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WO2002022543A1 - Procede de preparation d'un derive d'acide carboxylique optiquement actif - Google Patents

Procede de preparation d'un derive d'acide carboxylique optiquement actif Download PDF

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Publication number
WO2002022543A1
WO2002022543A1 PCT/JP2001/007508 JP0107508W WO0222543A1 WO 2002022543 A1 WO2002022543 A1 WO 2002022543A1 JP 0107508 W JP0107508 W JP 0107508W WO 0222543 A1 WO0222543 A1 WO 0222543A1
Authority
WO
WIPO (PCT)
Prior art keywords
optically active
acid
dimethylcyclopropanecarboxylic acid
cis
diastereomer
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP2001/007508
Other languages
English (en)
Japanese (ja)
Inventor
Kohichi Fujita
Masafumi Minomura
Junko Koizumi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ajinomoto Co Inc
Original Assignee
Ajinomoto Co 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 Ajinomoto Co Inc filed Critical Ajinomoto Co Inc
Priority to AU2001282565A priority Critical patent/AU2001282565A1/en
Publication of WO2002022543A1 publication Critical patent/WO2002022543A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/42—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • 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
    • C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to a novel method for producing optically active 2,2-dimethylcyclopropanecarboxylic acid, particularly an S-form thereof, and more specifically, an optically active 2,2-dimethylcyclopropanecarboxylic acid which is important as an intermediate for agricultural chemicals, pharmaceuticals, etc.
  • the present invention relates to a method for producing optically active 2,2-dimethylcyclopropanecarboxylic acid, a novel diastereomer salt which is a novel intermediate therefor, and an optical resolving agent used therefor; and an optically active cis-1-benzylaminocyclohexane methanol.
  • Optically active 2,2 "dimethylcyclopropanecarboxylic acid, especially its optically active form (S-form etc.) is used for pesticides such as insecticides (see British Patent No. 1,260,847) or pharmaceutical intermediates. (Chemistry and biology,! ⁇ 204 (1981); EP0, 048, 301, etc.) It is an extremely useful compound, especially the S-form ((S)-(+) -2, 2-Dime thy 1 Cyclopropane carboxyl ic acid) is a compound represented by the following formula (1), and is a more useful optically active compound as a production intermediate.
  • An object of the present invention is to provide an important optical activity from a racemic 2,2-dimethylcyclopropanecarboxylic acid or from an optically impure 2,2-dimethylcyclopropanecarboxylic acid as an intermediate for producing agricultural chemicals, pharmaceuticals, and the like.
  • 2,2-Dimethylcyclopropane force As a method for separating and purifying rubonic acid, it has superior optical purity and yield compared to conventional methods, for example, diastereomer resolution method using 1-menthol or phenylethylamine.
  • An object of the present invention is to develop a method capable of performing the resolution and purification of the objective optically active substance. Disclosure of the invention
  • optically active cis-l-benzylaminocyclohexane methanol was converted to an optically resolving agent for optically active 2,2-dimethylcyclopropanecarboxylic acid. Easily produce (form) a novel diastereomer monosalt, and separate the salt precipitated and crystallized in this way to easily purify the desired free optically active compound by the desalting process with high optical purity. And high yield And completed the present invention.
  • optically active form, S-form and R-form obtained by the present invention are all useful as important intermediates for production.
  • the other optically active substance is separated and recovered for isolation and purification, and then subjected to a racemization step.
  • the one optically active substance can be recycled and reused in the production of the optically active substance, so that optical resolution or separation and purification of another optically active substance to which the present invention is applied is also useful.
  • the present invention to separate the other optically active substance, it is possible to use it for concentration or separation of the one optically active substance which is more useful as an intermediate.
  • the present invention relates to a racemic 2,2-dimethylcyclopropanecarboxylic acid or an optically active 2,2-dimethylcyclopropane containing at least an optical isomer thereof as an impurity, and an optically active cis-2-benzyl.
  • the present invention relates to a method for producing optically active dimethylcyclopropane carboxylic acid, which is characterized by forming an optically active diastereomeric salt of 2,2-dimethylcyclopropanecarboxylic acid by reacting aminocyclohexane methyl.
  • the present invention provides an optically active 2,2-dimethylcyclopropanecarboxylic acid characterized in that it is in the form of a diastereomer monosalt with cis-1-benzylaminocyclohexanemethanol,
  • An optically resolving agent for the separation of optically active 2,2-dimethylcyclopropanecarboxylic acid by forming diastereomeric salts characterized by containing benzylaminocyclohexanemethanol is also present.
  • optically active 2,2-dimethylcyclopropane sulfonic acid in the form of diastereomer monosalt with cis-2-benzylaminocyclohexanemethanol is subjected to a desalting step.
  • the present invention also includes a method for producing optically active 2,2-dimethylcyclopropanecarboxylic acid, which is characterized in that its free form is produced by the reaction.
  • the present invention typically includes a method for producing a desired optically active substance by forming (generating) a salt of the optically active substance by a diastereomer method, separating, and desalting as necessary.
  • a desired optically active substance by forming (generating) a salt of the optically active substance by a diastereomer method, separating, and desalting as necessary.
  • the division / purification means and operation of the diastereomer method itself can be performed by using a conventionally known technique relating to the diastereomer method.
  • the starting materials used in the present invention include racemic 2,2-dimethylcyclopropanecarboxylic acid, a mixture containing the racemate, an optically active substance containing at least an optical isomer thereof as an impurity with respect to one optically active substance, 2-dimethylcyclopropane carboxylic acid, a mixture thereof and the like are used.
