Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-11-12
2001-04-17
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S517000, C548S400000
Reexamination Certificate
active
06218550
ABSTRACT:
CROSS-REFERENCE
This is a 371 of PCT/JP98/02225 filed May 21, 1998
Intermediates useful for the manufacture of carbapenem and a stereoselective manufacturing method therefor
FIELD OF THE INVENTION
The present invention relates to intermediates useful for the manufacture of carbapenem compound useful as antibacterial agents and also to a method for manufacturing the same.
2. PRIOR ART
With regard to antibiotics of a carbapenem series, synthetic studies for many compounds have been carried out since the discovery of thienamycin in 1976. Recently, there are many studies on carbapenem compounds having a 2-substituted pyrrolidine-4-thio group at the 2-position of a carbapenem skeleton and, among them, there is a disclosure on the following carbapenem compounds having an excellent antibacterial activity to
Pseudomonas aeruginosa
in Drugs of the Future, 1996, 21(4):361-365.
In addition, compounds related thereto are disclosed in JP-A 8-73462 etc.
Manufacture of the carbapenem compounds described in those reports are carried out by a condensation of a reactive compound of a carbapenem skeleton with an optically active pyrrolidine-4-thiol compound (VIII):
(wherein, PNZ is a p-nitrobenzyloxycarbonyl group), and the optically active pyrrolidine-4-thiol compound (VIII) is manufactured according to the steps as shown in the following reaction formulae:
(wherein, Boc is a tert-butoxycarbonyl group, PNZ is a p-nitrobenzyloxycarbonyl group and TBDMS is a tert-butyldimethylsilyl group.)
However, according to the disclosed method, a diastereomer having the unnecessary configuration is also obtained in the first step and, therefore, there is the following industrial disadvantage judging from preparing the diastereomer having the desired configuration only. Thus, 1) the diastereomer having the unnecessary configuration is to be separated and removed; and 2) yield of the diastereomer having the desired configuration is low.
DISCLOSURE OF THE INVENTION
An object of the present invention is to overcome the above disadvantages or, in other words, to manufacture only the diastereomer having the desired configuration selectively and in a high yield.
As a result of an intensive investigation, the present inventors have found that the method for the manufacture of stereoselective pyrrolidine-4-thiol compounds as mentioned below is able to solve the above problems and have accomplished the present invention.
Namely, the present invention is a method for the manufacture of (2S,4S)-2-[[(R)-hydroxy-(3R)-cyclic amine-3-yl]methyl]pyrrolidine-4-thiol represented by the formula (II):
(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):
(wherein, R
1
is a lower alkylsulfonyl group, an optionally substituted arylsulfonyl group or an alkylsilyl group; and R
2
is a protecting group for an amino group) with a (4R)-3-(&ohgr;-substituted alkanoyl) oxazolidin-2-one (or thiazolidin-2-thione) compound represented by the formula (IV):
(wherein, R
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-(&ohgr;-substituted alkyl)-3-(R)-hydroxy-1-oxo-3-(2S,4R)-2-pyrrolidinyl]propyl]oxazolidin-2-one (or thiazolidin-2-thione) compound represented by the formula (I):
(wherein, R
1
is a lower alkylsufonyl group, an optionally substituted arylsulfonyl group or an alkylsilyl group; R
2
is a protecting group for an amino group; R
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):
(wherein, R
1
is a lower alkylsulfonyl group, an optionally substituted arylsulfonyl group or an alkylsilyl group; R
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):
(wherein, R
1
is a lower alkylsulfonyl group, an optionally substituted arylsulfonyl group or an alkylsilyl group; R
2
is an protecting group for an amino group; R
4
is a hydrogen atom or a protecting group for an amino group; and n is an integer of 1 to 4); when R
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):
(wherein, R
2
is a protecting group for an amino group; R
4
is a hydrogen atom or a protecting group for an amino group; R
5
is an acyl group; and n is an integer of 1 to 4); and then eliminating the protecting group(s). Further, the present invention relates to novel intermediates, i.e. a (4R)-[3-[2-(&ohgr;-substituted alkyl)-3-(R)-hydroxy-1-oxo-3-(2S, 4R)-2-pyrrolidinyl]propyl]oxazolidin-2-one (or thiazolidine-2-thione) compound and (2S,4S)-2-[[(R)-hydroxy-(3R)-cyclic amine-3-yl]methyl]pyrrolidin-4-thiol or salts thereof.
A (2S,4S)-2-[[(R)-hydroxy-(3R)-cyclic amine-3-yl]methyl]pyrrolidin-4-thiol, which is a novel intermediate, is capable of forming a salt in the presence of an acid and it goes without saying that such a salt is also covered by the present invention. Examples of the salt include hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, trifluoroacetate and sulfonates such as methanesulfonate, p-toluenesulfonate, etc.
In the present invention, examples of the lower alkylsulfonyl group found in the definition for R
1
include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, etc.; examples of the arylsulfonyl group found therein include a phenylsulfonyl group, a p-toluenesulfonyl group, etc.; and examples of the alkylsilyl group found in the definition for R
1
include a trimethylsilyl group, a triethylsilyl group, an isopropyldimethylsilyl group, an tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, a vinyldimethylsilyl group, etc.
Examples of the protecting group for an amino group found in the definitions of R
2
and R
4
include substituted or unsubstituted lower alkanoyl groups such as a formyl group, an acetyl group, a chloroacetyl group, a dichloroacetyl group, a propionyl group, a phenylacetyl group, a thienylacetyl group etc., or substituted or unsubstituted lower alkoxycarbonyl groups such as a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, a p-bromobenzyloxycarbonyl group, a 2,4-dichlorobenzyloxycarbonyl group, etc.
Examples of the substituted or unsubstituted lower alkyl group found in the definition of R
3
include a methyl group, an ethyl group, an isopropyl group, a benzyl group, etc., while an example of the aryl group found therein include a phenyl group, etc.
Examples of the acyl group found in the definition of R
5
include the groups derived from saturated or unsaturated fatty acids such as a formyl group, an acetyl group, a propionyl group, an acryloyl group, etc., the groups derived from carbocyclic carboxylic acids such as a cyclohexylcarbonyl group, a benzoyl group, a toluoyl group a cinnamoyl group, etc., the groups derived from heterocyclic carboxylic acids such as a nicotinoyl group, a thenoyl group, etc., a morpholinylacetyl group, a thiomorpholinylacetyl group, etc.
DETAILED DESCRIPTION OF THE INVENTION
The manufacturing method according to the present inventio
Ashizawa Kazuhide
Kamada Atsushi
Sasho Manabu
Sato Nobuaki
Sugiyama Isao
Desai Rita
Eisai Co. Ltd.
Flynn ,Thiel, Boutell & Tanis, P.C.
Rotman Alan L.
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