Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-12-13
2001-01-09
Chang, Ceila (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C560S122000, C560S128000, C562S045000, C562S113000
Reexamination Certificate
active
06172238
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field
The invention relates to a process for manufacturing 1-[3-cyclopentyl-2(r)-[1(r)-hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperidine, to a process for producing useful intermediates, and to the intermediates themselves.
2. Description
Compounds, including the compound of formula:
are known from U.S. Pat. No. 5,614,625, issued Mar. 25, 1997 to Broadhurst et al., the contents of which are herein incorporated by reference. These compounds are collagenase inhibitors useful in the control or prevention of degenerative joint diseases, such as in the capacity of a cartilage protective agent.
SUMMARY OF THE INVENTION
A process for manufacturing a compound of formula:
which comprises:
a) reacting a compound of formula:
wherein R
2
is a hydrolytically cleavable group and
R
1
is methyl, ethyl, propyl, butyl, pentyl, hexyl or t-butyl,
with 3-bromomethyl-1,5,5-trimethylhydantoin in the presence of a base to yield a compound of formula:
wherein R
1
and R
2
are as defined above;
b) hydrolyzing the compound of formula III in the presence of a metal catalyst, subsequently decarboxylating the hydrolyzed compound in the presence of a base, and purifying the thus-obtained product by adding a further base which is suitable for salt formation to yield a salt of a compound of formula:
wherein R
1
is as defined above;
c) reacting the compound of formula IV with piperidine and activating the carboxylic acid to yield a compound of formula:
wherein R
1
is as defined above;
d) reacting the compound of formula V in which R
1
is methyl, ethyl, propyl, butyl, pentyl or hexyl with benzylhydroxylamine hydrochloride that has been activated by means of an alkylmagnesium halide to yield a compound of formula:
and hydrolytically cleaving the benzyl group to give the compound of formula I, or
e) cleaving the t-butyl group in the compound of formula V in which R
1
is tert-butyl with a mixture of a mineral acid and (i) a carboxylic acid, (ii) a carboxylic acid ester, or (iii) a mixture of a carboxylic acid and a carboxylic acid ester,
or cleaving the ester group in the compound of formula V in which R
1
is methyl, ethyl, propyl, butyl, pentyl or hexyl with an alkali or alkaline earth metal hydroxide to yield a compound of formula:
and either
(1) subsequently reacting the compound of formula VI with benzylhydroxylamine hydrochloride with the addition of an activating agent to yield the compound VII and hydrolytically cleaving the benzyl group in compound of formula VII to yield the compound of formula I, or
(2) reacting the compound of formula VI with trimethylsilyl-hydroxylamine or tetrahydropyranyl-hydroxylamine and cleaving the trimethylsilyl or tetrahydropyranyl group to yield the compound of formula I.
A process for the preparing a compound of formula:
wherein R
1
is methyl, ethyl, propyl, butyl, pentyl, hexyl or t-butyl and R
2
is a hydrolytically cleavable group, which comprises:
a) reacting a compound of formula:
with methylenecyclopentane in the presence of catalytic amounts of (R)-binaphthyloxytitanium catalyst to yield a compound of formula:
wherein R
2
is a hydrolytically cleavable group;
b) activating a compound of formula IX with a sulphonyl halide R
3
—SO
2
—X, wherein R
3
is trifluoromethyl, phenyl, phenyl substituted with nitro or phenyl substituted with halogen, and X is halogen, to yield a compound of formula:
wherein R
2
and R
3
are as above; and
c) reacting, in the presence of a base, a compound of formula X with a compound of formula:
R
1
O
2
CCH
2
CO
2
R
2
XI
wherein R
2
is as above and R
1
is methyl, ethyl, propyl, butyl, pentyl, hexyl or t-butyl, to yield a compound of formula II.
DETAILED DESCRIPTION OF THE INVENTION
The subject invention will now be described in terms of its preferred embodiments. These embodiments are to aid in understanding the invention, but are not to be construed as limiting.
