WO2002022543A1 - Process for preparing optically active carboxylic acid derivative - Google Patents

Abstract

A process of making optically active cis-2-benzylamino- cyclohexanemethanol act on racemic 2,2-dimethylcyclopropane- carboxylic acid or optically active 2,2-dimethylcyclopropane- carboxylic acid contaminated at least with the other optical isomer thereof to form (e.g., precipitate or crystallize) diastereomeric salts of optically active 2,2-dimethylcyclo- propanecarboxylic acid, and thereby separating and purifying optically active 2,2-dimethylcyclopropanecarboxylic acid effectively. The invention also provides novel diastereomeric salts being intermediates for the process and a reagent for optical resolution (consisting of optically active cis-2-benzylamino- cyclohexanemethanol). The process for optical resolution or purification of 2,2-dimethylcyclopropanecarboxylic acid excellent in optical purity and yield makes it possible to provide a process for separation or purification of optically active 2,2-dimethyl- cyclopropanecarboxylic acid important as an intermediate in the preparation of agricultural chemicals, drugs or the like.

Description

 Description Method for producing optically active carboxylic acid derivative

Technical field

 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. From the racemic form or from an optically impure 2,2-dimethylcyclopropanecarboxylic acid by cis-12-benzylaminocyclohexanemethanol diastereomer monosalt formation (formation) (precipitation, crystallization) 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. Background art

 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.

これまでに、 光学活性 2， 2—ジメチルシクロプロパンカルボン酸の光学分割 法が幾つか報告されている。 例えば、 キラルなアルコールとのジァステレオマー エステルゃキラルなァミンとのジァステレオマ一塩に誘導後、 結晶化による光学 分割法 （英国第 1, 260, 847号明細書、 特開昭 60- 25956号公報、 特開昭 60-56936号 公報等参照。 ） 等が知られている。 ジァステレオマー法は不斉合成法に比べ、 特 殊な試剤を用いる必要がないが、 光学純度や収率の改善が求められている。 例えば、 フエニルェチルァミンによる光学分割法によれば、 収量、 光学純度共 に不十分であり、 1 -メントールとのエステルによる方法 （参照。 ) によれば、 満足のいく光学純度を与えるが、 酸クロリドに誘導する等、 比較的手間がかかる 以上のような情況下に、 ジァステレオマー法による光学分割或いは光学的精製 法の更なる改良が求められている。 発明の課題

To date, several optical resolution methods for optically active 2,2-dimethylcyclopropanecarboxylic acid have been reported. For example, a diastereomer ester with a chiral alcohol and a diastereomer monosalt with a chiral amine are derived, and then an optical resolution method by crystallization (British No. 1,260,847, JP-A-60-25956, See Japanese Unexamined Patent Publication No. 60-56936, etc.) The diastereomer method does not require special reagents as compared with the asymmetric synthesis method, but requires improvement in optical purity and yield. For example, according to the optical resolution method using phenylethylamine, both the yield and the optical purity are insufficient, and the method using an ester with 1-menthol (see) gives a satisfactory optical purity. However, it is relatively troublesome to induce acid chloride, etc. Under the circumstances described above, further improvement of the optical resolution or optical purification method by the diastereomer method is required. Problems of the Invention

 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

The present inventors have conducted intensive studies in order to solve the above-mentioned problems. As a result, 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.

 The optically active form, S-form and R-form obtained by the present invention are all useful as important intermediates for production. In the present invention, when the production of one optically active substance is required as an intermediate, the other optically active substance is separated and recovered for isolation and purification, and then subjected to a racemization step. As a result, 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. Similarly, by applying 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.

 That is, 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.

 Furthermore, 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. In another embodiment of the production method, 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. Embodiment

Hereinafter, embodiments of the present invention will be described. 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. By mainly describing this method, the description of this method and other aspects of the present invention, for example, the novel intermediate and the novel optical resolving agent of the present invention, is also given in related parts. A person skilled in the art can easily carry out all of the present invention including the description of the following examples.

 In the present invention, 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.

 Numerous synthetic examples of such racemic 2,2-dimethylcyclopropanecarponic acid have been reported and can be easily synthesized (ER Nelson, J. Am. Chem. Soc., 79, 3467 (1957), etc.).

 The 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.

When the target compound to be resolved or separated is (S) — (+)-2,2-dimethylcyclopropanecarboxylic acid, 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. On the other hand, when 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- The use of sun methanol enables the formation and separation of the desired diastereomer monosalt.

 (2)

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. For example, when a racemate is used as a starting material and is subjected to optical resolution, 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.

 In the present invention, the diasteremer salt can be carried out in a suitable solvent. As a usable 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. Preferably, a homogeneous solvent of water, a neutral organic solvent and a mixture of a plurality thereof is more preferable. It is preferable to use a solvent which has a predetermined solubility for the salt to be formed and at the same time allows the salt to precipitate and crystallize (recrystallize, etc.) from the solvent. Of course, a different solvent system can be selected for salt formation, salt recrystallization, and reprecipitation.

 As the organic solvent, 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.

Poor optical purity when diastereomers are formed in a solvent and salts obtained by precipitation, crystallization, etc. are separated, especially when diastereomers are formed from racemic forms. In many cases, the optical purity can be increased to high purity by recrystallization. As the solvent used for such 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. In the case of the step of treating with a strong acid, 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. Among them, hexane (n-hexane and the like) is particularly preferably used. After extraction, such an extraction solvent can be easily separated and removed from the free optically active 2,2-dimethylcyclopropane-l-ruponic acid by, for example, distillation.

