HU201079B - New process for producing 6-((hexahydro-1h-azepin-1-yl)-methylenamino)-penicillanic acid (mecillinam) - Google Patents

Abstract

By a novel method 6(7 hexa:hydro-1H-azepine -1-yl)-methylene-amino) penicillanic-acid (mecillinam) is prepd. from 6-amino-penicillanic-acid and N-formyl-hexa-methylene -ammino-di:methyl-sulphate complex in the presence of a tertiary, pref. tri:ethyl-amine. The reaction medium is a bi-polar aprotic solvent as acetonitrile or mixt. of an aprotic solvent and a polar or protic solvent. A catalyst is used. The reaction mix is concentrated in vacuo and the prod. is isolated from its acetone soln. by the addn. of p-toluene-sulphonic-acid of pref. 10 vol.%.

Description

The present invention relates to a process for the preparation of 6 - [(hexahydro-1H-azepin-1-yl) methyleneamino] penicillanic acid (mecylamine) by reacting 6-aminopenicillanic acid with an N-formylhexamethylenimine dimethyl sulfate complex. reaction in a dipolar aprotic solvent, preferably acetonitrile, or a mixture of dipolar aprotic solvent and apolar or protic solvent in the presence of a catalyst. After deprotection of the reaction mixture, the mecillin is isolated from acetone, preferably with a 10% solution of p-toluenesulfonic acid.

The process of the invention is suitable for the simple and economical production of mecillin dynamically on an industrial scale.

Mecillin has a significant antibacterial effect, especially against gram-negative bacteria. Its advantage is that its toxicity is extremely low.

It is known that the mecillin mine can be prepared essentially in two ways.

On the one hand, by reacting a reactive 6-aminopenicillanic acid derivative with hexamethylenimine as disclosed in U.S. Patent Nos. 2,530,299 and British Patent Specification 1,312,030, a 6-formylaminopenicillanic acid derivative and an equivalent amount of 1 A mixture of 1-dichloro-dimethyl ether with hexamethyleneimine. The reaction is difficult to carry out on an industrial scale due to the long reaction time and the difficulty in preparing, purifying and storing the reactants.

On the other hand, mecylamine can be prepared by reaction of 6-aminopenicillanic acid with a reactive hexamethyleneimine derivative. This can be done with chloroformimine chloride from N-formylhexamethylenimine in U.S. Patent Nos. 2,055,531, 2,440,587, 2,311,131, UK 1,312,030, US 4,089,963 and US 84,031, 90,544. , Polish Patent Specification 162,258.

The disadvantage of the method is that it cannot be used as an industrial solution due to the extreme reaction conditions (-70 ° C) and the production and degradation of the reactive chloroformimine chloride.

In the German Patent Nos. 2,404,587, 2,530,299, 3,012,667 and Spanish Patent Nos. 459,103, an iminium ether derivative such as N-formylhexamethylenimine dimethyl sulfate or fluorosulfonate complex is used as the reactive hexamethylenimine derivative.

Given that the N-formylhexaraethylenimine dimethylsulfate complex is easy to prepare and purify and store for several months (Bér. 96 1350, 1962), it is also possible for industrial scale production. However, the previously known methods using the N-formylhexamethylenimine dimethylsulfate complex have a relatively low yield (68-74%).

It is an object of the present invention to provide a simple and economical process for the production of mecillin in industrial scale.

The patents mentioned above use a protic or apolar solvent as the reaction medium. It has been found that the reaction is carried out in a dipolar aprotic solvent, preferably acetonitrile, with a yield greater than 15%. It is further recognized that in the presence of catalytic amounts of potassium iodide, methyl iodide, or potassium um-rhodanide, the reaction time is reduced by half, thereby reducing side reactions and, at the same time, increasing yields to produce a purer product. This multiple positive effect is probably due to the increased reactivity of the complex due to the anion exchange.

The same good results were obtained when working with a mixture of acetonitrile in different ratios with different apolar or protic solvents.

According to the process of the invention, 6-aminopenicillanic acid is present in the presence of 2.0 to 3.0 equivalents of tertiary amine, preferably triethylamine, in a dipolar aprotic solvent, preferably acetonitrile, of 1.0 to 2.0, preferably 1.3 -1.5 equivalents of N-formylhexamethylenimine dimethyl sulfate complex are reacted at -10 to +30 ° C, preferably 20-25 ° C for one hour. The reaction mixture is de-solvented and the residue is dissolved in acetone and the final product is isolated by a solution of p-toluenesulfonic acid in pH 7.2-7.5, preferably 10% acetone.

The mecillin obtained in this way is of sufficient purity and can be used without further purification.

The process of the present invention is illustrated by the following examples, without limiting our claims.

Example 1

216 g (1 mol) of 6-aminopenicillanic acid

Suspend in 800 mL of acetonitrile, add 420 mL (3 mol) of triethylamine, add 330 g (1.3 mol) of N-formylhexamethylenimine dimethyl sulfate complex, catalytic amount of potassium rhodanide, and 20-25 ° C. stir for 1 hour.

