DD204915B1 - METHOD OF PREPARING PURE N- (4- (BETA-WELDED BRACKET ON 2-METHOXY-5-CHLORO-BENZAMIDO WELDED BRACKET TO -ETHYL) -PHENYLSULFONYL) -N'-CYCLOHEXYL HARDILLARY - Google Patents

Description

Field of application of the invention

The invention relates to a process for the preparation of pure N- [4- (/ 3- {2-methoxy-5-chloro-benzamido} -ethyl) -phthalylsulfonyl] -N'-cyclohexylurea (I) which, when administered orally, strongly reduces blood sugar acts

Characteristic of the known technical solutions

I can ζ B according to the Dutch Patent Application No. 6610580 by prolonged heating of the N- [4- (ß- {2-methoxy-5-ch! Orbenzamido} -ethyl) phenylsulfonyl] urea with cyclohexylamine in toluene or by reacting 4 [/ 3- (2-methoxy-5-chlorobenzamidoylethyl) phenylsulfonamide (II) are prepared with cyclohexyl isocyanate in acetone / K ₂ CO ₃ (see also DE-AS 1301812)

In DE-AS 1283837, the preparation of I, inter alia, by reacting N- [4- (/ 3- {2-methoxy-5-chlorbenzamido} -ethyl) -phenylsulfonylM 1-pentamethylensemicarbazid with cyclohexylamine in dioxane described as other methods of preparation the reactions of II with dichloroacetic acid cyclohexylamide (DD-PS 99161, DE-OS 2213602) or of N- [4 - (/) - {2-methoxy-S-chlorobenzamido-1-hydroxy-phenylsulfonyl] -immo-IS-oxathiolane with cyclohexylamine (DD) PS 105215) cited these known production process but still adhere to various shortcomings, such as longer reaction times at higher temperatures, which favored because of the thermal instability of I decomposition reactions and thereby unfavorable influence on yield and purity In the preparation of I from the corresponding 1 3-Oxathiolan Although a very pure product is obtained, but the use of carbon disulfide requires an increased technical effort Also in the preferred literature according to the literature For the preparation of I, the reaction of II with cyclohexyl isocyanate in acetone in the presence of potassium carbonate, a crude product containing several percent of unreacted II and dicyclohexylurea impurities is obtained. Because of the similar solubility properties, II and the dicyclohexylurea are difficult to remove from I.

In the recrystallization from methanol (NL-OS 6610580) occur due to the alcoholysis large losses and the cleaning effect is insufficient

The dicyclohexylurea can be separated according to DD-PS 91647 by dissolving the crude product in 25 parts of 0.1 η potassium hydroxide solution. This procedure, however, is very laborious and expensive in terms of volume and leads to no significant reduction of the II content It is also known from Canadian Patent No. 889876 (& DE-AS 2144303) that the purification of I is very difficult and that itself is not removed from I, so that another cleaning operation must be carried out to remove this contamination Multiple recrystallizations do not lead to a product which is sufficiently pure by chromatography. According to this patent, a purification is achieved when I is first converted into an alkali metal salt and released from it by acidification with excess acetic acid in methanol. However, sodium methylate and ether are used for the preparation of the sodium salt required

As extensive own experiments on this point, this process for the complete separation of II, which is used in most technical processes as a starting material, not optimal Since Il is also the hydrolysis product of I, when purifying I over the salts or recrystallization From I the possibilities for hydrolysis are excluded

In the vast majority of examples, methanol is used as recrystallization solvent. Methanol and other alcohols, however, are unsuitable for recrystallization because I is cleaved on heating and the resulting 4- [8- (2-methoxy-5-chlorobenzamido) -ethyl] - This results in considerable yield losses and the product used is additionally contaminated by the urethane or its Cyclohexylaminsalz (see DD-PS 91647) The technical preparation of a sufficiently pure for pharmaceutical uses product according to the known methods therefore remains a particular problem

-2- 235 807 0

Object of the invention

The invention makes it possible to produce I in high yield and purity in a technically simple manner and under optimum conditions both during the reaction and during the purification

Explanation of the essence of the invention

The object of the invention is to find a technically simple process for the preparation of a pure I which meets the high requirements of an active substance intended for pharmaceutical use. The invention is achieved by heating II with potassium carbonate in a mixture of acetone and dimethylformamide, wherein the potassium salt of Il is formed, which is partially dissolved in it, and by the addition of cyclohexyl isocyanate and subsequent further reaction to the potassium salt of I, which precipitates as sparingly soluble salt already at boiling temperature as by-products fall potassium bicarbonate and N, N'-dicyclohexy! urea The condensation product is filtered off with the by-products and a small amount of the starting material Ii and boiled with an alcohol, expediently with methanol or ethanol, wherein the Ν, Ν'-dicyclohexylurea completely and unreacted II are leached out for the most part The salt mixture obtained is suspended in water and acidified with an inorganic or organic acid, preferably hydrochloric acid, to give a very pure I whose content of II ~ 0.2%

If desired, by twice boiling the obtained potassium salt of I with alcohol, the content of II can be further reduced so that pure egg is obtained after acidification. Finally, the resulting product is either suspended at boiling temperature in acetone, or by dropwise addition of dimethylformamide brought in solution, treated with activated charcoal and I precipitated again by dropwise addition of water below 50 ⁰ C or recrystallized from Athylenclorid By both variants of Knknstallisation (final cleaning) is a pure, crystalline I It is particularly advantageous if one in the reaction, the solvent Acetone and dimethylformamide in the ratio 3 1 to 3 · 2 is used

