NL8901110A - PROCESS FOR THE PREPARATION OF 1-ACETOXYETHYL ESTERS FROM CEFUROXIM. - Google Patents

Description

- 1 - f r>

Process for the preparation of 1-acetoxyethyl esters of cefuroxime.

This invention concerns improvements in the field of cephalosporins. More particularly, these are processes for the preparation of the oral antibiotic cefuroxime axetil.

Cefuroxime axetil, the 1-acetoxyethyl ester of 5 (6R, 7R) -3-carbamoyloxymethyl-7- / (Z) -2- (fur-2-y1) -2-methoxyimino-acetamido 7cef-3-em- carboxylic acid (cefuroxime) is described in British Patent No. 1,571,683. Cefuroxime axetil is a particularly valuable cephalosporin as it can be administered orally. The compound has shown that when administered orally, it has good antibiotic activity against a wide spectrum of gram-positive and gram-negative bacteria and good resistance to 8-lactamases.

Cephalosporin esters are usually prepared by acylating an appropriate 7-aminocephalosporin with a compound that serves to introduce a preformed 7-substituent, or by esterifying the 4-carboxyl group of the corresponding cephalosporin, for example by reaction with a halogen ester. These general methods are described in British Patent No. 1,571,683, also for the preparation of cefuroxime axetil.

A process has now been devised for the preparation of cefuroxime axetil and its protected derivatives, wherein the O-methyloxim group is introduced by oxidation as the last important chemical step of the synthesis.

Thus, this invention relates to a process for preparing compounds of the general formula 1, wherein R represents a hydrogen atom or a carbamoyl protecting group (ZS or SK) and the dotted line indicates that the compound is a cef-2-em or cef -3-em compound is to which a compound 30 according to formula 2, wherein R, Z and the dotted line have the definitions given above, is reacted with an O-methyl oximation agent, for example with methoxylamine or a salt thereof.

Oximation can be performed in aqueous and non-aqueous media 8901110: • - 2 -

J

suitable at a temperature between -20 ° and + 100 ° C, for example between 0 ° and + 75 ° C.

Examples of reaction media that can be used are water, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, dioxane, diethyl ether and diglyme, amides such as dimethyl formamide, dimethyl acetamide and hexamethylphosphoramide, nitriles such as acetonitrile, nitroalkanes such as nitro methane, sulfoxides such as dimethyls sulfones such as sulfolane, halohydrocarbons such as dichloromethane and esters such as ethyl acetate, as well as mixtures of two or more such liquids.

If the oxidation is done in an aqueous reaction medium, it is desirable that a Lewis acid such as magnesium chloride or zinc chloride or BF2 is present (the latter suitably in the form of a solvate, eg an etherate).

As. the reaction takes place in water, which can suitably take place at a pH between 2.0 and 9.0, preferably between 3 and 8.

The pH may suitably be kept within this range by adding a suitable acid or base, for example, a mineral acid such as hydrochloric or sulfuric acid or an alkali metal carbonate or bicarbonate, eg NaHCO3.

The oxidation can, if desired, be followed by the conversion of the initially formed compound of formula 1 into another compound of formula 1, for example with one of the following reactions: (i) reduction of a compound in which Z is SK) to a compound in which Z is sulfur, 2 3 (ii) conversion of a Δ-isomer to a Δ-isomer, (iii) removal of an optional carbamoyl protecting group.

The reactions can be carried out by conventional methods and in any order.

If desired, a Δ-cephalosporin obtained according to the invention can be converted into the corresponding Δ-derivative, for example by treating the Δ-ester with a base such as pyridine or triethylamine.

A cef-2-em reaction product can also be oxidized to the corresponding cef-3-em-1 oxide, for example with a peracid such as peracetic acid or m-chloroperbenzoic acid; the resulting sulfoxide can then be reduced to the corresponding cef-3-em sulfide in a manner to be described below.

If a compound of formula 1 is obtained in which Z is S + O, it can be converted to the corresponding sulfide, if desired, for example, by reduction of the corresponding acyloxysulfonium or alkoxy sulfonium salt prepared in situ by reaction with e.g. acetyl chloride in the case of an acetoxysulfonium salt, after which the reduction is carried out, for example, with sodium dithionite or with iodide, with, for example, acetic acid, acetone, tetrahydrofuran, dioxane, dimethylformamide or dimethyl acetamide as solvent. The reaction can be carried out at a temperature between -20 ° and 50 ° C.

