JP2008007457A - POST-TREATMENT METHOD OF beta-HYDROXYCARBONYL COMPOUND - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an environmentally friendly practical post-treatment method that does not require an extraction- or liquid-separating operation and the like and thus permits decrease in the amount of used organic solvents. <P>SOLUTION: The post-treatment method of a β-hydroxycarbonyl compound, after the β-hydroxycarbonyl compound is manufactured by causing a ketone or an aldehyde to react with an aldehyde in the presence of a catalyst using an aqueous solvent or an organic solvent or without using a solvent, comprises adding water to wash the organic layer, removing water and isolating the β-hydroxycarbonyl compound by distillation or recrystallization. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a post-treatment method for a β-hydroxycarbonyl compound produced by an aldol reaction. In particular, the reaction is carried out using water or a very small amount of solvent as a solvent, or without using a solvent. The present invention relates to a post-treatment method for a β-hydroxycarbonyl compound produced by an aldol reaction.

  The aldol reaction is an excellent reaction for producing a β-hydroxycarbonyl compound. β-hydroxycarbonyl compounds are important optically active synthetic intermediates found in the basic skeletons of many useful biologically active compounds, pharmaceuticals, agricultural chemicals and the like.

  As an excellent method for producing an optically active aldol compound, there is an asymmetric catalytic aldol reaction. Non-Patent Documents 1 and 2 listed below disclose a method in which a ketone or ester is once led to silyl enol ether or ketene silyl acetal and an optically active Lewis acid catalyst is allowed to act.

  Non-Patent Document 3 below discloses that a derivative obtained by substituting the carboxylic acid moiety of proline with sulfonamide can obtain a very high asymmetric yield of 98% ee in the aldol reaction of acetone and nitrobenzaldehyde. Non-Patent Document 4 below discloses that Wu et al. Give a very high asymmetric yield when a proline amide having a diphenylaminoethanol moiety is used for a catalyst having a modified amide moiety. .

In Non-Patent Document 5, an adduct is obtained with a high optical yield in a reaction using a silyl enol ether and an optically active Lewis acid catalyst as an activator as a reaction performed in a mixed system of water and an organic solvent. It is disclosed.
Modern Aldol Reactions Vols 1,2; Mahrwald, R. Ed ,; Wiley-VCH: Weinheim, 2004. Comprehensive Asymmetric Catalysis I-III; Jacobsen, EN; Pfaltz, A .; Yamamoto, H. Eds .; Springer: Berlin, 1999. A. Berkessel, B. Koch,. Lex, Adv. Synth. Catal., 346, 1141 (2004) Z. Tang, F. Jiang, X. Cui, L. Gong, A. Mi, Y. Jiang, Y. Wu, Proc. Natl. Acad. Sci. USA, 101, 5755 (2004) Hamada, T .; Manabe, K .; Ishikawa, S .; Nagayama, S .; Shiro, M .; Kobayashi, SJ Am. Chem. Soc. 2003, 125, 2989

However, in the reactions of Non-Patent Documents 1 to 5, reaction solvents that can be used are DMSO (dimethyl sulfoxide), DMF (dimethylformamide), NMP (1-methyl-2-pyrrolidone), CH ₃ CN (acetonitrile), and the like. The polar solvent was limited. Moreover, when these polar organic solvents were used, extraction and liquid separation operation had to be performed after completion of the reaction. In addition, since the solvent is mixed in the aqueous layer, there is a problem in processing the aqueous layer.

  The present invention has been made in view of the above problems, and it is not necessary to perform extraction, liquid separation operation, and the like, and the amount of organic solvent used can be reduced. Furthermore, in order to suppress the usage-amount of an organic solvent, it aims at providing an environmentally friendly and practical post-processing method.

  As a result of intensive studies to solve the above problems, the present inventors have used water as a solvent, or in an aldol reaction without using water, the catalyst and the solvent can be obtained by silica gel or column chromatography, or By removing the organic layer by washing with water, it was found that the β-hydroxycarbonyl compound can be taken out without performing extraction and liquid separation operations, and the present invention has been completed. More specifically, the present invention provides the following.

