JPS5910647B2 - Asymmetric synthesis method of optically active alcohols - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for asymmetrically synthesizing optically active alcohols useful in pharmaceutical and chemical synthesis.

More specifically, the present invention relates to the general formula (”■□<:.

,,0... [wherein R represents an alkyl group, a cycloalkyl group, an aralkyl group, or an aryl group] A complex produced by reacting LiAlH4 with an optically active cyclic amine derivative represented by the formula 2 >C=0 (formerly, R1 and R2 are different from each other and represent an alkyl group, a cycloalkyl group, an aralkyl group, or an aryl group, or an asymmetric cyclic structure in which R" and R" are bonded) show.

] This is an asymmetric synthesis method for optically active alcohols represented by the general formula 2>c<(■) [wherein R1 and R2 have the same meanings as above].

In the above general formula (1), the alkyl group represented by R is a linear or branched alkyl group having about 1 to 6 carbon atoms (e.g. methyl, ethyl, n-propyl, i-propyl, n -butyl, i-butyl, t-butyl, n-pentyl, n-hexyl, etc.) are preferred, and branched alkyl groups are particularly preferred. As the cycloalkyl group, a cycloalkyl group having about 5 to 7 carbon atoms (eg, cyclopentyl, cyclohexyl, cycloheptyl group) is preferable. Examples of the aralkyl group include a benzyl group, a phenethyl group, an α-methylbenzyl group, a diphenylmethyl group, and the like. Examples of the aryl group include phenyl group, naphthyl group, tolyl group, and xylyl group. These alkyl groups, cycloalkyl groups,
The aralkyl group and aryl group may have an appropriate substituent (eg, alkoxy, aryloxy, alkylthio, arylthio, amino, substituted amino, hydroxy, mercapto group, etc.) as long as it does not interfere with the reaction. In the above general formulas () and (), the alkyl group represented by R1 or R2 is linear or branched and has 1 to 1 carbon atoms.
Alkyl groups of about 22 (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, 2-ethylbutyl, n-hexyl, octyldodecyl, octadecyl groups, etc.) are preferred.

As the aralkyl group and the aryl group, each of the above R
A similar group can be mentioned. Examples of the asymmetric cyclic structure in which R1 and R2 are bonded include 2-methylcyclopentanone, 3-methylcyclohexanone, Trans
-β-decalone, α-tetralone, and ketosteroids (eg, pregnanedione, prednisolone, etc.). These alkyl groups, aralkyl groups, aryl groups, and asymmetric cyclic structures may have substituents that do not interfere with the same reaction as in R above. The reaction between the cyclic amide 7 derivative (1) and LiAlH4 is carried out using an appropriate solvent (e.g.
It is convenient to carry out the reaction in ether, tetrahydrofuran, dioxane, monoglyme, methanol, ethanol, etc.) under ice cooling or under reflux.

The amount of LiAlH4 used is preferably about 0.5 to 2.5 moles per 1 mole of compound (1). The above reaction forms a complex represented by the following general formula (). [In the formula, R
has the same meaning as above.

M represents a lithium atom, and A represents an aluminum atom. ]
The complex () thus produced can be used directly without isolation from the reaction solvent, or after isolation in an appropriate solvent to reduce the compound of general formula ().

The reaction between the compound () and the composite () is usually carried out by adding about 0.5 to 1.0 mol of () to 1 mol of () at a reaction temperature of about -80 to 100°C for about 10 minutes. This is carried out by reacting for about 10 hours. Through this reaction, the compound () is reduced in an asymmetric manner, and an optically active alcohol () corresponding to the optical isomerism of the starting compound (1) can be produced with extremely good reaction yield and optical yield. . The desired optically active alcohol (2) can be easily isolated and purified from the reaction mixture by conventional separation and purification means, such as recrystallization, distillation, solvent extraction, column chromatography, etc.

