Patent ID: 6218550
Filing Date: 2001-04-17
Classification: C07D,Y02P

Abstract:
A method for the manufacture of a (2S,4S)-2-[[(R)-hydroxy-(3R)-cyclic amine-3-yl]methyl]pyrrolidine-4-thiol represented by the formula (II): ##STR27##wherein n is an integer of 1 to 4, or a salt thereof, which comprises the steps of treating a (2S,4R)-pyrrolidine-2-carbaldehyde compound represented by the formula (III): ##STR28##wherein R.sup.1 is a lower alkylsulfonyl group, an optionally substituted arylsulfonyl group or an alkylsilyl group; and R.sup.2 is a protecting group for an amino group, with a (4R)-3-(.omega.-substituted alkanoyl)oxazolidin-2-one, or thiazolidin-2-thione, compound represented by the formula (IV): ##STR29##wherein R.sup.3 is a substituted or unsubstituted lower alkyl group or an aryl group; X is an oxygen atom or a sulfur atom; Y is an azide group or a nitro group; and m is an integer of 2 to 5, to give a (4R)-[3-[2-(.omega.-substituted alkyl)-3-(R)-hydroxy-1-oxo-3-(2S,4R)-2-pyrrolidinyl]propyl]oxazolidin-2-on e, or thiazolidin-2-thione, compound represented by the formula (I): ##STR30##wherein R.sup.1 is a lower alkylsulfonyl group, an optionally substituted arylsulfonyl group or an alkylsilyl group; R.sup.2 is a protecting group for an amino group; R.sup.3 is a substituted or unsubstituted lower alkyl group or an aryl group; X is an oxygen atom or a sulfur atom; Y is an azide group or a nitro group; and n is an integer of 1 to 4, reducing the azide group or the nitro group thereof to give a (3S)-[[(R)-hydroxy-(2S, 4R)-2-pyrrolidinyl]methyl]lactam compound represented by the formula (V): ##STR31##wherein R.sup.1 is a lower alkylsulfonyl group, an optionally substituted arylsulfonyl group or an alkylsilyl group; R.sup.2 is a protecting group for an amino group; and n is an integer of 1 to 4, reducing the carbonyl group therein with or without protecting the NH group of the resulting cyclic amide to give a (2S,4R)-2-[[(R)-hydroxy-(3R)-cyclic amine-3-yl]methyl]pyrrolidine compound represented by the formula (VI): ##STR32##wherein R.sup.1 is a lower alkylsulfonyl group, an optionally substituted arylsulfonyl group or an alkylsilyl group; R.sup.2 is a protecting group for an amino group; R.sup.4 is a hydrogen atom or a protecting group for an amino group; and n is an integer of 1 to 4, when R.sup.1 is an alkylsilyl group, eliminating the alkylsilyl group selectively, followed by converting to a lower alkylsulfonyl group or an optionally substituted arylsulfonyl group and making it into an acylthio group to give a (2S,4S)-2-[[(R)-hydroxy-(3R)-cyclic amine-3-yl]methyl]-4-acylthiopyrrolidine compound represented by the formula (VII): ##STR33##wherein R.sup.2 is a protecting group for an amino group; R.sup.4 is a hydrogen atom or a protecting group for an amino group; R.sup.5 is an acyl group; and n is an integer of 1 to 4, and then eliminating the protective group(s).