Process for producing stereoisomer of pyrrolidine derivative

Details Process for producing stereoisomer of pyrrolidine derivative Process for producing stereoisomer of pyrrolidine derivative

2002-05-08

2003-09-16

McKane, Joseph K. (Department: 1628)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06620945

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a process for producing an optically active 3-hydroxy-4-methoxypyrrolidine, which is a synthesis intermediate of a quinuclidine derivative useful, as a squalene synthetase inhibitor, for prevention and treatment of hyperlipemia such as arteriosclerotic disease, ischemic heart disease and the like.
BACKGROUND OF THE INVENTION
At present, an HMG-CoA reductase inhibitor is widely used as a cholesterol-decreasing agent. Since this inhibitor produces an effect on metabolic materials other than cholesterol, a side effect thereof is becoming a problem. A squalene synthetase functions in the lower course than an HMG-CoA reductase and an isoprene synthesis system in the biosynthesis system of cholesterol. Therefore, it is expected that the squalene synthetase overcomes the side effect problem of the HMG-CoA reductase inhibitor. However, no squalene synthetase inhibitor which produces only a small side effect and exhibits sufficient efficacy as hyperlipemia therapeutic agent has been created before.
After eager researches, the present inventors found that a quinuclidine derivative comprising 3-hydroxy-4-methoxypyrrolidine or the like has a superior squalene synthetase inhibiting effect and is useful as a hyperlipemia therapeutic agent. The inventors then filed a Patent Application about the quinuclidine derivative (WO 01/23383).
In a process for producing a quinuclidine derivative comprising 3-hydroxy-4-methoxypyrrolidine or the like, described in this Patent Application (WO 01/23383), 3-hydroxy-4-methoxypyrrolidine, which is concerned with the present invention, is not used as an intermediate. Therefore, this process is unsatisfactory as an industrial process for producing the quinuclidine derivative in light of a large number of the steps included in the process and the yield thereof as a whole. 3-Hydroxy-4-methoxypyrrolidine is new as a racemic body or an optically active substance, and has not been known so far.
SUMMARY OF THE INVENTION
An object of the present invention is to provide a useful process for producing optically active 3-hydroxy-4-methoxypyrrolidine, which is an intermediate for producing the above-mentioned quinuclidine derivative.
In the present invention, 3-hydroxy-4-methoxypyrrolidine is used. Therefore, the number of steps in the method of the present invention can be smaller than that of the above-mentioned process (WO 01/23383). Accordingly, the present invention can be used to produce the quinuclidine derivative effectively and industrially.
The inventors have found out a useful process for producing optically active 3-hydroxy-4-methoxypyrrolidine, that is, the following inventions <1> to <11>:
<1> A process for producing optically active 3-hydroxy-4-methocypyrrolidine represented by the following formula (1-7):
 wherein R
1a
and R
1b
are different from each other, and each of R
1a
and R
1b
represents a hydrogen atom or a hydroxyl group, and R
2a
and R
2b
are different from each other, and each of R
2a
and R
2b
represents a hydrogen atom or a methoxy group], a salt thereof or a hydrate thereof, comprising the steps of:
subjecting a pyrrolidine derivative represented by the following formula (1-4):
 wherein R
1a
, R
1b
, R
2a
and R
2b
have the same definition as mentioned above, and R
3a
and R
3b
are different 1 mm each other, and each of R
3a
and R
3b
represents a hydrogen atom or a methyl group, to optical division purification by using an optically active dibenzoyltartaric acid derivative represented by the following formula (1-5):
 wherein R
6a
, R
6b
, R
6c
and R
6d
each independently represents a hydrogen atom, a halogen atom, a C1-6 alkoxy group or a C1-6 alkyl group, and R
4
and R
5
are different tram each other, and each of R
4
