IE910464A1

IE910464A1 - A process for the preparation of¹7-amino-3-methoxymethylceph-3-em-4-carboxylic acid

Info

Publication number: IE910464A1
Application number: IE046491A
Authority: IE
Original assignee: Hoechst Ag
Priority date: 1990-02-13
Filing date: 1991-02-12
Publication date: 1991-08-14
Also published as: NZ237063A; NO910556L; JPH04211088A; DE4004370A1; CS33291A2; MY105374A; HUT59687A; ZA911025B; CN1054984A; PL289034A1; IL97210A0; EP0442385A2; NO910556D0; AU7095691A; FI910662A0; KR910015584A; EP0442385A3; MA22061A1; HU910466D0; FI910662A

Abstract

Process for the preparation of the compound of the formula by reaction of a compound of the formula or a suitable salt thereof with a mixture of methanol, methanesulphonic acid and trifluoromethanesulphonic acid.

Description

A process for the preparation of 7-amino-3-methoxymethylceph-3-em-4-carboxylic acid 7-Amino-3-alkoxymethylceph-3-em-4-carboxylic acids are valuable starting materials for the preparation of cephalosporins which can be administered orally, by subsequent acylation of the amino group, such as, for example, those described in EP-B-134,420 and EP-A10 329,008.

The exchange processes which have hitherto been disclosed for the preparation of compounds of the general formula A in which R is an alkyl radical, are distinguished by reaction conditions which considerably restrict preparation on the industrial scale. Thus, for example, EP-A262,744 describes a process in which compounds of the formula A are obtained by reaction of the corresponding alcohol with a large excess of inorganic Lewis acid catalysts and subsequent chromatography on ion exchangers. A process of this type cannot be carried out with industrial and ecological efficiency. Derivatives of the formula A are prepared in EP-A-204,657 using gaseous boron trifluoride, which is difficult to handle industrially, and using solvents. The derivatives obtained in this way must usually be further purified.

Another process, described in Japanese Application JP 59/163,387, makes use of strong organic acids as cata30 lysts and chlorinated hydrocarbons as solubilizers.

IE 91464 Repetition of the described process provided the desired products in low yield (about 30 %) and purity (about 30 40 % pure).

We have now found a distinctly improved process which, 5 surprisingly, provides these compounds in considerably higher yield and high purity.

Hence the invention relates to a process for the preparation of the compounds of the formula I which comprises reacting 7-aminocephalosporanic acid (7ACS) of the formula II (II) or a suitable salt thereof, with a mixture of methanesulfonic acid, trifluoromethanesulfonic acid and methanol and, after the reaction is complete, precipitating the product of the formula I out of the reaction solution. 7-ACS or salts thereof can either be introduced as powder into the reaction mixture or suspended in a portion of the methanol used and added to the reaction solution in this way. It is also possible to introduce the 7-ACS or salts thereof into a methanesulfonic acid/trifluoromethanesulfonic acid solution and subsequently to add the methanol.

IE 91464 _________ - 3 The amount of methanesulfonic acid used can be between 7 and 40, preferably between 8 and 12, in particular be 10, equivalents relative to 7-ACS employed. The amount of trifluoromethanesulfonic acid can be about 0.5 to 5, preferably 0.8 to 1.5, in particular 1, equivalent relative to the 7-ACS. The methanol component can be added in an amount of about 2 to 20, preferably 4 to 7, in particular 5, equivalents, once again relative to the 7-ACS employed.

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

The reaction time can be, depending on the reaction temperature, about 5 minutes to 3 hours, preferably 2 to 2.5 hours .

Suitable salts of 7-ACS are those which are stable and have with their acid component a defined stoichiometric composition.

Particularly suitable salts of 7-ACS are those with aromatic sulfonic acids, such as, for example, with benzenesulfonic acid, preferably those with alkylbenzenesulfonic acids, such as, for example, with pmethyl- or p-ethylbenzenesulfonic acid. 7-ACS p-toluenesulfonate dihydrate, which is described in German Auslegeschrift 1,545,898, and the anhydrous form thereof, is particularly suitable.