  • optically active cis-1-benzylaminocyclohexane methanol used in the present invention can be easily synthesized (see The Chemical Society of Japan, 1979 (6), 754). In addition, commercial products can be purchased and used.
  • the optically active cis-1-benzylaminocyclo used as the optical resolving agent is converted to
  • the objective is to use the (1S, 2R) -isomer, ie, cis- (1S, 2R)-(_)-12-benzylaminocyclohexanemethanol (see formula (2) below), as xanmethanol. (Sedimentation, crystallization, etc.), and this is separated if necessary.
  • the target compound to be separated is (R) — (1) —2,2-dimethylcyclopropanecarboxylic acid
  • the optically active cis-12-benzylaminocyclohexanemethanol (1 R, 2 S)-body, ie cis-(1 R, 2 S)-(+)-2-
  • sun methanol enables the formation and separation of the desired diastereomer monosalt.
  • the amount of the resolving agent to be used is preferably 1 to 0.1 in a molar ratio to the optically active 2,2-dimethylcyclopropanecarboxylic acid present in the starting material in order to form the desired diastereomer salt. ⁇ 5, more preferably about 1: 0.8 ⁇ 3, and even more preferably about 1: 1-2.
  • the resolving agent can be calculated and used at the above-mentioned usage ratio with respect to the amount of the optically active substance corresponding to half of the racemate.
  • the diasteremer salt can be carried out in a suitable solvent.
  • a suitable solvent it is desirable to select a solvent that can sufficiently dissolve both the above compounds (including a mixture of a plurality of solvents) and that does not react with each of the substances forming the diastereomer.
  • a homogeneous solvent of water, a neutral organic solvent and a mixture of a plurality thereof is more preferable.
  • a different solvent system can be selected for salt formation, salt recrystallization, and reprecipitation.
  • alcohols such as methanol, ethanol, and propanol (such as isopropanol), particularly alcohols having 1 to 4 carbon atoms, can be used alone or in combination. Of these, isopropanol is particularly preferred.
  • the optical purity can be increased to high purity by recrystallization.
  • a suitable solvent from among the solvents used for the production of the diasteremer salt for example, a lower alcohol having 1 to 4 carbon atoms, or a mixture of a plurality of these solvents is used. Can be done. Again, isopropanol is more preferred.
  • Optically active 2,2-dimethylcyclopropane sorbate can be produced from the separated diastereomer salt by subjecting the salt to a desalting step, for example, by contact with a strong acid (hydrochloric acid, sulfuric acid, etc.). Can be achieved.
  • a strong acid hydrochloric acid, sulfuric acid, etc.
  • the treatment can be carried out in an aqueous medium, but the amount of water used should be selected so that the salt of the strong acid and the amine formed at this time is sufficiently dissolved.
  • Most of the free optically active 2,2-dimethylcyclopropanecarbonic acid obtained is separated as an oil, and a part is dissolved in the aqueous phase. Melting angle in aqueous phase? In the case of separating a portion where the reaction is carried out, for example, extraction and separation can be performed with a non-polar solvent.
  • the nonpolar solvent is preferably a hydrocarbon having 5 to 8 carbon atoms, for example, pentane, hexane, heptane, octane, cyclohexane, methylcyclohexane, etc., an ester such as ethyl acetate, etc.
  • hexane n-hexane and the like
  • extraction solvent can be easily separated and removed from the free optically active 2,2-dimethylcyclopropane-l-ruponic acid by, for example, distillation.
  • optically active 2,2-dimethylcyclopropanecarboxylic acid thus obtained can be further purified by distillation or the like, if necessary.
  • the optical purity can be further improved by repeating the formation of the diastereomer of the present invention for the obtained optically active 2,2-dimethylcyclopropanecarboxylic acid.
  • This optically active compound can be easily converted to the corresponding amide by treating an acid chloride (acid chloride) obtained from an acid with thionyl chloride with, for example, aqueous ammonia. Can also be converted to
  • the 2,2-dimethylcyclopropanecarboxylic acid contained in the mother liquor obtained after separation of the formed diastereomer salt or in the crystal separation mother liquor after recrystallization has been recovered by a known method and, if necessary, racemized by a known method.
  • the production method of the present invention can be applied again.
  • optically active cis-2-benzylaminocyclohexanemethanol of the resolving agent can be added to the optically active cis-2-benzylaminocyclohexanmethanol salt obtained after separation from the diastereomer monosalt, such as a strong base (sodium hydroxide). Solution, etc.), and can be recovered by an extraction method or the like.
  • the optically active substance obtained by the method of the present invention is optically extremely high in purity and therefore can be used for various intermediates.In view of the good yield, the present invention is extremely useful as an industrial method. is there.
  • the optical purity of the optically active substance obtained in the present invention is preferably at least 98% ee (98% ee or more)), more preferably at least 98.5% ee, and still more preferably at least 99% ee.
  • a highly pure compound as ee can be obtained with high yield.
  • Example 1 A conventional resolution method was performed using 88.4% ee (S) — (+) — 2,2-dimethylcyclopropanecarboxylic acid used as the starting material in Example 1 above, and the results were obtained as described above. The results are shown in Table 1 in comparison with the results of Example 1.
  • the eQ value of the resolving agent represents the molar ratio of the resolving agent to the substance to be separated (the above-mentioned dimethyl cyclopropanecarboxylic acid) except for one menthol. In the case of 1-menthol, it indicates the molar ratio to the corresponding acid chloride.
  • optically active 2,2-dimethylcyclopropanecarboxylic acid which is important as an intermediate for agricultural chemicals, pharmaceuticals, etc., can be obtained from its racemic form or from optically impure 2,2-dimethylcyclopropanecarboxylic acid.
  • the target compound can be efficiently produced by efficiently separating and purifying the target compound.
  • the present invention is extremely useful industrially because an optically active substance can be produced.
  • Ruponic acid-optically active cis-2-benzylaminocyclohexanemethanol diastereomer salt is also provided.

