Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-08-03
2001-02-13
Richter, Johann (Department: 1613)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06187932
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for producing captopril of formula (1)
from a substrate compound of the general formula (2)
wherein R represents alkyl or alkoxy. Captopril, which has the above formula (1), is an antihypertensive compound having high angiotensin-converting enzyme inhibitory activity (e.g. Biochemistry, 16, 5487, 1977).
BACKGROUND ART
As a method of synthesizing captopril of the above formula (1) from a substrate compound of the above general formula (2) [hereinafter referred to as substrate compound (2)], experimental examples of the reaction under basic conditions using an alkali metal hydroxide or the like have heretofore been reported (e.g. U.S. Pat. No. 4,105,776 and Japanese Kokai Publication Hei-3-169856 and Hei-5-221966).
As can be understood from the following reaction schema, any reaction under such basic conditions is a stoichiometric reaction in which at least 3 moles of an alkali metal hydroxide, for instance, may be consumed for each mole of substrate compound (2) (Japanese Kokai Publication Hei-3-169856).
wherein R is as defined hereinbefore; M represents an alkali metal ion such as Na.
The above reaction is disadvantageous in that it gives rise to a disulfide of the following formula (7) as a byproduct contaminating the product captopril.
Once the disulfide of formula (7) is by-produced, it takes much time and labor to remove the byproduct [Chemical Pharmaceutical Bulletin, 30 (9), 3139-3146, 1982; Chinese Patent 1034920A].
It is known that the by-production of the disulfide of formula (7) and other impurities is chiefly attributable to oxidation reactions involving molecular oxygen [Shigeru Ohba: Organosulfur Chemistry, Reaction Mechanisms, Kagaku Dojin).
For suppressing by-production of said disulfide of formula (7), the production of captopril from substrate compound (2) is generally carried out in an inert atmosphere such as nitrogen gas, helium gas, argon gas, or hydrogen gas [e.g. Japanese Kokai Publication Hei-5-221966].
However, the use of such an inert atmosphere for the reaction is a mere negative contrivance designed to prevent infiltration of oxygen and once oxygen has found its way into the reaction system, the by-production of said disulfide of formula (7) can hardly be inhibited.
It is difficult to completely eliminate oxygen and any residual oxygen has a serious adverse effect. For example, in the reaction giving rise to said byproduct disulfide of formula (7) from captopril and molecular oxygen, one mole of oxygen may consume as many as 4 moles of captopril as shown below (Japanese Kokai Publication Hei-3-169856).
In the above reaction schema, R
1
represents a captopril residue of the following formula.
Furthermore, the captopril obtained by the above reaction may contain N-(&agr;-methyl-&bgr;-(&bgr;-methyl-&bgr;-hydroxycarbonyl) ethylthiopropionyl)-L-proline of the following formula (8) as an onerous impurity.
Thus, N-(&agr;-methyl-&bgr;-(&bgr;-methyl-&bgr;-hydroxycarbonyl) ethylthiopropionyl)-L-proline of formula (8) can hardly be removed by a purification procedure and its elimination calls for a great deal of effort (Japanese Kokai Publication Hei-5-221966).
The investigation made by the inventors of the present invention (as disclosed in Japanese Patent Application Hei-7-286886) revealed that this N-(&agr;-methyl-&bgr;-(&bgr;-methyl-&bgr;-hydroxycarbonyl)ethylthiopropionyl)-L-proline of formula (8) is derived from the compound of the following general formula (3) and/or the compound of the following formula (4) which are/is present concomitantly with said substrate compound (2) in the reaction system for synthesis of captopril.
wherein R is as defined hereinbefore; n represents an integer of 2 to 4.
Therefore, it is important to inhibit or suppress the conversion of the compound of general formula (3) [hereinafter referred to as compound (3)] and/or the compound of formula (4) [hereinafter referred to as compound (4)] to said N-(&agr;-methyl-&bgr;-(&bgr;-methyl-&bgr;-hydroxycarbonyl) ethylthiopropionyl)-L-proline of general formula (8).
The above compound (3) and/or compound (4) is readily by-produced in the course of the synthesis of said substrate compound (2) by, for example, the Schotten-Baumann reaction between an acid halide of the following general formula (5) and L-proline of the following formula (6) under basic conditions.
wherein R is as defined hereinbefore; X represents halogen.
It has been discovered that in the course of cleavage of RCO under basic conditions, the byproduct compound is converted to the above-mentioned compound of formula (8).
SUMMARY OF THE INVENTION
In view of the above state of the art, the present invention has for its object to provide a highly convenient process for producing high-quality captopril in high yield and at low cost, which is conducive to minimized by-production of impurities which are hardly removed by purification.
The present invention, therefore, is directed to a process for producing captopril which comprises subjecting substrate compound (2) to hydrolysis reaction in aqueous medium to eliminate RCO group and isolating, said hydrolysis reaction in aqueous medium being conducted in the presence of a strong acid at pH not over 1 and a temperature not below 40° C.
The present invention is now described in detail.
DETAILED DESCRIPTION OF THE INVENTION
The substrate compound (2) for use in the present invention can be prepared by any of the processes described in U.S. Pat. No. 4,105,776, Japanese Kokai Publication Hei-4-305565, and other literature.
When the substrate compound (2) is to be produced by the Schotten-Baumann reaction of an acid halide of general formula (5) with L-proline of formula (6) under basic conditions, the amount of said compounds (3) and (4), which are precursors of N-(&agr;-methyl-&bgr;-(&bgr;-methyl-&bgr;-hydroxycarbonyl)ethylthiopropionyl)-L-proline of formula (8), is preferably as small as possible.
The substrate compound (2) that contains small amounts of said compound (3) and/or compound (4) is described in Japanese Patent Application Hei-7-286886 and can be advantageously provided by the following reaction procedure (A) or (B) and/or the following purification procedure (C) or (D) as followed either alone or in a suitable combination.
(A) The above-mentioned Schotten-Baumann reaction of an acid halide of general formula (5) with L-proline of formula (6) in a basic aqueous medium in the presence of a deacidifying condensing agent is conducted at pH 7-10 and a reaction temperature of not over 10° C. to thereby suppress by-production of said compound (3) and/or compound (4).
(B) The Schotten-Baumann reaction of an acid halide of general formula (5) with L-proline of formula (6) in a basic aqueous medium in the presence of a deacidifying condensing agent is conducted using potassium hydrogen carbonate as the deacidifying condensing agent preferably at a reaction temperature of not over 10° C. to thereby suppress by-production of said compound (3) and/or compound (4).
The above reaction procedure (A) is advantageous in that the reaction under weakly alkaline conditions and at a low temperature is highly conducive to inhibition of by-production of said compound (3) and/or compound (4). The reaction procedure (B) is advantageous in that since potassium hydrogen carbonate is used as the deacidifying condensing agent, the desired weakly alkaline conditions can be easily maintained without the need to control the reaction pH by any specific means, with the result that the by-production of said compound (3) and/or compound (4) can be effectively inhibited.
To prevent contamination of captopril with said byproduct compounds (3) and (4),
(C) the substrate compound (2) is caused to crystallize out from the aqueous medium containing it at a temperature of 35-100° C. and under acidic conditions, preferably at pH 1-4, to thereby remove the contaminant compound (3) and/or compound (4), and
(D) the aqueous medium containing said substrate compound (2) is treated wit
Kano Fumihiko
Kinoshita Koichi
Okubo Takahiro
Ueda Yasuyoshi
Kaneka Corporation
Oswecki Jane C.
Pollock Vande Sande & Amernick
Richter Johann
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