The carbamoyl protecting group in compounds of formula 1 and intermediates therefor is suitably a group which is easy to remove in an appropriate phase of the reaction, for example an acyl group and especially a lower alkanoyl group such as acetyl, one with halogen substituted lower alkanoyl group such as mono-, di- or trichloroacetyl, a chlorosulfonyl or bromosulfonyl group, a dihalophosphonyl group such as dichlorophosphonyl, or a halooxycarbonyl group such as 2,2,2-trichloroethoxycarbonyl.

An optional carbamoyl protecting group in the compounds of formula 1 can be removed, if desired, by methods known in the art. Labile groups such as chlorosulfonyl, dichlorophosphonyl and trichloroacetyl can generally be cleaved with an acid or base catalyzed hydrolysis (eg with sodium bicarbonate). Halogen-containing groups such as 2,2,2-trichloroethoxycarbonyl can be split off reducingly, and groups such as chloroacetyl can also be treated by treatment with thioamides such as thiourea.

The reaction product can be separated from the reaction mixture which may contain, for example, unaltered cephalosporin and other substances, by a variety of operations including extraction, recrystallization, ionophoresis, column chromatography, high pressure liquid chromatography, ion exchange chromatography and crosslinked resin chromatography.

If a compound of formula 1 is formed as a mixture of isomers, the syn isomer can be recovered by conventional methods, such as crystallization or chromatophy.

8901 110? - 4 - r

The product can also be obtained in a mixture with an approximately 1: 1 ratio between R and S isomers in the ester group, for example as described in British Patent Specification 2,145,409.

A preferred embodiment of the invention relates to the preparation of cefuroxime axetil or its protected derivative, ie the compound of formula 1 wherein R represents a hydrogen atom or a carbamoyl protecting group, Z is sulfur and the dotted line is a cef-3 em- compound, if desired, followed by in situ removal of the protecting group.

For example, a compound of formula 2 can be prepared by esterification of a compound of formula 3, wherein R, Z and the dotted line have the definitions given above, or a salt thereof (eg an alkali metal salt such as the sodium or potassium salt) or an onium salt (e.g. a quaternary ammonium salt) by reaction with an appropriate halogen ester, e.g. with 1-acetoxyethyl bromide.

The reaction is suitably carried out in an inert solvent, for example in an amide such as dimethylformamide or dimethyl acetamide, a ketone such as acetone, a sulfoxide such as dimethyl sulfoxide, a halohydrocarbon such as dichloromethane or in a nitrile such as acetonitrile. The reaction can take place at a temperature between -50 ° and + 150 ° C, eg between -10 ° and + 50 ° C, suitably between -10 ° and room temperature.

If the free acid serves as the starting material, the reaction preferably takes place in the presence of a base which creates an anion from the 4-carboxyl function. Suitable bases are, for example, inorganic bases such as the alkali metal carbonates, e.g.

30 sodium and potassium carbonate.

For example, a compound of formula 3 can be prepared with conventional acylations, such as described in British Patent No. 1,453,049.

The invention is illustrated by the following examples. All temperatures are in ° C. The term "dried" refers to drying at 80 DEG C. or MgSO 4, and "petroleum" refers to petroleum ether having a boiling range of 40 to 60 ° C.

8901110.

- 5 - * Λ

Intermediate 1

Diphenylmethyl- (6R, 7R) -3- (carbamoyloxymethyl) -7- (fury 1-2) -glyoxamido-1-em-4-carboxylate

4.28 g of the p-toluenesulfonic acid salt of diphenyl-5 methyl (6R, 7R) -7-amino-3-carbamoyloxymethylceph-3-em-4-carboxylate was dissolved in 200 ml of ethyl acetate and 2 ml of NaHCO 2 solution . The ethyl acetate layer was separated, washed with water, dried and cooled to 0 ° C. To this solution, solutions of 1.46 g of dicyclohexylearbodiimide and 991 mg of 10 2-furylglycolic acid in ethyl acetate were added. The reaction mixture was stirred at 0 ° C for 20 minutes and then filtered, and the filtrate was evaporated in vacuo. Stirring the residue with ethanol gave 3.53 g of the title compound, m.p. 169-171 ° C.

