CS218027B1 - Method of making the ureidopenicilline - Google Patents

Description

The invention relates to a process for the production of ureidopenicillins of the formula I c CH. ( ^S ) / ³ S-CHCONH-CH-CHC-CH 2 _H ^{III 3}

CO-N — CHCOOH

NH O

IX as <n ^{r 1 L} (/) in which R is hydrogen or methanesulfonyl.

Ureidoipenicillins, such as the clinically used formulations of azlocilin and meslocilin, represent a class of semi-synthetic thiotic antibiotics derived from aminopenicillins, particularly ampicillin. They have an extended antimicrobial spectrum, supplemented especially with azocillin by antipseudomonadic activity.

A known method for preparing these antibiotics usually consists in acylating ampicillin with 2-imidazolidinone N-carbonyl chloride. This substance, which is the product of the phosgenation of ethylene-urea, ie 2-imidazolidinone, is known to react with many organic solvents, further containing impurities in the form of by-products, for example the product resulting from the reaction of ethylene urea enolform with phosgene . In addition, this substance has an irritating effect, decomposes over time with air humidity and releases hydrogen chloride gas, so that it is very unpleasant, harmful to health and requires extraordinary safety precautions.

These drawbacks are overcome by the process for the preparation of the ureidopenicillins of the general formula (I) according to the invention, without the use of the aggressive agent. The process according to the invention is characterized in that ampicillin in the form of a salt with an organic tertiary base, preferably triethylamine, is acylated with an ester of N-carbonyl-2-imidazolidinone of the formula II

XX tf-N ^ NCOO-VT-X i Vf ^XX (II) a

in which X is a chlorine or fluorine atom and R is the same as in formula I in an inert inert solvent of the halogenated C1-C2-alkane type, preferably methylene chloride.

The esters of formula (II) are well identifiable and characterizable chemical individuals, readily accessible by reaction of N-carbonyl chloride-2-imidazoline with penitachloro- or pentafluorophenol. Smooth reaction to give ampicillin and mezlocillin ureidopeniciliny azocilin ¹ in good yield and high purity, without previous unpleasant complications.

The details of the method according to the invention are illustrated by the following examples, which are illustrative but not limiting.

Example 1

1.0 g of the desired product, which is identical to azlocillin, m.p. 168-170 ° C.

Example 2

D-α- (1-Imldazolidin-2-Gn-1-ylcarbonylamino) -benzylpenicillin (azlocillin)

To a solution of ampicillin triethylammonium salt obtained from 1.7 g ampicillin trihydrate and 1.0 g triethylamine in 20 ml anhydrous methylene chloride was added 2.06 g 1-carbonylpentachlorophenoxy-2-imidazolidinone and the resulting suspension was stirred at room temperature for 48 hours. hours. The reaction mixture is then shaken with 20 ml of water, clarified with charcoal, filtered and the filtrate acidified. It is obtained

D-a - [, (3-methanesulfonylimidazolidin-2-one-1-yl) -carbonylamino] benzylpenicillin

(a) To a solution of the triethylammonium salt of ampicillin prepared from 1,2 g of ampicillin trihydrate and 0,6 g of triethylamine in 20 ml of methylene chloride, 1,1 g of 1-carbonylpentafluorpheinoxy-β-methanesulfonyl-2-imidazolidinone is added immediately giving a clear solution . After standing for 2 h, the solution is extracted 3 times with 10 ml of water each time, the aqueous extracts are combined, filtered and freed of methylene chloride residues. Value ¹ The pH of this aqueous solution is adjusted by adding dilute hydrochloric acid to 2.5, the crystalline product is sucked off, washed with water and dried. 1.1 g of meslocillin identical to the authentic sample are obtained.

b) To a solution of triethylammonium ampicillin table, prepared from 1.74 g of anhydrous ampicillin and 1.01 g of triethylamine in 20 ml of methylene chloride, was added a solution of 2.5 g of 1-carbomylpentachlorophenoxy-3-methanesulfionyl-2-imidazolidinone in a small amount of methylene chloride. The reaction mixture was stirred at room temperature for 6 h and treated as in paragraph a. 1.4 g of meslocillin at a decomposition temperature of 155-165 ° C were obtained.

Claims (1)

Process for preparing ureldopenicillins of the general formula I S CH » Z \ / ^J CHCONH-CH-CH C ^ _{Cu Cu} | III _nh . _o co-n-chcooh ¹ X (I) wherein R is a hydrogen atom or a methanesulfonyl group, characterized in that ampielline in the form of a salt with an organic tertiary base, preferably triethylamine, is acylated with an N-carbonyl-2- ester imidazolidinone of formula (II) wherein X is chlorine or mustard and R is the same as in formula (I) in an inert organic solvent of a halogenated alkane of 1 to 2 carbon atoms, preferably methylene chloride.