DE1795590A1 - New 7-amino-cephalosporanic acid esters - Google Patents

Description

CIBA-GEIGYAG, BASEL (SWITZERLAND). 1795590

Case 5.259 / 1-Vb '

Germany

New 7-amino-cephalosporanic acid esters.

The production of 7-amino-cephalosporanic acid esters g with a free amino group from cephalosporin C has presented considerable difficulties so far because the amide group of the ß-lactam ring is much more sensitive to hydrolyzing agents than the amide group in the 7-position, in the German application P 14 45 619.O-44 (5259 / 1-4) describes a new process for the preparation of 7-amino-cephalosporanic acid esters.

The present divisional application relates to new 7-amino-cephalosporanic acid esters, namely esters whose alcohol

OFTIGiNAL

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component is benzhydrol or ρ, ρ-dimethoxybenzhydrol. These Esters can be prepared by the process described in the application mentioned.

The esters can be converted into the free 7-aminocephalosporanic acid by hydrolysis be converted, preferably by means of trifluoroacetic acid 'and anisole.

The invention is described in the following example. The temperatures are given in degrees Celsius.

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Example :

12.6 g of Cephalosporin C-di-benzhydryl ester are -in 2 liters of abs. Dissolved methylene chloride, with 2 ml of 2-n. aqueous' acetic acid and left to stand for 8 days at 22 in the dark. It is evaporated in a vacuum and takes the.-. Residue in a mixture of 5 parts of toluene, 2 parts of '' ethyl acetate, 3 parts of alcohol and 3 parts of 2-n. ' aqueous hydrochloric acid. After complete dissolution, with vigorous shaking, the phases are separated and the Ünterphase with two other top phase _(r 5 parts toluene and 2 parts Essigester) extracted. The 3 upper phases are again ^ times with 'alcohol-2-n. Hydrochloric acid (l: l) extracted. The product-containing sub-phases are combined with 50 percent.

aqueous tripotassium phosphate solution adjusted to pH 6 and freed from alcohol in vacuo. Then one introduces the (j Trikaliumphosphatlosung to pH 8.0 and extracted with ~ $ max Essigester The dried over sodium sulfate, the extract is by evaporation of the Y-amino-cephalosporanic acid benzhydryl ester, which combined from ether to drusen in 'needles crystallized. P 122-124 °; in the thin-layer chromatogram on silica gel in the system, n-butanol _r glacial acetic acid (10: 1) saturated with water / water an Rf value of 0.64 (dirty yellow spot with ninhydrin-collidine) Λ

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■ ·. The ester can be converted into the free 7-aminoeephalo-sporic acid as follows: 6.8 g = 1 part of ester is dissolved. in 1 part of anisole and mixed with 5 parts of trifluoroacetic acid. You then immediately vaporize at 0.2 mm of mercury.

'within, 20 minutes' one, takes up ml of ethyl acetate in JO and pours the solution at the same time with approx. 13 ml of 50 percent. aqueous tripotassium phosphate solution with stirring to 20 ml-3 percent. aqueous dipotassium hydrogen phosphate solution. The two inflows are to be measured in such a way that the pH fluctuates between 6-8 and at the end of the day stays at 7. The separated aqueous phase is mixed twice with 10 ml / 'ethyl acetate each time. ■ "* 'and the 3 Essigesterphasen are washed 2 times with 5 ml j5-proz." Aqueous dipotassium hydrogen phosphate solution. It discards the organic phases are pooled, the aqueous and provides approximately k ml of conc. Hydrochloric acid to pH 3.5 .. The The product deposited after 15 hours of standing at 0 is filtered off, washed with a little ice water and dried, giving 3.90 g (= 92% of theory) of pure 7-amino-cephalosporanic acid.

209812 / mO 'BADOWaiH «.

The cephalosporin C-di-benzhydryl ester used as starting material can be prepared as follows:

A suspension of 4.82 g of 85% cephalosporin C sodium salt (♦ 2 HpO; 8.7 mmol) in 80 ml of methanol is mixed with ΐβ, 7 ml of 1.5 N-methanolic hydrochloric acid and the clear solution at 0. 1 mm Hg evaporated. The residue contains crude cephalosporin G hydrochloride that is then dissolved in 100 ml of dimethylformamide and esterified with 10 g of diphenyldiazome.thane for 20 minutes at 20 °. Evaporation, digestion with petroleum ether, absorption in ethyl acetate, washing with 10 dipotassium phosphate solution, drying over sodium sulfate and. Evaporation in vacuo gives 7.26 g (approx. 70%) of cephalosporin C-dibenzhydryl ester as a colorless foam. In the thin-layer chromatogram on silica gel G, the compound shows the following Rf values: 0.65 in the n-butanol-glacial acetic acid system (10: 1) saturated with water; 0.78 in the n-butanol-pyridine-glacial acetic acid-water system (38: 24: 8: 30); 0.12 in the toluene-acetone system (7: 3); typical red-violet spot with ninhydrin collidine. pK ^ = 6.35. * MCS

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Claims (2)

Patent claims: 1. 7-Aminocephalosporanic acid benzhydryl ester. 2. 7-Aminocephalosporanic acid benzhydryl ester (pjp-di methoxy) benzhydryl ester ^ 209812/1740 - _{offle (NAL}