  (1) After producing a β-hydroxycarbonyl compound by reacting a ketone and an aldehyde, or an aldehyde and an aldehyde in the presence of a catalyst, using an aqueous solvent or an organic solvent, or without using a solvent, A post-treatment method of a β-hydroxycarbonyl compound in which water is added, the organic layer is washed, the water is removed, and the β-hydroxycarbonyl compound is extracted by distillation or recrystallization.

  According to the post-treatment method of the present invention, after completion of the reaction, water can be added, and the organic layer can be washed with water, so that the catalyst can be included in the aqueous layer that is the washing liquid. Therefore, after that, the organic layer and the aqueous layer can be easily separated from each other by separating the organic layer and the aqueous layer by pipetting or separating the aqueous layer. Therefore, the target compound can be taken out without performing the extraction operation, and the amount of the organic solvent used can be suppressed.

  In addition, since no extraction operation is performed, a step of adding a desiccant to the extract and filtering can be omitted, so that the operation can be simplified.

  (2) The post-treatment method of the β-hydroxycarbonyl compound according to (1), wherein the organic solvent is 5 equivalents or less with respect to the ketone or aldehyde.

  According to this aspect, since the amount of the organic solvent is slightly larger than or less than that of the reaction product, it can be easily removed by distillation or recrystallization after removing water. The amount of the organic solvent is preferably 5 equivalents or less, more preferably 3 equivalents or less, with respect to the ketone or aldehyde.

  (3) A β-hydroxycarbonyl compound is produced by reacting a ketone and an aldehyde, or an aldehyde and an aldehyde in the presence of a catalyst in an aqueous solvent or without using a solvent, and then adding silica gel, adding the water and A post-treatment method for a β-hydroxycarbonyl compound in which the catalyst is adsorbed on silica gel, then the silica gel is removed, and the β-hydroxycarbonyl compound is extracted by distillation or recrystallization.

  According to the post-treatment method of the present invention, since the catalyst and the aqueous solvent can be removed using silica gel, the product solution can be produced by filtration and washing with an organic solvent. Therefore, by removing the organic solvent used for filtration by distillation or recrystallization, it is not necessary to perform an extraction operation or a liquid separation operation, and the target product can be easily obtained.

  (4) A β-hydroxycarbonyl compound is produced by reacting a ketone and an aldehyde, or an aldehyde and an aldehyde in the presence of a catalyst in an aqueous solvent or without using a solvent, and then the β-hydroxycarbonyl compound is prepared by column chromatography. A post-treatment method for removing a hydroxycarbonyl compound.

  According to the post-treatment method of the present invention, the catalyst can be removed by column chromatography after the reaction. Therefore, only the product can be easily obtained.

  (5) The post-treatment method for a β-hydroxycarbonyl compound according to any one of (1) to (4), wherein the catalyst is a compound represented by the following general formulas (9-1) to (9-10).

（式中Ｒ^１は、アルキル基、またはアリール基を示す。なお、それぞれのＲ^１は同一または異なっていてもよい。Ｒ^２は、アルキル基、アリール基、アシル基、トリアルキルシリル基、ジアルキルアリールシリル基、またはアルキルジアリールシリル基を示す。Ｒ^４は、アルキル基、またはアリール基を示す。Ｒ^５は、官能基を有してもよいアルキル基、置換基を有してもよいアリール基、または置換基を有してもよいヘテロアリール基を示す。ｎは１から１５の整数を示す。）

(In the formula, R ¹ represents an alkyl group or an aryl group. Each R ¹ may be the same or different. R ² represents an alkyl group, an aryl group, an acyl group, a trialkylsilyl group, a dialkyl group. An arylsilyl group or an alkyldiarylsilyl group, R ⁴ represents an alkyl group or an aryl group, and R ⁵ represents an alkyl group which may have a functional group or an aryl group which may have a substituent. Or a heteroaryl group which may have a substituent, n represents an integer of 1 to 15.)