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

Abstract

L'invention concerne un procédé de fabrication de cis-2-benzylamino-cyclohexaneméthanol optiquement actif agissant sur un acide 2, 2-diméthylcyclopropanecarboxylique racémique ou un acide 2, 2-diméthylcyclopropanecarboxylique optiquement actif contaminé au moins par l'autre isomère optique afin de former (notamment, précipiter ou cristalliser) des sels diastéréomères de l'acide 2, 2-diméthylcyclopropanecarboxylique optiquement actif, et de séparer et purifier ainsi, de manière efficace, l'acide 2, 2-diméthylcyclopropanecarboxylique optiquement actif. L'invention concerne également des sels diastéréomères qui sont des intermédiaires utilisés dans le procédé et un réactif destiné à la résolution optique (consistant en du cis-2-benzylamino-cyclohexaneméthanol optiquement actif). Le procédé de purification et de résolution optique de l'acide 2, 2-diméthylcyclopropanecarboxylique d'une pureté et d'un rendement optique excellent permet de produire un procédé de séparation ou de purification de cet acide qui est important comme intermédiaire dans la préparation de produits chimiques agricoles, de médicaments ou analogue.
PCT/JP2001/007508 2000-09-05 2001-08-30 Procede de preparation d'un derive d'acide carboxylique optiquement actif Ceased WO2002022543A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001282565A AU2001282565A1 (en) 2000-09-05 2001-08-30 Process for preparing optically active carboxylic acid derivative

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2000-268302 2000-09-05
JP2000268302 2000-09-05

Publications (1)

Publication Number Publication Date
WO2002022543A1 true WO2002022543A1 (fr) 2002-03-21

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PCT/JP2001/007508 Ceased WO2002022543A1 (fr) 2000-09-05 2001-08-30 Procede de preparation d'un derive d'acide carboxylique optiquement actif

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AU (1) AU2001282565A1 (fr)
WO (1) WO2002022543A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003074464A1 (fr) * 2002-03-06 2003-09-12 Ajinomoto Co., Inc. Procede de production d'acide carboxylique optiquement actif
CN102329241A (zh) * 2011-09-09 2012-01-25 诚达药业股份有限公司 1,2-环己二胺的化学拆分方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1260847A (en) * 1968-12-06 1972-01-19 Nat Res Dev Esters of cyclopropane carboxylic acids
EP0298480A1 (fr) * 1987-07-10 1989-01-11 Kuraray Co., Ltd. Procédé pour le dédoublement optique d'acide (+)-cis ou (+)-trans-perméthrique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1260847A (en) * 1968-12-06 1972-01-19 Nat Res Dev Esters of cyclopropane carboxylic acids
EP0298480A1 (fr) * 1987-07-10 1989-01-11 Kuraray Co., Ltd. Procédé pour le dédoublement optique d'acide (+)-cis ou (+)-trans-perméthrique

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003074464A1 (fr) * 2002-03-06 2003-09-12 Ajinomoto Co., Inc. Procede de production d'acide carboxylique optiquement actif
US7592480B2 (en) 2002-03-06 2009-09-22 Ajinomoto Co., Inc. Process for producing optically active carboxylic acid
CN102329241A (zh) * 2011-09-09 2012-01-25 诚达药业股份有限公司 1,2-环己二胺的化学拆分方法

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AU2001282565A1 (en) 2002-03-26

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