JPH07502538A - Method for producing 3(S)-methylheptanoic acid and its intermediates - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] hard study The present invention is based on the absolute stereochemical formula (1) 3(S)-Methylhebutanoic acid production method and intermediates thereof It is something that 3(S)-methylhebutanoic acid of the above formula (1) (with the present inventor) Pending U.S. patent application Ser. No. 07/346°118 (1989 (filed on February 21, 1989) and No. 07/341.350 (filed on February 21, 1989) 1) (These are incorporated herein by reference) (Ko3ki 11 & Saku II ) ('In the formula, R4 and R5 are each hydrogen, or one of R4 and R5 is water. and the others are (CI-C6)alkyl or (C6-C8)nochlor (JT) is used as an intermediate for the production of immunomodulators.

The method used to produce 3(S)-methylhebutanoic acid is described in U.S. Patent Application No. 07/3. It is described in No. 41.350 and is as follows.

U.S. Patent Application No. 07/346.118 has the formula (III) (III) and trans-4-alkesy 3 ('', R is methyl or ethyl) The synthesis of butanoic acid from -ol to 5-3-alkyl is described. In that case, the above Formula (Ill) represents titanium tetraisopropoxide and tartaric acid L-(+)- an amount sufficient to oxidize the S-enantiomer in an inert solvent in the presence of sopropyl by the action of t-butyl hydroperoxide of formula (IV) (IV) and in the second step, the above reaction product is converted into tri[(CI- C3)-alkyl]orthoacetate and isolated. The intermediate allyl-enol ether is prepared in the presence of an acid in an inert reaction solvent without Rearrange the absolute stereochemical formula (V) (V) (CI-C3)alkyl 3(R)-alkyl-4-hepenoate of This can be hydrogenated to give the desired 5-3-alkylhebutanoic acid.

Optically pure 3(S)-methylhebutanoic acid (1) is not suitable for fFJ at -15°C. Crystallization of quinine salt several times (8 times) at low temperature Manufactured in unspecified yields from mint. [Leveno et al., J. Biol. Chem, pp. 95.1-24, 1932, p. 18, 2-n-butyl butyl It is called acid-4]. Subsequently, optically active 3-methylhebutanoic acid was synthesized by numerous other (Soai et al., J. Chew, Soc, Che. m, Commun, 1985, pp. 496-470; 0ppolzer et al. ) Ielv, Chim, Acta 68. pp. 212-215 (1985); Ohno et al., U.S. Patent 4.564.620 (1986); Mori et al. 5ynthesis 1982, pp. 752-753; 0ppolzer et al. He1va, Chim, Acta, 64. pp. 2808-2811 (198 1); Mukaiyama et al., Chew, Lett, 1981, 913 ~Page 916: Po5ner et al., J. Aoll, Chem, Soc, 1 03.2886-2888 (1981); Mukaiyama et al., Bul l, Chem, Sac, Japan, pp. 51.3368-3372 (19 78); Meyers et al., J. Am. Chem. Soc. 98.22 90-2294 (1976)].

The production described above generally suffers from one or more disadvantages: the product acid The reaction temperature was disadvantageously low, between -78°C and -30°C. , requires the use of organometallic reagents that are difficult to handle on a large scale, and the overall Yields are low; and/or the necessary reagents are not readily available.

Legs summary The present invention relates to a novel method for producing 3(S)-methylhebutanoic acid, and The method is (a) Racemic 3-methylhebutanoic acid and (S)-α-methylbenzylamine reacting to form a mixture of diastereomeric salts; (b) the diastereoisomer of step (a); The rheomer salt is separated by recrystallization to form (S)-α-methylbenzylammonium 3(S)-methylhebutanoate obtained; (C) The above (S)-α-methylpencylammonium 3(S)-method of step (b) treating tylheptanoate with acid to convert it to 3(S)-methylhebutanoic acid; It consists of a continuous process.

In another aspect, the invention provides acetonitrile as the recrystallization solvent in step (b). In yet another aspect, the invention provides (S)-α-methylbenzylammonium 3(S)-Methylheptanony 1.

In yet another aspect, the invention provides 3R and Production of 3(S)-methylhebutanoic acid from a concentrated mixture of It consists of the method of Contains about 7096 3(S)-methylhebutanoic acids The concentrated mixtures described above are described by Meyers et al., J.; Am. Che m. Soc. , 98, 2290-2294 (1976). I can do it.

Demoulding into a loquat As used herein, the expression "inert reaction solvent" means that the components are starting materials, adversely affect the yield or purity of the drug, intermediate or product and the desired product. A solvent system that does not react in such a manner.

Racemic 3-methylhebutanoic acid is produced by Organic Synthesis, C oil.

Volume 5, 762-766 (J song n Wiley & Sons, 1973) (which is incorporated herein by reference). Wear.

(S)-α-Methylbenzylamine, Milwaukee, WI 53233 Key Aldrich Chemical Company (Aldric+Chemical Co. ) available from

Racemic 3-methylbutanoic acid is dissolved in an inert reaction solvent and approximately 1 mol. of (S)-α-methylbenzylamine is slowly added. Solvent selection is critical However, the diastereomeric salts are easily separated from the preferred solvent, acetonitrile. It was found that it precipitated.

Although the temperature for salt formation is not critical, room temperature has been found to be convenient and preferred. Ta.

