CZ156194A3 - PROCESS FOR PREPARING 5H-DIBENZO (b,f) AZEPINE-5-CARBOXAMIDE - Google Patents

Abstract

The prepn. of 5H-dibenz(b,f)azepine-5-carboxamide (I) comprises reacting imino-stilbene with an alkali cyanate in ethanoic acid, ethanoic acid/water or ethanoic acid/alcohol mixts..

Description

5H-dibenzo [b, f] azepine-5-carboxyamide

Technical field

AND

The invention relates to a method of manufacture

5H-dibenzo [b, f] azepine-5-carboxyamide. This substance is introduced in medicine under the name carbamazepine. It has rare physiological properties.

BACKGROUND OF THE INVENTION

Carbamazepine is used to treat many diseases of the central nervous system.

Several methods are known for the synthesis of carbamazepine.

Thus, carbamazepine can be produced by:

the reaction of iminostilbene with phosgene to

5H-dibenzo [b, f] azepine-5-carboxylic acid chloride followed by addition of ammonia to either the isolated compound or also to the reaction mixture obtained as disclosed in US-PS 2 948

718, DD-PS 297 962 and 298 508 as well as EP 423 679 or

Reaction of 10,1,1-dihydric-5H-dibenzo [b, f] azepine

1,3-dibromo-5,5-dimethylhydantoin, ammonia carbonate according to GB-PS 1 245 606, or

reaction of iminostilbene with an acyloisocyanide to

5H-dibenzo [b, f] azepine-5- (N-acyl) carboxamide and subsequent hydrolysis, see DE-OS 23 07 174 or

- by reacting 5- (methylisothiocarbamoyl) -5H-dibenzo [b, f] azepine hydrosubstance with phosgene, potassium and iodide with an alkali, as disclosed in DE-OS 26 37 666, or

- acid or alkaline hydrolysis

5-cyano-5H-dibenz (b, f) azepine as disclosed in EP 029 '409.

These known processes have a number of disadvantages. For example, many of these processes require the use of highly toxic phosgene or halogenate. In the synthesis - according to DE-OS 23 07 174, an unstable and difficult to access acylisocyanide is required. DE-OS 26 37 666 produces toxic methylmercaptan as a by-product.

Carbamazepine can be further produced by:

- by reacting iminostilbene with cyanoic acid in an organic solvent or mixture in the presence of an acidifying agent - see 277 EP 277 095. The acidifying agent participates only catalytically in the reaction and serves to increase the reaction rate of iminostilbene and cyanoic acid,

The cyano acid required for the reaction is introduced into the reaction mixture as a gas, but can also be obtained by treating the cyano acid salt with an acid. Since cyanoic acid produces undesirable side reactions with water, alcohols and amines, the reaction takes place under additional conditions, i.e. preferably in organic solutions without water, alcohols and amines, and with the exclusion of water vapor.

These conditions make the overall reaction difficult and require additional material and technical costs.

SUMMARY OF THE INVENTION

The present invention resides. .based. A technically simple process for the production of carbamazepine, which has no advantage. _. According to the present invention. s_e will surprise v.g. This is achieved by reacting iminostilbene in acetic acid, aqueous acetic acid solution or in alcoholic acetic acid solution with alkali cyanides.

The reaction of iminostilbenes with an alkali cyanide such as sodium or potassium cyanide can be carried out at temperatures of 20 to 100 ° C.

A preferred embodiment of the process according to the invention consists in slowly adding alkali cyanide to the mixed suspension iminostilbene in acetic acid solution at 60 ° C, the excess cyanide being about 50 mol%, based on iminostilbene.

According to the process according to the invention, the water content of the aqueous acetic acid solution can be up to 20% by weight.

If the reaction according to the invention is carried out in an alcoholic acetic acid solution, this solution may contain up to 10% by weight of acetic acid. alcohol. . ....... _....... ...... ............... -Preferably used for this reaction from alcohols - • • methanol ^: and ethanol; '' ~ '

The gradual addition of the alkali cyanide may be effected in portions. However, it is preferable to add an aqueous alkaline cyanide solution dropwise, especially when slightly water soluble potassium cyanide is used. By dropwise addition of an aqueous alkali cyanide solution, the process according to the invention can be realized in a particularly simple manner technically.

The solvent mixture used for the reaction of iminostilbene with an alkaline cyanide can be used for the further reaction according to the invention after distillation from the reaction mixture.

The result of the process according to the invention is surprising in many respects.

Although it is known in the literature that many aromatic primary amines can react in aqueous acetic acid with alkali cyanides to the corresponding urea derivatives. According to Kurzer (Org. Synth. Col. Volume IV, p. 49), acetic acid-water is employed in a ratio of 1:10 to 1: 1.

However, under these conditions, the reaction of iminostilbene, a secondary diarylamine, with alkaline cyanides fails. Firstly, iminostilbene has a very low alkalinity over said aromatic primary amines, and secondly, iminostilbene has a much lower solubility in acetic acid than these amines. This low solubility is further reduced by the addition of water as well as by the addition of alcohol.

