JP3498332B2 - Asymmetric reducing agent and method for producing optically active substance using said asymmetric reducing agent - Google Patents

Description

Detailed Description of the Invention

[0001]

The present invention relates to the general formula [I] or [I '] (Chemical formula 6)

[Chemical 6] (In the formula, R ¹ represents an alkyl group, an allyl group, an aryl group, an aralkyl group or a halogen atom, R ² represents an alkyl group, an aryl group or an aralkyl group, and R ² ′ represents a hydrogen atom, an alkyl group, an aryl group or an aralkyl group. Group, R ³
Represents an alkyl group, an aryl group or an aralkyl group. Further, * represents an asymmetric carbon. ), An asymmetric reducing agent obtained from an optically active oxazaborolidine, a metal borohydride and an acid, and a method for producing an optically active amine derivative or alcohol derivative using the asymmetric reducing agent.

[0002]

As the optically active oxazaborolidine, for example,
Although 3,2- (2,5-diphenyl-3,4-dimethyl) oxazaborolidine is known, (Tetrahedron Lett. 30 5
551-54, (1989)), when an oxime derivative is reduced using an asymmetric reducing agent obtained from the oxazaborolidine derivative and borane, there is a problem that the selectivity of the optically active amine derivative is low.

As a result of intensive studies on the asymmetric reducing agent, the present inventors have found that an optically active oxazaborolidine derivative is
We have found that optically active amines can be obtained with extremely high selectivity by reducing the oxime derivative using an asymmetric reducing agent obtained by adding metal borohydride and an acid instead of borane. Completed the invention.

[0004]

That is, the present invention provides a compound represented by the general formula [I] or [I ']

[Chemical 7] (In the formula, R ¹ , R ² , R ² ', R ³ and * have the same meanings as described above.) Asymmetric reduction obtained from an optically active oxazaborolidine, a metal borohydride and an acid. The present invention provides a method for producing an optically active amine derivative or alcohol derivative using the agent and the asymmetric reducing agent.

The present invention will be described in detail below. R ¹ in the optically active oxazaborolidine represented by the general formula [I] or [I ′] constituting the asymmetric reducing agent of the present invention is an alkyl group, an allyl group, an aryl group, an aralkyl group or a halogen atom. Represent. Examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, cyclohexyl, heptyl,
C1-C8 alkyl groups such as diethylpropyl and octyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 1-iodoethyl, 2-fluoroethyl,
Examples thereof include a halogen-substituted alkyl group having 1 to 8 carbon atoms such as 3-chloropropyl and 3-trifluoropropyl. Examples of the allyl group include those having 1 to 8 carbon atoms such as ethenyl, propenyl, isopropenyl, butenyl and cyclohexenyl.

Examples of the aryl group include a phenyl group, a substituted phenyl group, a 1-naphthyl group and a 2-naphthyl group. Examples of the substituted phenyl group include o
-, M-, p-methylphenyl, o-, m-, p-ethylphenyl, o-, m-, p-ethenylphenyl, o
-, M-, p-butylphenyl, 2,3-, 2,4-,
Phenyl groups substituted with an alkyl group or an allyl group having 1 to 8 carbon atoms such as 2,5-, 2,6-, 3,4-, 3,5-dimethylphenyl, o-, m-, p- Methoxyphenyl, o-, m-, p-ethoxyphenyl, o-, m
-, P-propoxyphenyl, 2,3-, 2,4-,
A phenyl group substituted with a linear or branched alkoxy group having 1 to 8 carbon atoms such as 2,5-, 2,6-, 3,4-, 3,5-, 3,6-dimethoxyphenyl, o -, M
-, P-chlorophenyl, o-, m-, p-bromophenyl, o-, m-, p-fluorophenyl, o-, m
-, P-iodophenyl, 2,3-, 2,4-, 2,5
-, 2,6-, 3,4-, 3,5-, 3,6-difluorophenyl, 2,3,4-, 2,3,5-, 2,3,6
A phenyl group substituted with halogen such as-, 2,4,5-, 2,4,6-, 3,4,5-trifluorophenyl,
4-bromo-3,5-dimethylphenyl, 4-bromo-
Phenyl groups substituted with halogen atoms and alkyl groups such as 2,6-dimethylphenyl and 4-fluoro-3,5-dimethylphenyl, 2-chloro-5-methoxyphenyl, 2-bromo-5-methoxyphenyl, 2 A phenyl group substituted with a halogen atom and an alkoxy group such as -fluoro-5-methoxyphenyl, 2-iodo-5-methoxyphenyl, 3-bromo-5-methoxyphenyl, 4-ethoxy-2,3-difluorophenyl, 2- (chloromethyl) phenyl, 2- (bromomethyl) phenyl,
2- (fluoromethyl) phenyl, 3- (trifluoromethyl) phenyl, o-, m-, p- (1-chloroethyl) phenyl, o-, m-, p- (1-bromoethyl)
Examples thereof include a phenyl group substituted with a halogenated alkyl group such as phenyl, o-, m-, p- (3-chloropropyl) phenyl and 2-bromomethyl-6-methylphenyl.

Examples of the aralkyl group include benzyl,
o-, m-, p-tolylmethyl, o-, m-, p-ethylbenzyl, o-, m-, p-methoxybenzyl, o
-, M-, p-ethoxybenzyl, 2,3-, 2,4
-, 2,5-, 2,6-, 3,4-, 3,5-, 3,6
-Dimethylbenzyl, (2,3-, 2,4-, 2,5
Examples thereof include those having 7 to 12 carbon atoms such as-, 2,6-, 3,4-, 3,5-, 3,6-dimethylphenyl) ethyl. Examples of the halogen atom include fluorine, chlorine, bromine, iodine and the like.

