JP4591998B2 - Method for producing optically active alcohol derivative - Google Patents

Description

  The present invention relates to a method for separating optical isomers from each other by selectively carbamerizing one optical isomer of an alcohol compound having a carbonyl group in the vicinity or having a low optical purity.

Optically active alcohol compounds having a carbonyl group, including hydroxy acids, are useful as pharmaceutical and agrochemical intermediates. As a method for producing such a compound, an optical resolution method using an inexpensive racemate is advantageous in terms of cost. As a method for optical resolution of hydroxy acid, there are a biochemical method such as lipase and bacterial cell catalyst, a method using an optical resolution agent such as asymmetric modification and a fractional crystallization method, and a method using a catalyst. However, the method using a lipase or a bacterial cell catalyst has substrate specificity and is difficult to produce, and the method using an optical resolution agent has the disadvantage that the selection of the resolution agent and the crystallization conditions are not general. As an example using a catalyst, there is a method of Deng et al., Which has a high optical selectivity, but has a drawback that the amount of catalyst is as high as 10 mol% and cannot be applied to hydroxyketone (patent) Reference 1). Moreover, although there exists kinetic resolution | decomposition of the alcohol using an isocyanate, only a few asymmetric yields are obtained (refer nonpatent literature 1).
International Publication No. 02/10096 Pamphlet VM Potapov et al., “Zhurnal Obshchei Khimii” (Russia) 1981, 51 (6), p. 1214-1218

  An object of the present invention is to provide a versatile and highly productive method for producing an optically active alcohol compound having a carbonyl group.

  As a result of intensive studies to solve the above problems, the present inventor has found that optical resolution can be carried out kinetically by carbamerizing a hydroxyl group in the presence of a metal catalyst having an asymmetric ligand. It came to complete.

  That is, the present invention has a carbonyl group characterized by kinetic resolution of an alcohol compound having a carbonyl group in the presence of a metal ligand consisting of a metal compound and an asymmetric ligand, and an isocyanate. It is a manufacturing method of an optically active alcohol compound.

  As described above, the method for producing an optically active alcohol of the present invention is versatile and can efficiently produce an optically active alcohol compound having a carbonyl group. The optically active alcohol having a carbonyl group is useful as various industrial products such as agricultural chemicals and pharmaceuticals and intermediates thereof, and it can be said that the value of the present invention is high.

  The metal complex used by the manufacturing method of this invention will not be specifically limited if it consists of a metal compound and an asymmetric ligand. The metal compound used is selected from copper, zinc, magnesium, nickel, iron, cobalt and their compounds, among which zinc, nickel, copper or their compounds are preferred, and monovalent or divalent The case where copper or a compound thereof is used is particularly suitable. Specific examples of such a copper compound include copper halides such as cuprous chloride, cupric chloride and cuprous iodide, copper (II) triflate, and the like. These complexes can be used alone or in combination of two or more. Further, the amount to be used is not particularly limited. Specifically, the range of 0.01 to 20 mol% can be exemplified with respect to the alcohol compound having a carbonyl group, and more preferably 0.05 to 10 mol%. A range can be illustrated.

  The asymmetric ligand is not particularly limited as long as it is a ligand having one or more asymmetric sources in the molecule.

（式中、Ｒ¹及びＲ¹¹は、それぞれ独立に、置換基を有しても良いアルキル基、置換基を有しても良いアルケニル基、置換基を有しても良いアルキニル基、置換基を有しても良いシクロアルキル基、置換基を有しても良いアラルキル基または置換基を有しても良いアリール基を表し、
Ｒ²、Ｒ²¹、Ｒ³及びＲ³¹は、それぞれ独立に、水素原子、置換基を有しても良いアルキル基、置換基を有しても良いアルケニル基、置換基を有しても良いアルキニル基、置換基を有しても良いシクロアルキル基、置換基を有しても良いアラルキル基または置換基を有しても良いアリール基を表す。
また、Ｒ¹は、Ｒ²またはＲ³と、Ｒ¹¹は、Ｒ²¹またはＲ³¹と、結合して環を形成しても良い。
Ａは単結合、置換基を有しても良いアルキレン、置換基を有しても良いシクロアルキレン、置換基を有しても良いアリレン、または置換基を有しても良い２価のヘテロ環を表す。
＊は不斉炭素原子であることを表す。）
または、式（２）