*

According to the explanation in EP 277 095, the skilled person even had to assume that the traces of water such as contained in the air are negat- ing outside and, if necessary, preventing it from reacting unexpectedly.

Therefore, it could not be assumed that the reaction of iminostilbene with alkali cyanides would occur easily and with a very good yield in acetic acid solution with up to 20% by weight. water, based on the total amount of solvent.

Just as surprisingly, the high yield of the reaction according to the invention in an alcoholic acetic acid solution was surprising.

...... ...........As. . yyh.o.da_s.e. ". .first. It has been shown to carry out the reaction according to the invention in acetic acid solution, with very good results. . It is believed that one of the following examples is m.n.o. s-5-a--10 =% -v-y-n-e-bo-a-k-o-1-u- in this solution.

DETAILED DESCRIPTION OF THE INVENTION

The method according to the invention is based on the fact that it is also possible to help. of the following exemplary embodiments.

Example 1

The mixed suspension of 100 g of iminostilbene in 1000 ml of acetic acid is heated to 60 ° C. Then 54 g of 90 percent sodium cyanide are added in eleven portions over 160 minutes.

During the reaction, iminostilbene almost completely dissolves before crystallization of carbamazepine begins. After the addition of sodium cyanide was complete, the reaction mixture was further stirred at 60 ° for 20 minutes. Finally, it is cooled to 18-20 °

C and stirred at this temperature for two hours.

The carbamazepine formed is aspirated, washed with 60 ml of anhydrous acetic acid and dried.

___ ___ ___ ___ .0 .0 - .0 .0 - _1 .0 .0 .0 .0 .0 .0 .0 .0 .0 .0 .0 .0 .0 .0 .0 .0 .0 .0 .0 .0 .0 .0 .0 .0 .0 .0 .0

193 to 194 ^° C. From the mother liquor, the water stream is removed.

distills off acetic acid. Sodium acetate is separated from the remaining residue with water, carbamazepine is filtered off with suction, dried and recrystallized from toluene. This gives an additional 9.8 g, i.e., 8%, of carbamazepane with a flow point of 191-193 ^° C. The total yield of the carbamazepane is 95 ° C. ------ ----- - - · ·· ...................- .......

Example 2

A suspension of 100 g of iminostilbene in a solution of 900 ml of anhydrous acetic acid and 100 ml of water is heated to 60 DEG C. with stirring. Then 58.3 g of ninety percent sodium cyanide are added in 16 portions over 2.75 hours. After two hours of reaction, a brief heating at 80 ° C is performed to convert the undissolved iminostilbene into solution.

After completion of the addition of sodium cyanide, the reaction mixture is cooled to 18-20 ° C and stirred at this temperature for 0.5 h. The resulting carbamazepine is filtered off, washed with a solution of 63 ml of acetic acid and 9 ml of water and dried se.

The yield is 110.1 g, i.e. 89.8%, the flow point being

131-195 ° C.

From the mother residue remaining, carbamazepine is obtained, further dried, the lye is distilled off with water, the acetate is separated and recrystallized in a solvent. From sodium, aspirate with toluene. Thus, g, i.e. 4.1X, of carbamazepine with a flow point

188 DEG-190 DEG C. The overall yield is 93.9%.

Example 3

A suspension of 30 g of iminostilbene in a solution of 225 ml of acetic acid and 45 ml of water is heated to 60 DEG C. while stirring. Then 17.5 g of ninety percent sodium cyanide are added in 16 portions over a period of 2.75 hours. After a 1.5 hour reaction, the reaction mixture is briefly heated to 80 ° C to dissolve a small amount of undissolved iminostilbene.

After the addition of sodium cyanide was complete, the reaction was continued

....., - S-Ei. held for 10 min. at 60 ° -6 °. -POtOm-se-cooled and held at ------ 20 ° C for 1 hour. at this temperature. It sucks off emerging

- ca rb amaz ep-i na- prearný va = s e- 2 0- - ml- roz to ku'-ky setin y · ό © vé “Vé” v od ν '“'“ l_.? L.Dried., ..............., ________...._____________________ _______________________

Yield: 32.9 g (89.2%), flow point 189-191 ° C. . distills off the remainder. solvent. Sodium acetate is separated from the remaining residue with water and dried with water. The recrystallization is also carried out in toluene. This gives an additional 1.8 g, i.e. 4.8%, of carbamazepine with a flow point of 191-193 ° C. This gives a total yield of 94%.

Example 4

A suspension of 60 g of iminostilbene in 600 ml of acetic acid is heated to 60 ° C with stirring. A solution is then formed from 40 g of 90% potassium cyanide and 66 ml of water and added dropwise over two hours. In the meantime, the reaction mixture is briefly heated to 80 ° C to dissolve the undissolved iminostilbene.

After the addition of potassium cyanide is complete, the reaction mixture is cooled to room temperature, the carbamazepine is aspirated and dried. 33 g (89.9%) of carbamazepine having a melting point of 33% is obtained. Other- 1-9-0 — a-z — 1-9-3- ° - G- .---- · ----------------- ^: —— By treatment of the mother liquor analogous to Example 3, an additional 3.3 g of carbamazepine is obtained. This yields a total of 93.2%.

