NZ237063A

NZ237063A - Preparation of 7-amino-3-methoxymethyl-ceph-3-em-4-carboxylic acid

Info

Publication number: NZ237063A
Application number: NZ237063A
Authority: NZ
Inventors: Friedhelm Adam; Walter Durckheimer; Rolf Horlein; Burghard Mencke
Original assignee: Hoechst Ag
Priority date: 1990-02-13
Filing date: 1991-02-11
Publication date: 1992-04-28
Also published as: IE910464A1; DE4004370A1; MA22061A1; ZA911025B; FI910662A; HU910466D0; PL289034A1; FI910662A0; JPH04211088A; NO910556L; CS33291A2; CA2036208A1; PT96729A; EP0442385A3; IL97210A0; KR910015584A; MY105374A; AU7095691A; HUT59687A; CN1054984A

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £37063 23 7 0 6 Henry Hughes Ltd Patents Form 5 N.Z. No. HEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION A PROCESS FOR THE PREPARATION OF 7-AMINO-3-METHQXYMETHYL-CEPH-3-EM-4-CARBOXYLIC ACID We, HOECHST AKTIENGESELLSHAFT, a Corporation organized under the laws of the Federal Republic of Germany, of D-6230 Frankfurt am Main 80, Federal Republic of Germany, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement - 1 - (Followed by 1A) HOTrrHgT axTTFMnpc^T.T.cir'HAFT—HOE 90/F 0<15 Description '^ Dr. ItA/rh 237 0 6 A process for the preparation of 7-amino-3-methoxymethyl-ceph-3-em-4-carboxylic acid 10 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-A-329,008. The exchange processes which have hitherto been disclosed for the preparation of compounds of the general formula A (A) 15 in which R is an alkyl radical, are distinguished by reaction conditions which considerably restrict preparation on the industrial scale. Thus, for example, EP-A-2 62,744 describes a process in which compounds of the formula A are obtained by reaction of the corresponding 20 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 25 boron trifluoride, which is difficult to handle industri ally, and using solvents. The derivatives obtained in this way must usually be further purified. 30 Another process, described in Japanese Application JP 59/163,387, makes use of strong organic acids as catalysts and chlorinated hydrocarbons as solubilizers. V - 2 - 237 06 3 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, 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 10 which comprises reacting 7-aminocephalosporanic acid (7- ACS) of the formula II h2N J CH2OCOCH3 ° T 2H (II) or a suitable salt thereof, with a mixture of methane-sulfonic acid, trifluoromethanesulfonic acid and methanol 15 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 20 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. 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 trif luoromethanesulfonic 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 alkyl-benzenesulfonic acids, such as, for example, with p-methyl- or p-ethylbenzenesulfonic acid. 7-ACS p-toluene-sulfonate 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, 10 - 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 ci manner. - 4 - 23 7 0 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 5 and no longer requires further purification. The examples which follow illustrate the present invention but without restricting it to them. Example 1 7-Amino-3-methoxymethylceph-3-em-4-carboxylie acid 10 20 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 15 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 20 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 % accord-25 ing to HPLC were obtained. XH NMR (270 MHz, DMSO-d6) : 6 = 3.20 (s, 3H, OCH3), 3.35-3.60 (AB system, 2H, -S-CH2-) , 4.15 (s, 2H, -CH2-0-) , 4.76 (d, J = 4 Hz, 1H, 6-H), 4.98 (d, J = 4 Hz, 1H, C-7). IR (KBr): 1800 cm"1 (^-lactam carbonyl) 30 C H N S C9H12N204S calc. 44.25 4.95 11.47 13.13 (244.265) found 44.0 5.0 11.4 13.5 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 237 0 6 3 Example 2 10 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 20°C for 10 2.5 hours, the pH was adjusted to 2.5 with about 40 ml of 40 % 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 15 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. WHAT WE CLAIM IS: - 6 - 237063 A process for the preparation of the compound of the formula I ch2och3 (I) which comprises reacting the compound of the formula II H2N\ XS j—*;ch2ococh3;c02h;(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 I 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.;•( ^ o-;mar mi1;• ■ " 7 " # ? 3 7 0 6;5. The use of the compound of the formula I obtained as votfe.;claimed in anyl of claims 1 to 4 for the preparation of a cephalosporin antibiotic by acylation of the amino group.;6. A process according to claim 1 substantially as herein described or exemplified.;tS Anj navel—featm'n—err—novel—c.ombinafci-on—ert—fiiaLuviu -;diocloocd—hereini;HOECHST AKTIENGESELLSCHAFT By Their Attorneys /;HENRY HUGHES LIMITED;a* 1 EN / ,:2 10 mar j992 V </div>