Wherein R ¹ and R ¹¹ are each independently an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, or a substituent. A cycloalkyl group which may have a substituent, an aralkyl group which may have a substituent or an aryl group which may have a substituent,
R ² , R ²¹ , R ³ and R ³¹ each independently have a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, or a substituent. It represents an alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted aralkyl group or an optionally substituted aryl group.
R ¹ may be bonded to R ² or R ³ , and R ¹¹ may be bonded to R ²¹ or R ³¹ to form a ring.
A is a single bond, alkylene that may have a substituent, cycloalkylene that may have a substituent, arylene that may have a substituent, or a divalent heterocyclic ring that may have a substituent. Represents.
* Represents an asymmetric carbon atom. )
Or the formula (2)

（式中、Ｒ⁴、Ｒ⁴¹、Ｒ⁵、およびＲ⁵¹は、それぞれ独立して水素原子、置換基を有しても良いアルキル基、置換基を有しても良いシクロアルキル基、置換基を有しても良いアラルキル基または置換基を有しても良いアリール基を表す。
また、Ｒ⁴とＲ⁵、またはＲ⁴¹とＲ⁵¹は、結合して環を形成しても良い。ただし、Ｒ⁴及びＲ⁵、またはＲ⁴¹およびＲ⁵¹が、同時に水素原子である場合を除く。
Ｒ⁶及びＲ⁶¹は、それぞれ独立して、置換基を有しても良いアルキル基、置換基を有しても良いシクロアルキル基、置換基を有しても良いアラルキル基または置換基を有しても良いアリール基を表す。
また、Ｒ⁶とＲ⁶¹は、結合して環を形成しても良い。
Ａ¹は単結合、置換基を有しても良いアルキレン、置換基を有しても良いシクロアルキレン、置換基を有しても良いアリレン、または置換基を有しても良い２価のヘテロ環を表す。
＊は不斉炭素原子であることを表す。）
で表される化合物を好ましく例示することができる。

(Wherein R ⁴ , R ⁴¹ , R ⁵ , and R ⁵¹ are each independently a hydrogen atom, an alkyl group that may have a substituent, a cycloalkyl group that may have a substituent, or a substituent. Represents an aralkyl group which may have an aryl group or an aryl group which may have a substituent.
R ⁴ and R ⁵ , or R ⁴¹ and R ⁵¹ may combine to form a ring. However, the case where R ⁴ and R ⁵ , or R ⁴¹ and R ⁵¹ are hydrogen atoms at the same time is excluded.
R ⁶ and R ⁶¹ each independently have an alkyl group that may have a substituent, a cycloalkyl group that may have a substituent, an aralkyl group that may have a substituent, or a substituent. Represents an aryl group which may be substituted.
R ⁶ and R ⁶¹ may combine to form a ring.
A ¹ is a single bond, alkylene which may have a substituent, cycloalkylene which may have a substituent, arylene which may have a substituent, or divalent hetero which may have a substituent. Represents a ring.
* Represents an asymmetric carbon atom. )
The compound represented by can be illustrated preferably.

In the formula (1), R ¹ , R ² , R ³ , R ¹¹ , R ²¹ , and R ³¹ alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, Pentyl and its isomer, hexyl and its isomer, heptyl and its isomer, nonyl and its isomer, dodecyl and the like;
Examples of the alkenyl group include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl and 2-hexenyl. , 3-hexenyl, 4-hexenyl, 5-hexenyl and the like;
Examples of the alkynyl group include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl and the like;
As the cycloalkyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like;
Aralkyl groups include benzyl, 1-phenylethyl, 2-phenylethyl, 1-methyl-naphthyl, 2-methyl-naphthyl, 1-ethylnaphthyl, 2-ethylnaphthyl and the like;
Examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 9-phenanthryl, 10-phenanthryl, and the like;
Can be specifically exemplified.