  According to this aspect, by using the above catalyst, an aldol reaction obtained by reacting with a solvent using water, a very small amount of solvent, or reacting without using a solvent is obtained in a high yield, and further high. Since enantioselectivity and diastereoselectivity can be obtained, the post-treatment method of the present invention can be preferably used.

  According to the post-treatment method of the β-hydroxycarbonyl compound of the present invention, since the compound can be taken out without performing a liquid separation operation and an extraction operation, the efficiency of the reaction can be improved. In addition, since the amount of the organic solvent used can be reduced, an environmentally friendly and practical manufacturing method can be provided.

  Hereinafter, the present invention will be described in more detail.

<First Embodiment>
In the post-treatment method of the first embodiment of the present invention, a ketone and an aldehyde, or an aldehyde and an aldehyde are reacted in the presence of a catalyst to produce a β-hydroxycarbonyl compound, and then water is added to the organic layer. After washing, the water is removed, and the β-hydroxycarbonyl compound is removed by distillation or recrystallization to remove the β-hydroxycarbonyl compound.

[Production Process of β-Hydroxy Compound]
The β-hydroxy compound is produced by reacting a ketone represented by the following general formula (1) with an aldehyde represented by the following general formula (2) in the presence of the catalyst (10).

The ketone represented by the general formula (1) is not particularly limited, and a commonly used ketone can be used. R ¹¹ and R ¹² may be an alkyl group, an alkenyl group, Or it is preferable that it is an alkynyl group. R ¹¹ and R ¹² may be combined to form a ring. In addition, the aldehyde represented by the general formula (2) is not particularly limited, and a commonly used aldehyde can be used. R ¹³ may be an aryl group, a heterocycle, an alkyl which may have a substituent. It is preferably a group, an alkenyl group or an alkynyl group.

  Moreover, the aldehyde represented by the following general formula (4) and the aldehyde represented by the following general formula (5) may be reacted in the presence of the catalyst (10).

The aldehyde represented by the general formula (4) is not particularly limited, and a commonly used aldehyde can be used, but R ¹⁴ is an alkyl group, alkenyl group, or alkynyl group which may have a substituent. It is preferable that Moreover, as an aldehyde represented by General formula (5), the aldehyde similar to the aldehyde represented by General formula (2) mentioned above can be used.

  As the catalyst used in the above reaction, compounds represented by the following formulas (9-1) to (9-10) can be used.

In the formula, R ¹ represents an alkyl group or an aryl group. The alkyl group is preferably a linear or branched alkyl group having 1 to 20 carbon atoms, and the aryl group has a phenyl group or a linear or branched alkyl group having 1 to 20 carbon atoms. An aryl group is preferred. Also, each R ³ may be the same or different.

R ² represents an alkyl group, an aryl group, an acyl group, a trialkylsilyl group, a dialkylarylsilyl group, or an alkyldiarylsilyl group. The alkyl group is preferably a linear or branched alkyl group having 1 to 20 carbon atoms, and the aryl group has a phenyl group or a linear or branched alkyl group having 1 to 20 carbon atoms. An aryl group is preferred. In addition, the acyl group preferably has 1 to 20 carbon atoms. Further, trialkylsilyl groups, dialkylarylsilyl silyl group or an alkyl group alkyldiarylsilyl group, the aryl group include an alkyl group similar to R ^2, the aryl group.

R ³ represents hydrogen, an alkyl group, or an aryl group. The alkyl group is preferably a linear or branched alkyl group having 1 to 20 carbon atoms, and the aryl group has a phenyl group or a linear or branched alkyl group having 1 to 20 carbon atoms. An aryl group is preferred.

R ⁴ represents an alkyl group or an aryl group. The alkyl group is preferably a linear or branched alkyl group having 1 to 20 carbon atoms, and the aryl group has a phenyl group or a linear or branched alkyl group having 1 to 20 carbon atoms. An aryl group is preferred.