R ² represents an alkyl group, an aryl group or an aralkyl group. Examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, se
Examples thereof include those having 1 to 6 carbon atoms such as c-butyl, tert-butyl, pentyl and hexyl. Examples of the aryl group include a phenyl group, a phenyl group substituted with the same alkyl group as described above, methoxy, ethoxy, propoxy,
Examples thereof include a phenyl group substituted with an alkoxy group having 1 to 6 carbon atoms such as butoxy, pentyloxy, hexyloxy, an α-naphthyl group, a β-naphthyl group, and the like. Examples of the aralkyl group include those having 7 to 12 carbon atoms such as benzyl, phenylethyl, phenylpropyl, phenylpentyl, and phenylhexyl. R ² 'represents a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group. The alkyl group, aryl group and aralkyl group are R
Same as ² .

R ³ represents an alkyl group, an aryl group or an aralkyl group. As the alkyl group, for example,
Methyl, ethyl, propyl, isopropyl, butyl, s
Examples thereof include those having 1 to 6 carbon atoms such as ec-butyl, tert-butyl, pentyl and hexyl. Examples of the aryl group include a phenyl group, a phenyl group substituted with the same alkyl group as described above, a phenyl group substituted with an alkoxy group having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, butoxy, pentyloxy, and hexyloxy. Base, α
Examples include -naphthyl group and β-naphthyl group. Examples of the aralkyl group include those having 7 to 12 carbon atoms such as benzyl, phenylethyl, phenylpropyl, phenylpentyl, and phenylhexyl.

Specific examples of oxazaborolidine represented by the general formula [I] or [I '] include 1,3,2- (2,2)
4 dimethyl-5-phenyl) oxazaborolidine, 1,
3,2- (2-ethyl-4-methyl-5-phenyl) oxazaborolidine, 1,3,2- (2-propyl-4-
Methyl-5-phenyl) oxazaborolidine, 1,3,
2- (2-butyl-4-methyl-5-phenyl) oxazaborolidine, 1,3,2- (4-methyl-2,5-diphenyl) oxazaborolidine, 1,3,2- (2 −
(O-Fluorophenyl) -4-methyl-5-phenyl) oxazaborolidine, 1,3,2- (2- (m-fluorophenyl) -4-methyl-5-phenyl) oxazaborolidine, 1 , 3,2- (2- (p-Fluorophenyl) -4-methyl-5-phenyl) oxazaborolidine, 1,3,2- (2- (2,4-difluorophenyl) -4-methyl- 5-phenyl) oxazaborolidine, 1,3,2- (2- (2,5-difluorophenyl) -4-methyl-5-phenyl) oxazaborolidine, 1,3,2- (2- ( 2,6-Difluorophenyl) -4-methyl-5-phenyl) oxazaborolidine, 1,3,2- (2- (2,3,4-trifluorophenyl) -4-methyl-5-phenyl) Oxazaborolidine, 1,3,2- (2- (2 , 5-Trifluorophenyl) -4-methyl-5-phenyl) oxazaborolidine, 1,3,2- (2- (2,4,5-trifluorophenyl) -4-methyl-5-phenyl) Oxazaborolidine, 1,3,2- (2- (2,4,6-trifluorophenyl) -4-methyl-5-phenyl) oxazaborolidine, 1,3,2- (2- (3 , 4,5-Trifluorophenyl) -4-methyl-5-phenyl) oxazaborolidine,

1,3,2- (2- (2-chlorophenyl) -4-methyl-5-phenyl) oxazaborolidine, 1,3,2- (2- (3-chlorophenyl) -4-
Methyl-5-phenyl) oxazaborolidine, 1,3,
2- (2- (2,3-dichlorophenyl) -4-methyl-5-phenyl) oxazaborolidine, 1,3,2-
(2- (2,6-dichlorophenyl) -4-methyl-5
-Phenyl) oxazaborolidine, 1,3,2- (2-
(3,5-Dichlorophenyl) -4-methyl-5-phenyl) oxazaborolidine, 1,3,2- (2- (o-
Methoxyphenyl) -4-methyl-5-phenyl) oxazaborolidine, 1,3,2- (2- (m-methoxyphenyl) -4-methyl-5-phenyl) oxazaborolidine, 1,3,2. 2- (2- (p-methoxyphenyl)-
4-methyl-5-phenyl) oxazaborolidine, 1,
3,2- (2- (2,5-dimethoxyphenyl) -4-
Methyl-5-phenyl) oxazaborolidine, 1,3,
2- (2- (o-tolyl) -4-methyl-5-phenyl) oxazaborolidine, 1,3,2- (2- (m-tolyl) -4-methyl-5-phenyl) oxazaborol Lysine, 1,3,2- (2- (p-tolyl) -4-methyl-
5-phenyl) oxazaborolidine,

1,3,2- (2- (2,5-dimethylphenyl) -4-methyl-5-phenyl) oxazaborolidine, 1,3,2- (2-methyl-4,5-diphenyl) ) Oxazaborolidine, 1,3,2- (2-methyl-
4,5- (2-naphthyl)) oxazaborolidine, 1,
3,2- (2-methyl-4- (2-methylpropyl)-
5-phenyl) oxazaborolidine, 1,3,2- (2
-Methyl-4- (1-methylpropyl) -5-phenyl) oxazaborolidine, 1,3,2- (2-methyl-
4- (1-methylethyl) -5-phenyl) oxazaborolidine, 1,3,2- (2-methyl-4- (1,1-
Dimethylethyl) -5-phenyl) oxazaborolidine, 1,3,2- (2-methyl-4- (phenylmethyl) -5-phenyl) oxazaborolidine, 1,3,2
-(2-Methyl-4-phenyl-5- (p-tolyl))
Oxazaborolidine, 1,3,2- (2,4-dimethyl-5- (2,5-dimethylphenyl)) oxazaborolidine, 1,3,2- (2,4-dimethyl-5- ( 2,5
-Dimethoxyphenyl)) oxazaborolidine,