R ¹ , R ² , R ³ , R ¹¹ , R ²¹ , and R ³¹ may have a substituent on an appropriate carbon atom. Specific examples of such substituent include fluorine, chlorine Halogen atoms such as bromine atoms;
Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl, isooctyl, cyclopropyl, cyclobutyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl An alkyl group of
Aryl groups such as phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl;
Methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy group, isobutyloxy, s-butyloxy, t-butyloxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyloxy, cyclobutyloxy, 2 -Alkoxy groups such as methylcyclopropyloxy, cyclopropylmethyloxy, cyclopentyloxy, cyclohexyloxy;
Examples thereof include aralkyl groups such as benzyl, 2-phenylethyl, 1-naphthylmethyl, 2-naphthylmethyl and the like. Here, 1 or 2 or more substituents may be present, and the substitution position is not particularly limited.

R ¹ and R ² or R ³ , R ¹¹ and R ²¹ or R ³¹ may be bonded to form a ring, and specific examples of such compounds include compounds represented by the following formulae. be able to.

In the formula (1), as the alkylene of A, methylene, ethylene, propylene, butylene, pentylene, heptylene and the like;
Examples of cycloalkylene include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene and the like;
Arylene includes 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene, 1,3-naphthylene, 1,4-naphthylene, 1,5-naphthylene, 1,6- Naphthylene, 1,7-naphthylene, 1,8-naphthylene, 2,3-naphthylene, 2,4-naphthylene, 2,5-naphthylene, 2,6-naphthylene, 2,7-naphthylene, 2,8-naphthylene, etc. ;
Examples of the divalent heterocyclic ring include furan, thiophene, pyrrole, oxazole, isoxazole, thiazol, isothiazol, imidazole, pyrazole, pyridine, pyrimidine, pyrazine, 1,3-dioxolane, 1,4- Dioxane and the like can be mentioned. Specific examples of the compound of the formula (1) having a heterocycle in A include the compounds shown below.

A (an alkylene group which may have a substituent, a cycloalkylene group which may have a substituent, an arylene group which may have a substituent or a divalent heterocyclic ring which may have a substituent ) As a substituent, a halogen atom such as fluorine, chlorine or bromine;
An alkyl group of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl, isooctyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopentyl, cyclohexyl;
Aryl groups such as phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl;
Methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy group, isobutyloxy, s-butyloxy, t-butyloxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyloxy, cyclobutyloxy, 2 -Alkoxy groups such as methylcyclopropyloxy, cyclopropylmethyloxy, cyclopentyloxy, cyclohexyloxy;
Examples thereof include aralkyl groups such as benzyl, 2-phenylethyl, 1-naphthylmethyl, 2-naphthylmethyl and the like. Here, one or more substituents may be present, and the substitution position is not particularly limited.

As the alkyl group of R ⁴ , R ⁴¹ , R ⁵ , R ⁵¹ , R ⁶ and R ^{61 in} the formula (2),
Alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, heptyl, nonyl and dodecyl;
Examples of the cycloalkyl group include cyclopropyl, cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentyl, cyclohexyl, cyclohexyl, cyclohexyl and the like;
Aralkyl groups include benzyl, 1-phenylethyl, 2-phenylethyl, 1-methyl-naphthyl, 2-methyl-naphthyl, 1-ethylnaphthyl, 2-ethylnaphthyl and the like;
Examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 9-phenanthryl, 10-phenanthryl, and the like;
Can be mentioned.

R ⁴ , R ⁴¹ , R ⁵ , R ⁵¹ , R ⁶ , and R ⁶¹ (the alkyl group which may have a substituent, the cycloalkyl group which may have a substituent, or the substituent As a substituent of a good aralkyl group or an aryl group which may have a substituent, a halogen atom such as fluorine, chlorine or bromine atom;
Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl, isooctyl, cyclopropyl, cyclobutyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl An alkyl group of
Aryl groups such as phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl;
Methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy group, isobutyloxy, s-butyloxy, t-butyloxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyloxy, cyclobutyloxy, 2 -Alkoxy groups such as methylcyclopropyloxy, cyclopropylmethyloxy, cyclopentyloxy, cyclohexyloxy;
Examples thereof include aralkyl groups such as benzyl, 2-phenylethyl, 1-naphthylmethyl and 2-naphthylmethyl. Here, one or more substituents may be present, and the substitution position is not particularly limited.
R ⁴ and R ⁵ and R ⁴¹ and R ⁵¹ may combine to form a ring. An example is shown below.