end R
5
represents a hydrogen atom or a carboxyl group, to yield a compound (1-6) represented by the following formula (1-6):
 wherein R
1a
, R
1b
, R
2a
, R
2b
, R
3a
and R
3b
have the same definition as mentioned above; and
removing the 1-phenylethyl group of the compound (1-6), to yield the 3-hydroxy-4-methoxypyrrolidine, the salt thereof or the hydrate thereof;
<2> A process for producing optically active 3-hydroxy-4-methoxypyrrolidine represented by the following formula (1-7):
 wherein R
1a
and R
1b
are different from each other, and each of R
1a
and R
1b
represents a hydrogen atom or a hydroxyl group and R
2a
and R
2b
are different from each other, and each of R
2a
and R
2b
represents a hydrogen atom or a methoxy group, a salt thereof or a hydrate thereof, comprising the steps of:
reacting an oxysilafle derivative represented by the following formula (1-1)
 wherein L
1
represents a halogen atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group, with an amine derivative represented by the following formula (1-2)
 wherein R
3a
and R
3b
are different from each other, and each of R
3a
and R
3b
represents a hydrogen atom or a methyl group, to yield a pyrrolidine derivative (1-3) represented by the following formula (1-3):
 wherein R
3a
and R
3b
have the same definition as mentioned above;
reacting the derivative (1-3) with a methoxylating agent, to yield a pyrrolidine derivative (1-4):
 wherein R
1a
, R
1b
, R
2a
, R
2b
, R
3a
and R
3b
have the same definition as mentioned above;
subjecting the derivative (1-4) to optical division purification by using an optically active dibenzoyltartaric acid derivative represented by the following formula (1-5):
 wherein R
6a
, R
6b
, R
6c
and R
6d
each independently represents a hydrogen atom, a halogen atom, a C1-6 alkoxy group or a C1-6 alkyl group, and R
4
and R
5
are different from each other, and each of R
4
and R
5
represents a hydrogen atom or a carboxyl group, to yield a compound (1-6) represented by the following formula (1-6):
 wherein R
1a
, R
1b
, R
2a
, R
2b
, R
3a
and R
3b
have the same definition as mentioned above; and
removing the 1-phenylethyl group of the compound (1-8), to yield the 3-hydroxy-4-methoxypyrrolidine, the salt thereof or the hydrate thereof;
<3> The method according to the above-mentioned item <1> or <2>, wherein each of R
1a
and R
2b
represents a hydrogen atom;
<4> The method according to the above-mentioned item <1> or <2>, wherein each of R
1b
and R
2a
represents a hydrogen atom;
<5> The method according to any one of the above-mentioned items <1> to <4>, wherein R
3a
represents a methyl group;
<6> The method according to any one of the above-mentioned items <1> to <4>, wherein R
3b
represents a methyl group;
<7> The method according to any one of the above-mentioned items <1> to <6>, wherein said compound (1-4) represents a mixture of compounds represented by the following formulae (1-4a) and (1-4b) (wherein R
3a
and R
3b
are different from each other, and each of R
3a
and R
3b
represents hydrogen atom or a methyl group), in which the mixture having a given mixture ratio of compound (1-4a) to (1-4b):
<8> The method according to the above-mentioned item <7>, wherein said compound (1-4) is said mixture of said compounds (1-4a) and (1-4b) having a ratio of 1:1 of said compounds (1-4a) to (1-4b);
<9> The method according to any one of the above-mentioned items <1> to <8>. wherein R
4
represents a hydrogen atom;
<10> The method according to any one of the above-mentioned items <1> to <8>, wherein R
5
represents a hydrogen atom; and
<11> The method according to any one of the above-mentioned items <1> to <10>, wherein each of R
6a
, R
6b
, R
6c
and R
6d
represents a hydrogen atom.
DETAILED DESCRIPTION OF THE REFERRED EMBODIMENT
The present invention will be described in detail hereinafter.
First, meanings of terms, symbols and the like described hereinafter will be defined.
In the present specification and claims, a structural formula of a compound may conveniently represent a given isome

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