WO1993022269A1 - Processus de preparation d'acide 3(s)-methylheptanoique et intermediaires utilises a cet effet - Google Patents

Processus de preparation d'acide 3(s)-methylheptanoique et intermediaires utilises a cet effet Download PDF

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Publication number
WO1993022269A1
WO1993022269A1 PCT/US1993/000726 US9300726W WO9322269A1 WO 1993022269 A1 WO1993022269 A1 WO 1993022269A1 US 9300726 W US9300726 W US 9300726W WO 9322269 A1 WO9322269 A1 WO 9322269A1
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WO
WIPO (PCT)
Prior art keywords
acid
methylheptanoic
methylheptanoic acid
methyl
mixture
Prior art date
Application number
PCT/US1993/000726
Other languages
English (en)
Inventor
Charles K-F Chiu
Original Assignee
Pfizer Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer Inc. filed Critical Pfizer Inc.
Priority to EP93903682A priority Critical patent/EP0638059A1/fr
Priority to JP5519230A priority patent/JPH07502538A/ja
Publication of WO1993022269A1 publication Critical patent/WO1993022269A1/fr
Priority to FI945119A priority patent/FI945119A/fi

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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)

Abstract

L'on prépare de l'acide 3(S)-méthylheptanoïque par une étape de cristallisation fractionnelle du sel d'acide 3-méthylheptanoïque racémique avec une amine de (S)-α-méthylbenzyle, suivie par une étape d'acidification du produit obtenu.
PCT/US1993/000726 1992-05-01 1993-02-02 Processus de preparation d'acide 3(s)-methylheptanoique et intermediaires utilises a cet effet WO1993022269A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP93903682A EP0638059A1 (fr) 1992-05-01 1993-02-02 Processus de preparation d'acide 3(s)-methylheptanoique et intermediaires utilises a cet effet
JP5519230A JPH07502538A (ja) 1992-05-01 1993-02-02 ３（ｓ）−メチルヘプタン酸の製造方法およびその中間体
FI945119A FI945119A (fi) 1992-05-01 1994-10-31 Menetelmä 3(S)-metyyliheptaanihapon valmistamiseksi ja välituotteet

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US87756492A 1992-05-01 1992-05-01
US877,564 1992-05-01

Publications (1)

Publication Number Publication Date
WO1993022269A1 true WO1993022269A1 (fr) 1993-11-11

Family

ID=25370235

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1993/000726 WO1993022269A1 (fr) 1992-05-01 1993-02-02 Processus de preparation d'acide 3(s)-methylheptanoique et intermediaires utilises a cet effet

Country Status (5)

Country Link
EP (1) EP0638059A1 (fr)
JP (1) JPH07502538A (fr)
CA (1) CA2134093A1 (fr)
FI (1) FI945119A (fr)
WO (1) WO1993022269A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996022272A1 (fr) * 1995-01-19 1996-07-25 Basf Aktiengesellschaft Procede de preparation de 2-haloacides propioniques a activite optique
US7534908B2 (en) 2004-05-27 2009-05-19 Wacker Chemie Ag Method for the production of optically active 3-alkylcarboxylic acids and the intermediate products thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB957990A (en) * 1961-03-14 1964-05-13 Merck & Co Inc Salts of substituted indoles
GB1264340A (fr) * 1968-08-15 1972-02-23
FR2262652A1 (en) * 1974-02-28 1975-09-26 Rhone Poulenc Ind Resolving optical isomers of cyclonic dicarboxylic acids - by forming salt with alpha-phenyl ethyl amine enantiomer
US4289711A (en) * 1975-09-05 1981-09-15 Burroughs Wellcome Co. Ester synthesis

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0395188A (ja) * 1989-09-08 1991-04-19 Mitsui Petrochem Ind Ltd 二量体アルカロイド類の連続的製造方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB957990A (en) * 1961-03-14 1964-05-13 Merck & Co Inc Salts of substituted indoles
GB1264340A (fr) * 1968-08-15 1972-02-23
FR2262652A1 (en) * 1974-02-28 1975-09-26 Rhone Poulenc Ind Resolving optical isomers of cyclonic dicarboxylic acids - by forming salt with alpha-phenyl ethyl amine enantiomer
US4289711A (en) * 1975-09-05 1981-09-15 Burroughs Wellcome Co. Ester synthesis

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996022272A1 (fr) * 1995-01-19 1996-07-25 Basf Aktiengesellschaft Procede de preparation de 2-haloacides propioniques a activite optique
US5763659A (en) * 1995-01-19 1998-06-09 Basf Aktiengesellschaft Preparation of optically active 2-halopropionic acids
AU699638B2 (en) * 1995-01-19 1998-12-10 Basf Aktiengesellschaft Process for the preparation of optically active 2-halopropionic acids
CN1069630C (zh) * 1995-01-19 2001-08-15 巴斯福股份公司 光学活性的2－卤代丙酸的制备方法
US7534908B2 (en) 2004-05-27 2009-05-19 Wacker Chemie Ag Method for the production of optically active 3-alkylcarboxylic acids and the intermediate products thereof

Also Published As

Publication number Publication date
FI945119A0 (fi) 1994-10-31
CA2134093A1 (fr) 1993-11-11
FI945119A (fi) 1994-10-31
JPH07502538A (ja) 1995-03-16
EP0638059A1 (fr) 1995-02-15

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