R ⁶ and R ⁶¹ may be bonded to each other to form a ring. An example is shown below.

In the formula (2), as the alkylene of A ¹ , methylene, ethylene, propylene, butylene, pentylene, heptylene and the like;
Examples of cycloalkylene include cycloalkyl groups such as cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene;
Arylene includes 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene, 1,3-naphthylene, 1,4-naphthylene, 1,5-naphthylene, 1,6- Naphthylene, 1,7-naphthylene, 1,8-naphthylene, 2,3-naphthylene, 2,4-naphthylene, 2,5-naphthylene, 2,6-naphthylene, 2,7-naphthylene, 2,8-naphthylene, etc. ;
Examples of divalent heterocycles are furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazol, imidazole, pyrazole, pyridine, pyrimidine, pyrazine, 1,3-dioxolane, 1,4-dioxane. Etc.

A ¹ (an alkylene group which may have a substituent, a cycloalkylene group which may have a substituent, an arylene group which may have a substituent or a divalent hetero which may have a substituent) Ring) as a substituent such as a halogen atom such as a fluorine, chlorine or bromine atom;
Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl, isooctyl, cyclopropyl, cyclobutyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl An alkyl group of
Aryl groups such as phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl;
Methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy group, isobutyloxy, s-butyloxy, t-butyloxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyloxy, cyclobutyloxy, 2 -Alkoxy groups such as methylcyclopropyloxy, cyclopropylmethyloxy, cyclopentyloxy, cyclohexyloxy;
Examples thereof include aralkyl groups such as benzyl, 2-phenylethyl, 1-naphthylmethyl and 2-naphthylmethyl. One or more substituents may be present, and the substitution position is not particularly limited.

  The substrate applicable to the present invention is not particularly limited as long as it has a hydroxyl group and a carbonyl group.

（式中、Ｒ⁷は置換基を有しても良いアルキル基、置換基を有しても良いアルケニル基、置換基を有しても良いアルキニル基、置換基を有しても良いシクロアルキル基、置換基を有しても良いアラルキル基、置換基を有しても良いアリール基、置換基を有しても良いヘテロ環、置換基を有しても良いアルコキシ基、置換基を有しても良いシクロアルキルオキシ基、置換基を有しても良いアラルキルオキシ基、置換基を有しても良いアルキルアミノ基、置換基を有しても良いシクロアルキルアミノ基、置換基を有しても良いアラルキルアミノ基、置換基を有しても良いアリールアミノ基、置換基を有しても良いアルキルチオ基、置換基を有しても良いシクロアルキルチオ基、置換基を有しても良いアラルキルチオ基または置換基を有しても良いアリールチオ基を表し、
Ｒ⁸は置換基を有しても良いアルキル基、置換基を有しても良いアルケニル基、置換基を有しても良いアルキニル基、置換基を有しても良いシクロアルキル基、置換基を有しても良いアラルキル基、置換基を有しても良いアリール基または置換基を有しても良いヘテロ環を表す。
Ｒ⁷とＲ⁸は結合して環を形成しても良い。
Ｂは単結合、置換基を有しても良いアルキレン、置換基を有しても良いシクロアルキレン、置換基を有しても良いアリレン、または置換基を有しても良い２価のヘテロ環を表す。）
で示されるアルコール化合物への適用が好適である。これらのアルコール化合物はラセミ体であっても光学活性な化合物であっても本反応の適用をすることができる。

(Wherein R ⁷ is an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, or a cycloalkyl which may have a substituent. Group, an aralkyl group which may have a substituent, an aryl group which may have a substituent, a heterocyclic ring which may have a substituent, an alkoxy group which may have a substituent, and a substituent. A cycloalkyloxy group that may have a substituent, an aralkyloxy group that may have a substituent, an alkylamino group that may have a substituent, a cycloalkylamino group that may have a substituent, and a substituent. An aralkylamino group that may have a substituent, an alkylamino group that may have a substituent, a cycloalkylthio group that may have a substituent, and a substituent May have a good aralkylthio group or substituent It represents a Riruchio group,
R ⁸ represents an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, a cycloalkyl group which may have a substituent, a substituent Represents an aralkyl group which may have a substituent, an aryl group which may have a substituent, or a heterocyclic ring which may have a substituent.
R ⁷ and R ⁸ may combine to form a ring.
B is a single bond, alkylene that may have a substituent, cycloalkylene that may have a substituent, arylene that may have a substituent, or a divalent heterocyclic ring that may have a substituent. Represents. )
Application to an alcohol compound represented by Even if these alcohol compounds are racemic or optically active compounds, this reaction can be applied.