R ⁵ represents an alkyl group that may have a functional group, an aryl group that may have a substituent, or a heteroaryl group that may have a substituent. As a functional group, an alkoxy group or an acyl group can be mentioned, for example. Examples of the substituent include a methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxy group, or an alkyl group substituted with a halogen atom. Examples of the alkyl group substituted with a halogen atom include a trifluoromethyl group. The alkyl group preferably has 1 to 20 carbon atoms, and the aryl group is preferably a phenyl group or an aryl group having an alkyl group having 1 to 20 carbon atoms. Further, R ⁷ is preferably a phenyl group or 3,5-bistrifluorophenyl. Each R ⁷ may be the same or different.

  Furthermore, the catalyst is a catalyst represented by the following formulas (11) to (34) from the viewpoint of solubility in water and the steric positional relationship between the amine, which is a reaction point, an acidic proton, and a fat-soluble site. preferable.

  The said catalyst can be manufactured by the method shown below, for example. Addition of a silylating agent and a base to 3-hydroxyproline or 4-hydroxyproline as a starting material, and silylation of alcohol can be performed to obtain catalysts (11), (12) and (13) in one step. .

  Catalysts (11) to (13) and (20) to (25) can be produced, for example, by the method shown below. The starting material 3-hydroxyproline or 4-hydroxyproline is reacted with a benzyloxycarbonylation reagent, for example, benzyloxycarbonyl chloride, under basic conditions, and the nitrogen atom is converted into a benzyloxycarbonyl group (Z group, Cbz group). Protect. A benzylating agent such as benzyl chloride and a base are added to make the carboxylic acid a benzyl ester. In the presence of an amine salt, a silylating agent such as silyl chloride is added to silylate the hydroxyl group. Catalysts (11) to (13) and (20) to (25) can be obtained by subjecting the obtained compound to catalytic hydrogenation and deprotection.

  Further, in the catalysts (14) to (19), a starting material, 4-hydroxyproline, is reacted with a benzyloxycarbonylation reaction reagent such as benzyloxycarbonyl chloride under basic conditions to protect the nitrogen atom with a Z group. A benzylating agent such as benzyl chloride and a base are added to benzylate the carboxylic acid. In the presence of a base, an acylating agent such as acyl chloride is allowed to act to give an ester. Catalysts (14) to (19) are obtained by catalytic hydrogenation and deprotection of the resulting compound.

  In the catalysts (26) to (28), a starting material, 4-hydroxyproline, is reacted with a benzyloxycarbonylation reaction reagent such as benzyloxycarbonyl chloride under basic conditions, and the nitrogen atom is protected with a Z group. For example, chloroformate is allowed to act on carboxylic acid in the presence of a base, and then ammonia is allowed to act to obtain an amide. The amide is reacted with, for example, phosphorous oxychloride in the presence of a base to obtain a nitrile. For example, sodium azide is allowed to act on the nitrile to convert it into tetrazole. Catalysts (26) to (28) can be obtained by subjecting the obtained compound to catalytic hydrogenation and deprotection.

  The catalyst represented by the general formula (9-7) causes proline to act on a benzyloxycarbonylation reaction reagent such as benzyloxycarbonyl chloride in the presence of a base to protect the nitrogen atom with a Z group. Next, p-nitrophenol is allowed to act in the presence of a condensing agent and a base to lead the carboxylic acid to an ester of p-nitrophenol. In this case, for example, DCC (1,3-dicyclohexylcarbodiimide) or the like is used as the condensing agent, and pyridine is used as the base. The corresponding sulfonic acid amide is allowed to act on this active ester in the presence of a base. At this time, for example, sodium hydride is used as the base. The catalyst represented by the general formula (9-7) can be obtained by performing catalytic hydrogenation on the obtained sulfonic acid amide and deprotecting the Z group.

  As the benzyloxycarbonylation reaction reagent used for the production of the above catalyst, benzylcyanoformate, dibenzyl carbonate and the like can be used in addition to benzyloxycarbonyl chloride. As a catalyst used also for catalytic hydrogenation, a palladium-carbon catalyst, a palladium hydroxide catalyst, etc. can be used.

  In the method for producing the catalyst, a benzyloxycarbonyl group (Z group) is used for protecting nitrogen, but a t-butoxycarbonyl group (Boc group) can be used. As a reagent in this case, di-t-butyl dicarbonate or the like can be used. When the Boc group is used, it can be produced not by catalytic hydrogenation but by deprotection with an acid.