1,3,2- (2-methyl-4-phenyl) oxazaborolidine, 1,3,2- (2,4-diphenyl) oxazaborolidine, 1,3,2- (2,2) 4-
Dimethyl) oxazaborolidine, 1,3,2- (2-methyl-4- (1-methylpropyl)) oxazaborolidine, 1,3,2- (2-methyl-4- (2-methylpropyl) )) Oxazaborolidine, 1,3,2- (2-methyl-4- (t-butyl)) oxazaborolidine, 1,
3,2- (2-methyl-4,5,5-triphenyl) oxazaborolidine, 1,3,2- (2-methyl-4-benzyl-5,5-diphenyl) oxazaborolidine,
1,3,2- (2,5,5-trimethyl-4- (t-butyl)) oxazaborolidine, 1,3,2- (2,4-
Dimethyl-5,5-di (o-methylphenyl)) oxazaborolidine, 1,3,2- (2,4-dimethyl-5,
5-dibenzyl) oxazaborolidine, 1,3,2-
(2,4-dimethyl-5,5-di (p-methoxyphenyl) oxazaborolidine and the like can be mentioned.

Oxazaborolidine [I] or [I ']
Is a compound represented by the general formula [VI] or [VI ']

[Chemical 8] (Wherein R ² , R ² ′, R ³ and * have the same meanings as described above), the amino alcohol represented by the general formula [VI
I] (Chem. 9)

[Chemical 9] (Wherein R ¹ has the same meaning as described above) or a boronic acid represented by the general formula [VIII]

[Chemical 10] (In the formula, R ¹ has the same meaning as described above.) It can be easily produced by acting a boroxine derivative.

R ² , R in amino alcohol [VI]
² ', R ³ are as defined above. Specific examples of the amino alcohol [VI] include, for example, optically active norephedrine and 2-amino-1- (2-methylphenyl)-
1-propanol, 2-amino-1- (4-methylphenyl) -1-propanol, 2-amino-1- (2-ethylphenyl) -1-propanol, 2-amino-1-
(2-Methoxyphenyl) -1-propanol, 2-amino-1- (4-methoxyphenyl) -1-propanol, 2-amino-1- (2-ethoxyphenyl) -1-
Propanol, 2-amino-1- (2,5-diethylphenyl) -1-propanol, 2-amino-1- (2,
5-dimethoxyphenyl) -1-propanol, 2-amino-1- (2,5-diethoxyphenyl) -1-propanol, 2-amino-1- (2-methoxy-5-methylphenyl) -1-propanol , 2-amino-1-phenyl-1-butanol,

2-amino-1- (2-methylphenyl)
-1-butanol, 2-amino-1- (2-ethylphenyl) -1-butanol, 2-amino-1-phenyl-
1-Pentanol, 2-amino-1- (2,5-dimethoxyphenyl) -1-pentanol, 2-amino-2-
Phenyl-1-tolyl-1-propanol, 2-amino-3-methyl-1-phenyl-butanol, 2-amino-1-phenyl-butanol, 2-amino-4-methyl-1-phenyl-1-pentanol , 2-amino-3-
Methyl-1-phenyl-pentanol, 2-amino-
1,3-diphenyl-1-propanol, 2-amino-
1,2-diphenyl-1-ethanol, 2-amino-
1,2-bis (1-naphthyl) -1-ethanol, 2-
Amino-1,2-bis (2-naphthyl) -1-ethanol, 2-amino-2-phenyl-1-ethanol, 2-
Amino-1-propanol, 2-amino-3,3-dimethyl-1-butanol, 2-amino-3-methyl-1-
Pentanol, 2-amino-4-methyl-1-pentanol, 2-amino-1,1,2-triphenyl-1-ethanol, 2-amino-1,1,3-triphenyl-1
-Propanol, 2-amino-1,1,3,3-tetramethyl-1-butanol, 2-amino-1,1-di (o
-Methylphenyl) -1-propanol, 2-amino-
1,1-di (p-methoxyphenyl) -1-propanol etc. are mentioned.

In the boronic acid [VII], R ¹ has the same meaning as described above. Specific compounds include, for example, methylboronic acid, ethylboronic acid, propylboronic acid, butylboronic acid, pentylboronic acid, hexylboronic acid,
Ethenylboronic acid, propenylboronic acid, isopropenylboronic acid, butenylboronic acid, phenylboronic acid,
α, β-naphthylboronic acid, o-, m-, p-methylphenylboronic acid, 2,3-, 2,4-, 2,5-, 2
6-, 3,4-, 3,5-dimethylphenylboronic acid,
Mesitylboronic acid, o-, m-, p-fluorophenylboronic acid, o-, m-, p-chlorophenylboronic acid,
o-, m-, p-bromophenylboronic acid, 2,3-,
2,4-, 2,5-, 2,6-, 3,4-, 3,5-difluorophenylboronic acid, 2,3,4-, 2,3,5
-, 2,3,6-, 2,4,5-, 2,4,6-, 3,
4,5-trifluorophenylboronic acid, o-, m-,
p-methoxyphenylboronic acid, benzylboronic acid, o
-, M-, p-tolylmethylboronic acid, 2,3-, 2,
4-, 2,5-, 2,6-, 3,4-, 3,5-dimethylbenzylboronic acid and the like can be mentioned.

