Process for preparing optically active alcoholic compounds

Details Process for preparing optically active alcoholic compounds Process for preparing optically active alcoholic compounds

1999-07-15

2001-02-13

Shippen, Michael L. (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Oxygen containing

C568S814000, C568S880000

Reexamination Certificate

active

06187966

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a process for preparing optically active alcoholic compounds by treating a prochiral carbonyl compound with an optically active diaryloxyaluminum alkoxide to conduct asymmetric reduction. The optically active alcoholic compounds obtained by the process of the present invention, such as (R)-2-chloro-1-(m-hydroxyphenyl) ethanol, are compounds of great value as intermediates for the production of medicines; therefore, the present invention is very useful as a process for preparing the intermediates for the production of medicines.
BACKGROUND ART
As the so-far known practical methods of reducing carbonyl compounds, there may be mentioned Meerwein-Ponndorf-Varley reduction (MPV reduction), the reduction using diisobutylaluminum hydride (DIBAH) and so on.
The MPV reduction is a method of reducing carbonyl compounds using an aluminum trialkoxide, such as Al(OiPr)
3
, as a reducing agent or a reducing catalyst. This method is in frequent use as an economical method of reducing various ketones and aldehydes, since aluminum trialkoxide used there and alcohol such as isopropanol are inexpensive (Organic Reactions, volume 2, page 178 (1944)).
The technologies for asymmetric reduction of carbonyl compounds using MPV reduction can include, for example, the known method which uses aluminum as a center metal of a catalyst and uses an optically active alcohol as a chiral resource as well as a hydrogen transfer resource; however, its optical purity generally tends to be low and the chiral resource needed is theoretically in an equimolecular amount or more to the substrate (Asymmetric Organic Reactions, Prentice-Hall Inc. (1971)).
As examples of other technologies for asymmetric reduction, there can be exemplified the asymmetric reduction by (−)-isoborneol using a porphyrin complex with aluminum as a catalyst (Journal of Organic Chemistry, volume 55, page 816 (1990)), and the asymmetric reduction by isopropanol using a complex of an optically active alcohol with lanthanoid (Journal of American Chemical Society, volume 15, page 9800, (1993)). Said technologies, however, have problems that the chiral resources and the metal catalysts are expensive.
SUMMARY OF THE INVENTION
In view of the foregoing, it is an object of the present invention to provide a process for preparing optically active alcoholic compounds by asymmetric reduction of a carbonyl compound in an economical and practical manner.
The process for preparing optically active alcoholic compounds according to the present invention comprises treating a prochiral carbonyl compound represented by the general formula (1);
wherein R
1
and R
2
are different from each other and represent a substituted or unsubstituted alkyl group containing 1 to 20 carbon atoms, a substituted or unsubstituted aralkyl group containing 7 to 30 carbon atoms, a substituted or unsubstituted aryl group containing 6 to 30 carbon atoms, a substituted or unsubstituted alkoxycarbonyl group containing 1 to 20 carbon atoms, or a cyano group, provided that at least one of R
1
and R
2
represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryl group; and R
1
and R
2
may link together and form a ring;
with an optically active organoaluminum compound represented by the general formula (2);
wherein R
3
represents a substituted or unsubstituted alkyl group containing 1 to 20 carbon atoms, or a substituted or unsubstituted aralkyl group containing 7 to 30 carbon atoms; and R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
and R
11
are the same or different from each other and represent a substituted or unsubstituted alkyl group containing 1 to 20 carbon atoms, a substituted or unsubstituted aralkyl group containing 7 to 30 carbon atoms, a substituted or unsubstituted aryl group containing 6 to 30 carbon atoms, a substituted or unsubstituted silyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted alkoxyl group containing 1 to 20 carbon atoms, a cyano group, an alkoxycarbonyl group containing 1 to 20 carbon atoms, a substituted or unsubstituted phosphorus atom, a substituted or unsubstituted sulfur atom, a halogen atom, or a hydrogen atom, and R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
or R
11
may link with each of them and form a substituted or unsubstituted, condensed ring;
to conduct asymmetric reduction, thereby preparing an optically active alcoholic compound of the general formula (3);
wherein R
1
and R
2
are the same as defined above.
DETAILED DESCRIPTION OF THE INVENTION
In the following, the present invention is described in detail.
In the present invention, the above-mentioned R
1
and R
2
in the general formula (1) always represent different groups from each other: consequently, the alcoholic compound prepared by the process of the present invention necessarily has a chiral carbon atom.
The R
1
and R
2
represent a substituted or unsubstituted alkyl group containing 1 to 20 carbon atoms, a substituted or unsubstituted aralkyl group containing 7 to 30 carbon atoms, a substituted or unsubstituted aryl group containing 6 to 30 carbon atoms, a substituted or unsubstituted alkoxycarbonyl group containing 1 to 20 carbon atoms, or a cyano group, provided that at least one of R
1
and R
2
represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryl group. In addition, the R
1
and R
2
may link together and form a ring.
Said substituent group can include, but is not particularly limited to, for example, a halogen atom, an alkoxycarbonyl group, an amino group, a hydroxyl group, an alkoxyl group, a cyano group, a nitro group, a sulfinyl group, a sulfonyl group, an alkylthio group and the like. It is also possible to be substituted by two or more of such a substituted group.
Said substituted or unsubstituted alkyl group containing 1 to 20 carbon atoms can include, but is not particularly limited to, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, cyclohexyl group, chloromethyl group, dichloromethyl group, trichloromethyl group, carbomethoxymethyl group, cyanomethyl group, nitromethyl group and the like.
Said substituted or unsubstituted aralkyl group containing 7 to 30 carbon atoms can include, but is not particularly limited to, for example, benzyl group, phenylpropyl group, phenylethyl group, p-methoxybenzyl group, p-hydroxybenzyl group and the like.
Said substituted or unsubstituted aryl group containing 6 to 30 carbon atoms can include, but is not particularly limited to, for example, phenyl group, p-hydroxylphenyl group, p-chlorophenyl group, p-nitrophenyl group, naphthyl group and the like.
Said alkoxycarbonyl group containing 1 to 20 carbon atoms can include, for example, methoxycarbonyl group, ethoxycarbonyl group, benzyloxycarbonyl group, t-butoxycarbonyl group and the like.
The above-mentioned carbonyl compound of the general formula (1) can include, but is not particularly limited to, ketones such as acetophenone, propiophenone, cyclohexanone, ethyl acetoacetate, ethyl benzoylformate, ethyl 4-chloroacetoacetate, 2,2,2-trichloroacetophenone, benzoyl cyanide and the like.
The above-mentioned R
3
represents a substituted or unsubstituted alkyl group containing 1 to 20 carbon atoms, or a substituted or unsubstituted aralkyl group containing 7 to 30 carbon atoms. As examples of them, there may be mentioned isopropyl group, benzhydryl group, cyclohexyl group, 2,4-dimethyl-3-pentyl group, t-butyl group, ethyl group and the like. Preferred groups are isopropyl and benzhydryl groups.
The above-mentioned R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
and R
11
are the same or different from each other and represent a substituted or unsubstituted alkyl group containing 1 to 20 carbon atoms, a substituted or unsubstituted aralkyl group containing 7 to 30 carbon atoms, a substituted or unsubstituted aryl group containing 6 to 30 carbon atoms, a substituted or unsubstituted silyl group, a

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