In the method for producing a β-hydroxycarbonyl compound, the reaction temperature is −20 ° C. to 50 ° C., the reaction time is 1 hour to 48 hours, and the reaction can be performed without using water, an organic solvent, or a solvent. . Examples of the organic solvent include hexane, CH ₂ Cl ₂ (dichloromethane), AcOEt (ethyl acetate), THF (tetrahydrofuran), toluene, benzene, Et ₂ O (diethyl ether), CHCl ₃ (chloroform), dioxane, DME (dimethoxyethane). ), Acetonitrile and the like can be used. The amount of the organic solvent is preferably 5 equivalents or less with respect to the raw material ketone or aldehyde.

[Water addition process]
After the production of the β-hydroxycarbonyl compound, water can be added to the reaction solution, and the organic layer can be washed with water, whereby the catalyst can be contained in the aqueous layer that is the washing solution. The amount of water added may be an amount that can dissolve the catalyst and separate the water layer and the organic layer. For example, the water may be added in the range of 10% by mass to 200% by mass with respect to the reaction solution. preferable.

  By washing with water, the catalyst can be dissolved in water, so that the organic layer in which only the β-hydroxycarbonyl compound is dissolved can be easily taken out. In addition, when water is used as the reaction solvent, if the amount of water is small, the water is dispersed in the reaction solution after the completion of the reaction. Therefore, by adding water, the organic layer and the aqueous layer are separated. It can be performed.

[Water removal process]
Next, water is removed from the reaction solution. As a removal method, it can carry out by a conventionally known method. For example, the aqueous layer can be removed using a pipette or the like that separates using a separating funnel. As a result, the catalyst used in the reaction can be removed, and there is no need to extract and separate the organic layer with an organic solvent as in the prior art, and the organic layer in which the β-hydroxycarbonyl compound is dissolved. Can be obtained. Therefore, the organic layer can be easily taken out by the following isolation step.

[Isolation process]
Next, the β-hydroxycarbonyl compound is isolated from the organic layer obtained by the liquid separation step by distillation or recrystallization. When the produced β-hydroxycarbonyl compound is a solution, it is removed by distillation. When the β-hydroxycarbonyl compound is a crystal, it is preferably taken out by recrystallization.

  It does not specifically limit as a distillation method, It can distill by a conventionally well-known method. The conditions for the distillation can be appropriately selected and used depending on the raw material, the produced β-hydroxycarbonyl compound and the organic solvent used for filtration.

  Further, the recrystallization method is not particularly limited, and can be performed by a conventionally known method. Specifically, the β-hydroxycarbonyl compound is dissolved in a solvent that can be used for filtration, for example, and cooled to a temperature at which the β-hydroxycarbonyl compound precipitates from a temperature equal to or higher than the melting point. To precipitate. After the precipitated β-hydroxycarbonyl compound is obtained by filtration or centrifugation, the β-hydroxycarbonyl compound can be taken out by drying and removing the solvent.

Second Embodiment
In the post-treatment method of the second embodiment of the present invention, a β-hydroxycarbonyl compound is produced by reacting a ketone and an aldehyde or an aldehyde and an aldehyde in the presence of a catalyst in an aqueous solvent or without using a solvent. After the silica gel is added, the water and the catalyst are adsorbed on the silica gel, the silica gel is removed, and the β-hydroxycarbonyl compound is removed by distillation or recrystallization. is there.

[Manufacturing process]
The β-hydroxycarbonyl compound can be produced using the same raw materials and catalyst as in the first embodiment except that the production method is carried out in an aqueous solvent or without using a solvent. Moreover, in order to improve the solubility of an aldehyde and a ketone, a small amount of organic solvents can also be added. Examples of the organic solvent include hexane, CH ₂ Cl ₂ (dichloromethane), AcOEt (ethyl acetate), THF (tetrahydrofuran), toluene, benzene, Et ₂ O (diethyl ether), CHCl ₃ (chloroform), dioxane, DME (dimethoxyethane). ), Acetonitrile and the like can be used.

