 2808-2811 (1981); Mukaϊyama et al., Chem. Lett. 1981 , pp. 913-916; Posner et al., J. Am. Chem. Soc 103, pp. 2886-2888 (1981); Mukaiyamaet al., Bull. Chem. Soc. Japan, 51 , pp. 3368-3372 (1978); Meyers etal., J. Am. Chem. Soc. 98, pp. 2290-2294 (1976)]. The above described preparations generally suffer from one or more disadvantages: the product acid is not optically pure, the reaction temperatures are inconveniently low, between -78° C and -30° C, use of organometallic reagents, which are difficult to handle on a large scale, is required, overall yields are low; and/or the required reagents are not readily available.

Summary of the Invention

This invention relates to a novel process for the preparation of 3(S)- methylheptanoic acid which comprises the sequential steps of;

(a) reaction of racemic 3-methylheptanoic acid with (S)-oc-methylbenzyl amine to form a mixture of diastereomeric salts; (b) separation of the diastereomeric salts from step (a) by recrystallization to yield (S)-oc-methylbenzylammonium 3(S)-methylheptanoate;

(c) conversion of said (S)-α-methylbenzyΙammonium 3(S)-methyl heptanoate of step (b) to 3(S)-methylheptanoic acid by treatment with acid.

In another aspect, this invention relates to the use of acetonitrile as the recrystallizing solvent in step (b).

In yet another aspect this invention relates to the compound (S)-cc- methyibenzyIammonium^*3(S)-methyIheptanoate.

In yet another aspect this invention comprises a process for preparation of 3(S)- methylheptanoic acid from an enriched mixture of 3R and 3S-methylheptanoic acid which contains a preponderance of the (S) isomer. Such an enriched mixture containing about 70% 3(S)-methylheptanoic acid is available from the procedure of

Meyers, et al., J. Am. Chem. Soc, 98_f 2290-2294, (1976).

Detailed Description of the Invention As used here, the expression "reaction inert solvent" refers to a solvent system in which the components do not react with starting materials, reagents, intermediates or products in a manner which adversely affects the yield or purity of the desired product. Racemic 3-methylheptanoic acid is readily available by the procedure of Organic Synthesis, Coll. Vol. 5, 762-766, (John Wiley & Sons, 1973) which is herein incorporated by reference.

(S)-oc methylbenzylamine is available from the Aldrich Chemical Co., Milwaukee, WI 53233.

Racemic 3-methylheptanoic acid is dissolved in a reaction inert solvent and an approximate molar amount of (S)-oc methylbenzylamine is added slowly. The choice of solvent is not critical, but it was found that the diastereomeric salt readily precipitates from acetonitrile which is the preferred solvent. The temperature of the salt formation is not critical, but room temperature was found to be convenient and is preferred.

The diastereomeric salt of racemic 3-methylheptanoic acid and (S)-cc- methylbenzylamine is purified by recrystallization to isolate the desired (S)-oc- methylbenzylammonium (S)-3-methylheptanoate which is generally less soluble than the other diastereomeric salt i.e., R-acid/S-amine. Acetonitrile is the preferred solvent for recrystallization. Multiple recrystallizations may be required to obtain the required optical purity and three crystallizations were found to yield a 98% optically pure product. It was found to be convenient to dissolve the salt in boiling solvent and cool slowly over several hours until the product has precipitated. 3(S)-me_hylheptanoic acid is obtained from the salt by acidification of a solution of the salt with strong acid at room temperature. The temperature, solvent and acid are not critical. Any strong mineral acid is effective; hydrochloric acid is preferred. The preferred solvent is a two phase system employing n-hexanes or ethylacetate and water, but any reaction inert solvent system would be acceptable.

The following examples are provided solely for the purpose of further illustration and are not intended to limit the invention which is defined by the claims.

Example 1

Preparation of the Diastereomeric Salt of 3-Methylheptanoic Acid and (S)-oc -Methyl Benzylamine A solution of racemic 3-methylheptanoic acid (3.1 g, 21.5 mmol) in acetonitrile (20 mL) was treated with dropwise addition of (S)-o -methylbenzylamine (2.8 mL, 21.5 mmol).

