CS236800B2 - Processing of halogenmethyl-1,1-dioxypenicillinyloxymethyl-carbonyl - Google Patents

Abstract

The invention discloses a method for producing new ones halomethyl-1,1-dioxopsnicilanoyloxymethyl carbonates, which are useful as defaults substances for preparation antibacterial of the active 6- (2-amino-2-phenylacetamidopenicilanoyloxymethyl-1,1-dioxopenicilanoyloxymethyl-carbonates).

Description

The present invention provides a process for the preparation of novel halomethyl-1,1-dioxopsnicilanoyloxymethyl carbonates which are useful as starting materials for the preparation of antibacterially active 6- (2-amino-2-phenylacetamidopenicilanoyloxymethyl-1,1-dioxopenicilanoyloxymethyl carbonates). Related Czechoslovak Patent Publication No. 236,779.

Accordingly, the present invention provides a process for the preparation of compounds of the general formula ΙΙΓ

^CH ' ^CH 3' COOGH, OCOCKX ¢ - and ίΟ tm ') in which

X is chlorine, bromine or iodine, characterized in that the compound of formula III '

in which

M is a salt-forming cation on the carboxyl group, reacted with a compound of formula

XCH2OCOOCH2X in which

X is as defined above.

The process for the preparation of the compounds of formula III according to the invention can be described by the following reaction scheme c = ^oCHCH

in which

M and X are as defined above.

The reaction is carried out by reacting the penicillinic acid 1,1-dioxide starting salt of formula III 'with at least an equimolar amount, but preferably with an excess of up to 10-fold molar excess, the bis-halomethyl carbonate in the presence of an inert organic solvent at a temperature about -20 to 60 ° C, preferably at a temperature of 0 to 30 ° C. Solvents which can be used successfully in this reaction include relatively polar organic solvents, the use of which reduces the required reaction time to a minimum. Typical usable solvents include N, N-dimethylformamide, Ν, Ν-dimethylacetamide, N-methylpyrrolldone, dimethylsulfoxide, ethyl acetate, dichloromethane, chloroform, acetone, and hexamethylphosphoric triamide. the nature of the reactants, the reaction temperature and the solvent.

The carboxylic acid salts of formula (III) are prepared from the corresponding carboxylic acid. In a preferred process for preparing those salts in which M is an alkali metal, such as sodium or potassium, the corresponding 2-ethylhexanoic acid salt is used as the base. Typically, the carboxylic acid corresponding to formula III ', in which M is hydrogen, is dissolved in ethyl acetate, an equimolar amount of sodium or potassium 2-ethylhexanoate is added with stirring, and the precipitated salt of formula III' is isolated by filtration.

Appropriate salts corresponding to formula III 'in which M is tetrabutylammonium ion can be obtained from the corresponding acid, for example, by neutralization with an aqueous solution of tetrabutylammonium hydroxide in the presence of a water-immiscible organic solvent, preferably in the presence of chloroform. The solvent layer was separated and the product was isolated by evaporation of the solvent. Alternatively, the sodium or potassium salt corresponding to formula III 'is reacted with an equimolar amount of an aqueous solution of tetrabutylammonium hydrogen sulfate in the presence of a water-immiscible solvent, the precipitated alkali metal hydrogen sulfate is filtered off and the product isolated by evaporation of the solvent.

Bis-chloromethyl carbonate is prepared by photochemical chlorination of dimethyl carbonate according to the method of Kling et al., Compt. rend. 170, 111, 234 (1920); Chem. Abstr. 14, 1304 (1920). Bis-bromomethyl carbonate and bis-iodomethyl carbonate are obtained from the bis-chloromethyl derivative by reaction with, for example, sodium bromide or potassium iodide using methods known in the art.

The invention relates to a process for the preparation of penicillanic acid derivatives corresponding to a structural formula

In penicillanic acid derivatives, the intermittent bond (......) of the substituent to the bicyclic nucleus indicates that the substituent is above the plane of the nucleus. Such a substituent is referred to as a substituent having a N-configuration. In contrast, enhanced bonding of the substituent to the bicyclic nucleus means that the substituent is located above the plane of the nucleus and is referred to as the β-configuration. Binding of a substituent to the bicyclic nucleus, performed by the normal solid line (-), means that the substituent may be in both the α-configuration and the β-configuration.

The compounds of the formula (ΙΙΓ) produced by the process of the invention are named as carbonic acid diesters. For example, compounds of formula obecného in which X is iodine are referred to as iodomethyl-1,1-dioxopenicilanoyloxymethyl carbonate.

