Processes for the preparation of tricyclic amino alcohol...

Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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C549S058000, C549S460000

Reexamination Certificate

active

06696573

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a novel process for the preparation of tricyclic amino alcohol derivatives of the formula (1):
wherein
R
1
represents a hydrogen or halogen atom, or a hydroxyl group,
R
3
represents a lower alkyl group or a benzyl group,
*1 represents an asymmetric carbon atom, and
A represents one of the following groups:
 wherein X represents NH, O or S, R
5
represents a hydrogen atom or a hydroxyl, amino or acetylamino group, and *2 represents an asymmetric carbon atom when R
5
is not a hydrogen atom, or salts thereof, which are useful in the treatment and prevention of diabetes, obesity, hyperlipidemia and the like; and intermediates useful for the process.
BACKGROUND OF THE INVENTION
JP-A-9-249623 (WO97/25311) and WO99/01431 disclose in detail processes for the preparation of compounds of the abovementioned formula (1) and also describe that these compounds are very useful for treating and preventing diabetes, obesity, hyperlipidemia and the like.
However, the study on the above known processes carried out by the present inventors has shown that these processes are not necessarily practical. There would be a need for a more convenient, practical preparation process with low cost which comprises a small number of steps with good industrial efficiency.
DISCLOSURE OF THE INVENTION
Chapter 1
The study carried out by the present inventors showed some disadvantages involved in the conventional processes for the preparation of a compound of the formula (1) set forth above, wherein the disadvantages were that the processes require many reaction steps and several purifying operation including column chromatography, and did not necessarily provide a good yield. In addition, if an optical isomer, such as R-form, of a compound of the formula (1) is to be finally obtained according to the synthesizing route disclosed in the above patent publications, the carbonyl group should be reduced with a borane as a reducing agent in the presence of a chiral auxiliary agent of the following formula (15):
This chiral auxiliary agent is very expensive and the process for the preparation thereof is very complicated. The chiral auxiliary agent is a hazardous, combustible substance and an asymmetric reduction using the said chiral auxiliary agent requires strictly anhydrous conditions, strict temperature controls, complicated works and the like, which will become problematic when the chiral auxiliary agent is industrially used.
In order to solve the above problems, the present inventors have examined a variety of synthesizing processes. As a result, the present inventors have established preferred synthesizing processes successfully and completed the present invention.
That is, the present invention is a process for the preparation of a compound of the formula (1):
wherein R
1
represents a hydrogen or halogen atom, or a hydroxyl group, R
3
represents a lower alkyl group or a benzyl group, *1 represents an asymmetric carbon atom, and A represents one of the following groups:
wherein X represents NH, O or S, R
5
represents a hydrogen atom, or a hydroxyl, amino or acetylamino group, *2 represents an asymmetric carbon atom when R
5
is not a hydrogen atom,
said process comprising:
reducing a compound of the formula (7):
 wherein R
11
represents a hydrogen or halogen atom, or a protected hydroxyl group, B represents a chlorine or bromine atom, to give a halohydrin of the formula (6):
 wherein R
11
, B and *1 are as defined above; and,
converting the halohydrin under alkaline conditions into an epoxy compound of the formula (5):
 wherein R
11
and *1 are as defined above; and,
reacting the epoxy compound with a compound of the formula (9):
 wherein R
2
represents an amino-protecting group, and A′ represents one of the following groups:
 wherein X represents NH, O or S, R
51
