Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-05-27
2001-04-10
Gerstl, Robert (Department: 1609)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06214997
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the preparation of crystalline (Z)-2-(2-tert.-butoxycarbonyl prop-2-oxyimino)-2-(2-triphenylmethylaminothiazol-4-yl) acetic acid of the following formula:
which is useful in the synthesis of &bgr;-lactam antibiotics such as ceftazidime.
BACKGROUND OF THE INVENTION
One general method of preparing ceftazidime which is disclosed in U.S. Pat. No. 4,258,041 involves a series of reactions to form the side-chain acid of ceftazidime or a reactive derivative thereof followed by coupling with the 7-&bgr;-amino cephalosporin nucleus. Two of the intermediates described in such a series of reactions for the preparation of a protected form of the 7-side chain are (Z)-2-(2-tert.-butoxycarbonylprop-2-oxyimino)-2-(2-triphenylmethylaminothiazol-4-yl) acetic acid and its ethyl ester. However, these intermediates suffer from a number of disadvantages on a manufacturing scale. This material has a variable form which changes on mechanical handling, thus making it difficult to filter satisfactorily.
To overcome the problems faced at a manufacturing scale, an improved form of the intermediate was prepared, such as crystalline (Z)-2-(2-tert.-butoxycarbonylprop-2-oxyimino)-2-(2-triphenylmethylaminothiazol-4-yl)acetic acid associated with 0.1 to 0.6 moles of dioxan per mole of acid. This process is disclosed in U.S. Pat. No. 4,493,933. In U.S. Pat. No. 4,665,167, a crystalline (Z)-2-(2-tert.-butoxycarbonylprop-2-oxyimino)-2-(2-triphenylmethylarinothiazol-4-yl)acetic acid is claimed which contains from 0.8 to 1.8 moles of methanol per mole of acid. The dioxan and methanol-associated acid also suffers from certain disadvantages on a commercial scale. Dioxan and methanol are highly flammable solvents and difficult to handle on a manufacturing scale.
The known methods in the literature for the preparation of (Z)-2-(2-tert.- butoxycarbonylprop-2-oxyimino)-2-(2-triphenylmethylaminothiazol-4-yl)acetic acid (IV) involves the selective hydrolysis of Ethyl (Z)-2-(2-tert.-butoxycarbonylprop-2-oxyimino)-2-(2-triphenylmethylaminothiazol-4-yl)acetate of Formula (VI) (Scheme II).
These methods give (Z)-2-(2-carboxylprop-2-oxyimino)-2-(2-triphenylmethylaminothiazol-4-yl) acetic acid as a side product, which is difficult to remove. Removal of this impurity is possible only by repeated crystallizations at the cost of the yield.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a method for the preparation of the compound of Formula (IV) which eliminates the use of hazardous solvents and is convenient to operate on a manufacturing scale.
It is a further object of the present invention to provide a process which is efficient, cost effective and yields the product in high purity. We have found that new N,N-dimethylformamide-associated acid of Formula (IV) provides a number of advantages on a manufacturing scale. N,N-dimethylformamide is a commercially available solvent and convenient to handle. We have also found that if the process for the preparation of N,N-dimethylformamide-associated acid of Formula (IV) is carried out according to the reaction sequence as shown in Scheme I, side products are formed in minor amounts and the product obtained is very pure.
Accordingly the present invention provides a process for the preparation of crystalline (Z)-2-(2-tert.-butoxycarbonylprop-2-oxyimino)-2-(2-triphenylmethylaminothiazol-4-yl) acetic acid of Formula (IV) in association with 0.3 to 0.6 moles of N, N-dimethylformamide per mole of acid which comprises treatment of ethyl (Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate of Formula (I) with tert.-butyl-2-bromoisobutyrate to give ethyl (Z)-2-(2-aminothiazole-4-yl)-2-(2-tert.-butoxycarbonylprop-2-oxyimino) acetate of Formula (II), which is converted into acid of Formula (III) followed by tritylation to give a solution of (Z)-2-(2-tert.-butoxycarbonylprop-2-oxyimino)-2-(2-triphenylmethylaminothiazol-4-yl) acetic acid and N, N-dimethylformamide from which the desired compound of Formula (IV) associated with N, N-dimethylformamide is precipitated. Preferably, the precipitation of the compound of Formula (IV) is assisted by addition of water. The compound of Formula (IV) in association with N, N-dimethylformamide prepared in the present invention is in the form of free-flowing material.
The N,N-dimethylformamide-associated acid of Formula (IV) prepared according to the process of the present invention may be coupled with 7&bgr;-amino cephalosporin nucleus by methods known in the art to form the desired antibiotic.
Major advantages of the present invention compared to the prior art processes are: (1) the process is safe and convenient to handle at a commercial scale; (2) the process is cost effective; (3) the product obtained has a high degree of purity (>98% HPLC purity); (4) no further purification is required; and (5) yield is high.
The following specific examples illustrate the process of this invention, but they should not be construed as limiting the scope of this invention in any way.
REFERENCES:
patent: 4258041 (1981-03-01), O'Callaghan et al.
patent: 4493933 (1985-01-01), Brodie
patent: 4497956 (1985-02-01), Looker
patent: 4665167 (1987-05-01), Looker
Gupta Surinder Mohan
Handa Vijay Kumar
Maheshwari Nittin
Rohatgi Amit
Deshmukh Jayadeep R.
Gerstl Robert
Ranbaxy Laboratories Limited
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