White solid was observed to precipitate, and the resulting white suspension was stirred at room temperature for 3.5 hours. The white solid was collected by suction filtration and dried in vacuum (house vacuum, 48° C) overnight. 4.65 g of the diastereomeric salt was obtained (82% yield).

Example 2 Recrystallization of the Diastereomeric Salt; (S)--^χ-methyΙbenzylammonium 3(S)- methylheptanoate

A slurry of the 3-methylheptanoic acid/(S)-oc -methylbenzylamine salt (30 g) from

Example 1 in acetonitrile (300 mL) was stirred mechanically under nitrogen and heated with an oil bath until complete dissolution was observed. The solution was allowed to cool slowly as white solid precipitated. The resulting suspension was stirred overnight and the white solid was collected by suction filtration. After drying in a vacuum oven, 20.77 g of salt was obtained (37% ee by rotation, [^*χf_D ⁵ =-11.27°, C=5.05,CHCI₃). The above procedure was repeated twice to provide 10.98 g of the salt (73% yield of theoretical). The optical purity was judged to be 97%ee ([cc]_D =-13.66°, C=5.05, CHC by comparing the rotations of diastereomeric salts from optically pure acid prepared by the method of U.S. Serial No. 07/341 ,350 and the title compound.

Example 3 3(S,-Methylheptano.c Acid A. The salt from Example 2 (1.59 g, 5.99 mmol) in a mixture of ethyl acetate (20 mL) and water (10 mL) was treated with 1N HCl (10 mL) and stirred at room temperature for 1.25 hours. The aqueous layer was separated from the organic and extracted with ethyl acetate (20 mL). The organic layer and extract were combined, washed with water (10 mL) and then brine. After drying over sodium sulfate, the solvent was removed to provide the acid as a colorless oil in quantitative yield.

B. The salt from Example 2 (1.0 g, 3.77 mmol) in a mixture of n-hexanes (10 mL) and water (5 mL) was treated with 1N HCl (5 mL) and stirred at room temperature for 3.5 hourε. The aqueous layer (pH^"1) was separated from the organic and extracted with n-hexanes (2x20 mL). The organic layer and extracts were combined, washed with water (10 mL) and then brine. After drying over sodium sulfate, the solvent was removed to provide the acid aε a colorless oil (0.54 g, 99.4% yield).

Claims

1. A proceεε for the preparation of 3(S)-methylheptanoic acid which comprises the sequential steps of: (a) reaction of racemic 3-methylheptanoic acid with (S)-oc -methyl benzylamine to form a mixture of diastereomeric salts;

(b) separation of the diastereomeric salts from step (a) by recrystallization to yield (S)-cc -methyl benzylammonium 3(S)-methylheptanoate;

(c) conversion of said (3)-^*χ -methyl benzylammonium 3(S)-methyl heptanoate of step (b) to 3(S)-methylheptanoic acid by treatment with acid.

2. The procesε of claim 1 in which εaid recryεtallization of εtep (b) iε accomplished uεing acetonitrile aε εolvent.

3. The compound (S)- ^χ -methylbenzyl ammonium 3-(S)-methyiheptanoate.

4. A proceεε for the εeparation of 3(S)-methylheptanoic acid from a mixture of 3(S)- and 3(R)-methylheptanoic acidε which contains a preponderance of 3(S)- methylheptanoic acid which compriεeε the εequential εtepε of:

(a) reaction of εaid mixture of 3-methylheptanoic acidε with (S)-oc- methylbenzylamine to form a mixture of diaεtereomeric εaltε;

(b) separation of the diastereomeric saltε from εtep (a) by recryεtallization to yield (S)-cc -methyl benzylammonium 3(S)-methylheptanoate;

(c) converεion of εaid (S)-α -methyl benzylammonium 3(S)-methyl heptanoate of εtep (b) to 3(S)-methylheptanoic acid by treatment with acid.