In the boroxine derivative [VIII], R ¹
Represents the same meaning as described above. Specific compounds include, for example, trimethylboroxine, triethylboroxine,
Tripropylboroxine, tributylboroxine, triisobutylboroxine, tripentylboroxine, trihexylboroxine, trioctylboroxine, tris (1-methylethyl) boroxine, tris (1,1-dimethylethyl) boroxine, tris (1-methylpropyl) boroxine, tris (1,1-diethylpropyl)
Boroxine, tris (1-chloroethyl) boroxine,
Tris (3-chloropropyl) boroxine, tris (3,3,3-trifluoropropyl) boroxine, triethenylboroxine, tripropenylboroxine, triisopropenylboroxine, tri-1-butenylboroxine,

Triphenylboroxine, tri-1-cyclohexen-1-yl-boroxine, tris (2-methylphenyl) boroxine, tris (3-methylphenyl) boroxine, tris (4-methylphenyl) boroxine, tris (2 -Ethylphenyl) boroxine, tris (3-ethylphenyl) boroxine, tris (4-ethylphenyl) boroxine, tris (2,3-dimethylphenyl) boroxine, tris (2,4-dimethylphenyl) boroxine, Tris (2,2 5-dimethylphenyl) boroxine, tris (2,6-dimethylphenyl)
Boroxine, tris (3,4-dimethylphenyl) boroxine, tris (3,5-dimethylphenyl) boroxine, tris (3-ethenylphenyl) boroxine, tris (4-ethenylphenyl) boroxine,

Tris (2-methoxyphenyl) boroxine, Tris (3-methoxyphenyl) boroxine, Tris (4-methoxyphenyl) boroxine, Tris (2-
Ethoxyphenyl) boroxine, tris (2-propoxyphenyl) boroxine, tris (2-chlorophenyl) boroxine, tris (3-chlorophenyl) boroxine, tris (4-chlorophenyl) boroxine, tris (3-bromophenyl) boroxine, Tris (3 -Fluorophenyl) boroxine, tris (4-chlorophenyl) boroxine, tris (4-bromophenyl) boroxine, tris (4-fluorophenyl) boroxine,
Tris (4-iodophenyl) boroxine, Tris (2,3-difluorophenyl) boroxine, Tris (2,4-difluorophenyl) boroxine, Tris (2,5-difluorophenyl) boroxine, Tris (2,6-difluorophenyl) ) Boroxin, tris (3,4-difluorophenyl) boroxine, tris (3,5-difluorophenyl) boroxine, tris (4-bromo-2,6-dimethylphenyl) boroxine, tris (4-bromo-3,5-) Dimethylphenyl)
Boroxine, tris (4-bromo-3,6-dimethylphenyl) boroxine,

Tris (2-chloro-5-methoxyphenyl) boroxine, tris (2-bromo-5-methoxyphenyl) boroxine, tris (2-iodo-5-methoxyphenyl) boroxine, tris (2-fluoro-5-)
Methoxyphenyl) boroxine, tris (5-bromo)
2-methoxyphenyl) boroxine, tris (4-chloro-3-methoxyphenyl) boroxine, tris (4-
Ethoxy-2,3-difluorophenyl) boroxine,
Tris (2- (chloromethyl) phenyl) boroxine,
Tris (2- (bromomethyl) phenyl) boroxine,
Tris (4- (bromomethyl) phenyl) boroxine,
Tris (o- (1-bromoethyl) phenyl) boroxine, tris (m- (1-bromoethyl) phenyl) boroxine, tris (p- (1-chloroethyl) phenyl)
Boroxin, tris (p- (1-bromoethyl) phenyl) boroxine, tris (p- (dibromomethyl) phenyl) boroxine, tris (m- (trichloromethyl)
Phenyl) boroxine, tris (o- (1,2-dibromoethyl) phenyl) boroxine,

Tris (2- (trifluoromethyl) phenyl) boroxine, tris (3- (trifluoromethyl) phenyl) boroxine, tris (4- (trifluoromethyl) phenyl) boroxine, tris (2- (bromomethyl)- 6-methylphenyl) boroxine, tris (phenylethyl) boroxine, trichloroboroxine, tribromoboroxine, trifluoroboroxine,
Examples include triiodoboroxine.

In producing oxazaborolidine,
The amount of boronic acid [VII] used is amino alcohol [VI]
It is usually 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent. When the boroxine derivative [IV] is used, its amount is 0.3 to 1 equivalent, preferably 0.3 to 0.8.
It is equivalent. The reaction is usually performed in the presence of a solvent. The solvent used is not particularly limited as long as it is an aprotic solvent, for example, toluene, aromatic hydrocarbons such as benzene,
Aliphatic hydrocarbons such as hexane and heptane, halogenated hydrocarbons such as chloroform and chlorobenzene are used. The reaction temperature is usually 0 to 150 ° C., preferably 1
At 0 to 120 ° C., the reaction time is usually about 10 minutes to 8 hours. Oxazaborolidine [I] or [I ′] can be isolated from the reaction mixture by a conventional means such as concentration and distillation, if necessary.

An asymmetric reducing agent obtained from an optically active oxazaborolidine [I] or [I '], a metal borohydride and an acid can be used in the reduction reaction of a prochiral compound, and examples thereof include oxime derivatives, A ketone derivative or the like is reduced to give an optically active amine derivative, an optically active alcohol derivative, or the like. For example, the general formula [II]

[Chemical 11] (Wherein R ⁴ represents a hydrogen atom, an alkyl group, an aralkyl group or an alkyl-substituted silyl group, and R ⁵ and R ⁶ are different from each other and represent an alkyl group, an aryl group or an aralkyl group). When the anti-form or syn-form or a mixture rich in one of them is applied, the compound of the general formula [III]

[Chemical 12] (In the formula, R ⁵ , R ⁶ and * have the same meanings as described above.) The optically active amine derivative represented by the formula can be produced.

The oxime derivative represented by the general formula [II] may be an anti-form, a syn-form, or a compound rich in any of these. R ⁴ represents a hydrogen atom, an alkyl group, an aralkyl group or an alkyl-substituted silyl group. Examples of the alkyl group include those having 1 to 10 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl, cyclopentyl, hexyl, cyclohexyl, heptyl, cycloheptyl, octyl, cyclooctyl, nonyl and decyl. Examples of the aralkyl group include benzyl, β-phenethyl, naphthylmethyl and the like having 7 to 1 carbon atoms.
There are two. Examples of the alkyl-substituted silyl group include those having 3 to 12 carbon atoms such as trimethylsilyl, dimethyl-t-butylsilyl, tri-n-propylsilyl and tri-n-butylsilyl.

