Process for preparation of cefdinir

Details Process for preparation of cefdinir Process for preparation of cefdinir

1998-05-18

2000-07-25

Berch, Mark L.

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C07D50104, C07D50122

Patent

active

060938145

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to a process for preparing cefdinir represented by the following formula (I) as a cephalosporin antibiotics: ##STR2##


BACKGROUND ART

Cefdinir of formula (I) above has a chemical name of 7.beta.-[2-(2-aminothiazol-4-yl)-2-(Z)-(hydroxyimino)acetamido]-3-vinyl-3- cep-hem-4-carboxylic acid. It is the third generation of cephalosporin antibiotics for oral administration and has a broader antibacterial spectrum over the general gram positive and gram negative bacteria than other antibiotics for oral administration. Particularly, it has been reported that cefdinir has an excellent antibacterial activity against Staphylococci and Streptococci.
In U.S. Pat. No. 4,559,334 is disclosed a process for preparing cefdinir as represented in the following reaction scheme 1. ##STR3##
In the above reaction, 7-amino-3-vinyl-3-cephem-4-carboxylic acid ester(A) is reacted with a reactive carboxylic acid derivative to obtain an 7-amido compound(B), and this compound is treated with a nitrosating agent to prepare an N-oxime compound(C). Continually, the compound(C) is cyclized with thiourea to prepare an aminothiazol compound(D), and then finally cefdinir of formula (I) is prepared by removing the carboxy protecting group.
In case cefdinir is prepared according to the reaction scheme 1, however, there can occur many problems such that the process for preparing the 7-amido compound(B) should be carried out at a temperature below -20.degree. C. under an anhydrous condition and that the isolation of the N-oxime compound(C) may cause a lot of troubles in the procedure of industrialization since the compound(C) is obtained as a solid having a syrup or a foam phase after the solvent is distilled off under reduced pressure. In addition, the aminothiazole compound(D) is obtained in a poor yield and purity and with a brownish poor color, which finally exerts a harmful influence upon the purity and color of the desired cefdinir. Further, in the reaction scheme 1, since cefdinir is synthesized through a complicated reaction consisting of 4 steps from the expensive 7-amino-3-vinyl-3-cephem-4-carboxylic acid derivative, the cost for production of cefdinir increases according as the whole reaction yield decreases.


DISCLOSURE OF INVENTION

Thus, the present inventors have extensively studied to develop a novel process by which cefdinir can conveniently be prepared in a good yield and a high purity. As a result, we have identified that such a purpose can be achieved by using a novel cefdinir intermediate represented by the following formula (II) as a starting substance and then completed the present invention. ##STR4## in which Ph represents phenyl,
Thus, it is an object of the present invention to provide a novel process for preparing cefdinir using the intermediate of formula (II) as a starting substance.
It is another object of the present invention to provide a novel intermediate of formula (II), as defined above, and process for preparation thereof.


BEST MODE FOR CARRYING OUT THE INVENTION

In one aspect, the present invention pertains to a process for preparing cefdinir of formula (I) characterized in that a trityl protecting group in the cefdinir intermediate of formula (II) is removed in the presence of an acid. The process is depicted in the following reaction scheme 2. ##STR5##
The most important feature in the process for preparing cefdinir according to the present invention is that the novel cefdinir intermediate of formula (II) which is very excellent in yield and purity is used as a starting material.
As the acid which can be used in the process for preparing cefdinir according to the present invention, an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, Lewis acid, etc.; an organic acid such as acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.; or an acidic hydrogen ion exchange resin can be mentioned, wherein Lewis acid includes boron trifluoride, boron trifluoride

REFERENCES:
Tsuji, Tet. Letters, pp. 2793-2796, 1979.
Chemical Abstracts, vol. 114, No. 7, Feb. 18, 1991 (Columbus, Ohio, USA), p. 656 Col. 1, abstract No. 61761t, Sakane K. et al.: "Studies on FK482 (Cefdinir). III. Synthesis and structure-activity relationships of 7B-[(Z)-2-aryl-2-hydroxyimio=acetamido]-3-vinyl-3-vinyl-3-cephem-4-carboxy lic acid derivatives", & Yakagaku Zasshi 1990, 110(9), 658-64 (Japan).
Chemical Abstracts, vol. 114, No. 15, Apr. 15, 1991 (columbus, Ohio, USA), p. 734, col. 1, abstract No. 142931a, Inamoto Y. et al.: "Studies on FK482 (Cefdinir). IV. Synthesis and structure-activity relationships of 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-=hydroxyiminacetamido]-3-substitute cephalosporin derivatives", and Yakagaku Zasshi 1990, 110(12), 908-15 (Japan).

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