CS210739B1 - Process for preparing anhydrous crystalline benzylpenicillin sulfoxide - Google Patents

Abstract

The invention relates to a method for producing anhydrous crystalline benzylpenicillin sulfoxide, an important intermediate in the production of semi-synthetic cephalosporin antibiotics, in the form of a definable chemical individual, by dehydration of the hydrated form of penicillin sulfoxide during crystallization from an ester of acetic acid with a lower alkanol, preferably from ethyl acetate.

Description

The invention relates to a process for the manufacture of anhydrous crystalline benzylpenicillin sulfoxide, an important intermediate of the synthesis of the cephalospolarin antibiotic cefaloxin.

Penicillanic acid sulfoxides are key intermediates for the Pummerer reaction, which converts the penam skeleton into cephem. In particular, anhydrous benzylpenicillin sulfoxide is used, which can be converted into cephalexin / J by a shortened procedure. de Koning et al., J. Org. Chem. 40, 1346, 1975]. The preparation of anhydrous benzylpenicillin sulfoxide with potassium periodate is also described, wherein the end product is isolated by precipitation with ether, which is added to a concentrated chloroform solution of benzylpenicillin sulfoxide.

The product is obtained as an amorphous, largely first as an oil, which solidifies over time and does not decompose. If the less pure benzylpenicillin potassium salt is used for the oxidation, the final product in solid form can only be partially obtained.

A simple, economically and technically advantageous method of oxidizing a benzylpenicillin potassium salt with a commercially available solution of industrial peracetic acid admixed with hydrogen peroxide in an operationally safe aqueous medium, providing almost pure quantitative yield of benzylpenicillin sulfoxide in crystalline form, characterized as a dihydrate.

It has also been found that this crystalline form can also be obtained by stirring a chloroform solution of the crude benzylpenicillin sulfoxide obtained by any known oxidation method for a period of time with a small amount of water, whereupon the sparingly soluble benzylpenicillin sulfoxide dihydrate crystallizes.

This finding led to the theoretical consideration that when dissolving benzylpenicillin sulfoxide dihydrate in a suitable solvent that dissolves the dihydrate well and in which the anhydrous form is as poorly soluble as possible, by analogy the desired anhydrous form should crystallize in a pure state as a definable individual.

This theoretical assumption has been experimentally confirmed. Based on the findings and results, a process for the production of anhydrous crystalline benzylpenicillin sulfoxide according to the invention has been developed, which comprises the hydrated form of benzylpenicillin sulfoxide, for example dihydrate as a definable chemical individual or crude residue resulting from the reaction mixture after oxidation of benzylpenicillin to sulfoxide. it first dissolves in the amount of acetic acid ester having a C 1 -C 5 alkanol, preferably in ethyl acetate or butyl acetate, at a temperature above 60 ° C, preferably at the boiling point of the resulting solution, whereupon the anhydrous crystalline product precipitated is isolated.

In a preferred embodiment of the process of the invention, the oxidation of the benzylpenicillin potassium salt to benzylpenicillin sulfoxide dihydrate can be combined in one production sequence to give the anhydrous crystalline form.

Although the dihydrate is isolated, it is not purified and dried and is further processed in the raw state. For example, it has been found that the aspirated dried sulfoxide dihydrate is transferred at elevated temperature to a water-immiscible organic solvent capable of forming an azeotropic mixture with water; depending on the water content of the starting crude dihydrate, this solution can be largely dewatered by gravitational separation of eventually precipitated water in the separating funnel and removal of residual moisture by either azeotropic distillation or a suitable desiccant, for example anhydrous magnesium sulfate.

By distilling off the solvent at as low a temperature as possible, preferably under reduced pressure, a syrup-like residue is obtained which is crystallized in the last phase from the amount of acetic acid selected in the last step.

As a water-immiscible organic solvent capable of forming an azeotropic mixture with water, it is possible to dissolve the starting hydrated form of benzylpenicillin sulfoxide, for example ha210739, a hydrocarbon, in particular dichloromethane, chloroform, trichlorethylene and the like. most often a ratio of 1: 3 to 1: 5 (weight: volume).

In the final step, ethyl acetate, in which the dihydrate dissolves best when boiling, is best suited to finally obtain the anhydrous form of benzylpenicillin sulfoxide. Its required amount is in the range of about 200 to 400 ml per 100 g of dihydrate. In the case of butyl acetate, about twice the amount is required.

Cooling the ethyl acetate or butyl acetate solution precipitates anhydrous benzylpenicillin sulfoxide in beautifully developed crystals having a m.p.

An additional portion of the product can be obtained from the mother liquor after isolation of the first portion by diluting with petroleum ether. However, it is preferable to use the mother liquor either wholly or partially to dissolve another batch of benzylpenicillin sulfoxide dihydrate so that losses are minimized.

