PL153029B1 - Method for manufacturing n,n-/dibenzohexatrenyl/-ureas - Google Patents

Description

RZECZPOSPOLITA PATENT DESCRIPTION 153 029 POLAND

OFFICE

PATENT

RP

Additional patent to patent no - Int. Cl. ^s C07D 223/22

Reported: 88 07 06 '(P. 273553)

Priority - CZY1ELHU

DGÓL H

Application announced: 90 01 08

Patent description published: 1991 11 29

Inventor - Holder of the patent: Ciba - Geigy AG., Basel (Switzerland)

Method for the production of N, N- (dibenzohexatrienylene) ureas

The invention relates to a process for the preparation of N, N- (dibenzohexatrienylene) urea, especially 5H-doubenzo [b, f] azepinecarbonamide-5.

The method according to the invention consists in reacting a suitable N, N- (dibenzohexatrienylene) amine, in particular 5H-dibenzo [b, f] azepine (commonly known as iminostilbene), with cyanic acid.

5H-doubeneo [b, f] azepinocarbonamide-5, known under the trade name Carbamazepin as an active drug substance, is prepared according to US Pat. US US-PS No. 2,948,718 by reacting iminostilbene with phosgene to give 5H-dibeneo [b, f] azepine-5-carboxylic acid chloride, and further reacting the chloride with ammonia. In the process according to DE-A1, DE-A 2 307 174, iminostilbene is reacted with acyl isocyanate and the 5H-dibenzo [b, f] azepine-N-acyl / carbonamide-5 formed is subjected to basic hydrolysis. These known methods have significant disadvantages. Thus, it is always necessary to carry out two separate reaction steps, the first step of the process according to US Pat. US In US-PS No. 2,948,718 it is necessary to use equimolar amounts of highly toxic phosgene.

Therefore, the hitherto unresolved problem of developing such a method, which in one step would lead directly to 5H-dibeneo [b, f] aeepinocarbonamide-5, was taken as the basis of the invention.

The proposed solution according to the invention is very surprising, since it is known that iminostilbene and alkyl isocyanates do not react to the corresponding 5H-dibenzo [b, f] azepine / LN-alkyl / -carbonamides-5 (German Federal Laid-Open Document DE-A1 No. 2,307 174), and the reaction of N, N- (dibenzobutadienyl amines) with sodium cyanate and trifluoroacetic acid in benzene could not be transferred to N, N- (benzobutadienylene) amines and N, N- (dibenzobutadienylene) amines such as indole or carbazole (Chem. and Ind. 1965, pp. 1428-9).

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The cyanic acid used according to the invention to introduce the 5-carbamyl group is usually prepared by pyrolysis of cyanuric acid, by oxidizing the formamide with oxygen over a silver or copper contact, or by treating a solution and / or suspension of a salt of cyanate, preferably sodium or potassium cyanate, with an acid. . Free form cyanic acid is not stable. It undergoes numerous polymerization and self-condensation reactions, easily attaching water, alcohols, amines and the like. Cyanic acid solutions in suitable organic solvents, however, are sufficiently stable for the purpose of the invention.

The reaction according to the invention therefore preferably takes place in an organic solution, i.e. in an organic solvent medium or in an organic solvent mixture, cyanic acid primarily in the gaseous state, preferably diluted with an inert gas such as nitrogen or argon, being blown into the reaction system or released into the reaction system. it by treating the solution and / or suspension of a salt thereof, preferably sodium or potassium cyanate, with an acid.

Suitable organic solvents are those which do not react with the isocyanate acid or react so slowly that the reaction according to the invention is not adversely affected by the formation of undesirable intermediates. For example, aromatic or araliphatic hydrocarbons such as benzene or toluene, halogenoaliphatic compounds, e.g. 1,2-dichloroethane, aliphatic carboxylic acids and their aliphatic esters, such as lower alkanoic acids, e.g. acetic acid, or lower alkyl esters of lower alkanecarboxylic acids, are suitable. for example, ethyl acetate, further aliphatic ethers such as diethyl ether, dioxane, tetrahydrofuran and the like and mixtures thereof.