Examples of the alkyl group for R ⁷ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and its isomer, hexyl and its isomer, heptyl and its isomer, nonyl and its isomer, dodecyl, etc. ;
Examples of the alkenyl group include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl and 2-hexenyl. , 3-hexenyl, 4-hexenyl, 5-hexenyl and the like;
Examples of the alkynyl group include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl and the like;
As the cycloalkyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like;
Aralkyl groups include benzyl, 1-phenylethyl, 2-phenylethyl, 1-methyl-naphthyl, 2-methyl-naphthyl, 1-ethylnaphthyl, 2-ethylnaphthyl and the like;
Examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 9-phenanthryl, 10-phenanthryl, and the like;
Examples of the heterocycle include furan, thiophene, pyrrole, oxazole, isoxazole, thiazol, isothiazol, imidazole, pyrazole, pyridine, pyrimidine, pyrazine and the like;
Examples of the alkoxy group include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, t-butoxy and the like;
Examples of the cycloalkyloxy group include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like;
As the aralkyloxy group, benzyloxy, 1-phenylethyloxy, 2-phenylethyloxy and the like;
Examples of the alkylamino group include methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, t-butylamino, pentylamino, hexylamino, heptylamino, nonylamino, dodecylamino and the like;
As the cycloalkylamino group, cyclopropylamino, cyclobutylamino, cyclopentyl, cyclohexyl and the like;
As the aralkylamino group, benzylamino, 1-phenylethylamino, 2-phenylethylamino and the like;
Examples of arylamino groups include phenylamino, 1-naphthylamino, 2-naphthylamino, 1-anthrylamino, 2-anthrylamino, 9-anthrylamino, 1-phenanthrylamino, 9-phenanthryl. Amino, 10-phenanthrylamino and the like;
Examples of the alkylthio group include methylthio, ethylthioethyl, n-propylthio, iso-propylthio, n-butylthio, iso-butylthio, sec-butylthio, t-butylthio and the like;
Examples of the cycloalkylthio group include cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthiooxy and the like;
As the aralkylthio group, benzylthio, 1-phenylethylthio, 2-phenylethylthio and the like;
As the arylthio group, phenylthio, 1-naphthylthio, 2-naphthylthio, 1-anthrylthio, 2-anthrylthio, 9-anthrylthio, 1-phenanthrylthio, 9-phenanthrylthio, 10-phenanthrylthio and the like;
Can be mentioned.

R ⁷ (alkyl group which may have a substituent, alkenyl group which may have a substituent, alkynyl group which may have a substituent, cycloalkyl group which may have a substituent, substituted An aralkyl group which may have a group, an aryl group which may have a substituent, a heterocyclic ring which may have a substituent, an alkoxy group which may have a substituent, and a substituent A good cycloalkyloxy group, an aralkyloxy group which may have a substituent, an alkylamino group which may have a substituent, a cycloalkylamino group which may have a substituent, and a substituent Good aralkylamino group, arylamino group which may have a substituent, alkylthio group which may have a substituent, cycloalkylthio group which may have a substituent, aralkylthio which may have a substituent Aryl which may have a group or substituent Examples of the substituent of the thio),
Halogen atoms such as fluorine, chlorine and bromine atoms;
Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl, isooctyl, cyclopropyl, cyclobutyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl An alkyl group of
Aryl groups such as phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl;
Methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy group, isobutyloxy, s-butyloxy, t-butyloxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyloxy, cyclobutyloxy, 2 -Alkoxy groups such as methylcyclopropyloxy, cyclopropylmethyloxy, cyclopentyloxy, cyclohexyloxy;
Examples thereof include aralkyl groups such as benzyl, 2-phenylethyl, 1-naphthylmethyl and 2-naphthylmethyl. One or more substituents may be present, and the substitution position is not particularly limited.