The present invention is concerned with a process for the manufacture of a compound of formula I
by carrying out the following steps:
a) reaction of a compound of formula II
wherein R
2
signifies a hydrogenolytically cleavable group and R
1
signifies methyl, ethyl, propyl, butyl, pentyl, hexyl or t-butyl,
with 3-bromomethyl-1,5,5-trimethylhydantoin in the presence of a base to give a compound of formula III
wherein R
1
and R
2
have the significances previously defined,
b) hydrogenolysis of compound III in the presence of a metal catalyst, subsequent decarboxylation in the presence of a base and purification of the thus-obtained product by addition of a further base which is suitable for salt formation to give a compound of formula IV
wherein R
1
is as defined above,
which is obtained as a salt,
c) reaction of a compound of formula IV with piperidine with activation of the carboxylic acid to give a compound of formula V
wherein R
1
has the significance given above,
d) reaction of a compound of formula V in which R
1
signifies methyl, ethyl, propyl, butyl, pentyl or hexyl with benzylhydroxylamine hydrochloride activated by means of an alkylmagnesium halide to give compound VII
and hydrogenolytic cleavage of the benzyl group to give compound I, or
e) cleavage of the t-butyl group in a compound of formula V in which R
1
signifies tert-butyl with a mixture of a mineral acid and a carboxylic acid and/or a carboxylic acid ester,
or cleavage of the ester group of a compound of formula V in which R
1
signifies methyl, ethyl, propyl, butyl, pentyl or hexyl with an alkali or alkaline earth metal hydroxide to give compound VI
and either
subsequent reaction of compound VI with benzylhydroxylamine hydrochloride with the addition of an activating agent to give compound VII and hydrogenolytic cleavage of the benzyl group in compound VII to give compound I, or
reaction of compound VI with trimethylsilyl-hydroxylamine or tetrahydropyranyl-hydroxylamine and cleavage of the trimethylsilyl or tetrahydropyranyl group according to methods known per se to give compound I.
Compound I is known and is described, for example, in U.S. Pat. No. 5,614,625, which corresponds to European Publication No. EP 0 684 240 A1. The compound has valuable pharmacological properties and can accordingly be used for the treatment and prevention of illnesses.
In accordance with the present invention a compound of formula I can be obtained, inter alia, by the purification of an intermediate via salt formation and an improved cleavage of the selected ester groups in a purer form and in a higher yield than according to the process described in the state of the art.
The term “hydrogenolytically cleavable group” denoted by R
2
signifies a group which can be cleaved off using methods known to a person skilled in the art, such as, for example, using hydrogen and a noble metal catalyst. Ester groups which are cleavable in this manner are e.g. the phenacyl ester, diphenylmethyl ester, p-methoxybenzyl ester or benzyl ester. Preferably, R
2
is benzyl in any of the compounds described hereinbefore or hereinafter.
The term “lower” denotes residues having a maximum of 7, preferably a maximum of 4, carbon atoms. The term “alkyl” denotes straight-chain or branched, saturated hydrocarbon residues such as methyl, ethyl, propyl, isopropyl, n-butyl and t-butyl.
All temperatures are in degrees Celsius.
The alkylation of the triester II with 3-bromomethyl-1,5,5-trimethylhydantoin is effected by firstly deprotonizing the triester with a base such as an alkali or alkaline earth metal hydroxide or alkoxide or a metal hydride, preferably sodium hydride, in a solvent such as an ether, e.g. 1,2-dimethoxyethane, or a sulphoxide, e.g. dimethyl sulphoxide, or an ester, e.g. ethyl acetate, or a formamide, preferably dimethylformamide, at a temperature of 0° to 100°, preferably 10° to 30°, and reacting the hydantoin with the triester II in the same solvent. Conveniently, the metal malonate is added to 3-bromomethyl-1,5,5-trimethylhydantoin at a temperature of −20° to 50
Brown Paul Anthony
Hilpert Hans
Chang Ceila
Epstein William H.
Hoffmann-La Roche Inc.
Johnston George W.
Parise John P.
LandOfFree
Process for manufacturing... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for manufacturing..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for manufacturing... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2509513