Dialysis of racemic 3-methylhebutanoic acid and (S)-α-methylbenzylamine Stereomeric salts are purified by recrystallization to generally produce other diastereomeric salts, i.e. The desired (S)-α-methylbenzyl ammo is less soluble than the R-acid/S-amine. (S)-3-methylheptanoate is isolated. Acetonitrile is recrystallized is the preferred solvent for Multiple recrystallizations are required to obtain the required optical purity. and that three crystallizations yield a product with optical purity of 98%. I understand. Dissolve the salt in a boiling solvent and wait for several hours until the product precipitates. It has been found advantageous to cool gradually over time. 3(S)-methyl Hebutanoic acid is obtained from the salt by acidifying the salt solution with a strong acid at room temperature. temperature, Solvent and acid are not critical. Any strong inorganic acid is effective; hydrochloric acid is preferred . The preferred solvent is a two-phase system using n-hexane or ethyl acetate and water. However, any inert reaction solvent system could be used.

The following examples are provided solely for further illustrative purposes and are It is not intended to limit the invention as defined in scope.

Jo Shishi-1 Thiaste bundle of 3-methylpencylamine and S)-α-methylpencylamine 1-≧ → Button Sukesuke Racemic 3-methylhebutanoic acid (3.1 g, 21.5 mmol) in acetonate Tolyl (20+nl) solution was added (S)-α-methylbenzylamine (2°bl, 2 1.5 mmol) was added dropwise. Precipitation of a white solid was observed; The resulting white suspension was stirred at room temperature for 3.5 hours. White solids can be removed by suction filtration. Collected and dried under vacuum (household vacuum, 48° C.) overnight. 4.65 g Diastereomeric salts were obtained (yield: 82-6).

Actual example) 2 Input SAT 9th stop, 1 missing cup, 2nd cup, re-visiting profit 3-Methylhebutanoic acid/(S)-α-methylbenzylamide obtained from Example 1 A slurry of salt (30g) in acetonitrile (300+nl) was mechanically evaporated under nitrogen. Stir continuously and heat in an oil bath until completely dissolved. The solution contains a white solid The mixture was gradually cooled while precipitation occurred. The resulting suspension was stirred overnight and filtered with suction. Therefore, a white solid was collected. After drying in a vacuum oven, 20.77 g of salt was obtained (approx. 3706 depending on the optical rotation, [α125=-11,27°, C=5. 05, CHCl3).

The above method was repeated twice to obtain 10.98 g of salt (theoretical yield of 7306 amount). Optically pure produced by the method of U.S. patent application Ser. No. 07/341.350 By comparing the optical rotation of the title compound with the diastereomeric salt obtained from the acid, Therefore, the optical purity is about 9796 ([α]25=-13°66°, C=5.0 5, CHC13).

Actually, IL example 1 】-℃3 m=-4-chino and 5 p-acid A acid-resistant edil (20ml) and water The salt of Example 2 (1, 59 g, 5.99 mmol) in a mixture of (10 ml) I Treated with N HC1 (1.0 ml) and stirred at room temperature for 1.25 hours. aqueous The phase was separated from the organic phase and extracted with ethyl acetate (20ml). Organic phase and extraction The materials were combined and washed with water (10 ml) and then brine. with sodium sulfate After drying, the solvent was removed to give the acid as a colorless oil in quantitative yield.

B, the salt of Example 2 (1, 0 g, 3.77 mmol) was treated with IN HCl (5 Inl) and kept at room temperature. The mixture was stirred for 3.5 hours. Separate the aqueous phase (pH 1) from the organic phase and (2 x 20 ml). Combine the organic phase and extract and add water (10ml). and then washed with saline. After drying with sodium sulfate, remove the solvent and remove the acid. Obtained as a colorless oil (0.54 g, yield 99.406).

international search report ,,-N, PCT/US 93100726

Claims (4)

[Claims] 1. (a) Racemic 3-methylheptanoic acid and (S)-α-methylbenzylamide react to form a mixture of diastereomeric salts: (b) The diastereomeric salt of step (a) is separated by recrystallization to form (S)-α- Obtain methylbenzylammonium 3(S)-methylheptanoate; (c) (S)-α-methylbenzylammonium 3(S)- in step (b) above Treating methylheptanoate with acid to convert it to 3(S)-methylheptanoic acid , A method for producing 3(S)-methylheptanoic acid comprising a continuous process. 2. The recrystallization of step (b) above is accomplished using acetonitrile as a solvent. 2. The method according to claim 1. 3. Compound (S)-α-methylbenzylammonium 3-(S)-methylhepta Noate. 4.3(S)- and 3(R) Preferentially Containing 3(S)-Methylheptanoic Acid - A method for separating 3(S)-methylheptanoic acid from a mixture of methylheptanoic acids. Therefore, the method is (a) The above mixture of 3-methylheptanoic acid was added to (S)-α-methylbenzylamine. (b) reacting with the diastereomeric salts of step (a) to form a mixture of diastereomeric salts; The teleomer salt is separated by recrystallization to form (S)-α-methylbenzylammonium. Mu3(S)-methylheptanoate was obtained; (c) (S)-α-methylbenzylammonium 3(S)- in step (b) above Treating methylheptanoate with acid to convert it to 3(S)-methylheptanoic acid , It consists of a continuous process.