Examples of the alkyl group for R ⁸ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, heptyl, nonyl, dodecyl and the like;
Examples of the alkenyl group include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl and 2-hexenyl. , 3-hexenyl, 4-hexenyl, 5-hexenyl and the like;
Examples of the alkynyl group include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl and the like;
As the cycloalkyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc .;
Aralkyl groups include benzyl, 1-phenylethyl, 2-phenylethyl, 1-methyl-naphthyl, 2-methyl-naphthyl, 1-ethylnaphthyl, 2-ethylnaphthyl and the like;
Examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 9-phenanthryl, 10-phenanthryl, and the like;
Examples of the heterocycle include furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazol, imidazole, pyrazole, pyridine, pyrimidine, pyrazine and the like.
R ⁸ (alkyl group which may have a substituent, alkenyl group which may have a substituent, alkynyl group which may have a substituent, cycloalkyl group which may have a substituent, substituted As a substituent of an aralkyl group which may have a group, an aryl group which may have a substituent, or a heterocyclic ring which may have a substituent,
Halogen atoms such as fluorine, chlorine and bromine atoms;
Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl, isooctyl, cyclopropyl, cyclobutyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl An alkyl group of
Aryl groups such as phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl;
Methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy group, isobutyloxy, s-butyloxy, t-butyloxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyloxy, cyclobutyloxy, 2 -Alkoxy groups such as methylcyclopropyloxy, cyclopropylmethyloxy, cyclopentyloxy, cyclohexyloxy;
Examples thereof include aralkyl groups such as benzyl, 2-phenylethyl, 1-naphthylmethyl and 2-naphthylmethyl. One or more substituents may be present, and the substitution position is not particularly limited.

R ⁷ and R ⁸ may combine to form a ring. Specific examples thereof include compounds having the following structure, and a typical example thereof is pantolactone.

（Ｘは炭素原子、酸素原子、窒素原子または硫黄原子を示し、Ｑは置換基を有しても良いアルキレン）

(X represents a carbon atom, an oxygen atom, a nitrogen atom or a sulfur atom, and Q is an alkylene which may have a substituent)

  The isocyanate used in the present invention is not particularly limited, but the formula (4)

（式中、Ｒ⁹は置換基を有しても良いアルキル基、置換基を有しても良いシクロアルキル基、置換基を有しても良いアラルキル基または置換基を有しても良いアリール基を表す。）
で表される化合物が好適である。

(In the formula, R ⁹ is an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, an aralkyl group which may have a substituent, or an aryl which may have a substituent. Represents a group.)
Is preferred.

As the alkyl group for R ⁹ , methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl, isooctyl, cyclopropyl, cyclobutyl alkyl group;
As the cycloalkyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like;
Aralkyl groups include benzyl, 1-phenylethyl, 2-phenylethyl, 1-methyl-naphthyl, 2-methyl-naphthyl, 1-ethylnaphthyl, 2-ethylnaphthyl and the like;
Examples of the aryl group include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 9-phenanthryl, 10-phenanthryl and the like.

R ⁹ (alkyl group which may have a substituent, cycloalkyl group which may have a substituent, aralkyl group which may have a substituent, aryl group which may have a substituent) As a substituent,
Halogen atoms such as fluorine, chlorine and bromine atoms;
Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl, isooctyl, cyclopropyl, cyclobutyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl An alkyl group of
Aryl groups such as phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl;
Methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy group, isobutyloxy, s-butyloxy, t-butyloxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyloxy, cyclobutyloxy, 2 -Alkoxy groups such as methylcyclopropyloxy, cyclopropylmethyloxy, cyclopentyloxy, cyclohexyloxy;
Examples thereof include aralkyl groups such as benzyl, 2-phenylethyl, 1-naphthylmethyl, 2-naphthylmethyl and the like. One or more substituents may be present, and the substitution position is not particularly limited.

  In the present invention, the carbamate compound is kinetically resolved by reacting the isocyanate compound with the alcohol compound having the carbonyl group in the presence of the metal complex composed of the metal compound and the asymmetric ligand. An optically active alcohol compound having a carbonyl group in a stereoselective manner can be produced. For example, when the compound represented by the formula (3) is used as a raw material and the compound represented by the formula (4) is used as an isocyanate, the following reaction formula is shown as an example.