Since cyanic acid undergoes undesirable side reactions with water, alcohols, amines and the like, the reaction according to the invention is preferably carried out under highly aprotic conditions, i.e. in an organic solution almost free of water, alcohols and amines, and excluding the access of water vapor. These precautions are no longer necessary when working up the reaction mixture and isolating the addition product formed.

In the reaction according to the invention, at least an equimolar amount of cyanoic acid is needed relative to the amount of N, N- (dibenzohexatrienylene) amine used. In order to achieve a higher conversion, however, preferably about 1.05-2.5 molar, in particular about 1.25-2.25 molar, e.g. about 1.3-2.0 molar amount of cyanic acid, i.e. about

5-150%, preferably about 25-125%, such as about 30-100% excess of cyanic acid.

For liberating cyanic acid from its salts, which is a particularly preferred embodiment of the process according to the invention, generally all protic acids are suitable, the acidic strength of which is sufficient to displace cyanic acid from its salts. For example, inorganic acids, e.g. hydrochloric acid or sulfuric acid, organic sulfonic acids, such as C1-C7-alanesulfonic acids or optionally halogen- or C1-C4alkyl-substituted benzenesulfonic acids, e.g. methan-, ethane-, benzene- , p-toluene or p-bromobenzene sulfonic acid or organic carboxylic acids whose acid strength in the solvent used is at least in practice equivalent to that of formic acid, such as 2-mono-, 2,2-di- or 2,2-acids, 2-trihalocarboxylic acids with 2-7 carbon atoms, e.g. trichloroacetic acid.

The reaction of the N, N- (dibenzohexatrienyl) amine component with cyanic acid is spontaneous and slightly exothermic. The reaction parameters are not limiting. The reaction can, for example, be carried out at a temperature of about 0-120 ° C in a homogeneous or preferably heterogeneous phase. Nevertheless, the conversion and the reaction rate are accelerated by mild heating and / or the presence of an acidic agent. The reaction is therefore preferably carried out at room temperature, ie, from about 20 ° C, to about 100 ° C, and in the presence of an acidic agent. Since this agent only participates catalytically in the reaction, catalytic amounts of acid are generally sufficient. Generally, for 1 mole of N, N- (dibenzohexatrienylene) amine about 0.01-0.15, such as about 0.04-0.05, of the acid agent is quite sufficient. Only when using polybasic acids with distinctly different degrees of acidity, it should be taken into account when carrying out the reactions in the heterogeneous phase that acid salts may precipitate out, as a result of which some of the acid introduced is blocked.

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When sulfuric acid is used, therefore, for 1 mol of N, N- (dibenzohexatrienylene) amine, for example, up to 1.5, in particular about 1.105-1.4 molar equivalents of the acid are needed, which corresponds to about 0.525-0.7 mol of acid, i.e. An excess of 40% if the variant wherein cyanic acid is liberated from its salt is used and if the reaction is carried out in a heterogeneous phase. Of course, the acid catalytic agent may also be present or added in the form of the corresponding N, N- (dibenzohexatrienylene) amine salt.

Suitable acidic agents are, for example, the above-mentioned protic acids for the release of cyanoic acid, for example in the foregoing discussion of the release of cyanoic acid, and moreover, aliphatic carboxylic acids, such as alkanoic acids with 1 to 7 carbon atoms, e.g. acetic acid, in particular when the acid simultaneously serves as solvent. When a variant is used in which cyanic acid is released from its salt in situ, it is generally preferably low, i.e. about 0.5-10%, for example about 1-5%, and when using e.g. sulfuric acid, however, for the reasons discussed above about 5-40%, such as a 32% excess of acid used to liberate cyanic acid.