The addition of dimethylformamide to the acetone, the reaction of Il with cyclohexyl isocyanate to I wesent I improved so that I in about 99% conversion is obtained Since the potassium salt of Il in this solvent mixture /.um part dissolved, the reaction with The potassium salt of I which is formed in the reaction is very sparingly soluble in the solvent combination according to the invention and precipitates completely, which likewise promotes quantitative conversion. 2% unreacted Il and several percent dicyclohexylurea, which always arises from the Cydlohexylisocyanat with at

By boil-out of the potassium salt of I with an alcohol, the dicyclohexylurea completely and at the same time also the unreacted II are largely leached out. The I obtained after the subsequent acidification shows next to the main spot (I) in the thin-layer chromatogram only a small spot of II in the order of -0.2% By contrast, according to the procedure described in DD-PS 91647, although the dicyclohexylurea could be completely separated off, whereas the separation of about 1% of II is no longer possible. Also, when heating I with potassium hydroxide solution immei there is a risk that part of I hydrolyzes again

It was completely surprising and unexpected that when boiling the potassium salt of I with alcohols such as methanol or ethanol, no alcoholysis occurs to form the urethane, which takes place immediately upon heating I In the reclabelling of I, for example, from ethylene chloride or when dissolving in Acetone / dimethylformamide and precipitation with water at low temperatures excludes hydrolysis

The success of the inventive method was not expected and completely surprising, since once reactions in pure dimethylformamide brought no advantages in terms of yield and purity of the crude product over the prior art procedure in acetone and the boiling out of the condensation product with alcoholein an alcoholysis should occur to form the corresponding urethane Furthermore, it was completely surprising that in addition to the N, N'-Dicyclohexylhamstoff also the largest part of Il is removed with

exemplary

41 g of 4- [j8- (2-methoxy-5-chlorobenzamido) -ethyl] -phenyl-sulfonamide (II) are refluxed with 31 g of potassium carbonate in 80 ml of dimethylformamide and 220 ml of acetone under stirring for 3 hours 1 hour 15.5 ml of cyclohexyl isocyanate, dissolved in 20 ml of acetone, to the boiling solution and stirred for a further 5 hours under reflux. Cooling is suctioned off, washed with 50 ml of acetone and the condensation product is boiled with 500 ml of methanol or ethanol for 30 minutes with stirring. After cooling to 3O ⁰ C is the undissolved filtered off, washed with 50 ml of the alcohol, suspended in 800 ml of water and acidified slowly with 1 1 of dilute hydrochloric acid while stirring to pH = 1 and 3 hours nachgeruhrt The N- [4- (ß- {2-methoxy-5-chlorbenzamido } -ethyl) -phenylsulfonyl-N'-cyclohexylurea (I) is filtered off with suction, washed neutral with water and dried

Yield 52.5 g - 95%, mp 171-172 ⁰ C.

Dunnaschichtchromatogramm 0.2% starting material (II)

52.5g I are suspended in 360ml acetone! heated to boiling By dropwise addition of about 66ml of dimethylformamide to the boiling mixture, the product is just put into solution After addition of 4g of activated charcoal and lOminutigen heating, the solution is filtered and added to the clear solution below 50 ° C 200 ml of water is added dropwise Let proceed under stirring , stirred for 3 hours at room temperature and sucks off the crystals, which are washed with water and acetone After drying, 46 g = 84% I, mp 173-174 ° C.

Thin layer chromatogram traces up to 0.2% starting material (II)

Recrystallization from ethylene chloride gives 48 g = 87.5% of theory, mp 173-174 ° C.

Claims (3)

-ι- 235 807 0 Invention claim. 1 Process for the preparation of pure N- [4 - (/ 3 {2-methoxy-5-chloro-benzamido-ethyl) -phenylsulfonyl] -N'-cyclohexylurea (I) from 4 - [/ 3- (2-methoxy-) 5-chloro-benzamido) -thyl] phenylsulfonamide (II) and cyclohexyl isocyanate in a dipolaraprotomschen solvent in the presence of potassium carbonate, characterized in that II is heated with potassium carbonate in a mixture with acetone and dimethylformamide and the reaction mixture obtained by adding cyclohexyl isocyanate further heating to the potassium salt of I, this is separated, boiled with alcohol, the residue is suspended in water and I precipitated by acidification and optionally for further purification a) suspended in acetone in the boiling heat, brought by dropwise addition of dimethylformamide in solution, optionally treated with activated charcoal, precipitated at temperatures below 50 ⁰ C by addition of water, the I and optionally umklestallisiert from Athylenclond, b) recrystallized from Athylenclorid 2 Process according to item 1, characterized in that the solvents acetone and dimethylformamide are preferably used in the ratio 3 1 to 3.2 3. The method according to points 1 and 2, characterized in that the boil-out with alcohols preferably with Methanol or ethanol, if necessary several times durchfuhrt
4 Process according to points 1 to 3, characterized in that one uses for acidification inorganic or organic acids, expediently hydrochloric acid