（式中、Ｂ、Ｒ⁷、Ｒ⁸およびＲ⁹は上記と同じで意味を示す）

(In the formula, B, R ⁷ , R ⁸ and R ⁹ have the same meaning as above)

  The usage-amount of the metal complex in this reaction is 0.01-20 mol% with respect to the alcohol compound which has a carbonyl group, Preferably it is 0.05-10 mol%. Solvents that can be used are not particularly limited as long as they are inert to the reaction. For example, hydrocarbon solvents such as pentane, hexane, heptane, benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, four Halogen solvents such as carbon chloride, ether solvents such as diethyl ether, dioxane, tetrahydrofuran, N, N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), or a mixture of two or more of these solvents And mixed solvent systems.

  The temperature of this reaction is in the range of −50 ° C. to the boiling point of the solvent, preferably in the range of −30 ° C. to room temperature. The reaction time varies depending on the amount and temperature of the reaction reagent, but is in the range of 30 minutes to 100 hours. After completion of the reaction, the product can be easily separated and purified by known and commonly used production methods such as fractional crystallization, distillation, column chromatography and the like.

EXAMPLES Next, although an Example demonstrates this invention in detail, this invention is not limited only to these. In addition, the apparatus used for the measurement of the physical property in each Example is as follows.
NMR spectrum: JNM-AL300 (300 MHz), JEOL high performance liquid chromatography: LC-10Advp, SPD-10Avp, Shimadzu Corporation gas chromatography: GC-17A, Shimadzu Corporation

Example 1
Kinetic resolution of methyl mandelate In 4 ml of methylene chloride, 20 μl of 3,3-pentylidenebis [(4S) -t-butyl-2-oxazoline] (0.062 mmol: compound (5)) and 18 mg of copper (II) triflate (0.05 mmol) was added and dissolved by ultrasonic irradiation (ultrasonic cleaner). Insoluble matter was filtered and 0.17 g (1 mmol) of methyl mandelate was added and dissolved, and then 40 μl (0.5 mmol) of ethyl isocyanate was added and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was subjected to silica gel column chromatography to remove the catalyst, followed by HPLC analysis (column: Chiral Pack AD-H, manufactured by Daicel Corporation, hexane / isopropanol 96/4,. 5 ml / min), the conversion was 49%, the optical purity of the N-ethyl carbamate was 73% ee, and the optical purity of the remaining raw material was 65% ee. The value obtained from the equation for determining the reaction rate ratio (s = ln [1-C (1 + ee)] / ln [1-C (1-ee)]; where C is the conversion rate and ee is the optical purity of the product) s = about 13.

Examples 2-8
Experiments were performed under the same conditions as in Example 1 except that the catalyst ligand was changed to Table 1, and the results shown in Table 1 were obtained.

Examples 9-16
Experiments were performed under the same conditions as in Example 1 except that the substrate was changed as shown below, and the results shown in Table 2 were obtained.

Examples 18-19
An experiment was performed under the same conditions as in Example 1 except that the reaction time was changed with the metal compound, and the results shown in Table 3 were obtained.

Examples 20-22
An experiment was performed under the same conditions as in Example 1 except that the isocyanate was changed as shown in Table 4, and the results shown in Table 4 were obtained.

Example 23
Kinetic resolution of 3-Hydroxy-3-phenyl-propionic acid ethyl ester

  When 3-Hydroxy-3-phenyl-propionic acid ethyl ester was subjected to kinetic optical resolution in the same manner as in Example 1 using ligand (5) in Table 1, N-ethyl carbamate The optical purity of the body was 47% ee, the optical purity of the remaining raw material was 38% ee, and s = 4.

