Process for producing pyrrolidine derivative and salt thereof

Details Process for producing pyrrolidine derivative and salt thereof Process for producing pyrrolidine derivative and salt thereof

1994-12-30

1996-08-06

Fan, Jane

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

548518, 5483147, 5483641, 544333, 544405, 544238, 544180, 544255, 5462784, C07D40106

Patent

active

055435254

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to an industrial process for producing pyrrolidine derivative or a salt thereof represented by the following general formula (I): ##STR2## wherein
R.sup.1 is heterocyclic(lower)alkyl,
R.sup.2 is acyl, and
R.sup.3 is carboxy(lower)alkyl or protected carboxy(lower)alkyl, and is applicable in the medical field.


BACKGROUND ART

Pyrrolidine derivatives of the above general formula (I), or salts thereof and a method for producing them are known as disclosed in Japanese Patent Publication No. 2-152960.


DISCLOSURE OF INVENTION

The method described in the above-mentioned bulletin for the production of compounds of general formula (I) is disadvantageous in that it requires a long series of steps complicating the production and provides only a very low overall yield rendering the production cost high.
The object of this invention is to provide an industrially excellent production method for producing compounds of general formula (I) and salts thereof which is superior to the above known production process in simplicity and in yield.
The method for producing said pyrrolidine derivative (I) according to this invention is as follows. ##STR3## wherein R.sup.1 R.sup.2 and R.sup.3 are each as defined above,
R.sup.4 is aryl, and
Y.sup.- is an anion.
The starting compound (II) is novel and can be produced by the following processes. ##STR4## wherein
R.sup.1 and R.sup.2 are each as defined above,
R.sup.5 is carboxy or protected carboxy,
R.sub.a.sup.5 is protected carboxy
R.sup.6 is lower alkyl,
M is an alkali metal,
X.sup.1 and X.sup.2 are each a leaving group, and
X.sup.3 is halogen.
In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention include within the scope thereof are explained in detail as follows.
The term "lower" is intended to mean, unless otherwise indicated, 1 to 6 carbon atoms.
Suitable "lower alkyl" and "lower alkyl moiety" in the terms "heterocyclic(lower)alkyl", "carboxy(lower)alkyl" and "protected carboxy(lower)alkyl" may include straight or branched one having 1 to 6 carbon atom(s) such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, hexyl and the like, preferably one having 1 to 4 carbon atom(s).
Suitable "aryl" may include phenyl, naphthyl, and the like.
Suitable "heterocyclic moiety" in the term "heterocyclic(lower)alkyl" means saturated or unsaturated hetero-monocyclic or -polycyclic group containing at least one hetero-atom such as oxygen, sulfur and nitrogen atoms. The particularly preferred heterocyclic group may be
unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl (e.g.-4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl, etc.), etc.;
saturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), such as pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.;
unsaturated condensed. heterocyclic group containing 1 to 5 nitrogen atom(s), such as indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl (e.g. tetrazolo[1,5-b]pyridazinyl, etc.), dihydrotriazolopyridazinyl, etc.;
unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), such as oxazolyl, isoxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;
saturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), such as morpholinyl, etc.;
unsatur

REFERENCES:
patent: 4876262 (1989-10-01), Oinuma et al.
Yadav et al. CA 119:27898, 1993. Takuma et al. CA 115:255891, 1991.
Main et al. CA 117: 233411, 1992. Beaulieu et al. CA 115: 9267, 1991.
Zjawiony et al. CA 114: 185330, 1991. Moiseenkov et al. CA 111: 174466, 1989.

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