At the end of the reaction, the mixture was evaporated and the residue was dissolved in 1 liter of acetone and 10% p-toluenesulfonic acid solution was added to pH 7.5. The precipitated crystals were filtered off, washed with acetone and dried in vacuo.

Yield: 262 g (80%)

158-160 ° C

IR (in KBr): 1760, 1680, 1605 cm @ -1 @ ¹ H NMR: (DMSO, 200 MHz):

1.58 ppm, 1.72 ppm [s, 3H, C-2, (CH ₃ ) ₂ ]; 1.4-2.0 ppm [m, 8H, (CH2 M]; 3.45-3.9 ppm (m, 4H, CH2-N-CH2); 4.34 ppm (s, 1H, C-3H); 5.62

HU 201079 Β ppm (d, 1H, C-5H); 5.47 ppm (d, 1H, C-6H); 8.03 ppm (s, 1H, N-CH = N);

^ 0 = + 285 (c = 1, 0.1 N 11 Cl)

Example 2

To a suspension of 21.6 g (0.1 mol) of 6-aminopenicillanic acid in 80 ml of acetonitrile was added 42 ml (0.3 mol) of triethylamine. To the resulting solution was added 33 g (0.13 mol) of N-formylhexamethylenimine dimethyl sulfate complex and a catalytic amount of potassium iodide at 20-25 ° C. The reaction mixture was stirred for half an hour and then concentrated in vacuo. Mecillinamide was removed by filtration, washed with acetone and dried in vacuo to give 28.2 g (86.5%) of m.p. 158-160. C

The final product has the same quality parameters as in Example 1.

Example 3

To a suspension of 21.6 g (0.1 mol) of 6-aminopenicillanic acid in 70 ml of acetonitrile and 10 ml of dichloromethane is added 36 ml (0.25 mol) of triethylamine. To the resulting solution was added 33 g (0.13 mol) of N-formylhexamethylenimine dimethyl sulfate complex and a catalytic amount of methyl iodide with stirring at 20-25 ° C. The reaction mixture was stirred for half an hour and then stripped of solvent. The residue is dissolved in 100 ml of acetone and the product is precipitated with 10% p-toluenesulfonic acid at pH 7.2-7.5. The precipitate was filtered off, washed with acetone and dried in vacuo.

Yield: 28.2 g (86.5%) M.p .: 158-160 ° C

The quality parameters of the final product are the same as those given in Example 1.

Example 4

To a suspension of 21.6 g (0.1 mol) of 6-aminopenicillanic acid in 80 ml of acetonitrile containing 10% methanol was added 36 ml (0.25 mol) of triethylamine. To the resulting solution was added 33 g (0.13 mol) of N-forrylhexamethylenimine dimethyl sulfate complex and a catalytic amount of methyl iodide with stirring at 20-25 ° C. The reaction mixture was stirred for half an hour and then stripped of solvent. The residue is dissolved in 100 ml of acetone and the product is precipitated with 10% p-toluenesulfonic acid at pH 7.2-7.5. The precipitate was filtered off, washed with acetone and dried in vacuo.

Yield: 28.4 g (87.2%) M.p .: 158-160 ° C

The final product has the same quality parameters as in Example 1.

The process according to the invention can be carried out in a much simpler manner than in the prior art in a very short time, in 82-87% yield, and the product thus obtained can be used directly without further purification.

Claims (4)

Process for the preparation of 6 - [(hexahydro-1H-azepin-1-yl) methyleneamino] penicillanic acid (mecillin) by reaction of a complex of 6-aminopenicillanic acid with N-formylhexamethylenimine dimethyl sulfate, preferably triethylamine In the presence of 25 and then concentrating the reaction mixture in vacuo, separating the final product with p-toluenesulfonic acid, characterized in that the reaction is carried out in a dipolar aprotic solvent (Debye: 2.5-2.8), preferably In acetonitrile or in a mixture of dipolar aprotic solvent and apolar (Debye: 1.1-1.8) or protic solvent in the presence of methyl iodide, potassium iodide or potassium rhodanide as catalyst and then concentrating the reaction mixture in vacuo. in a manner known per se, the final product is isolated from acetone with p-toluenesulfonic acid, preferably 10% by weight. The method of claim 1, wherein 4θ characterized in that 2-3 molar equivalents of triethylamine are used when the appropriate solvent or mixture of solvents is used. Process according to claim 1 or 2, characterized in that the reaction temperature is maintained at -10 to +30 ° C, preferably at 20-25 ° C. 4. A method according to any one of the preceding claims, characterized in that i is used in the case of applying _this megfe50 IO solvent is N-formyl-hexamethyleneimine-dimethyl ezulfát complex is 1.0 to 2.0, preferably 1.3 to 1.5 equivalents.