[Adsorption process]
After the production of the β-hydroxycarbonyl compound, silica gel is added to the reaction solution, and an aqueous solvent and a catalyst are adsorbed on the silica gel. The addition amount of silica gel is preferably 2% or more and 100% or less, more preferably 5% or more and 30% or less by mass ratio with respect to the reaction solution. By setting it as the said range, water and a catalyst can fully be adsorbed.

[Filtering process]
Next, the silica gel is removed by filtration. The filtration method is not particularly limited, and filtration can be performed by a conventionally known method. For example, it can filter with a Nutsche type | formula filtration apparatus, a pressure filtration apparatus, etc. Moreover, the temperature in a filtration process is not specifically limited, It can carry out at arbitrary temperature.

  In the filtration step, filtration is performed easily, and an organic solvent is used to elute the β-hydroxycarbonyl compound, which is a product adsorbed on silica gel. The organic solvent to be used is not particularly limited as long as the product β-hydroxycarbonyl compound can be dissolved, and ethyl acetate, ether, chloroform, acetone, THF, and the like can be used.

[Isolation process]
Next, the β-hydroxycarbonyl compound is isolated by distillation or recrystallization from the solution filtered in the filtration step. As an isolation method, it can be isolated by the same method as in the first embodiment.

<Third Embodiment>
In the post-treatment method of the third embodiment of the present invention, a β-hydroxycarbonyl compound is produced by reacting a ketone and an aldehyde, or an aldehyde and an aldehyde in the presence of a catalyst in an aqueous solvent or without using a solvent. Thereafter, the β-hydroxycarbonyl compound is removed by column chromatography.

  The β-hydroxycarbonyl compound can be produced using the same raw materials and catalyst as in the first embodiment except that the production method is carried out in an aqueous solvent or without using a solvent.

  As an isolation method, the reaction solution after the production of the β-hydroxycarbonyl compound is directly processed by column chromatography, so that it is not necessary to perform a liquid separation operation and an extraction operation, and the isolation can be performed.

  The column chromatography method is not particularly limited, and can be performed by a conventionally known method. The filler to be used and the reaction conditions can be appropriately selected depending on the produced β-hydroxycarbonyl compound and the like. Specifically, the reaction solution is passed through a column filled with a packing material. Thereafter, the inside of the column is washed with water, and then the β-hydroxycarbonyl compound adsorbed on the column is passed through and eluted from the solvent used as the mobile phase to separate the β-hydroxycarbonyl compound and the catalyst. Thereafter, the β-hydroxycarbonyl compound can be taken out by removing the solvent by distillation.

  Hereinafter, the present invention will be described in more detail with reference to examples.

Example 1
<< Production of 2-hydroxymethylphenylcyclohexanone >>
As a catalyst, (2S, 4R) -4- (tert-butyldiphenylsilyloxy) -pyrrolidine-2-carboxylic acid (13) (259 mg, 0.70 mmol) was added at room temperature with benzaldehyde (7.4 g, 70 mmol), cyclohexanone ( 13.7 mL, 140 mmol) and water (3.8 mL, 210 mmol) in suspension. After stirring for 48 hours, silica gel (2.5 g) was added to the system. The mixture was filtered through silica gel with ethyl acetate (60 mL) and distilled to give 2-hydroxymethylphenylcyclohexanone (10 g, 70%) as a clear liquid.

Diastereoselectivity was determined by ¹ H NMR analysis and optical yield was determined by HPLC analysis. The results are shown below.
anti: syn = 10: 1 (by ¹ H NMR analysis of reaction crude product),
> 99% ee (by HPLC, (chiralcel OD-H column, λ = 213nm, iPrOH / hexane = 1: 100, 1.0ml / min, tr = 19.4min (major), tr = 25.9min (minor))).

