4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, 3,3-dimethyl-7-oxo-6-[(phenylacetyl)amino]- [2S-(2alpha,5alpha,6beta)]-, compd. with [1R-[1alpha(1R*,4aS*,10aR*),4abeta,10aalpha]]-N,N'-bis[[1,2,3,4,4a,9,10,10a-octahydro-1,4a-dimethyl-7-

Originator

Compocillin,Abbott,US ,1954

Manufacturing Process

A mixture of 142.5 g of "Rosin Amine D" containing about 70% dehydroabietylamine and 30% dihydro and tetrahydroabietylamine, 47.0 g of ethylene dibromide, and 60.6 g of triethylamine is dissolved in 350 cc of anhydrous xylene and refluxed for about 16 hours. Thereafter the triethylamine dibromide salt formed is separated from the solution by filtering the cool reaction mixture and washing with ether. The solution is then concentrated under reduced pressure to dryness to remove the ether, xylene and excess triethylamines present. The viscous oil resin is slurried twice with 250 cc portions of methanol to remove any unreacted primary amines. The oil residue after being washed with methanol is dissolved in ethyl alcohol and 75 cc of concentrated hydrochloric acid is added dropwise to the warm alcohol solution of the base. The dihydrochloride salts of the several hydroabietyl ethylenediamines precipitates immediately from solution. The salt is then separated by filtering and is washed twice with 100 cc portions of cooled ethyl alcohol. The dihydrochloride salts of the dehydroabietyl, dihydroabietyl and tetrahydroabietyl ethylenediamine mixture have a melting point of about 292°C to 295°C. On subjecting the mixture to solubility analyses it is found that the dehydroabietyl ethylenediamine is present in substantially the same proportion as is the dehydroabietylamine in the original "Rosin Amine D."
An amyl acetate-penicillin acid solution (10 liters) having a potency of 100,000 U/ml which is sufficient to supply 565 g (2 mols) of penicillin acid is added with constant agitation to 505 g of crude N,N'-bis-(dehydroabietyl)ethylenediamine dissolved in 500 ml of amyl acetate. A slight excess of the ethylenediamine bases is added to the mixture until precipitation is completed. The reaction is preferably carried out in a cold room having a temperature of about 5°C. The precipitation salts comprise about 70% N,N'bis-(dehydroabietyl)-ethylenediamine-dipenicillin salt and approximately 2530% of the N,N'-bis-(dihydroabietyl)-ethylenediamine-and N,N'-bis(tetrahydroabietyl)-ethylenediamine-dipenicillin salts are recovered by filtration and are washed with about 1/10 solution volume of amyl acetate. The crude preparation is further washed with 1/10 solution volume of diethyl ether and dried. The melting point of the product is about 153°C when taken on a microblock.
The total yield of the crude precipitation obtained in the above manner comprising about 1 kg is then dissolved in chloroform so as to form a 15% solution of a crude penicillin salt. To the filtered chloroform solution is added ethyl acetate slowly and with agitation until the solution becomes turbid as crystallization begins. Thereafter crystallization is allowed to proceed undisturbed for about 30-60 minutes in a cold room having a temperature of about 5°C. Sufficient ethyl acetate is slowly added to provide a final concentration of about 50% ethyl acetate and the mixture is allowed to stand in the cold room for one hour to complete crystallization. The precipitate is filtered and washed with about 750 ml of ethyl acetate and thereafter washed with the same volume of ether. The crystals are dried in vacuo and a yield of about 900 g of N,N'-bis-(dehydroabietyl)-ethylenediamine-dipenicillin G is obtained. The penicillin product melts with decomposition at a temperature of 170°C to 172°C on a Kofler hot stage. Solubility analysis of the product shows the product to be 95.3% pure.

Therapeutic Function

Antibacterial

Raw materials

Preparation Products