Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1992-09-28
1995-03-21
Rizzo, Nicholas
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D49900
Patent
active
053996780
DESCRIPTION:
BRIEF SUMMARY
This was filed under 35 U.S.C. .sctn. 371 based on PCT/US91/01765 filed on Mar. 15, 1991 which was a continuation of U.S. application Ser. No. 07/509,256, now abandoned, which was filed on Apr. 13, 1990.
TECHNICAL FIELD
The field of art to which this invention relates are methods of making haloalkyl esters of sulbactam.
BACKGROUND ART
The present invention is concerned with an improved method of preparing the chloromethyl ester of sulbactam ##STR1## a key intermediate in the manufacture of sultamicillin. See Bigham, U.S. Pat. Nos. 4,244,951 and Godfredsen et al., 4,342,772. Sulbactam and sultamicillin are the U.S.A.N. (U.S. Adopted Names) or generic names for penicillanic acid 1,1-dioxide and for the mixed methandiol ester with sulbactam/ampicillin, respectively.
The preparation of the ester intermediate of the formula (I) in high yield and quality by reaction of the carboxylate salt of the formula ##STR2## wherein X.sup.+ is a metal or ammonium cation, with chloroiodomethane or bromochloromethane suffers from the problem that the product is contaminated by the bis-ester of the formula ##STR3## The use of the salt of formula II, wherein X is tetrabutylammonium, by Jasys, commonly assigned U.S. Pat. No. 4,381,263, the disclosure of which is hereby incorporated by reference, improved the yield of the desired ester (I), but even here appreciable bis-ester (III) was formed [Binderup et al. Synthetic Communications, vol. 14, pages 857-864 (1984)].
More recently, Binderup et al. have employed chloromethyl chlorosulfate in place of chlorobromomethane or chloroiodomethane in reaction with the tetrabutylammonium salt of formula (II). Although the level of bis-ester is reduced thereby, use of chloromethyl chlorosulfate requires specialized equipment and handling for plant scale operations.
Commonly assigned U.S. Pat. No. 4,704,456 teaches a further variation for making the chloromethyl ester of sulbactam. That patent teaches the addition of, for example, tert-amines to improve the rate of chloromethyl ester formation, and the yield of the chloromethyl ester I (at the expense of the bis-ester (III)).
Although there are a variety of processes for producing the chloromethyl ester of sulbactam there is a continuing search in this field of art for more efficient high yielding processes.
SUMMARY OF THE INVENTION
This invention is directed to a simplified method for making the chloromethyl ester of sulbactam in which the step of drying and isolating the tetraalkylammonium sulbactam salt is eliminated. The method comprises reacting a tetraalkylammonium salt and a sulbactam salt in an aqueous solution to form an aqueous solution of tetraalkylammonium sulbactam. The tetraalkylammonium sulbactam is extracted into bromochloromethane or iodochloromethane, and water is removed from the organic layer to enhance the formation of the chloromethyl ester of sulbactam. The tetraalkylammonium sulbactam is reacted with bromochloromethane or iodochloromethane in the organic layer to form the chloromethyl ester of sulbactam.
DETAILED DESCRIPTION OF THE INVENTION
Any metal (e.g. potassium, sodium, or calcium) salt of sulbactam may be utilized as a starting material for this process, however the sodium salt is preferred. In addition, the free acid may also be used.
A wide variety of tetraalkylammonium salts can be used. However, it is preferred to use a tetrabutylammonium salt (e.g. tetrabutylammonium hydrogen sulfate, tetrabutylammonium hydroxide) as the sulbactam tetrabutylammonium salt (II) is readily extracted with the halochloromethanes described below.
Bromochloromethane or iodochloromethane is used as both the tetraalkylammonium sulbactam salt extraction solvent and the alkylating reagent for the making of the chloromethyl ester of sulbactam. Generally an excess is used to reduce the formation of the unwanted bisesters (III). Due to cost, stability, and better recoverability, chlorobromomethane is preferred over chloroiodomethane. Optionally a reaction-inert, water-immiscible cosolvent such as methylene chloride or ethyl a
REFERENCES:
patent: 4244951 (1981-01-01), Bigham
patent: 4342772 (1982-08-01), Godtfredsen et al.
patent: 4381263 (1983-04-01), Jasys
patent: 4704456 (1987-11-01), Adams
patent: 4942229 (1990-07-01), Seeki et al.
Binderup, E., et al., Chlorosulfates as Reagents in the Synthesis of Carboxylic Acid Esters Under Phase-Transfer Conditions; Synthetic Communications, 14(9), 857-865 (1984).
Godek Dennis M.
Morris Thomas A.
Benson Gregg C.
Olson A. Dean
Pfizer Inc.
Richardson Peter C.
Rizzo Nicholas
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