(Example 2)
<< Production of (2S, 1'R) -2- (hydroxy-o-chlorophenylmethyl) cyclopentan-1-one >>
To a mixture of o-chlorobenzaldehyde (7.9 mL, 70 mmol), L-proline (2.42 g, 21 mmol) and water (3.8 mL) was added cyclopentanone (30.9 mL, 350 mmol) at room temperature. After stirring at room temperature for 25 hours, water (40 mL) and brine (20 mL) were added and stirred for 10 minutes. After removal of the aqueous layer, distillation was performed at a pressure of 0.8 mmHg and a temperature of 140 ° C. 0.1 mmol) was obtained as a mixture of diastereomers (anti: syn = 1.7: 1, 99% ee (anti)) with a yield of 75%.

The compound was identified by NMR, IR, HRMS, and HPLC results. The compound identification results are shown below.
[NMR, IR, HRMS, HPLC of (2S, 1′R) -2- (hydroxy-o-chlorophenylmethyl) cyclopentan-1-one]
¹ H NMR (400MHz, CDCl ₃ ): δ 1.64-1.78 (3H, m), 1.93-2.07 (1H, m), 2.22-2.35 (1H, m), 2.36-2.52 (2H, m), 4.47 (1H , d, J = 1.2Hz), 5.29 (1H, br, d, J = 9.3Hz), 7.15-7.23 (1H, m), 7.26-7.36 (2H, m), 7.52 (1H, m);
¹³ C NMR (100 MHz, CDCl ₃ ): δ 20.5, 26.4, 38.7, 55.6, 70.4, 127.4, 128.4, 128.9, 129.3, 132.5, 139.2, 222.8;
IR (neat): ν 3447, 2965, 1735, 1695, 1440, 1402, 1156, 1024, 749 cm ^-1 ;
HRMS (FAB): [M + Na] calcd for [C ₁₂ H ₁₃ ClO ₂ Na]: 247.0604, found: 247.0506;
[α] _D ²² -51.7 (c 0.31, CHCl ₃ ), 94% ee for anti.
Enantiomeric excess was determined by HPLC with a Chiralpak AD-H column (100: 1 hexane: 2-propanol, λ = 220nm), 1.0mL / min; major enantiomer tr = 25.7min, minor enantiomer tr = 30.3min.

(Example 3)
<< Production of (2S, 1'R) -2- [hydroxy- (p-trifluoromethylphenyl) methyl] cyclohexane-1-one >>
Cyclohexanone (29.6 mL, 287 mmol) was added to a mixture of p-trifluoromethylbenzaldehyde (8.6 mL, 57.4 mmol), L-proline (1.98 g, 17.2 mmol) and water (3.1 mL) at room temperature. added. After stirring at room temperature for 96 hours, it was washed with water (50 mL) three times to remove proline, and the organic layer was concentrated under vacuum. Purification is performed by recrystallization using cyclohexane (57.6 mL) and (2S, 1′R) -2- [hydroxy- (p-trifluoromethylphenyl) methyl] cyclohexane-1-one (11.4 g, 41.8 mmol) (anti: syn => 20: 1, 99% ee (anti)) and obtained in a yield of 73%.

The compound was identified by NMR, IR, HRMS, and HPLC results. The compound identification results are shown below.
[NMR, IR, HRMS, HPLC of [(2S, 1′R) -2- [hydroxy- (p-trifluoromethylphenyl) methyl] cyclohexane-1-one]
¹ H NMR (400MHz, CDCl ₃ ): δ 1.24-1.37 (1H, m), 1.48-1.70 (3H, m), 1.77-1.82 (1H, m), 2.09 (1H, ddd, J = 1.2, 6.0, 12.8Hz), 2.34 (1H, ddt, J = 0.8, 6.0, 13.6Hz), 2.44-2.50 (1H, m), 2.54-2.61 (1H, m), 3.99 (1H, br s), 4.83 (1H, d, J = 8.8Hz), 7.42 (2H, d, J = 8.0Hz), 7.59 (2H, d, J = 8.0Hz);
¹³ C NMR (100 MHz, CDCl ₃ ): δ 24.7, 27.7, 30.7, 42.7, 57.2, 74.3, 123.2, 125.3, 127.4, 130.1, 144.9, 215.2 ,;
IR (KBr): ν 3752, 3361, 2948, 2910, 1700, 1328, 1170, 1138, 1109, 845 cm ^-1 ;
HRMS (FAB): [M + Na] calcd for [C ₁₄ H ₁₅ F ₃ O ₂ Na]: 295.0916, found: 295.0907;
[α] _D ²² -35.2 (c 1.00, MeOH),> 99% ee for anti.
Enantiomeric excess was determined by HPLC with a Chiralcel AD-H column (10: 1 hexane: 2-propanol, λ = 254nm), 1.0mL / min; major enantiomer tr = 12.9min, minor enantiomer tr = 9.5min.