The invention is illustrated by the following non-limiting examples. NMR spectra were measured in solutions in deuterochloroform or perdeuterodimethylsulfoxide, and signal positions are expressed in ppm values over tetramethylsilane. Signal shapes are indicated by the following abbreviations:

šs - wide singlet s = - singlet d - doublet t = triplet q = quartet m - multiplet

Preparation

Bis-chloromethyl carbonate

The method used essentially corresponds to that described by Kling et al. in Compt. rend. 170, 111-113, 234-236 (1920); Chem. Abstr. 14, 1304 (1920).

A solution of 59 ml of dimethyl carbonate in 120 ml of carbon tetrachloride was cooled in ice and chlorine gas was bubbled into it under irradiation with a daylight bulb until most of the starting material had reacted. Excess chlorine was removed by a stream of nitrogen, the solvent was evaporated, and the residue was distilled at 50 psi using a short distillation head. The desired product boils at 95 to 100 ^C C / 6.7 kPa. Yield 68 g.

Example 1

Bis-iodomethyl carbonate

To a solution of 10.7 ml (15.9 g, 0.1 mol) bis-chloromethyl) carbonate in 400 ml acetone was added 75 g (0.5 mol) sodium iodide, the mixture was heated under reflux for 2 hours under nitrogen. The reaction mixture was then allowed to stand overnight at room temperature and filtered. The filtrate is concentrated in vacuo, 500 ml of methylene chloride are added to the residue, and the mixture is filtered. The filtrate is concentrated to a volume of about 200 ml, 200 ml of water are added to the concentrate and the aqueous phase is adjusted to pH 7.5. Aqueous sodium thiosulfate solution was added to remove iodine, the organic phase was separated and dried over sodium sulfate. The dried methylene chloride solution is concentrated in vacuo to an oily residue which darkens on standing. The oily product is stirred with a mixture of 35 ml of hexane and 6 ml of diethyl ether at 0 ° C, the precipitated crystals are filtered off and washed with hexane and dried. There were obtained 10.0 g (29%) of a yellowish crystalline product, m.p. 49-51 ° C.

¹ H-NMR (CDCl 3, δ ppmj values):

5.94 (sj.

IC (nujol): 1756, 1775 cm @ -1

Example 2

Chloromethyl-1,1-dioxopenicilanoyloxymethyl carbonate

To a mixture of penicillanic acid 1,1-dioxide (1.17 g, 5 mmol), chloroform (50 ml) and water (10 ml) was added a 40% aqueous tetrabutylammonium hydroxide solution with vigorous stirring to pH 8.5. The chloroform layer was separated and the aqueous phase was extracted with fresh chloroform. The combined organic phases are dried and concentrated to a volume of about 20 ml.

A solution of tetrabutylammonium-1,1-dioxopenicillanate prepared above was added dropwise at 0 ° C to a solution of 1.5 g (10 mmol) of bis-chloromethyl carbonate in 15 ml of chloroform. After the addition was complete, the mixture was allowed to warm to room temperature and stirred overnight. The chloroform was then evaporated in vacuo and the crude product was purified by silica gel chromatography.

Example 3

Iodomethyl-1,1-dioxopenicilanoyloxymethyl carbonate

To a solution of 3.37 g (10 mmol) of chloromethyl 1,1-dioxopenicilanoyloxymethyl carbonate in 50 mL of acetone was added 7.5 g (50 mmol) of sodium iodide and the mixture was stirred at room temperature overnight. The acetone was evaporated in vacuo and the residue was partitioned between water and ethyl acetate. The aqueous phase is separated, the organic phase is washed with water and brine, dried over sodium sulphate and concentrated in vacuo. The desired iodomethyl derivative is obtained, which is optionally purified by silica gel chromatography.

If the above procedure was repeated using dimethylformamide instead of acetone and sodium bromide instead of sodium iodide as the reagent, bromomethyl-1,1-dioxopenicilanoyloxymethyl carbonate was obtained.

A process for the preparation of halomethyl 1,1-dioxopenicilanoyloxymethyl carbonates of the general formula ΙΙΓ

Claims (2)

SUBJECT I INVENT in which M is a salt-forming cation on the carboxyl group, reacted with a compound of formula XCH2OCOOCH2X (COOCH, OCOCH, X ') in which X is chlorine, bromine or iodine, characterized in that the compound of formula (III ⁾ in which: X is as defined above, in an inert organic solvent at a temperature of from -20 to 60 ° C. 2. The process of claim 1, wherein M is sodium, potassium or tetrabutylammonium.