FI64153C - MELLAN PRODUCTS FOR FRAMSTATING AV PHARMACEUTICAL ACTIVE 7-ACYL ACID 3-ACETOXIMETYL-CEFALOSPORINER - Google Patents

Description

This invention relates to an intermediate for the preparation of therapeutically active 7-acylated 3-acetoxymethyl-cephalosporins.

The intermediate according to the invention is characterized in that it is 1- (2-sulfaminoethyl) tetrazole-5-thiol of formula II

N N

HS - ^ j II

N —N

(CH2) 2-NHS03H

or a salt thereof.

The sulfaminoethyltetrazolithiol of formula II can be prepared by administering 1-aminoethyl-5- (2,4-dinitrophenylthio) tetrazole prepared from 2,4-dinitrofluorobenzene and 1-acetamidoethyltetrazole-5-thiol followed by acid hydrolysis of the acetamido moiety. react with the sulfur trioxide-trimethylamine complex followed by cleavage of the 2,4-dinitrophenyl protecting group. 1-Acetamidoethyltetrazole-5-thiol is prepared by reacting acetamidoethyl dithiocarbamate such as methyl 2-acetamidoethyl dithiocarbamate with an azide such as sodium azide. Acetamidoethyl dithiocarbamate is prepared by treating N- (2-aminoethyl) acetamide with carbon disulfide and an alkyl halide such as methyl iodides in the presence of a base such as triethylamine.

Therapeutically active 7-acylated cephalosporins have antibacterial activity when administered parenterally and have the formula Ί?

r1_n tyY

Y-V ^^ - Γιι

COOH N — N

(CH2) 2-NHS03H

wherein R 1 is one of the following acyl groups: - CH - C -, Y-CH 2 -C- and CF 3 -S-CH 2 -C-

OH

wherein Y is thienyl or tetrazolyl.

Compounds of formula I may be prepared as a compound of formula

H H

* u +0 · q / ch2occh3

COOH

wherein R 1 is as defined above, or a salt thereof is reacted with 1- (2-sulfaminoethyl) tetrazole-5-thiol

HsHf 1

N-N

(1H2) 2-NHS03H

after which the protecting group or groups are removed, if necessary, and the product obtained is acidified or otherwise converted into the free acid, if necessary, and optionally converted into a non-toxic pharmaceutically acceptable salt.

I! 64153 3

The following example illustrates the invention in more detail.

Example 1- (2-sulfaminoethyl) tetrazole-5-tolt

To a solution of 20.4 g (0.20 mol) of N- (2-aminoethyl) acetamide in 200 ml of 95% ethanol were added 27.9 ml (0.20 mol) of triethylamine and 12.0 ml of (0.20 moles) of carbon disulphide. Due to the exothermic reaction, the boiling mixture was refluxed, after which the mixture was cooled to ambient temperature over 1 1/2 hours. Methyl iodide (28.4 g, 0.20 mol) was added, again causing an exothermic reaction. After 1 3/4 hours, the reaction mixture was evaporated to dryness and the solid residue was dissolved in 200% water. The aqueous solution was extracted twice with 250 mL portions of ethyl acetate. The extracts were combined, shaken with sodium thiosulfate, dried (MgSO 4) and evaporated to dryness to give methyl 2-acetamidoethyldithiocarbamate.

To a solution of 38.4 g (0.198 mol) of methyl 2-acetamidoethyldithiocarbamate in 100 ml of 95% ethanol was added a solution of 13.5 g (0.208 mol) of sodium azide in 100 ml of water. The reaction mixture was heated at reflux for 24 hours, then cooled and evaporated under reduced pressure to about half volume. The solution was cooled to 15 ° C and 50 ml of 6 N sulfuric acid was added. The acidic solution was filtered and the filtrate was evaporated to a volume of about 100 ml and cooled to 5 ° C to crystallize 1- (2-acetamidoethyl) tetrazole-5-thiol, which product was collected by filtration, m.p. 139-139.5 ° C. Additional product was obtained by continuous extraction of the filtrate with ethyl acetate.

A solution of 9.3 g (0.050 moles) of 2,4-dinitrofluorobenzene in 50 ml of acetone was added to a solution of 64.343 g of 9.35 g (0.050 moles) of 1- (2-acetamidoethyl) tetrazole. thiol and 6.85 ral (0.050 mol) of triethylamine in 100 ml of acetone, and the reaction mixture was stirred for 1 hour. The solid was collected by filtration, and recrystallization from acetonitrile afforded 1- (2-acetamidoethyl) -5- (2,4-dinitrophenylthio) tetrazole, m.p. 197-198 ° C.

A mixture of 6.5 g (0.02 mol) of 1- (2-acetamidoethyl) -5- (2,4-dinitrophenylthio) tetrazole, 100 ml of 12N hydrochloric acid and 100 ml of 95% ethanol was heated at reflux for 4 1/2 hours. The mixture was evaporated to dryness to give a gummy residue which crystallized on addition of ethanol to give 1- (2-aminoethyl) -3- (2,4-dinitrophenylthio) tetrazole hydrochloride, m.p. 217-219 ° C (dec).

To a solution of 3.5 g (0.01 mol) of 1- (2-aminoethyl) -5- (2,4-dinitrophenylthio) tetrazole hydrochloride in 30 ml of dry dimethylformamide was added 1.4 g (0.01 mol) of sulfur trioxide trimethylamine complex and then 1.4 ml (0.01 mol) of triethylamine. The mixture was stirred for 1/2 hour, after which it was filtered. The filtrate was evaporated in vacuo, acetone was added to the residue, the precipitate was removed by filtration and the filtrate was evaporated to dryness. Methanol was added to the residue, and the solid formed on trituration was removed by filtration. The pH of the methanol filtrate was adjusted to 11.3 by the addition of 5% methanolic sodium methoxide solution, the mixture was stirred for 1 1/4 hours, after which it was filtered and diluted with 300 ml of ether. The solid formed was removed by filtration, the filtrate was evaporated to dryness and the resulting residue was triturated with 95% ethanol to crystallize. The solid product was collected by filtration and dissolved in methanol. The methanol solution was evaporated to a volume of 10 ml, diluted

II

641 53 5 75 ml of 95% ethanol and again evaporated to a volume of 5 ml of the product as 1- (2-sulfaminoethyl) tetrazole-5-thiol disodium salt, m.p. 122-127 ° C.

2 Na · 1.5 11.0 3 5 5 j 2 *

Calculated: 12.16% C, 2.72% H, 23.64% N

Found: 12.25% C, 2.98% H, 23.77% N

An aqueous solution of the 1- (2-sulfaminoethyl) tetrazole-5-thiol disodium salt is passed through an "Amberlite IR-120H" ion exchange resin column to give, after lyophilization, 1- (2-sulfaminoethyl) tetrazole-5-thiol.