Cyclic amine derivative (1) used in the method of the present invention
is a new compound and can be produced, for example, by the following synthetic route or a method analogous thereto. [In each formula, R has the same meaning as above.

] The optically active aminocarboxylic acid used in the above reaction may be used by dividing the synthetic DL unit by a known splitting method, or it may be an easily available natural optically active cyclic amino acid (e.g. L-proline, etc.) may also be used.

EXAMPLES The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited thereto.

Reference Example L-proline anilide 5.71f7 was dissolved in 15ml of methylene chloride, and this solution was dissolved in LiAlH42. O
t in 60 d of dry ether under stirring.
Add dropwise at 20°C.

After dropping the entire amount, the mixture was stirred and left at -20°C for 30 minutes, and then the temperature was gradually raised, and the mixture was returned to room temperature and left overnight.

The reaction mixture is cooled, saturated brine is added dropwise under stirring to stop the reaction, and the organic layer is separated. The residue was extracted with methylene chloride, combined with the organic layer, dried over boronic acid, concentrated, and distilled under reduced pressure to obtain 4.88f of the target product, 2-phenylaminomethylpyrrolidine. Boiling point (0.5511!H
g) 111-112℃0 +19.71 (C-1.00
, EtOH) Example 1 Ether solution of LiA1H4 (
1.02M/I! ) 2.26d in an argon atmosphere, 2
-Ether solution of phenylaminomethylpyrrolidine (4
68η/9mt) and left for 10 minutes under stirring at room temperature.

The reaction mixture is cooled to -78°C, an ethereal solution of acetophenone (214.87!11!/8mt) is added dropwise, and the mixture is stirred at -78°C for 2 hours. The reaction was stopped by adding saturated sodium sulfate water, the organic layer was separated, and the residue was further divided into 1
Extract with 0 ml of ether. The organic layer and extract were combined, washed with 0.5N hydrochloric acid, water, and saturated saline, and dried over boronic acid. The solvent was distilled off, and the residue was separated and purified by silica gel thin layer chromatography (developing solvent: methylene chloride) to obtain the desired product, 1-phenylethanol, with a weight of 146.6η. Boiling point (311Hg) 120℃ (0ve
ntemp. ) 0 coins - 32.6 ((Nml) Example 2 Ether solution of LiA1H (957!9/4.95d
) in an argon atmosphere, an ether solution of 2-phenylaminomethylpyrrolidine (528η/3d) was added dropwise to
Leave stirring at ℃ for 1 hour.

The reaction mixture was cooled to -100°C, an ether solution of 1-acetylcyclohexene (126η/3d) was added dropwise, and the mixture was stirred at -100°C for 3 hours. The reaction was stopped by adding water, the organic layer was separated, the residue was further extracted with ether, the organic layer and the extract were combined, washed with dilute hydrochloric acid, aqueous sodium bicarbonate, and saturated brine, and dried with boronic acid. (Ph represents the pheni' group, E
t does *.

The solvent was distilled off, and the residue was separated and purified using silica gel column chromatography and chromatography using ether/n-hexane (1:1) as the eluent solvent to obtain the target product 90, 1-(1-cyclohexenyl)ethanol. . 02h5-5.5(
C5.86, ClI, Cl,) Example 3 In the same manner as in Example 2, 2-phenylaminomethylpyrrolidine 2mM
、． LiA1H41.75T! 1 mM of various ketone formulas () was reduced using LM,l to obtain the corresponding optically active alcohols [formula ()] as shown in the table below.

Example 4 Using optically active 2-monosubstituted aminomethylpyrrolidine produced in the same manner as in Reference Example, formula (1), *(acetophenone) was reduced to obtain optically active 1-phenylethanol as shown in the table below. Ta.

Claims (1)

[Claims] 1. An optically active cyclic amine derivative represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. Depending on the complex formed by reacting, there are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [Formula A method for asymmetric synthesis of optically active alcohols, wherein R^1 and R^2 have the same meanings as above.