CS259750B1 - Process for preparing N * 1-butyl-N2- (p-methylbenzenesulfonyl) urea - Google Patents

Abstract

The solution concerns the production of the important oral antidiabetic N1-butyl-N2-.( p-methylbenzenesulfonyl)urea, known under various trade names. The reaction is carried out by distilling off water from wet tosylurea by azeotropic distillation with toluene and gasoline at temperatures from 80 to 96 degrees Celsius and subsequent boiling with butylamine at a temperature of 104 to 1'06 °C for 2 to 3 hours.

Description

The present invention relates to a process for the preparation of N-butyl-N ^from - (p-methylbenzenesulfonyl) urea, an important oral antidiabetic agent known under various trade names.

The processes known to date are based, for example, on p-toluenesulfochloride which, by reaction with O-methyl-N-n-butylisourea and subsequent hydrolysis of the resulting semi-product, provides the desired product.

However, most processes utilize the preparation of said product by reacting dry tosylurea with n-butylamine. Although this second process is considerably simpler than the first, it is demanding to carry out the reaction itself. The starting tosylurea must be perfectly dry, otherwise the yields and product quality will decrease. In view of these circumstances, as well as the need for maximum capacity, a special dryer is required with considerable purchase costs.

A further disadvantage of the reaction of tosylurea with n-butylamine is that it is limited to a relatively narrow temperature range above 104 ° C, which at technical boiling point of n-butylamine of 77.8 ° C raises technical problems when working in non-pressurized containers such as is required in production.

It has now been found that these deficiencies can be largely eliminated by the process for the preparation of N-butyl-N ( ² -p-methylbenzenesulfonyl) urea by reacting tosylurea with n-butylamine according to the invention. azeotropic distillation with toluene and petrol at temperatures from 80 to 96 ° C followed by boiling with n-butylamine at 104 to 106 ° C for 2 to 3 hours.

As experimentally confirmed, all the failures of the wet tosylurea experiments were that the azeotropic distillation must be conducted so that the temperature of the distilling reaction mixture was gradually from 80 to max. 96 ° C. This regime must be followed, as otherwise the cleavage of tosylurea into tosylamide occurs.

This was confirmed experimentally by studying the reaction of tosylurea with water versus temperature, the reaction of wet tosylurea and dry tosylurea with n-butylamine as a function of temperature. It has been found that tosylurea is already cleaved by water alone at a temperature above 90 ° C. Wet tosylurea is even easier to cleave with n-butylamine. In both cases, tosylamide is formed by cleavage of the carbamoyl group. In contrast, dry tosylurea does not undergo such cleavage and reacts with n-butylamine to provide the desired product.

The advantages of the process according to the invention are that it is not necessary to dry the starting tosylurea, thereby increasing the production capacity and saving the investment costs associated with the need for a corresponding dryer.

A further advantage is that it is operated in non-pressurized containers using a mixture of toluene and gasoline solvents in such a ratio that it is possible to reach a temperature of 104 to 106 ° C which is necessary for the reaction of tosylurea with n-butylamine to the desired product.

When all the water is distilled off, the reaction temperature is raised to 104-106 ° C and n-butylamine is added at this temperature. Boiling is continued for 2 to 3 hours. The product is isolated by generally known procedures, either by transfer to an aqueous-alkaline medium and separation from the toluene layer with a small amount of gasoline, or the solvents are distilled off, and the residue is precipitated with dilute hydrochloric acid after dissolution in water.

Further details will be apparent from the examples which illustrate the invention but do not limit it in any way.

Exemplary embodiment

Wet Tosylurea (71.9 g), corresponding to a dry matter of 47.5 g; 0.02 moles were added to the present toluene (219 g; 250 ml), gasoline (80 ml) was added and the reaction mixture was heated to boiling with stirring, which gradually increased from 82 to 96 ° C while distilling the toluene + mixture. gasoline and water. The time of azeptropical distillation takes about 60 minutes and about 120 to 140 ml of the mixture is distilled off. At the end of the distillation, when all the water had been removed, the temperature of the reaction mixture was raised to 104-106 ° C.

After this time, distillation was discontinued, the reaction mixture was cooled to 80 ° C, the distilled gasoline-toluene mixture was returned to the reaction, and more toluene (44 g; 50 mL) was added. N-Butylamine (17.25 g; 23 mL; 0.235 mol) was added to the reaction mixture over 15 minutes.

Again, the reaction mixture is heated to boiling (about 104-106 ° C) and boiled for a further 60 minutes. Additional n-butylamine (1.12 g; 1.5 mL; 0.025 mol) was then added and boiled again for 90 minutes. After this time, the reaction mixture is clear.

Now the reaction mixture can be worked up in two ways:

A) The mixture of toluene and petrol is distilled off to dryness from the reaction mixture under vacuum of the RV pump. The distillation residue was diluted with water (100 ml), 40% sodium hydroxide solution (NaOH; 8 ml) was added and the distillation residue dissolved at 50 ° C with stirring. The pH of the solution was adjusted to dilute the phenolphthalein paper with dilute hydrochloric acid (1: 1), charcoal was added and the solution was filtered.

Methanol (154 g; 195 ml) was added to the filtrate, the pH of the solution was adjusted again with a NaOH solution until a slightly pink color of phenolphthalein paper (about 0.3 ml), and after the addition of activated carbon was filtered again.

The filtrate temperature is adjusted to 33 ° C and acidified with dilute hydrochloric acid (1: 1) to pH 4.0 to 4.5 at this temperature.

259 excludes the desired product. After aspiration and washing with water (6 x 100 ml), the product is dried at 60 ° C to constant temperature. Scales. 45.25 g (75% based on tosylurea) of satisfactory quality of the prescribed USP were obtained.

b) The reaction mixture was cooled to 60 ° C and dilute sodium hydroxide solution (11 mL of 40% NaOH in 150 mL of water) was added.

After stirring for 15 minutes, the sodium salt product is transferred to an aqueous-alkaline layer which must be clear. If it is not, another sodium hydroxide solution must be added. In the separating funnel, this aqueous layer is separated from the toluene-gasoline layer and is further processed according to process a).

45.5 g of an American-quality product was obtained. pharmacopoeia (USP), which is in accordance with procedure a).

Claims (1)

Subject A process for the preparation of N ¹ -butyl-N ² - (p-methylbenzenesulfonyl) urea by reaction of tosylurea with n-butylamine, characterized in that the reaction is carried out by progressively distilling water from wet tosylurea by azeotropic invention by distillation with toluene / gasoline at 96 DEG C. followed by boiling with n-butylamine at 104 DEG-106 DEG C. for 2 to 3 hours.