CS33291A2 - Method of 7-amino-3-methoxymethylcef-3-em-4-carboxylic acid's preparation - Google Patents

Description

EP-A-204 657 discloses a process according to which the derivatives of formula A are prepared using technically difficult to handle boron trifluoride and using solvents. As a rule, the derivatives thus obtained must be further purified.

A further procedure, as described in Japanese Patent Application No. 59 / 163,387, uses as catalysts strong organic acids and chlorinated hydrocarbons as co-solvents. Additional processing of the process provides the desired products in low yield (about 30%) and purity (about 30-40%). %).

A significantly better process has now been found, which surprisingly yields the compounds in a substantially higher yield and purity.

SUMMARY OF THE INVENTION

The present invention provides a process for preparing a compound of Formula I

ch2och3 (I)

comprising 7-aminocephalosporanic acid (7-ACS) of formula II

The COOH-3- or a suitable salt thereof is reacted with a mixture of methanesulfonic acid, trifluoromethanesulfonic acid and methanol and upon completion of the reaction, the product of formula I is precipitated from the reaction solution.

The 7-aminocephalosporanic acid or its salts may be introduced into the reaction mixture as a powder or suspended in a portion of the methanol used and may be incorporated into the reaction solution in the form of a suspension. It is also possible to add 7-aminocephalosporanic acid or its salts to a solution of a mixture of methanesulfonic acid and trifluoromethanesulfonic acid and then add methanol.

The amount of methanesulfonic acid used can be between about 7 and 40, preferably between 8 and 12, in particular 10 equivalents based on the 7-aminocephalosporanic acid used. The amount of the trifluoromethanesulfonic acid may be about 0.5 to 5%, preferably 0.8 to 1.5, especially 1 equivalent, based on the 7-aminocephalosporanic acid. The methanol component can be added in an amount of from about 2 to about 20, preferably from about 4 to about 7 equivalents, especially from about 5 equivalents, also based on the amount of 7-aminocephalosporanic acid used.

The reaction temperature should be between about -10 ° C and + 40 ° C, preferably between + 5 ° C and + 15 ° C.

Depending on the reaction temperature, the reaction time can always be from 5 minutes to 3 hours, preferably from 2 to 2.5 hours.

Suitable salts of 7-aminocephalosporanic acid which are stable and have a corresponding stoichiometric composition with the corresponding acid component.

Particularly suitable salts of 7-aminocephalosporanic acid are the salts of aromatic acids such as benzenesulfonic acid, preferably with alkylbenzene sulfonic acids such as p-methyl or p-ethylbenzenesulfonic acid. - 4 -

Particularly suitable is 7-ACS-p-toluenesulfonethiohydride as described in DE-AS 15 45 898 and its anhydrous form.

The isolation of the compound of formula I is carried out after the addition of ice water by adding a base to the hydrolyzed reaction mixture and adjusting the pH to about 2.5 to 3.5. preferably about 40% aqueous sodium hydroxide solution. The precipitated product is then additionally washed, for example with water, acetone and ether, and dried in the usual manner.

The process according to the invention is characterized by the fact that it provides the compound of the formula I in a better yield and with a higher purity than the known methods. Furthermore, the product no longer contains 7-aminocephalosporanic acid and should not be further purified. The following examples illustrate the present invention.

However, these examples are not to be construed as limiting the scope of the invention in any way. (0.2 mol) of trifluoromethanesulfonic acid was added dropwise over 10 minutes to 20 ml of methanol at -10 ° C to + 5 ° C. Then, a pre-prepared mixture of 54.4 g (0.2 mol) of 7-aminocephalosporanic acid and 20 ml of methanol was added over 12 minutes to maintain the temperature between 4 and 6 ° C. Initially, the suspension passes slowly into solution. After 130 min, the reaction solution was poured into 200 mL of ice water. After stirring for 2.5 hours, the pH of the reaction mixture was adjusted by adding 40% aqueous sodium hydroxide while cooling (10-20 ° C) -5-5 to 2.5. The sand precipitate is filtered off, washed five times with water and then washed with acetone and dried. 27 g of the desired title compound are obtained, containing 90% pure by high performance liquid chromatography. 1 H-NMR spectrum (270 MHz, perdeuterated dimethylsulfoxide) = 3.20 (s, 3H, OCH 3), 3.35-3.60 (system AB, 2H, -S-CH 2 -), 4.15 (3, 2H, -CH 2 -O-), 4.76 (d, J = 4 Hz, 1H, 6-H), 4.98 (d, J = 4 Hz, 1H, C-7). IR spectrum (KBr technique): 1800 cm -1 · 1 · (carbonyl β-lactam)

% C, 44.25; H, 4.95; N, 11.47; S, 13.13; C, 44.0; Example 4 To a solution of 32.5 ml (0.5 mol) of methanesulfonic acid and 4.4 ml (0.05 mol) of trifluoromethanesulfonic acid was added 10 ml of methanol to a temperature of 2 to 5 ° C. and then 24 g (0.054 mol) of anhydrous 7-ACS-p-toluenesulfonate over 10 minutes. The initial suspension dissolves rapidly and 50 ml of ice water is added to the obtained solution after a total of 130 minutes of stirring. After stirring for 2.5 hours at 20 DEG C., the pH value of H is adjusted to 2.5 with 40 ml of 40% aqueous sodium hydroxide solution under ice-cooling. The precipitate formed is then filtered off and washed with ice water, acetone and diethyl ether. After drying, 7.2 g of the title compound of Example 1 is obtained, which is identical in its physical and chemical properties to that obtained in Example 1. According to high performance liquid chromatography, it contains at least 90% of the substance.

Claims (5)

JUDr. Mlloft VŠETEČKAadvokát PRAHA í, tntá '' - 6 '0> o O <OCO' 'S> 7> »7? ? ' T-J PATENT CLAIMS A process for preparing 7-amino-3-methoxymethylceph-3-em-4-carboxylic acid of formula I CH 2 CH 3 (I) characterized in that it is a compound of formula II or a suitable salt thereof is treated with a mixture of methanol, methanesulfonic acid and trifluoromethanesulfonic acid. 2. A process according to claim 1 wherein the salt is an aromatic sulfonic acid salt. 3. The process of clauses 1a2, wherein the salt is p-toluenesulfonate dihydrate of the compound of formula II or its anhydrous form. - 7 - 4. The process of claim 1 wherein the reaction is carried out at a ratio of 7-aminocephalosporanic acid from about 7 to 40 equivalents of methanesulfonic acid, about 0.5 to 5 equivalents of trifluoromethanesulfonic acid, and about 2 to 20 equivalents of ethanol. . Use of a compound of formula (I) obtained according to (1) to (4) for the production of a cephalosporin antibiotic acylation amino group.