Method for preparing crystalline cephalosporin derivative

The invention provides crystalline (6R, 7R)-7-[[2-(2-Amino-4-thiazolyl)-(Z)-2-(1-diphenylmethoxycarbonyl-1-methyle thoxy)imino ]acetamido]-3-(1-pyridiniummethyl)-3-cephem-4-carboxylate and a process for its production.

The present invention provides a new crystalline, highly pure and stable 
form of the syn-isomer of the cephalosporin derivative of formula 
##STR1## 
as well as a process for its production. 
The cephalosporin derivative of formula I is useful as an intermediate for 
the production of highly active cephalosporin antibiotics which can be 
administered parenterally and show a very broad spectrum of activity 
against pathogenic microorganisms, particularly in the gram negative area. 
The syn-isomer compound of formula I has usually been isolated in the form 
of a salt, such as the dihydrochloride or chloride hydrochloride. 
Hitherto, the free betaine form has only been isolated from complex 
solvent mistures which has resulted in a product, in particular a solvate, 
with less than optimal purity and stability. It has now surprisingly been 
found that the syn-isomer of the compound of formula I can be isolated in 
free betaine form, and free of acid or solvent adducts, in excellent yield 
and purity (.gtoreq.97%) as a stable highly crystalline product, direct 
from the reaction mixture used to produce it. The product has the physical 
characteristics set out in the Example hereinafter. 
The present invention provides more particularly a process for the 
production of the syn-isomer of compound of formula I in crystalline form, 
comprising reacting the syn-isomer of a compound of formula II and/or IIa 
##STR2## 
in which 
##STR3## 
signify a 5- or 6-membered heterocyclic ring which may contain in addition 
to the nitrogen atom one or two further hetero atoms for example oxygen, 
nitrogen or sulphor, and which may be substituted, and which may be fused 
to a benzene ring which may itself be substituted, with a compound of 
formula III, 
##STR4## 
in which R is hydrogen or an amino protecting group, or a salt thereof, 
e.g. the hydrochloride, mixing the resulting reaction mixture with a 
mixture of an acetic acid ester and a lower alkanol at a temperature of 
from 0.degree. to 40.degree. C., preferably 15.degree. to 25.degree., and 
recovering the precipitated product. In this manner, the product 
crystallises out in a matter of a few minutes to a few hours in 
practically quantitative yield and high purity (.gtoreq.97% yield and 
purity). Preferred acetic acid esters include C.sub.1-6 alkyl acetates, 
preferably ethyl, propyl and butyl acetate. Preferred lower alkanols 
include ethanol and particularly, methanol. The ratio of acetate to lower 
alkanol to reaction mixture depends on the chosen acetate and alkanol but 
is usually about 2-3:1:1 by volume, particularly in the case of ethyl or 
butylacetate and methanol. 
The nature of the "Het" ring in the compounds II and IIa is not critical, 
the preferred compounds being determined by such factors as availability 
of starting materials and ease of production. The preferred rings are 
2-pyridyl and, in particular 2-benzylthiazolyl or less preferably 
pyrimidinyl, triazolyl or thiazolyl, and the corresponding thiones as in 
compounds IIa. 
The compounds of formula II, IIa and III are known and may be produced in 
conventional manner.

In the following Example, which illustrates the invention of all 
temperatures are in .degree.C. 
Example: (6R, 
7R)-7-[[2-(2-Amino-4-thiazolyl)-(Z)-2-(1-diphenylmethoxycarbonyl-1-methyle 
thoxy)imino]acetamido]-3-(1pyridiniummethyl)-3-cephem-4-carboxylate 
212 g of 
2-(2-Amino-4-thiazolyl)-(Z)-2-(1-diphenylmethoxycarbonyl-1-methylethoxy)im 
inoacetic acid are suspended together with 138 g of triphenylphosphine in 
800 ml of methylene dichloride, the mixture is cooled to 0.degree. and 175 
g of mercaptobenzthiazole disulphide are added. After 2 hours stirring at 
0.degree., the formation of the thioester II or the corresponding compound 
IIa is complete (as determined by DC) and 260 g of 
7-amino-3-pyridiniummethylcephalosporanic acid hydrochloride and 61 g of 
triethylamine are added at 0.degree.. The mixture is stirred for 15 hours 
at 0.degree. until the reaction is complete (as determined by HPLC) and 
the reaction mixture (yellow-brown) (ca. 1400 ml) is introduced into a 
mixture of 1400 ml of methanol and 3.5 liters of butylacetate at about 
20.degree.. The resulting clear solution is stirred at room temperature 
for 2 hours and then at 0.degree. for a further 2 hours. The resulting 
highly crystalline precipitate is filtered off, washed with cold methanol 
and dried in vacuo. The highly pure (.gtoreq.97%) by weight, free-flowing 
heading compound results.