CZ279076B6 - Process for preparing semi-synthetic antibiotic sulbactam - Google Patents

Abstract

Process for preparing antibiotic sulbactame of formula I by dehalogenation of the derivate of penicillanic acid of general formula II, where X1 and X2 represent atoms of chlorine or bromide or X1 represents a hydrogen atom and Z represents an atom of hydrogen or alkaline metal, for example sodium or potassium, then hydrogenolysis by hydrogen, in the presence of a catalyst, which consists of a suspension of active charcoal in an aqueous solution of palladium chloride. The active catalyst is formed during the reaction "in situ". This measure economises the production, the purchase or preparation of the usual catalyst Pd/C is no longer necessary. Preferably palladium chloride is used from regeneration of the used catalyst.<IMAGE>

Description

The invention relates to a process for the preparation of the semisynthetic antibiotic sulbactam of the formula I

by dehalogenation of a penicillanic acid derivative of the formula II,

wherein X ₂ represents chlorine or bromine atoms or X ₃ represents hydrogen and Z represents hydrogen or an alkali metal such as sodium or potassium by hydrogenolysis with hydrogen in the presence of a palladium-containing catalyst.

The process described is most common, with palladium on carbon (Pd / C) typically being used as a catalyst, generally as a commercial product (DOS 3 008 257 ;, J. Org. Chem. 1982, 47,3344; CS 240 398). Palladium is recovered from spent catalyst, the catalyst is usually burnt, the residue is leached and purified, and the final stage is the preparation of palladium chloride, which is used to prepare a new Pd / C catalyst.

It has now surprisingly been found that in the preparation of the semisynthetic antibiotic sulbactam of formula I by dehalogenation of a penicillanic acid derivative of formula II by hydrogenolysis with hydrogen in the presence of a palladium catalyst, the preferred method of the present invention is in the presence of a catalyst consisting of a suspension of activated carbon in an aqueous solution of palladium (II) chloride in which the weight, Pd ²⁺ concentration is 0.1 to 10.0%, and the weight, palladium to activated carbon ratio is 1:99 to 20:80. When using the described catalyst, it is not necessary to change the hydrogenolysis of the penicillanic acid derivative of the formula II in the other process parameters, which are known (CS 240 398).

The conditions for preparing the catalyst from activated carbon and palladium chloride solution are simple and unpretentious and are not limited. It is possible to operate at a temperature of 0 to 40 ° C, the concentration of PD ²⁺ can be from 0.1 to 10% by weight, preferably in the range of 0.5 to 2.0% by weight, to in situ result in a catalyst having a Pd-on-carbon content of 1 to 20 wt. %, preferably 2 to 10 wt. Typically, a concentrated palladium chloride solution is added dropwise to a stirred suspension of activated carbon in water, typically 5 to 10 minutes, depending on the size of the feed. In particular, the types of activated carbon which are intended for catalysis are used. without admixtures and especially those having a large specific surface area (100 to 2,000 m ² / g).

-1GB 279076 B6

The process according to the invention is highly efficient, it is not necessary to purchase a commercial Pd / C catalyst, no catalyst preparation is required, ie reduction, activation, transport, etc., a commercial palladium chloride solution or a solution obtained from the used Pd / C catalyst is sufficient. The active catalyst itself is formed in situ under the reaction conditions.

The following examples illustrate the process of the invention, including the preparation of the catalyst, but do not limit it in any way.

Example 1

30 g of activated carbon are suspended in 150 ml of distilled water with stirring for 10 minutes and then 6.25 ml of a 40% strength aqueous solution of palladium chloride (palladium content 1.5 g) is added dropwise over 5 minutes with stirring. This suspension serves as a catalyst.

In an autoclave at a hydrogen pressure of 1.5 MPa was hydrogenolyzed mixture of 0.43 kg of 1,1-dioxide 6,6-dibrorpenicilananu potassium (formula II, X = X ₂ = Br, Z = K), 180 g of sodium bicarbonate, 1, 4 liters of water and catalyst slurry. After 2 hours of hydrogenolysis, during which the reaction mixture was degassed 4 times and pressurized again to 1.5 bar with hydrogen, the catalyst was filtered off and the filtrate was acidified with dilute hydrochloric acid to pH 1.5 in the presence of 1 liter of ethyl acetate.

The ethyl acetate was separated and the aqueous phase was extracted twice more with 700 ml of ethyl acetate. The combined ethyl acetate phases were dried with magnesium sulfate. After filtration, the sulbactam acid solution was precipitated with a solution of sodium alpha-ethyl caproate in ethyl acetate (450 ml of a solution containing about 140 g of precipitant).

After suction and washing, sulbactam sodium is obtained in a yield of 70% of theory (180 g). The yield was consistent with the procedure where a suspension of 30 g of a commercial palladium on carbon catalyst (5 wt% Pd) in 150 ml of water was used instead of a suspension of activated carbon in a palladium chloride solution.

Example 2

0.3 ml of a 40% palladium chloride solution was added dropwise to the suspension of activated carbon (2.5 g in 15 ml of water) over 5 minutes.

In a laboratory autoclave, a mixture of 90 ml of ethyl acetate solution containing 15.6 g of 6,6-dibromo-penicillanic acid 1,1-dioxide (pattern II, ^x 1 ^{= x} 2 ^{= Br} 1 ^{Z =} H) is hydrogenolysed under a hydrogen pressure of 1.5 MPa. , ¹¹ 9 of sodium bicarbonate, 50 mL water and the suspension of the catalyst obtained. After 90 minutes of reaction, the mixture was degassed 2 times and pressurized again to 1.5 bar with hydrogen, and the catalyst was filtered off.

The filtrate was acidified with hydrobromic acid (1: 1) to pH 1.4. The ethyl acetate was separated and the aqueous phase was extracted twice more with 40 ml of ethyl acetate. The combined ethyl acetate phases were treated with magnesium sulfate and charcoal to give a colorless filter.

-2GB 279076 B6 Extract filtrate. 25 ml of a 27.2 g sodium alpha-ethyl caproate solution per 100 ml of solution are precipitated.

After filtration, washing and drying, sulbactam sodium, 8.5 g, 94% by weight is obtained.

Example 3

The procedure of Example 2 was followed except that hydrogenolysis was carried out under a hydrogen pressure of 0.5 MPa for 2 hours, degassing 3 times.

Sulbactam sodium was obtained in the same yield and quality as in Example 2.

Claims (1)

PATENT CLAIMS A process for the preparation of a semisynthetic antibiotic sulbactam of formula I by dehalogenation of a penetilic acid derivative of formula II, (I ') wherein X 1 and X ₂ are chlorine or bromine atoms or X 2 are hydrogen and Z is hydrogen or alkali metal such as sodium or potassium hydrogenolysis with hydrogen in the presence of a palladium-containing catalyst, characterized in that the catalyst consists of a suspension of activated carbon in an aqueous solution of palladium (II) chloride, by weight of the catalyst. a ratio of palladium to activated carbon of 1:99 to 20:80 and a Pd concentration of 0.05 to 10.0 wt.