Example 5

The stirred suspension of 100 g of iminostilbene in a solution of 1000 ml of acetic acid and 150 ml of water is heated to 60 ° C. Then 98% potassium cyanide is added in 13 portions over a period of 5 hours.

After the addition of potassium cyanide, the reaction mixture is left for 30 min. The precipitated crystals are filtered off with suction, washed with 60 ml of acetic acid and 400 ml of water and dried.

The yield is 11.2 g, i.e. 90.2%, of carbamazepine with a flow point of 1.91 to 193 °. C. The solvent was distilled off from the mother liquor and potassium acetate was separated from the residue with water. The carbamazepine is aspirated, washed with water, recrystallized from toluene and dried. This gives an additional 7.5 g, i.e. 6.1%, of carbamazepine with a flow point of 190-192 ° C. The overall yield is thus clear 97%.

Example 6 kg of iminostilbene in a solution of 28.5 L of acid *

acetic acid and 1.5 L of water are heated to 60 ° C with stirring. 1.66 kg of 98 percent sodium cyanide are added over 2 hours, the mixture is cooled to 15 ° C, and the pellet is kept at 20-15 for 2 hours. C., carbamazepine is aspirated, washed with 2 L of acetic acid and dried.

The yield of carbamazepine is 3.39 kg, i.e. 92.5%, with a flow rate of 190-192 ° C. After distilling off 22 liters of acetic acid and adding 10 liters of water to the residue, stirring briefly, aspirating and washing with 5 liters of water and also drying a further 0.28 kg of product is obtained which, after recrystallization from toluene, is 0.23 kg, i.e. 6.3%. The total yield is 98.8%.

Example 7 ~ _? _ ^ ^Z Jg.Ln. ^on the eye tilbenuj _r soln * 3 6 0 1 ^ m ^ c aci yn-yo in Star and 50 ml of ethanol was warmed to 6 ° £ C_a pří_této temperature - the Sh-h em -1 -, - 5- Ίϊό (iT 'adds 20 g 9 ϊρ c t c 7 7 j j j du du or s s or), briefly warm to 80 ° C, stir for an hour at 50 ° C and cool to 15 ° C, suck off carbamazepine, followed by washing with 20 ml of acetic acid and drying.

The yield of carbamazepine is 29.4 g, i.e. 80.3%, the liquidity point being 18'9 to 1920 e. After adding 1 g of sodium cyanide to the mother liquor, distilling the mother liquor, adding water to the residue after distillation and recrystallizing dry For example, the carbamazepine product produced from toluene gave a further carbamazepine with a flow point of 190-193 ° C.

Claims (2)

A process for the preparation of SH-dibenzo [b, f] azepine-5-carboxyamide, characterized in that iminostilbene is reacted with alkali cyanides in acetic acid, in aqueous acetic acid or in alcoholic acetic acid. The process according to claim 1, wherein the aqueous acetic acid solution contains up to 20% by weight. water. The process of claim 1 wherein the acetic acid comprises up to 10 wt A process according to claim 1 and methanol or ethanol, in that the alcoholic. alcohol. 3 wherein the solution is an alcohol Process according to claims 1 to 4, characterized in that the alkali cyanide is added gradually to the reaction mixture. Process according to claims 1 to 5, characterized in that the cyanide is added in an aqueous solution. that is alkaline The process according to claims 1 to 6, wherein the alkaline cyanide is sodium cyanide or potassium cyanide. <2. technically particularly simple. _{_:} _____J rcg.s P £ ,, ^extended mouth Diluted one used for live and,. _The reaction with alkaline cyanide may be used for further reaction according to the invention after distillation. ____ The result of the process according to the invention is z reaction. blends in many ways surprising, too! Although it is known in the literature that many aromatic primary amines can react in aqueous acetic acid with alkali cyanides to give the corresponding urea derivatives. According to Kurzer (Org. Synth. Col. Volume IV, p. 49), acetic acid-water is employed in a ratio of 1:10 to 1: 1. However, under these conditions, the reaction of the immunity of 1bene, a secondary diarylamine, with alkaline cyanides fails. Firstly, iminostilbene has a very low alkalinity over said aromatic primary amines, and secondly, iminostilbene has a much lower solubility in acetic acid than these amines. This low solubility decreases further by the addition of water as well as by the addition of alcohol .........., ......... As explained in EP 277,095 even expert had to assume. That ..samy traces of water ·, ·· ja splaying-are obs'aženy 'in the air adversely affect ^one or zabraňují__o., Č.ekavan, é_r_e.ak-ci -._ '3' y It could not therefore be assumed that. the reaction of iminostilbene with alkali cyanides occurs readily and with very good yield in acetic acid solution with up to 20 wt. water, based on the total amount of solvent. Just as surprisingly, the high yield of the reaction according to the invention in an alcoholic acetic acid solution was surprising.