Optically active 1-phenyl-2-substituted propane derivatives...

Details Optically active 1-phenyl-2-substituted propane derivatives... Optically active 1-phenyl-2-substituted propane derivatives...

1998-12-10

2001-06-19

Barts, Samuel (Department: 1621)

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Preparing oxygen-containing organic compound

C435S130000, C558S044000, C558S056000, C568S649000

Reexamination Certificate

active

06248573

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to an optically active (S)- or (P)-1-phenyl-2-substituted propane derivative which is an important intermediate for synthesis of an (R,R)-1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanol derivative, and a method of producing the same. The present invention further relates to a method of producing the ethanol derivative which is useful as a medical compound or an intermediate product thereof.
BACKGROUND OF THE INVENTION
As anti-obesity agents or anti-diabetic agents belonging to a new category of agents without using insulin, 1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanol derivatives are noted since the derivatives act selectively on a &bgr;
3
-receptor in vivo, thus having extremely low side effects. Pharmacological studies on the 1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanol derivatives have revealed that the &bgr;
3
-action substantially depends on (R,R)-enantiomers thereof (see J. Med. Chem., 35, 3081 (1992), and U.S. Pat. No. 5,061,727). For example, the above-mentioned U.S. Patent discloses that an (R,R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylic acid disodium salt has a higher activity than the corresponding (S,S)-enantiomer by a factor of 47.
For the production of an optically active 1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanol derivative, there is known an optical resolution of a racemic form or a racemate, or an asymmetric synthesis.
For example, the above mentioned U.S. Pat. No. 5,061,727 discloses a method of producing an (R,R)-1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanol derivative which comprises (1) allowing a racemic 2-amino-1-phenylethanol derivative to react with a phenylacetone derivative and sodium cyanoborohydride to produce a mixture of four species of optical isomers of a 1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanol derivative, (2) isolating and removing an (R,S)-isomer and an (S,R)-isomer from the mixture, and (3) optically resoluting an (R,R)-isomer and an (S,S)-isomer by a diastereomer method. According to this method, however, it is necessary to isolate and purify only the (R,R)-isomer from the mixture of the four species of optical isomers, therefore, the processes are complicated and the yield is decreased. Further, since large quantities of raw materials are required, the method is also disadvantageous in economical factor.
The U.S. Patent and the Journal of Medicinal Chemistry as mentioned above disclose a method allowing an (R)-3-chlorostyrene oxide derivative to react with an (R)-1-methyl-2-phenylethylamine derivative. The (R)-1-methyl-2-phenylethylamine derivative used as a raw material or reactant in the method, however, has a strong antihypnotic or arousal action and it requires a particular attention when handled, therefore is not suited for a use in commercial production. Further, a lot of steps or processes are required to obtain the above-mentioned two reactants. For instance, the (R)-3-chlorostyrene oxide derivative is prepared from an acetophenone derivative through three steps, that is, chlorination, asymmetric reduction and epoxidation, and the (R)-1-methyl-2-phenylethylamine derivative is prepared from L-DOPA through six steps, namely, introduction of a protective group into an amino group, esterification, reduction of the resulting ester, converting a hydroxyl group to a mesyloxy group, removal of the protective group and reduction.
SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide an optically active compound which is useful for the efficient production of an (R,R)-1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanol derivative with a good yield.
It is another object of the invention to provide a process for producing the compound efficiently with high yield and optical purity.
Still another object of the invention is to provide an optically active compound which is useful for the production of the derivative and is available and easy to handle or treat.
It is a further object of the present invention to provide a process for producing an (R,R)-1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanol derivative having a higher optical purity efficiently with a high yield.
A yet further object of the present invention is to provide an optically active (R)-enantiomer which is suitable for the production of the optically active compound being useful for producing the (R,R)-1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanol derivative, and a process for producing the same.
The present invention further relates to a process for asymmetrically reducing an phenylacetone derivative to the optically active compound, and to a use of a microorganism in production of the optically active intermediate.
After much studies and efforts to accomplish the above mentioned objects, the present inventors found that an optically active (S)- or (R)-1-phenyl-2-substituted propane derivative having a high optical purity can be obtained with a high yield by permitting a microorganism capable of asymmetrically reducing a phenylacetone derivative to act on the phenylacetone derivative, and that an optically active (R,R)-1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanol derivative can easily or readily be produced from the (S)- or (R)-1-phenyl-2-substituted propane derivative with high yield and selectivity. The present invention has been accomplished based on the above findings.
Thus, the present invention provides an (S)-1-phenyl-2-substituted propane derivative shown by the following formula (I)
wherein R
1
and R
2
represent (a) the same or different, a hydrogen atom or a protective group for hydroxyl group, or (b) R
1
and R
2
may form an optionally substituted ring with the adjacent oxygen atoms; R
3
, R
4
and R
5
independently represent a hydrogen atom, a lower alkyl group, a lower haloalkyl group, a lower alkoxy group, a nitro group or a halogen atom; and X represent a hydroxyl group which may be protected with a protective group, an optionally substituted alkylsulfonyloxy group, an optionally substituted arylsulfonyloxy group or a halogen atom.
The (S)-1-phenyl-2-substituted propane derivative of the general formula (I) may be produced by, for example, a process which comprises:
permitting a microorganism which is capable of asymmetrically reducing a phenylacetone derivative shown by the following formula (II)
wherein R
1
, R
2
, R
3
, R
4
and R
5
have the same meanings as defined above, to a corresponding (S)-1-phenyl-2-propanol derivative shown by the following formula (III)
wherein R
1
, R
2
, R
3
, R
4
and R
5
have the same meanings as defined above, or a preparation thereof
to act on the phenylacetone derivative, and harvesting or recovering the product (S)-1-phenyl-2-propanol derivative.
Further, the (S)-1-phenyl-2-substituted propane derivative of the general formula (I) may also be obtained by, for instance, allowing a sulfonylating agent or a halogenating agent to react with the (S)-1-phenyl-2-propanol derivative of the general formula (III).
The (S)-1-phenyl-2-substituted propane derivative of the general formula (I) is useful for production of an (R,R)-1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanol derivative shown by the following formula (VI)
wherein R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
and Z have the same meanings as defined above, or a salt thereof.
The present invention further provides an (R)-1-phenyl-2-substituted propane derivative shown by the general formula (VII)
wherein R
1
, R
2
, R
3
, R
4
, R
5
and X have the same meanings as defined above.
The (R)-1-phenyl-2-substituted propane derivative of the general formula (VII) may be produced by, for instance, utilizing a function of a microorganism which is capable of asymmetrically reducing the phenylacetone derivative of the general formula (II) to produce the corresponding (R)-1-phenyl-2-propanol derivative shown by the following formula (VII′)
whe

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