Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Patent
1995-07-28
1996-06-11
Bond, Robert T.
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C07D49808
Patent
active
055257224
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a novel process for producing bicozamycin benzoate.
BACKGROUND ART
Bicozamycin benzoate is a substance known in the art (cf. e.g. Japanese Kokai Tokkyo Koho Sho 48-39497 and U.S. Pat. No. 3,923,790). It is currently on the market as a fishery drug and under development also as a veterinary drug. The process for producing bicozamycin benzoate as described in the above-cited patent specifications comprises reacting bicozamycin with benzoyl chloride. In said process, the selectivity of the esterification reaction is low and, as a result, the reaction product contains a significant amount of byproducts such as bicozamycin dibenzoate. For commercial production of the objective compound bicozamycin benzoate, said process is thus not fully satisfactory from the yield and production cost viewpoints.
For solving the above problems by attaining an increase in the yield of bicozamycin benzoate, among others, it is crucial to find out a way to increase the selectivity toward monoesterification.
DISCLOSURE OF THE INVENTION
As a result of intensive investigations made by the present inventors to solve the above problems, it was found that the selectivity toward monoesterification can be improved and the yield of bicozamycin benzoate can be much increased when bicozamycin is reacted with benzoic anhydride in the presence of 4-dimethylaminopyridine. Further studies based on this new finding have now led to completion of this invention.
The reaction involved in this invention may be illustrated as follows: ##STR1##
This invention consists in reacting bicozamycin with benzoic anhydride in the presence of 4-dimethylaminopyridine. Bicozamycin is the same substance as WS-4545 substance (cf. Japanese Patent Publication Sho 48-29158) produced by a microorganism belonging to the genus Streptomyces (e.g. Streptomyces sapporonensis ATCC 21532) and is known in the art. 4-Dimethylaminopyridine is used preferably in a catalytic amount.
This reaction is generally carried out in a solvent. As the solvent, there may be mentioned water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, tetrahydrofuran, ethyl acetate, ether, pyridine, N, N-dimethylacetamide, dimethyl sulfoxide, N, N-dimethylformamide, N-methylpyrrolidone, diglyme, triglyme, hexamethylphosphoramide and other ordinary organic solvents inert to the reaction. Further, the reaction of this invention is preferably performed in the presence of a base such as an alkali metal hydrogen carbonate, a trialkylamine, pyridine or the like. Among such bases, those that are liquid may be used also as solvents. Particularly favorable results may be obtained when this reaction is carried out in pyridine. Although the reaction temperature is not critical, the reaction can be carried out smoothly under cooling or at room temperature in most instances. The reaction product can be isolated, purified and recovered in the conventional manner.
The bicozamycin benzoate production process according to the invention has advantages over the prior art process in that it gives much improved yields of bicozamycin benzoate, that the contents of by-products (bicozamycin dibenzoate, bicozamycin tribenzoate, etc.) in the reaction product is low and that, therefore, the objective substance bicozamycin benzoate can be isolated and purified from the reaction product with ease, for instance. Said process thus remarkably contribute to cost reduction in the commercial production of bicozamycin benzoate.
In the following, the effects of this invention are illustrated by means of a test example.
TEST EXAMPLE (COMPARISON WITH PRIOR ART)
A 300-ml three-necked flask was charged with 150 ml of pyridine and 43.8 g (on the pure substance basis) of bicozamycin, and the mixture was stirred at room temperature for about 30 minutes for attaining dissolution. Then, while the liquid temperature was maintained at 20.degree. to 25.degree. C., 57.0 g of benzoyl chloride was added dropwise over about 30 minutes. After completion of the addition, the resultant m
REFERENCES:
patent: 3923790 (1975-12-01), Imanaka et al.
Kawakami Ryoichi
Nakamura Hitoshi
Shiina Kunihiko
Bond Robert T.
Fujisawa Pharmaceutical Co. Ltd.
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