In a preferred embodiment of the process according to the invention, a suspension of N, N- (dibenzohexatrienylbene) amine, in particular iminostilbene, and at least an equimolar, in particular about 1.75-2.25 mol, for example about 2 molar amounts of sodium cyanate in toluene at a temperature of about 20-30 ° C, for example at room temperature to about 25 ° C, about 1.005-1.05, for example 1.02 mole, i.e. about 0.5-5%, for example, is added per mole of sodium cyanate. about 2% excess of trichloroacetic acid and heated if necessary to a temperature of about 40-80 ° C, for example about 50-65 ° C, or a suspension of N, N- (dibenzohexatrienyl) amine, especially iminostilbene, in acetic acid is mixed with with about 1.05-1.40 molar equivalents, corresponding to about 0.525-0.7 moles, i.e. about 5-40% excess, of sulfuric acid and then, relative to the amount of N, N- (dibenzohexatrienylene) amine added, the least equimolar amount, for example, per 1 mole of this amine is added about 1.25-1 , 75, e.g. about 1.6 moles of sodium cyanate, the procedure being carried out for example at a temperature of about 10-120 ° C, or about 1.02-1.40 mol, for example, in a suspension of sodium isocyanate in ethyl acetate, 1.05 molar, i.e. 1.04-1.06 molar amount, i.e. a small, preferably about 2-10%, e.g. about 5%, i.e. 4-6% excess, hydrogen chloride and then the relative amount of sodium cyanate used is added N, N- (dibenzohexatrienylene) amine is at most an equimolar amount, for example about 5-50 mol% deficiency, i.e. about 0.6-0.9 mol, e.g. about 0.75 mol per mol of sodium cyanate iminostilbene, the procedure being carried out preferably at a temperature of about 0-80 ° C, e.g. by heating after the addition of the amine component to a temperature of about 40-70 ° C.

In another preferred embodiment of the process according to the invention, at least an equimolar, for example approximately 1.25-1.75 molar, preferably approximately 1.4-1 molar, preferably approximately 1.4-1 molar suspension in acetic acid is introduced into the suspension of N, N (dibenzohexatrienylbene) amine, especially iminostilbene. 6 molar amount, i.e. for example about 25-75%, preferably 40-60% excess, of cyanic acid and heated if necessary to a temperature of about 25-50 ° C, or to a suspension of N, N- (dibenzohexatrienylene) amine, especially of iminostilbene, in toluene, xylene, 1,2-dichloroethane or ethyl acetate, first about 1.01-0.15 mole, e.g. about 0.01-0.12 mole%, i.e. about 1-15 mole%, e.g. about 1-12 mole% of hydrogen chloride and then at least equimolar, such as about 1.25-1.75 mole, preferably about 1.4-1.6 mole%, i.e., for example about 25-75 mole%, preferably about 40- A 60% excess of cyanic acid and heated to about 50-125 ° C if necessary, for example to about 75-100 ° C. In a variation of this variant, for a suspension of a mixture of N, N- (dibenzohexatrienylene) amine and one of its acid addition salts, for example a mixture of about 0.8-0.96, preferably about 0.85-0.95, mole parts of iminostilbene and about 0.04-0.2, preferably about 0.05-0.15, mole parts of stilbene hydrochloride (sum of the mole parts equal to 1), is included at least equimolar, for example about 1.25-1.75 mole, preferably about 1.4-1.6 molar amount, e.g., about 25-75%, preferably about 40-60% excess, of cyanic acid and heated to about 60-100 ° C if necessary. ,

The examples below illustrate the process according to the invention in more detail. In the examples, the temperatures are given in degrees Celsius.

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EXAMPLE 1 723 g of trichloroacetic acid are dissolved in 600 ml of toluene, and 407 g of iminostilbene and 290 g of sodium cyanate in 600 ml of toluene are added to a suspension over 1.5 hours, keeping the temperature at 25 ° C by cooling.

It is further reacted for 0.5 hours at 25 ° C and 1 hour at 50 ° C, then slowly added to 1,300 ml of water. It is then cooled to 20 ° C and the product is filtered off. It is washed with toluene and water and dried at 85-90 ° C in vacuo. 475 g of Carbamazepine are obtained.

Example II. 25 g of iminostilbene are suspended in 180 ml of acetic acid and slowly mixed with 14 g of 96% sulfuric acid. 13.5 g of sodium cyanate are added with vigorous stirring at 30 ° C.

The mixture is stirred for 3 hours at 30 ° C, the product is filtered off and washed with acetic acid and then with water. After drying at 80 ° C in vacuo, it is obtained

29.5 Carbamezepins.

Example III. 68 g of sodium cyanate are suspended in 1000 ml of ethyl acetate and 40 g of gaseous hydrogen chloride are introduced while stirring at room temperature. After 4 hours, the sodium chloride formed was filtered off and the clear filtrate was mixed with 155 g of iminostilbene. The reaction mixture is kept for 4-5 hours at 50 ° C, cooled to 0 ° C and the product is filtered off. After washing with a little ethyl acetate and drying at 80 ° C in vacuo, 177 g of Carbamazepine are obtained.