represents a hydrogen atom, a protected hydroxyl group, a protected amino group or an acetylamino group, and *2 represents an asymmetric carbon atom when R
51
is not a hydrogen atom, to give an amino alcohol of the formula (4):
 wherein R
11
, R
2
, A′ and *1 are as defined above; and,
reducing the nitro group to give an aniline derivative of the formula (3):
 wherein R
11
, R
2
, A′ and *1 are as defined above; and,
reacting the aniline derivative with a sulfonating agent to give an amino alcohol of the formula (2):
 wherein R
3
, R
11
, R
2
, A′ and *1 are as defined above; and then,
simultaneously or sequentially removing the protecting groups to give the compound of the formula (1).
In the aspect of the synthesizing route set forth above, compounds of the formulae (7) and (5) are preferred intermediates which are good in crystallinity. These compounds do not need a column chromatography purifying step and may be used in the following reaction step after being subjected to a recrystallizing treatment and the like. Particularly, the compound of the formula (5), which can be improved in its optical purity by recrystallizing treatment, is useful intermediate.
Specific examples of the compound of the formula (7) include:
2-chloro-1-(3-nitrophenyl)ethanone,
2-chloro-1-(4-benzyloxy-3-nitrophenyl)ethanone,
2-chloro-1-(4-chloro-3-nitrophenyl)ethanone,
2-chloro-1-(4-bromo-3-nitrophenyl)ethanone,
2-bromo-1-(3-nitrophenyl)ethanone,
2-bromo-1-(4-benzyloxy-3-nitrophenyl)ethanone,
2-bromo-1-(4-chloro-3-nitrophenyl)ethanone,
2-bromo-1-(4-bromo-3-nitrophenyl)ethanone and the like.
Specific examples of the compound of the formula (5) include:
(±)-1-(3-nitrophenyl)oxirane,
(±)-1-(4-benzyloxy-3-nitrophenyl)oxirane,
(±)-1-(4-chloro-3-nitrophenyl)oxirane,
(±)-1-(4-bromo-3-nitrophenyl)oxirane and the like. Particularly preferred examples include:
(R)-1-(3-nitrophenyl)oxirane,
(R)-1-(4-benzyloxy-3-nitrophenyl)oxirane,
(R)-1-(4-chloro-3-nitrophenyl)oxirane,
(R)-1-(4-bromo-3-nitrophenyl)oxirane and the like.
In the steps above, the step of reducing the compound of the formula (7) to give a compound of the formula (6) is especially characteristic.
Specific examples of the compound of the formula (6) include:
(±)-2-chloro-1-(3-nitrophenyl)ethanol,
(±)-2-chloro-1-(4-benzyloxy-3-nitrophenyl)ethanol,
(±)-2-chloro-1-(4-chloro-3-nitrophenyl)ethanol,
(±)-2-chloro-1-(4-bromo-3-nitrophenyl)ethanol,
(±)-2-bromo-1-(3-nitrophenyl)ethanol,
(±)-2-bromo-1-(4-benzyloxy-3-nitrophenyl)ethanol,
(±)-2-bromo-1-(4-chloro-3-nitrophenyl)ethanol,
(±)-2-bromo-1-(4-bromo-3-nitrophenyl)ethanol and the like. Particularly preferred examples include:
(R)-2-chloro-1-(3-nitrophenyl)ethanol,
(R)-2-chloro-1-(4-benzyloxy-3-nitrophenyl)ethanol,
(R)-2-chloro-1-(4-chloro-3-nitrophenyl)ethanol,
(R)-2-chloro-1-(4-bromo-3-nitrophenyl)ethanol,
(R)-2-bromo-1-(3-nitrophenyl)ethanol,
(R)-2-bromo-1-(4-benzyloxy-3-nitrophenyl)ethanol,
(R)-2-bromo-1-(4-chloro-3-nitrophenyl)ethanol,
(R)-2-bromo-1-(4-bromo-3-nitrophenyl)ethanol and the like.
In addition, when one of optical isomers of a compound of the formula (1) is to be obtained in the steps set forth above, a compound of the formula (7) is preferably subjected to an asymmetrical reduction. In this case, the resulting halohydrin compound of the formula (6), and the resulting compounds of the formulae (5), (4), (3), (2) and (1) are obtained as one of their optical isomers, respectively. This step is characteristic of these steps.
In the synthesizing route set forth above, compounds of the formulae (4) and (3) are also preferred intermediates which are novel. This compound does not necessarily need a column chromatography purifying step and may be used in the following reaction step after being subjected to a recrystallizing treatment and the like.
Specific examples of the compounds of the formula (4) include:
(±)-2-[N-benzyl-N-[2-(9H-carbazol-2-yloxy)ethyl]]amino-1-(3-nitrophenyl)ethanol,
(±)-2-[N-benzyl-N-[2-(9H-carbazol-2-yloxy)ethyl]]amino-1-(4-benzyloxy-3-nitrophenyl)ethanol,
(±)-

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