The compound of the formula I is isolated after addition of ice-water by addition of a base to the hydrolyzed reaction mixture and adjustment of the pH to about 2.5 to 3.5. Examples of suitable bases are concentrated ammonia, - 40 % strength potassium hydroxide solution, preferably about 40 % strength sodium hydroxide solution. The precipitated product can then be washed, for example with water, acetone and ether, and dried in a customary manner.

The process according to the invention is distinguished by comparison with the known methods in that it provides the compound of the formula I in better yield and higher purity. Moreover, the product no longer contains 7-ACS and no longer requires further purification.

The examples which follow illustrate the present invention but without restricting it to them.

IE 91464 Example 1 7-Amino-3-methoxymethylceph-3-em-4-carboxylic acid ml of methanol were added dropwise within 10 minutes at -10°C to +5°C to 132.5 ml of methanesulfonic acid (2.0 mol) and 17.6 ml of trifluoromethanesulfonic acid (0.2 mol). Subsequently a previously prepared mixture of 54.4 g of 7-ACS (0.2 mol) and 20 ml of methanol were introduced within 12 minutes in such a way that the temperature remained between 4 and 6 °C. The initial suspension was gradually converted into a solution. After 130 minutes, the reaction solution was poured into 200 ml of ice-water. After stirring for 2.5 hours, the pH was adjusted to 2.5 with 40 % strength sodium hydroxide solution while cooling (10 to 20°C), and the sand-like precipitate was filtered off, washed five times with water and subsequently with acetone and dried. 27.6 g of the desired title compound with a content of 90 % accord25 ing to HPLC were obtained.

XH NMR (270 MHz, DMSO-ds) : S = 3.20 (s, 3H, OCH3) , 3.353.60 (AB system, 2H, -S-CH2-), 4.15 (s, 2H, -CH2-O-), 4.76 (d, J = 4 Hz, IH, 6-H), 4.98 (d, J = 4 Hz, IH, C-7).

IR (KBr): 1800 cm1 (0-lactam carbonyl) CgHlzN2O4S (244.265) calc. found C 44.25 44.0 H 4.95 .0 N 11.47 11.4 S 13.13 13.5 lEQl464 Example 2 ml of methanol and subsequently 24 g (0.054 mol) of anhydrous 7-ACS p-toluenesulfonate were introduced within 10 minutes into a solution of 32.5 ml (0.5 mol) of 5 methanesulfonic acid and 4.4 ml (0.05 mol) of trifluoromethanesulfonic acid at 2 - 5°C. The initial suspension was rapidly converted into a solution to which, after stirring at 2 - 5°C for a total of 130 minutes, 50 ml of ice-water were added. After stirring at 2O’C for 10 2.5 hours, the pH was adjusted to 2.5 with about 40 ml of % strength sodium hydroxide solution while cooling in ice. The precipitate which separated out was subsequently filtered off with suction and then washed with ice-water, acetone and diethyl ether. Drying resulted in 7.2 g of the desired title compound whose physical and chemical properties were identical to those of Example 1 and which had a content of at least 90 % according to HPLC.

Claims

1. Patent Claims

1. A process for the preparation of the compound of the formula I ch 2 och 3 (I) which comprises reacting the compound of the formula II (II) or a suitable salt thereof, with a mixture of methanol, methanesulfonic acid and trifluoromethanesulfonic acid.

2. The process as claimed in claim 1, wherein a salt with an aromatic sulfonic acid is used as suitable salt.

3. The process as claimed in any of claims 1 and 2, wherein the p-toluenesulfonate dihydrate of the compound II or its anhydrous form is used as salt.

4. The process as claimed in any of claims 1 to 3, wherein the reaction is carried out with a ratio of the components to the 7-ACS of about 7 to 40 equivalents of methanesulfonic acid, about 0.5 to 5 equivalents of trifluoromethanesulfonic acid and about 2 to 20 equivalents of methanol. IE 91464 6. 6. The use of the compound of the formula I obtained as claimed in any of claims 1 to 4 for the preparation of a cephalosporin antibiotic by acylation of the amino group. A process as claimed in claim 1 for the preparation of the. compound of the formula I given and defined therein, substantially as hereinbefore described with particular reference to the accompanying Examples. The compound of the formula I given in claim 1, whenever prepared by a process claimed in a preceding claim.