R ⁵ and R ⁶ are different from each other and represent an alkyl group, an aryl group or an aralkyl group. Examples of the alkyl group include an alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl, cyclopentyl, hexyl and cyclohexyl, chloromethyl, dichloromethyl, trichloromethyl, tribromomethyl, trifluoromethyl, Examples thereof include halogenated alkyl groups having 1 to 6 carbon atoms such as 2-chloroethyl, 3-chloropropyl and 4-chlorobutyl.

As the aryl group, a phenyl group, a substituted phenyl group, a 2-pyridyl group, a 3-pyridyl group, 4
And aryl groups having 5 to 17 carbon atoms such as -pyridyl group, α-naphthyl group and β-naphthyl group. Examples of the substituted phenyl group include o-, m-, p-chlorophenyl, o-, m-, p-bromophenyl, 2,3
-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5
-A halogen-substituted phenyl group such as dichlorophenyl, o
-, M-, p-methylphenyl, o-, m-, p-ethylphenyl, o-, m-, p-butylphenyl, 2,3
-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5
-A phenyl group substituted with an alkyl group having 1 to 6 carbon atoms such as dimethylphenyl, o-, m-, p-methoxyphenyl, o-, m-, p-ethoxyphenyl, o-, m
A phenyl group substituted with an alkoxy group having 1 to 6 carbon atoms such as-, p-propoxyphenyl, o-, m-, p-
Benzyloxyphenyl, 2-benzyloxy-3-methylphenyl, 2-benzyloxy-4-methylphenyl, 2-benzyloxy-5-methylphenyl, 2-benzyloxy-5-t-butylphenyl, 2-benzyloxy -3-methoxyphenyl, 2-benzyloxy-
Phenyl group substituted with benzyloxy group such as 4-methoxyphenyl, 2-benzyloxy-5-methoxyphenyl, 2-benzyloxy-3,5-dichlorophenyl, cyano such as o-, m-, p-cyanophenyl Examples thereof include a phenyl group substituted with a group.

Examples of the aralkyl group include benzyl, o-, m-, p-tolylmethyl, o-, m-, p-.
Ethylbenzyl, o-, m-, p-methoxybenzyl,
o-, m-, p-ethoxybenzyl, 2,3-, 2,4
-, 2,5-, 2,6-, 3,4-, 3,5-dimethylbenzyl, 3-sulfamoyl-4-methoxybenzyl, (2,3-, 2,4-, 2,5-, 2 , 6-Dimethoxyphenyl) ethyl, 2-phenylethyl, 2- (o
-, M-, p-tolyl) ethyl, (2,3-, 2,4
Examples thereof include aralkyl groups having 7 to 11 carbon atoms such as-, 2,5-, 2,6-, 3,4-, 3,5-dimethylphenyl) ethyl, 3-phenylpropyl and naphthylmethyl.

Representative oxime derivatives include, for example, acetophenone, propiophenone, butyrophenone, chloromethyl (phenyl) ketone, bromomethyl (phenyl) ketone, 2-acetylpyridine, o-methoxyacetophenone, o-ethoxyacetophenone, o.
-Propoxyacetophenone, o-benzyloxyacetophenone, α-acetonaphthone, β-acetonaphthone, (p-chlorophenyl) methyl ketone, (p-bromophenyl) methyl ketone, (p-cyanophenyl) methyl ketone, 3-sulfamoyl-4-methoxybenzylmethyl Ketone, phenylbenzyl ketone, phenyl (o-tolylmethyl) ketone, phenyl (m-tolylmethyl) ketone, phenyl (p-tolylmethyl) ketone,
Phenyl (2-phenylethyl) ketone, 2-butanone, 2-pentanone, 2-hexanone, 2-heptanone, 2-octanone, 3-heptanone, 3-octanone, cyclohexylmethylketone, cyclohexylethylketone, cyclohexylbenzylketone, α -Phenylacetone, (2-phenylethyl) methylketone,
O-Methylsilyl such as (2-phenylethyl) ethylketone and (3-phenylpropyl) methylketone, o-
Examples thereof include oxime derivatives such as octylsilyl, o-cyclohexylsilyl, o-benzylsilyl, and o-trimethylsilyl, and anti-forms or syn-forms thereof or a mixture rich in one of them can be used.

The oxime derivative can be easily produced from the corresponding ketone by a known method. When one of the anti isomer and the syn isomer is used, the remaining separated isomers can be converted into the necessary isomers by performing an anti isomer / syn isomerization reaction. It can be used effectively.

The asymmetric reduction reaction proceeds by reacting an oxime derivative represented by the general formula [II] with an asymmetric reducing agent obtained from an optically active oxazaborolidine derivative, a metal borohydride and a Lewis acid. . The order of addition is not particularly limited, but a method of adding a Lewis acid or sulfuric acid after mixing the optically active oxazaborolidine and metal borohydride is preferable in terms of yield and optical purity. The preparation temperature of the reducing agent is usually -20 to 50 ° C, preferably 0 to 30 ° C.

Optically active oxazaborolidine derivative [I]
The amount used is usually 0.
It is at least 05 mol, preferably 0.1 to 1.5 mol.
Examples of the metal borohydride include lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride and the like, and sodium borohydride is usually used. The amount used is usually 0.3 to 8 mol per 1 mol of the oxime derivative,
It is preferably 0.3 to 5 mol.

Examples of the Lewis acid include zinc chloride, boron trifluoride, aluminum chloride, aluminum bromide,
Examples thereof include titanium tetrachloride, tin tetrachloride, tin dichloride, etc., and a mixture thereof can also be used. The amount used is usually 0.05 to 1.5 with respect to 1 mol of the oxime derivative.
It is about molar. Although about 97% sulfuric acid is usually used as the sulfuric acid, the reaction can be made to proceed more efficiently by using 100% sulfuric acid. The amount used is usually 0.0 with respect to 1 mol of the oxime derivative.
It is about 5 to 1.5 mol.