Intermediate 2 15 (6R, 7R) -3-carbamoyloxymethyl-7 - / * (fury1-2) glyoxamido Jcef-3-em-4-carboxylic acid

To a mixture of 5.5 ml of anisole and 1.84 g of intermediate 1 cooled to 0 ° C, 5.5 ml of trifluoroacetic acid was added with stirring. After 10 minutes, the reaction mixture was poured into 100 ml of aqueous NaHCO 2 and 100 ml of ethyl acetate. The water layer was separated, washed with 100 ml of ethyl acetate and acidified to pH = 2 under ethyl acetate. Insoluble material was filtered off and combined with the material obtained from the ethyl acetate layer by washing, drying and evaporating to dryness. The product was recrystallized from methanol to give 678 mg of the title compound.

/ cc = + 64 ° (c = 0.988 in aqueous NaHCO3).

Intermediate 3 (R and S) -1-acetoxyethyl- (6R, 7R) -3- (earbamoyloxymethyl) -7-30 f (furyl-2) glyoxamido-3-em-4-carboxylate

A solution of 3.00 g of intermediate No. 2 in 30 ml of dimethylformamide was stirred with 0.534 g of potassium carbonate under nitrogen at 22 ° C for 1 hour. After cooling to about 0 ° C, 1.394 g of (R, S) -1-acetoxyethyl bromide was added and stirred for 3 hours. Then the mixture was partitioned between 2N hydrochloric acid and ethyl acetate. The water layer was extracted twice with ethyl acetate and the organic layers were washed together with water, twice with saturated NaHCO 2 solution and with brine, dried and concentrated to about 15 ml When added to 88 01 11: 6-6 ft. petroleum, the title compound solidified down, yield 2.42 g; v (in CHBr ™): 1788 and 1736 cm ^ max 3 δ (in CDCl3) 8.07 (1H, d J 4 Hz), 8.01 (1H, d J 8 Hz) , 7.75 (1H, 5s), 7.09 and 6.97 (1H, q), 6.61 (1H, m), 5.80 (1H, m), 5.03 (1H, d J 8 Hz), 4.93 (2H, s), 4.81 and 5.08 (2H, m), 3.6 and 3.44 (2H, m), 2.02 (3H, s) and 1, 52 (3H, d J, 4 Hz).

Example 10 (R and S) -1-Acetoxyethyl- (6R, 7R) -3- (carbamoyloxymethyl) -7 - / * (Z) - 2- (furyl-2) -2- (methoxyimino) acetamido, 7cef-3 -em-4-carboxylate A suspension of 500 mg of intermediate no. 3 and 178 mg of methoxylamine hydrochloride in 10 ml of ethanol was stirred with 3 ml of dimethylformamide at about 0 ° C to give a solution. 0.36 ml of pyridine was added so that a sample exhibited a pH of 4.2 on shaking with water, and that mixture was stirred at 0 to 4 ° C for 50 hours. The solution was now partitioned between ethyl acetate and 2N hydrochloric acid, and the aqueous layer was separated and extracted with ethyl acetate. The organic 20 layers were washed together with water, with saturated NaHCO 2 solution and with brine, dried and concentrated to about 5 ml. When poured into petroleum, 258 mg of the title compound precipitated as a solid; this was identified by comparing it to an authentic sample of cefuroxime-axetil by HPLC.

8901 1 1 0.

Claims (6)

A process for the preparation of compounds of the general formula 1, wherein R represents a hydrogen atom or a carbamoyl protecting group (ZS or SK) and the dotted line indicates a cef-2-em or cef-3-em compound consisting of reacting a compound of formula 2, wherein R, Z and the dotted line have the definitions given above, with an O-methyl oxidizing agent, optionally followed by conversion of the compound of formula 1 thus obtained initially into another compound of formula 1 with one or more of the following reactions: (i) reduction of a compound in which Z is SK) to a compound in which Z is sulfur, 2 3 15 (ii) conversion of a Δ-isomer into a Δ-isomer (iii) removal of any carbamoyl substituents. A method according to claim 1, wherein the oxidation reaction takes place at a temperature between -20 ° and 100 ° C. The method of any preceding claim, wherein the oxidizing agent is methoxylamine or a salt thereof. 4. Process according to any one of the preceding claims, wherein a compound according to formula 2, in which R represents a hydrogen atom or a carbamoyl protecting group, Z is sulfur and the dotted line indicates a cef-3-em compound, with the said O-methyl oxidizing agent reacts. 4 -v 5. Compounds of the general formula 1, as defined in claim 1, when prepared by a method according to any one of the preceding claims. Cefuroxime axetil, when prepared by a process as defined in claim 4. -o-o-o-o-o- 89 01 11 0.