Example 4
<< (2S, 3S) -3-hydroxy-2-methylpentanal, production of (2S, 3R) -3-hydroxy-2-methylpentanal >>
As a catalyst, (S) -pyrrolidine-2-carboxamide (17 mg, 0.15 mmol) was added into a suspension of propanal (0.22 mL, 3.0 mmol), water (0.33 mL) at room temperature. After stirring for 11 hours, the reaction solution was directly purified by silica gel chromatography (hexane: ethyl acetate = 2: 1 to 1: 1) to obtain (2S, 3S) -3-hydroxy-2-methylpentanal and (2S , 3R) -3-Hydroxy-2-methylpentanal diastereomeric mixture (63 mg, 36% yield) was obtained as a clear liquid.

Diastereoselectivity was determined by ¹ H NMR analysis. The optical purity was determined by HPLC analysis of a monobenzoyl derivative obtained by reacting a diol obtained by reducing the product with sodium borohydride in pyridine with benzoyl chloride. The results are shown below.
anti: syn = 1: 1 (by ¹ H NMR analysis of the product),
78% ee (anti), 74% ee (syn) (By HPLC analysis, (Chiralpak IA column (hexane: 2-propanol = 100: 1 λ = 254nm), 1.0mL / min; major enantiomer (syn) tr = 24.6 min, minor enantiomer (syn) tr = 29.9min, major enantiomer (anti) tr = 31.5min, minor enantiomer (anti) tr = 34.4min.

Claims (5)

After producing a β-hydroxycarbonyl compound by reacting a ketone and an aldehyde, or an aldehyde and an aldehyde, in the presence of a catalyst, using an aqueous solvent, an organic solvent, or without using a solvent,
After adding water to wash the organic layer, the water is removed,
A post-treatment method for removing the β-hydroxycarbonyl compound by distillation or recrystallization.   The post-treatment method for a β-hydroxycarbonyl compound according to claim 1, wherein the organic solvent is 5 equivalents or less based on the ketone or aldehyde. After producing a β-hydroxycarbonyl compound by reacting a ketone and an aldehyde or an aldehyde and an aldehyde in the presence of a catalyst in an aqueous solvent or without using a solvent,
After adding silica gel and adsorbing the water and the catalyst on silica gel,
Remove the silica gel,
A post-treatment method for removing the β-hydroxycarbonyl compound by distillation or recrystallization. After producing a β-hydroxycarbonyl compound by reacting a ketone and an aldehyde or an aldehyde and an aldehyde in the presence of a catalyst in an aqueous solvent or without using a solvent,
A post-treatment method for a β-hydroxycarbonyl compound, wherein the β-hydroxycarbonyl compound is taken out by column chromatography. The post-treatment method for a β-hydroxycarbonyl compound according to any one of claims 1 to 4, wherein the catalyst is a compound represented by the following general formulas (9-1) to (9-10).

(In the formula, R ¹ represents an alkyl group or an aryl group. Each R ¹ may be the same or different. R ² represents an alkyl group, an aryl group, an acyl group, a trialkylsilyl group, a dialkyl group. An arylsilyl group or an alkyldiarylsilyl group, R ³ represents hydrogen, an alkyl group, or an aryl group, R ⁴ represents an alkyl group or an aryl group, and R ⁵ has a functional group. An alkyl group that may be substituted, an aryl group that may have a substituent, or a heteroaryl group that may have a substituent, where n represents an integer of 1 to 15.)