The asymmetric reduction reaction is usually carried out in the presence of a solvent. Examples of such a solvent include ethers such as dioxane, tetrahydrofuran and diglyme, sulfides such as dimethyl sulfide and diethyl sulfide,
A mixture of ethers and sulfides, and this mixture with benzene, toluene, xylene, chlorobenzene,
A mixed solvent with hydrocarbons such as 1,2-dichloroethane and the like can be mentioned, and the amount thereof is usually about 2 to 50 times by weight that of the oxime derivative. The reaction temperature of the asymmetric reduction reaction is usually 150 ° C or lower, preferably -20 to 100.
The temperature is ° C, and may be further heated if necessary.
The progress of the reaction can be confirmed by an analytical means such as gas chromatography.

After the completion of the reaction, for example, an acid such as hydrochloric acid is added to the reaction solution to deactivate the reducing agent to make it basic, and then an organic solvent such as toluene is added to the organic layer for the purpose. It is possible to extract the optically active amines and amino alcohol which is a raw material of oxazaborolidine. Here, examples of the extraction solvent include solvents such as hexane and toluene. By using these solvents, the optically active amine derivative and the amino alcohol can be transferred to the organic layer and the amino alcohol to the aqueous layer due to the difference in solubility between them, and then the usual separation means such as distillation can be used. By using, the optically active amine derivative and amino alcohol can be isolated and recovered. The optically active amine derivative thus obtained can be further purified, if necessary, by a purification means such as distillation or column chromatography.

Further, the asymmetric reducing agent obtained from the optically active oxazaborolidine [I] or [I '], the metal borohydride and the Lewis acid of the present invention is, for example, a compound represented by the general formula [IV] )

[Chemical 13] (In the formula, R ⁷ and R ⁸ are different from each other and represent an alkyl group, an aryl group or an aralkyl group.) When acting on a ketone derivative represented by the general formula [V]

[Chemical 14] (In the formula, R ⁷ , R ⁸ and * have the same meanings as described above.) The optically active alcohols represented by the formula can be produced.

In the ketone derivative, R ⁷ and R ⁸ are different from each other and represent an alkyl group, an aryl group or an aralkyl group. Examples of the alkyl group include an alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl, cyclopentyl, hexyl and cyclohexyl,
Examples thereof include halogenated alkyl groups having 1 to 6 carbon atoms such as chloromethyl, dichloromethyl, trichloromethyl, tribromomethyl, trifluoromethyl, 2-chloroethyl, 3-chloropropyl and 4-chlorobutyl.

As the aryl group, a phenyl group, a substituted phenyl group, a 2-pyridyl group, a 3-pyridyl group, 4
And aryl groups having 5 to 17 carbon atoms such as -pyridyl group, α-naphthyl group and β-naphthyl group. Examples of the substituted phenyl group include o-, m-, p-chlorophenyl, o-, m-, p-bromophenyl, 2,3
-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5
-A halogen-substituted phenyl group such as dichlorophenyl, o
-, M-, p-methylphenyl, o-, m-, p-ethylphenyl, o-, m-, p-butylphenyl, 2,3
-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5
-A phenyl group substituted with an alkyl group having 1 to 6 carbon atoms such as dimethylphenyl, o-, m-, p-methoxyphenyl, o-, m-, p-ethoxyphenyl, o-, m
A phenyl group substituted with an alkoxy group having 1 to 6 carbon atoms such as-, p-propoxyphenyl, o-, m-, p-
Benzyloxyphenyl, 2-benzyloxy-3-methylphenyl, 2-benzyloxy-4-methylphenyl, 2-benzyloxy-5-methylphenyl, 2-benzyloxy-5-t-butylphenyl, 2-benzyloxy -3-methoxyphenyl, 2-benzyloxy-
Phenyl group substituted with benzyloxy group such as 4-methoxyphenyl, 2-benzyloxy-5-methoxyphenyl, 2-benzyloxy-3,5-dichlorophenyl, cyano such as o-, m-, p-cyanophenyl Examples thereof include a phenyl group substituted with a group.

Examples of the aralkyl group include benzyl, o-, m-, p-tolylmethyl, o-, m-, p-.
Ethylbenzyl, o-, m-, p-methoxybenzyl,
o-, m-, p-ethoxybenzyl, 2,3-, 2,4
-, 2,5-, 2,6-, 3,4-, 3,5-dimethylbenzyl, 3-sulfamoyl-4-methoxybenzyl, (2,3-, 2,4-, 2,5-, 2 , 6-Dimethoxyphenyl) ethyl, 2-phenylethyl, 2- (o
-, M-, p-tolyl) ethyl, (2,3-, 2,4
Examples thereof include aralkyl groups having 7 to 11 carbon atoms such as-, 2,5-, 2,6-, 3,4-, 3,5-dimethylphenyl) ethyl, 3-phenylpropyl and naphthylmethyl.

As typical ketone derivatives, for example,
Acetophenone, propiophenone, butyrophenone,
Chloromethyl (phenyl) ketone, bromomethyl (phenyl) ketone, 2-acetylpyridine, o-methoxyacetophenone, o-ethoxyacetophenone, o-propoxyacetophenone, o-benzyloxyacetophenone, α-acetonaphthone, β-acetonaphthone, (p
-Chlorophenyl) methyl ketone, (p-bromophenyl) methyl ketone, (p-cyanophenyl) methyl ketone, 3-sulfamoyl-4-methoxybenzyl methyl ketone, phenylbenzyl ketone, phenyl (o-tolylmethyl) ketone, phenyl (m-tolylmethyl) Ketone, phenyl (p-tolylmethyl) ketone, phenyl (2-phenylethyl) ketone, 2-butanone, 2-pentanone, 2-hexanone, 2-heptanone, 2-octanone, 3-heptanone, 3-octanone, cyclohexylmethylketone. , Cyclohexyl ethyl ketone, cyclohexyl benzyl ketone, α-phenylacetone,
Examples include (2-phenylethyl) methyl ketone, (2-phenylethyl) ethyl ketone, and (3-phenylpropyl) methyl ketone.