  Example 24 Kinetic resolution of 3-Hydroxy-4,4-dimethyl-dihydro-furan-2-one (pantolactone)

To 4 ml of methylene chloride, 20 μl (0.062 mmol) of 3,3-pentylidenebis [(4S) -t-butyl-2-oxazoline] and 18 mg (0.05 mmol) of copper (II) triflate were added, and ultrasonic irradiation (ultrasonic) (Sonic cleaner). Insoluble matter was filtered, 0.13 g (1 mmol) of pantolactone was added and dissolved, 40 μl (0.5 mmol) of ethyl isocyanate was added, and the mixture was stirred for 75 minutes. When the reaction solution was analyzed by GC (column: CP Chirazil-DEX DB manufactured by Chrome Pack), the conversion was 48%, the optical purity of the N-ethylcarbamate was 88% ee, and the optical purity of the remaining raw material was 81% ee, s. = 40.
When 10 μl of ethyl isocyanate was further added and stirred for 1 hour, the conversion was 62%, the optical purity of the N-ethyl carbamate was 61% ee, and the optical purity of the remaining raw material was 98% ee.

Example 25 Kinetic resolution of ethyl mandelate (raw material 38% ee)
To 5 ml of methylene chloride was added 10 μl (0.031 mmol) of 3,3-pentylidenebis [(4S) -t-butyl-2-oxazoline] and 9 mg (0.025 mmol) of copper (II) triflate, and ultrasonic irradiation (ultrasonic) (Sonic cleaner). Insoluble matter was filtered, and after dissolving 0.45 g (2.5 mmol) of ethyl (R) -mandelate of 38% ee, 100 μl (1.25 mmol) of ethyl isocyanate was added and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was subjected to silica gel column chromatography to remove the catalyst, and then distilled with Kugelrohr to obtain pure ethyl mandelate. As a result of HPLC analysis (column: Chiral Pack OD-H manufactured by Daicel Corporation, hexane / isopropanol 90/10, 0.5 ml / min), the optical purity was 98% ee.

Claims (6)

A metal compound in which the metal atom is selected from copper, zinc, nickel, iron and cobalt , and formula (1)

Wherein R ¹ and R ¹¹ are each independently an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, or a substituent. A cycloalkyl group which may have a substituent, an aralkyl group which may have a substituent or an aryl group which may have a substituent,
R ² , R ²¹ , R ³ and R ³¹ each independently have a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, or a substituent. It represents an alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted aralkyl group or an optionally substituted aryl group.
R ¹ may be bonded to R ² or R ³ , and R ¹¹ may be bonded to R ²¹ or R ³¹ to form a ring.
A is a single bond, alkylene that may have a substituent, cycloalkylene that may have a substituent, arylene that may have a substituent, or a divalent heterocyclic ring that may have a substituent. Represents.
* Represents an asymmetric carbon atom. In the presence of a metal complex consisting of an asymmetric ligand represented by
Formula (3)

(Wherein R ₇ is an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, or a cycloalkyl which may have a substituent. Group, an aralkyl group which may have a substituent, an aryl group which may have a substituent, a heterocyclic ring which may have a substituent, an alkoxy group which may have a substituent, and a substituent. A cycloalkyloxy group that may have a substituent, an aralkyloxy group that may have a substituent, an alkylamino group that may have a substituent, a cycloalkylamino group that may have a substituent, and a substituent. An aralkylamino group that may have a substituent, an alkylamino group that may have a substituent, a cycloalkylthio group that may have a substituent, and a substituent May have a good aralkylthio group or substituent It represents a Riruchio group,
R ₈ represents an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, a cycloalkyl group which may have a substituent, a substituent Represents an aralkyl group which may have a substituent, an aryl group which may have a substituent, or a heterocyclic ring which may have a substituent.
R ₇ and R ₈ may combine to form a ring.
B represents a single bond, alkylene which may have a substituent, or cycloalkylene which may have a substituent. The method for producing an optically active alcohol compound having a carbonyl group is characterized by reacting an alcohol compound having a carbonyl group represented by formula (I) with an isocyanate to cause kinetic resolution. The production method according to claim 1 , wherein in formula (3), B is a single bond or methylene which may have a substituent. Isocyanate is represented by the formula (4)

(In the formula, R ⁹ is an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, an aralkyl group which may have a substituent, or an aryl which may have a substituent. Represents a group.)
The manufacturing method of Claim 1 or 2 represented by these. The method according to any one of claims 1 to 3 , wherein the metal compound is a monovalent or divalent copper compound. The method according to any one of claims 1 to 4 , wherein A in the formula (1) is methylene which may have a substituent. The method of any of claims. 1 to 4 A in the formula (1) is methylene, isopropylidene or 3 pentylidene.