Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-07-31
1999-06-29
Fan, Jane
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D20716
Patent
active
059170557
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a process for producing N-(D-.alpha.-methyl-.beta.-mercaptopropionyl)-L-proline of the formula (4) ##STR2## and its synthetic intermediate N-(D-.alpha.-methyl-.beta.-acylthiopropionyl)-L-proline of the formula (3) ##STR3## or N-(DL-.alpha.-methyl-.beta.-acylthiopropionyl)-L-proline.
BACKGROUND TECHNOLOGY
N-(D-.alpha.-methyl-.beta.-mercaptopropionyl)-L-proline (4) has potent angiotensin converting enzyme inhibiting activity and is an antihypertensive agent generically called captopril (erg. Biochemistry, 16, 5487 (1977)).
Various methods are known for the production of N-(D-.alpha.-methyl-.beta.-mercaptopropionyl)-L-proline (4) (hereinafter also called captopril). For instance, in Japanese Kokoku Publication Sho-60-56705, Japanese Kokai Publication Hei-5-17435 and Japanese Kokai Publication Hei-5-221966 and elsewhere, there are disclosed processes for producing captopril which comprises deriving an N-(D-.alpha.-methyl-.beta.-acylthiopropionyl)-L-proline (3) from a D-.alpha.-methyl-.beta.-acylthiopropionic acid halide or DL-.alpha.-methyl-.beta.-acylthiopropionic acid halide and L-proline by utilizing the Schotten-Baumann reaction and then subjecting the intermediate (3) to deacylation.
While the medical and medicinal expenses are on a growing trend, captopril is expectedly one of large-sale generic drugs and it is of great significance to develop a process for producing high-purity captopril at low cost and in easy and simple manner.
As for the specifications of captopril, the Japanese Pharmaceutical Index requires that the captopril bulk substance contains not less than 97.5% of captopril and has a melting point of 105.degree. C. to 110.degree. C. and that the content of captopril disulfide, which is one of related substances (organic impurities), is not more than 2.5%, among others. The U.S. Pharmacopeia requires, among others, that the content of .beta.-mercapto-.alpha.-methylpropionic acid as a related substance (organic impurity) is not more than 0.1%. In view of the nature of a medicine ingredient, it is needless to say that said bulk substance can hardly contain other related substances or organic impurities not referred to in such specifications or, in other words, it is strongly desired that their contents do not exceed 0.1%.
Concerning the quality of captopril products obtained by subjecting the above-mentioned acid halide and L-proline to Schotten-Baumann reaction, followed by deacylation, the impurities possibly contained therein and the methods of preventing the formation thereof, literature references disclose, for example, as follows:
In the above-cited Japanese Kokai Publication Hei-5-221966, it is described that -L-proline of the formula (7) given below, or N-acetyl-L-proline, among others, is formed as a by-product in the Schotten-Baumann reaction. ##STR4##
According to the teaching disclosed in said Japanese Kokai Publication Hei-5-221966, however, the Schotten-Baumann reaction and the subsequent deacylation are carried out in a continuous manner, so that it is not very certain in which step the above-mentioned by-products are formed as impurities. For preventing the formation of these products according to said teaching, the pH, temperature and D-.alpha.-methyl-.beta.-acylthiopropionic acid halide/L-proline mole ratio, among others, are important in carrying out the Schotten-Baumann reaction. As optimal values, there are mentioned an initial pH of 9.9 to 10.1, a final pH of 10.9 to 11.0, a reaction temperature of not higher than 10.degree. C., and a D-.alpha.-methyl-.beta.-acylthiopropionic acid halide/L-proline mole ratio of 1.0 to 1.1.
In U.S. Pat. No. 5,387,697, it is disclosed that the compound of the formula (8) ##STR5## is formed as a by-product during the Schotten-Baumann reaction and it is described that for preventing the formation of this impurity, the Schotten-Baumann reaction should be carried out at 0.degree. C. to 5.degree. C. in 0.25 M potassium phosphate buffer solution, while adjusting the pH to 7.5 to 8.5 with
REFERENCES:
patent: 5387697 (1995-02-01), Hen
Kanou Fumihiko
Kinoshita Koichi
Okubo Takahiro
Ueda Yasuyoshi
Fan Jane
Kaneka Corporation
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