 The optically active 2,2-dimethylcyclopropanecarboxylic acid thus obtained can be further purified by distillation or the like, if necessary.

 On the other hand, 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. Thus, the production method of the present invention can be applied again.

 The 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. In particular, 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

 Hereinafter, the present invention will be described in detail with reference to Examples and Comparative Examples, but the present invention is not limited by these Examples and the like.

 (Example 1)

88. Starting from 2.45 g (21.5 mmo 1) of (S) mono (+)-2,2-dimethylcyclopropanecarboxylic acid with 4% ee, isopropanol 79 m 1 and cis mono (1 (S, 2R)-(I) Add 1-benzylaminocyclohexylmethanol (4.70 g; 21.5 mmol; equimolar amount to the carboxylic acid) and heat to around 90 ° C. All solids were dissolved. After the system was completely dissolved, the resulting mixed solution was left to cool, and crystals were precipitated at 44 ° C. Then, after stirring at 25 ° C. for 1 hour, the precipitated crystals were filtered and separated. It was a flocculent white crystal (yield: 4.92 g), and the yield after drying was 69% (weight). After adjusting the pH value to 1 by adding hydrochloric acid to 3.43 g of the thus obtained crystals, the liberated optically active substance was extracted with ethyl acetate, washed with hydrochloric acid, dried over anhydrous sodium sulfate, and concentrated. (S)-(+) — 2,2-dimethylcyclopropanecarboxylic acid (yield: 0.963 g, yield: 82% [weight]; structural confirmation: ¹ HNMR). When this was analyzed by gas chromatography using an optically active column, the optical purity was> 99.8% (the R-isomer was below the detection limit).

 In the above Examples, instead of 88.4% ee of (S) — (+) — 2,2-dimethylcyclopropanecarboxylic acid, 0.5% ee of (S) — (+) 1-2,2- Using 31 g of dimethylcyclopropanecarboxylic acid, cis- (1S, 2R)-(-)-2-benzylaminocyclohexanemethanol instead of cis- (1R, 2S)-(+) — Example 1 was repeated without any change except that 59 g of 2-benzylaminocyclohexanemethanol was used to obtain a diastereomer monosalt, followed by four recrystallizations with isopropanol to give an optical purity of 98.7. % (Yield: 27% [Weight]) of (R)-(-1) -2,2-dimethylcyclopropanecarboxylic acid was obtained.

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.

[table 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.

 From the above results, it can be seen that the method of the present invention is superior to the conventional method, and particularly superior in optical purity. The invention's effect

 According to the present invention, 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.

 Excellent in both yield and optical purity, easily available optical resolving agent;

-Use the tool easily and conveniently The present invention is extremely useful industrially because an optically active substance can be produced.

Hexanemethanol) and intermediates (optically active 2,

Ruponic acid-optically active cis-2-benzylaminocyclohexanemethanol diastereomer salt) is also provided.

Claims

The scope of the claims 1.2 racemic 2,2-dimethylcyclopropanecarboxylic acid, or optically active 2,2-dimethylcyclopropanecarboxylic acid containing at least its optical isomer as an impurity, and optically active cis-1-benzylaminocyclohexanemethanol A method for producing optically active 2,2-dimethylcyclopropanecarboxylic acid, characterized in that a diastereomer of optically active 2,2-dimethylcyclopropanecarboxylic acid is produced by reacting the same. 2. The optically active 2,2-dimethylcyclopropanecarboxylic acid is in S-form 2. The method according to claim 1, wherein the optically active cis-1-benzylaminocyclohexanemethanol is (1S, 2R) integrated. 3. A process comprising the step of subjecting the diastereomer salt of the optically active 2,2-dimethylcyclopropanecarboxylic acid to a desalting step to produce a free form of the optically active 2,2-dimethylcyclopropanecarboxylic acid. Method according to 1 or 2. 4. The method according to claim 1 or 2, wherein the diastereomer salt formation reaction is performed in a solvent, and the solvent is at least one substance selected from alcohols. 5. The resulting diastereomeric salt is separated and subjected to a desalting step. The resulting optically active 2,2-dimethylcyclopropanecarboxylic acid is added again to the optically active cis-1-benzylaminocyclohexanemethanol. 3. The method according to claim 1, further comprising a step of producing a diastereomer salt of optically active 2,2-dimethylcyclopropanecarboxylic acid having improved optical purity by reacting the compound. 6. Diastere with cis-1 benzylaminocyclohexanemethanol Optically active 2,2-dimethylcyclopropane carboxylic acid, characterized in that it is in the form of oxa-monosalt. · 7. (S) one (+) -2 -(1 S, 2 R)-(I)-2

7. The compound according to claim 6, which is a salt. 8. It is required that the optically active 2,2-dimethylcyclopropanecarboxylic acid in the form of a diastereomer monosalt with cis-2-benzylaminocyclohexanemethanol be subjected to a desalting step to produce a free form thereof. A process for producing an optically active 2,2-dimethylcyclopropanecarboxylic acid. 9. The method according to claim 8, wherein the optically active 2,2-dimethylcyclopropanecarboxylic acid is in the S-form.