Example IV. 17.4 g of iminostilbene and 2.3 g of iminostilbene hydrochloride are suspended in 250 ml of toluene. The mixture is heated to 80 ° C and 6.5 g of monomeric cyanic acid are introduced in a nitrogen stream over 1.5 hours and then heated to 100 ° C for 0.5 hours. After cooling to 5 ° C, it is filtered, washed four times with cold toluene and dried at 60 ° C in vacuo. 18.5 g of Carbamazepine are obtained.

EXAMPLE 5 17.4 g of iminostilbene and 2.3 g of iminostilbene hydrochloride are suspended in 250 ml of xylene (mixture of xylene isomers). At 20 ° C, 6.5 g of monomeric cyanic acid are introduced in a nitrogen flow and reacted further for 4 hours at 30 ° C.

It is then cooled to 0 ° C, filtered and washed with xylene. After drying at 80 ° C. in vacuo, 22.1 g of carbamazepine are obtained.

Example VI. 19.3 g of iminostilbene are suspended in 200 ml of 1,2-dichloroethane. At a temperature of 25 [deg.] C., 4.5 g of hydrogen chloride are introduced first and then

6.5 g of gaseous cyanic acid (under a stream of nitrogen). This introduction is over 5 hours in small portions. It is further reacted for 1 hour, the product is filtered off and washed with 1,2-dichloroethane, then with water.

After drying at 60 ° C. in vacuo, 16.0 g of carbamazepine are obtained.

After the completion of the reaction, the batch performed in the same way was evaporated, the residue was cold extracted with toluene and filtered off. After washing with toluene and water and drying in a vacuum at 60 ° C, 22.5 g of Carbamazepine are obtained.

Example VII. 29.0 g of iminostilbene are suspended in 150 ml of ethyl acetate at 20 ° C. First, 0.6 g of hydrogen chloride are introduced and then 9.7 g of gaseous cyanic acid (in a nitrogen stream).

After stirring for 15 hours at 20 ° C, the product is filtered off, washed with ethyl acetate and then dried at 60 ° C in vacuo. 32.0 g of Carbamazepine are obtained.

In an analogous test carried out at a reaction temperature of 50 ° C, 29.4 g of Carbamazepine are obtained.

Example VIII. 19.3 g of iminostilbene are suspended in 200 ml of ethyl acetate and mixed with 1.0 ml of sulfuric acid (98% strength).

At a temperature of 25 [deg.] C., 6.5 g of monomeric cyanic acid (under a stream of nitrogen) are introduced. It is left to stand overnight, then evaporated to dryness in a vacuum and the residue is extracted with toluene. After filtration, washing with toluene and water and drying at 80 ° C in vacuo, 19.7 g of Carbamazepine are obtained.

Example IX. 19.3 g of iminostilbene are heated with 100 ml of acetic acid to 45 ° C. In 1.5 hours, 6.5 g of monomeric cyanic acid (stream

Nitrogen) and reacted further for 12 hours at 40 ° C. After cooling to 15 ° C, it is filtered, washed with cold acetic acid and dried in vacuo at 60 ° C. The obtained crude product was recrystallized from methanol / water (7: 3) yielding 19.1 g of Carbamazepine.

Example X. 29, 0 g iminostilbene is heated in 150 ml acetic acid to 45 ° C. 9.7 g of monomeric cyanic acid (under a stream of nitrogen) are introduced in 1.5 hours and reacted further for 2 hours at 40 ° C and for 12 hours at 20 ° C.

After adding 15 ml of water, it is cooled to 0 ° C and filtered after 1 hour. It is washed twice with 15 ml of acetic acid and water to give a crude product which, after recrystallization from methanol / water (7: 3), is 29.1 g of Carbamazepine.