The asymmetric reduction reaction proceeds by reacting the ketone derivative represented by the general formula [IV] with an asymmetric reducing agent obtained from an optically active oxazaborolidine derivative, a metal borohydride and a Lewis acid. . The order of addition is not particularly limited, but a method of adding a Lewis acid or sulfuric acid after mixing the optically active oxazaborolidine and metal borohydride to prepare a reducing agent is preferable in terms of yield and optical purity. .
The preparation temperature of the reducing agent is usually -20 to 50 ° C, preferably 0 to 30 ° C.

The amount of the optically active oxazaborolidine derivative used is usually 0.01 mol or more, preferably 0.05 to 1.5 mol, per 1 mol of the ketone derivative. As the metal borohydride, for example, the same one as in the case of the above oxime derivative is used. The amount used is usually 0.3 to 8 mol, preferably 0.3 to 5 mol, per 1 mol of the ketone derivative.

As the Lewis acid, for example, the same one as in the case of the above oxime derivative is used. The amount used is usually about 0.05 to 1.5 mol per mol of the ketone derivative. Although about 97% sulfuric acid is usually used as the sulfuric acid, the reaction can be made to proceed more efficiently by using 100% sulfuric acid. The amount used is usually from 0.05 to 1 mol of the ketone derivative.
It is about 1.5 mol. The asymmetric reduction reaction is usually carried out in the presence of a solvent. As such a solvent, for example, the same solvent as in the case of the above oxime derivative is used. The amount used is usually about 2 to 50 times the weight of the ketone derivative. The reaction temperature for the asymmetric reduction reaction is usually 150 ° C.
Hereinafter, it is preferably −20 to 100 ° C., and may be further heated if necessary. The progress of the reaction can be confirmed by an analytical means such as gas chromatography.

After the completion of the reaction, for example, an acid such as hydrochloric acid is added to the reaction solution to deactivate the reducing agent to make it basic, and then an organic solvent such as toluene is added to the reaction mixture to obtain a desired amount from the organic layer. The amino alcohol, which is a raw material of oxazaborolidine, can be extracted from the optically active alcohol derivative and the aqueous layer. Here, examples of the extraction solvent include solvents such as hexane and toluene. The optically active alcohol derivative thus obtained, if necessary, by distillation, purification means such as column chromatography,
It can be further purified.

[0045]

INDUSTRIAL APPLICABILITY By using an asymmetric reducing agent obtained from the optically active oxazaborolidine derivative [I] or [I ′] of the present invention, a metal borohydride and a Lewis acid, an optically active amine derivative can be efficiently produced. , And an optically active alcohol derivative can be produced.

[0046]

EXAMPLES The present invention will be further described below with reference to examples, but it goes without saying that the present invention is not limited to these examples.

Reference Example 1 Under nitrogen atmosphere, 2.81 g (13.2 mmol) of (+)-2-amino-1,2-diphenylethanol was dissolved in 20 ml of toluene, and 1.12 g (8.9 mmol) of trimethylboroxine was dissolved therein.
10 ml toluene solution of was added and stirred at 25 ° C. for 1 hour and then heated, and toluene was distilled off. The operation of adding 20 ml of toluene and distilling off was repeated 3 times, and the oily residue obtained by removing water and excess trimethylboroxine produced in the system together with toluene was distilled to obtain (4R) (5S ) -1,3,2-
(2-Methyl-4,5-diphenyl) oxazaborolidine 1.7
5 g was obtained. The yield was 56.0% based on (+)-2-amino-1,2-diphenylethanol. ¹¹ B-NMR; 33.8 ppm (BF ₃ / Et ₂ O is 0 ppm.)

Example 1 (4S) (5R) -1,3,2- (2-methyl-4,5) at room temperature under a nitrogen atmosphere.
-Diphenyl) oxazaborolidine 1.185 g (0.5 mmo
l) in tetrahydrofuran 1 ml solution, sodium borohydride 0.075 g (2.0 mmol) and triglyme 1 ml
Was added and stirred for 1 hour. To this suspension at room temperature, a toluene solution containing 10% titanium tetrachloride 1.9
g (1 mmol) was added dropwise over 10 minutes, and after stirring for 1 hour, a solution consisting of 0.239 g (1.0 mmol) of anti-phenyl (p-tolylmethyl) ketone (o-methyloxime) and 2 ml of toluene was added, The mixture was stirred at 25 ° C for 16 hours. Thereafter, 1.6 g of 10% hydrochloric acid was added, and the mixture was stirred at the same temperature for 1 hr, and the reaction liquid was concentrated under reduced pressure. An aqueous sodium hydroxide solution was added to the mixture to make it basic, which was then extracted with hexane. The separated hexane layer was concentrated to obtain 0.23 g of 1-phenyl-2- (p-tolyl) ethylamine. When analyzed by gas chromatography, the reaction rate was 67.9%, and the amine compound ratio (selectivity) in the product was 99.0%. The enantiomeric ratio of the amine compound was determined by high performance liquid chromatography analysis using an optically active column to give R compound 29.1%, S
The body was 70.9%.

Comparative Example 1 (4S) (5R) -1,3,2- (2,5-diphenyl-3,4-dimethyl) oxazaborolidine (0.5 mmol) and 1 ml of toluene at room temperature under a nitrogen atmosphere. To the solution was added 2.0 ml (2.0 mmol) of 1N borane tetrahydrofuran complex. Then, a solution consisting of 0.239 g (1.0 mmol) of anti-phenyl (p-tolylmethyl) ketone (o-methyloxime) and 2 ml of toluene was added, and the mixture was stirred at 25 ° C. for 48 hours. Then 10% hydrochloric acid
After adding 1.6 g and stirring at the same temperature for 1 hour, the reaction solution was concentrated under reduced pressure. Aqueous sodium hydroxide solution was added to the mixture to make it basic, followed by extraction with hexane. The separated hexane layer was concentrated to give 1-phenyl-2- (p-tolyl) ethylamine.
0.23 g was obtained. When analyzed by gas chromatography, the reaction rate was 81.0% and the amine compound ratio (selectivity) in the product was 51.1%.