The anhydrous crystalline benzylpenicillin sulfoxide obtained by the process of the invention is a product whose physicochemical characteristics (NMR spectrum, silica gel thin layer chromatography, melting points and others) confirm its purity and uniformity.

From the foregoing, it can be clearly seen that the process according to the invention by means of technically simple means, also applicable on a commercial scale, substantially facilitates the production of the basic intermediate of an important group of semi-synthetic cephalexin type antibiotics.

Further details of the process according to the invention can be seen from the following examples which illustrate the process but do not limit it to the substances, apparatus, process or conditions set forth therein.

He did

250 g of benzylpenicillin sulfoxide dihydrate containing about 9 wt. of water, dissolved in boiling in 700 ml of ethyl acetate. By cooling the resulting solution, 170 g of the anhydrous form of benzylpenicillin sulfoxide crystallized in beautifully developed crystals of m.p. 172-175 ° C, which were sucked off, washed with ether and petroleum ether. After diluting the mother liquor with petroleum ether, a further 15 g of product of the same characteristics crystallized.

TLC on silica gel, ethyl acetate: n-butanol: pyridine: acetic acid: water, 42: 21: 21: 6: 10, R R has properties identical to benzylpenicillin sulfoxide dihydrate} Can be dried without decomposition at 70 ° C at which the dihydrate turns yellow and decomposes.

NMR Spectrum (in DMSO-d6):

1. 20s / 3H / c - ch ₃ 1. 60s / 3H / c - ch ₃ 3. 59s / 2H / CHj-ar 4. 31s / 1H / 3 - H 5. 39s / 1H / I = 4.0 Hz 5-H 5. 7 9dd / 1H / I = 9.5; 4.0 Hz 6-H 7. 29s / 5H / Ar 7. 90d / 1H / = 9.5 Hz NH

Example 2.

100 g of crude benzylpenicillin sulphoxide dihydrate was dissolved in hot 400 ml of methylene chloride to give a cloudy solution which was dried by adding 30 g of anhydrous magnesium sulfate. After filtration and washing of the filter with a further 100 ml of hot methylene chloride, the combined filtrates were evaporated in vacuo to a syrupy residue.

This was dissolved in 200 ml of ethyl acetate while hot, and the solution was allowed to crystallize for 1 hour. The precipitated crystals were isolated as in Example 1. 83 g of benzylpenicillin anhydrous sulfoxide having the same properties as in Example 1 were obtained.

Example 3

To 40 ml of hot (about 80 ° C) butyl acetate was added 5 g of benzylpenicillin sulfoxide dihydrate with stirring. After cooling and isolation of the precipitated crystals as in Example 1, 3.0 g of the anhydrous form of benzylpenicillin sulphoxide are obtained as described above.

Example 4

245 g of benzylpenicillin potassium (92% content) are dissolved in a mixture of 1.5 l of water and 500 g of beaten ice. 205 g of a 28.3% by weight aqueous solution of peracetic acid are added dropwise with stirring. After stirring for 15 minutes, the product begins to precipitate in crystalline form. After adjusting the pH to pH 2.4 with dilute hydrochloric acid, the product remains.

After standing for 1 hour in the refrigerator, it is filtered off with suction and washed with water until the reaction to peroxides is lost. The crude wet product was placed in 1 liter of boiling methylene chloride, the separated water layer was separated in a separatory funnel, and the cloudy solution was dried with 60 g of anhydrous magnesium sulfate.

The desiccant was filtered off and washed with 200 ml of methylene chloride. The filtrate was evaporated on a rotary evaporator. The residue was dissolved in 400 ml of ethyl acetate at about 70 ° C and the solution was allowed to stand overnight in the refrigerator. The precipitated product is filtered off with suction, washed with 100 ml of ethyl acetate and 150 ml of petroleum ether and dried in air.

Yield 160 g of product of the above characteristics, with a water content of 0.3%. The ethyl acetate mother liquor was used to crystallize another batch of crude dihydrate.

Note: in addition to the benzylpenicillin potassium salt, its solution or the free acid solution as obtained at some stage of the treatment or treatment may be used for the oxidation to the sulphoxide. isolation of benzylpenicillin from fermented broth.

Claims (1)

SUBJECT OF THE INVENTION Process for preparing anhydrous crystalline benzylpenicillin sulfoxide, characterized in that a hydrated form of benzylpenicillin sulfoxide, for example a dihydrate as a defined chemical individual or a crude residue resulting from treatment of the reaction mixture after oxidation of benzylpenicillin to sulfoxide, initially dissolves in just the required amount of acetic acid ester with alkanol. C 1 to C 5, preferably in ethyl acetate or butyl acetate, at a temperature above 60 ° C, preferably at the boiling point of the resulting solution, whereupon the precipitated anhydrous crystalline product is isolated.