Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B57/00—Separation of optically-active compounds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
  • C07C51/42—Separation; Purification; Stabilisation; Use of additives
  • C07C51/487—Separation; Purification; Stabilisation; Use of additives by treatment giving rise to chemical modification

Definitions

• the present invention is directed to a process and intermediates for the manufacture of 3(S)-methylheptanoic acid of the absolute stereochemical formula (I)
• R 4 and R 5 are each hydrogen or one of R 4 and R 5 is hydrogen and the other is (C,-C 6 )alkyl or (C 6 -C 8 )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.
• 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.
• 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.
• This invention relates to a novel process for the preparation of 3(S)- methylheptanoic acid which comprises the sequential steps of;
• step (a) reaction of racemic 3-methylheptanoic acid with (S)-oc-methylbenzyl amine to form a mixture of diastereomeric salts;
• step (b) separation of the diastereomeric salts from step (a) by recrystallization to yield (S)-oc-methylbenzylammonium 3(S)-methylheptanoate;
• step (c) conversion of said (S)- ⁇ -methylbenzy ⁇ ammonium 3(S)-methyl heptanoate of step (b) to 3(S)-methylheptanoic acid by treatment with acid.
• this invention relates to the use of acetonitrile as the recrystallizing solvent in step (b).
• this invention relates to the compound (S)-cc- methyibenzyIammonium * 3(S)-methyIheptanoate.
• 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.
• an enriched mixture containing about 70% 3(S)-methylheptanoic acid is available from the procedure of
• 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.
• 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.
• 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.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Oil, Petroleum & Natural Gas (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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• 1993
  • 1993-02-02 JP JP5519230A patent/JPH07502538A/ja active Pending
  • 1993-02-02 WO PCT/US1993/000726 patent/WO1993022269A1/en not_active Application Discontinuation
  • 1993-02-02 EP EP93903682A patent/EP0638059A1/de not_active Withdrawn
  • 1993-02-02 CA CA 2134093 patent/CA2134093A1/en not_active Abandoned
• 1994
  • 1994-10-31 FI FI945119A patent/FI945119A0/fi not_active Application Discontinuation

Non-Patent Citations (1)

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