Comparative Example 2 In Comparative Example 1, (4S) (5R) -1,3,2- (2,5-diphenyl-
(4S) (5R) -1,3,2- (2-methyl-4,5-diphenyl) oxazaborolidine 0.5 mmol was used in place of 0.5 mmol of 3,4-dimethyl) oxazaborolidine at 25 ° C. The procedure of Comparative Example 1 was repeated except that the mixture was stirred for 24 hours. When analyzed by gas chromatography, the reaction rate was 89.5% and the amine compound ratio (selectivity) in the product was 69.9%.

[0051] Example In 2 Example 1 (4S) (5R) -1,3,2- (2 - methyltransferase -4,5 diphenyl) instead of oxazaborolidine 0.5 mmol (4
R) -1,3,2- (2-Methyl-4-phenyl) oxazaborolidine was used according to Example 1 except that 1 mmol was used. When analyzed by gas chromatography, the reaction rate was 72.9% and the amine compound ratio (selectivity) in the product was 99.2%. The enantiomeric ratio of the amine form was determined by high performance liquid chromatography analysis using an optically active column. R form 69.8%, S form 30.2%
Met.

Example 3 (4S) (5R) -1,3,2- (2-methyl-4,5) at room temperature under a nitrogen atmosphere.
-Diphenyl) oxazaborolidine 1.185 g (0.5 mmo
l) in tetrahydrofuran 1 ml solution, sodium borohydride 0.190 g (5.0 mmol) and triglyme 1 ml
Was added and stirred for 1 hour. To this suspension at room temperature, a toluene solution containing 20% titanium tetrachloride 0.9
5 g (1 mmol) was added dropwise over 10 minutes and after stirring for 1 hour, 0.670 g (5.0 mmol) of propiophenone and 2 ml of toluene
Was added and the mixture was stirred at 25 ° C. for 16 hours. Thereafter, 1.6 g of 10% hydrochloric acid was added, and the mixture was stirred at the same temperature for 1 hr, and the reaction liquid was concentrated under reduced pressure. It was extracted with hexane under acidic conditions, and the separated hexane layer was concentrated to obtain 1-phenylpropanol. When analyzed by gas chromatography, the reaction rate was 86.1%. Al in the product
The call selectivity was 100%. The enantiomeric ratio of the alcohol form was determined by high performance liquid chromatography analysis using an optically active column to find that the R form was 65.6%,
The S form was 34.4%.

Example 4 Instead of 1 mmol of (4S) (5R) -1,3,2- (2-methyl-4,5-diphenyl) oxazaborolidine in Example 3, ( 4R ) was used.
In Example 3 except that 1 mmol of -1,3,2- (2-methyl-4-phenyl) oxazaborolidine was used and 2.38 g (2.5 mmol) of a toluene solution containing 20% titanium tetrachloride was used. It carried out in conformity. When analyzed by gas chromatography, the reaction rate was 100%. A in the product
Lucor's selectivity was 100%. The enantiomeric ratio of the alcohol compound was determined by high performance liquid chromatography analysis using an optically active column, and the R compound was 35.1%.
, S form was 64.9%.

Example 5 In Example 3, 97% sulfuric acid 0.126 was used instead of 0.95 g (1 mmol) of a toluene solution containing 20% titanium tetrachloride.
It carried out based on Example 3 except using g. When analyzed by gas chromatography, the reaction rate was 90.2.
% Met. Alcohol selectivity in the product is 100%
there were. The enantiomeric ratio of the alcohol form was determined by high performance liquid chromatography analysis using an optically active column to find that the R form was 65.0% and the S form was 35.0%.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ identification code FI C07C 209/40 C07C 209/40 211/27 211/27 (58) Fields investigated (Int.Cl. ⁷ , DB name) C07B 31 / 00 C07B 53/00 CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (4)

(57) [Claims] 1. A compound represented by the general formula [I] or [I '] (Chemical formula 1) (In the formula, R ¹ represents an alkyl group, an allyl group, an aryl group, an aralkyl group or a halogen atom, R ² represents an alkyl group, an aryl group or an aralkyl group, and R ² ′ represents a hydrogen atom, an alkyl group, an aryl group, Or an aralkyl group,
R ³ represents an alkyl group, an aryl group, or an aralkyl group. Further, * represents an asymmetric carbon. ) An asymmetric reducing agent obtained from an optically active oxazaborolidine, a metal borohydride and an acid. 2. The asymmetric reducing agent according to claim 1, wherein the acid is Lewis acid or sulfuric acid. 3. The asymmetric reducing agent according to claim 1 or 2 is replaced by a compound represented by the general formula [II] (In the formula, R ⁴ represents a hydrogen atom, an alkyl group, an aralkyl group or an alkyl-substituted silyl group. R ⁵ and R ⁶ are different from each other and represent an alkyl group, an aryl group or an aralkyl group.) A compound represented by the general formula [III] (Chemical Formula 3) [Chemical Formula 3] characterized by acting on an anti-form, a syn-form or a mixture rich in one of them. (In the formula, R ⁵ , R ⁶ and * have the same meanings as described above.) A method for producing an optically active amine derivative. 4. A compound represented by the general formula [IV] (Chemical Formula 4): (In the formula, R ⁷ and R ⁸ are different from each other and each represents an alkyl group, an aryl group or an aralkyl group.) The compound represented by the general formula [V] (Chemical Formula 5) ] (In the formula, R ⁷ , R ⁸ and * have the same meanings as described above.) A process for producing an optically active alcohol derivative.