Claims (18)

Patent claims e 1. Method for the production of N, N- (dibenzohexatrienylene) ureas, characterized by The N, N- (dibenzohexatrienyl) amine is reacted with cyanic acid. 2. The method according to p. The process of claim 1, wherein the reaction is carried out in an organic solvent or organic solvent mixture and in the presence of an acidic agent. 3. The method according to p. The process of claim 2, wherein the organic solvent is an aliphatic carboxylic acid, an aliphatic ester of such acid, an aromatic or araliphatic hydrocarbon, a halogen-aliphatic compound or an aliphatic ether. 4. The method according to p. A process as claimed in claim 2 or 3, characterized in that the organic solvent is toluene, xylene, 1,2-dichloroethane, acetic acid or ethyl acetate. 5. The method according to p. A process as claimed in any one of the preceding claims, characterized in that the cyanic acid is released by treatment with acid of a solution and / or a suspension of the cyanic acid salt in an organic solvent and used without isolation. 6. The method according to p. 2, 3 or 4, characterized in that the acidic agent is an inorganic acid, organic sulfonic acid, aliphatic carboxylic acid or 2-mono, 2,2-di- or 2,2,2-tri-haloalkane carboxylic acid with 2-7 carbon atoms. 7. The method according to p. 2, 3, 4 or 5, characterized in that an inorganic acid, organic sulfonic acid or 2-mono-, 2,2-di- or 2,2,2-tri-haloalkane carboxylic acid with 2-7 carbon atoms. 8. The method according to p. A process according to any of the preceding claims, characterized in that the acidic agent is trichloroacetic acid, hydrochloric acid or sulfuric acid. 9. The method according to p. A process according to any of the preceding claims, characterized in that acetic acid is used as the acidic agent and simultaneously as the solvent. 10. The method according to p. A process as claimed in any of the preceding claims, wherein the procedure is carried out at a temperature from about 0 ° C to about 120 ° C. 11. The method according to p. 1 or 2 or 3 or 4 or 5 or 7 or 8, characterized in that the suspension of NN- (dibenzohexatrienylene) amine and about 1.75-2.25 molar amount of sodium cyanate in toluene at a temperature of about 20-30 ° C is with about 0.5-5% excess of trichloroacetic acid and heated to about 40-80 ° C. 12. The method according to p. 5. A process as claimed in any one of the preceding claims, characterized in that in the preparation of 5H-dibenzo [b, f] azepinocarbonamide-5, a slight excess of hydrogen chloride is introduced into the sodium cyanate suspension in ethyl acetate and then added to of the amount of sodium cyanate used, at most an equimolar amount of iminostilbene. 13. The method according to p. 1, 2, 3, 4, 5, 7 or 8, characterized in that about 2-10% excess of hydrogen chloride is introduced into the suspension of sodium isocyanate in ethyl acetate, and then, based on the amount of sodium cyanate introduced, about 0.16-0.9 molar amount of N, N- (dibenzohexatrienylene) amine and to a temperature of about 40-70 ° C. 153 029 14. The method according to p. 1 or 2 or 3 or 4 or 5 or 7 or 8, characterized in that in the preparation of 5H-dibenzo [b, fJazepinocarbonamide-5, the suspension of iminostilbene in acetic acid at a temperature from about + 10 ° C to about + 120 ° C sets about 5-40% of this excess sulfuric acid, and then adding at least an equimolar amount of sodium isocyanate relative to the amount of iminostilbene used. 15. The method according to p. 1 or 2 or 3 or 4 or 5 or 7 or 8, characterized in that the suspension of N, N- (dibenzohexatrienylene amine in acetic acid) is treated with about 5-40% of this excess sulfuric acid, and then to 1 mole of this amine About 1.25-1.75 moles of sodium isocyanate are added. 16. The method according to p. A process as claimed in any one of the preceding claims, characterized in that a 25-75% excess of cyano acid is introduced into the suspension of the N, N- (dibenzohexatrienylene amine in acetic acid). 17. The method according to p. A suspension composition according to any of the preceding claims N, N- (dibenzohexatrienyl) amines in toluene, xylene, 1,2-dichloroethane or ethyl acetate are first introduced with 1-15 mol% hydrogen chloride followed by about 25-75% excess cyanic acid. 18. The method according to p. A process as claimed in any one of the preceding claims, characterized in that about 0.8-0.96 mol parts of N, N- (dibenzohexathiienylene) amine to the suspension of the mixture and about O, (040.2 molar iminostilbene hydrochloride (sum of the molar parts equal to 11 in the araliphatic hydrocarbon, about 25-75% excess cyanic acid is introduced. Department of Publishing of the UP RP. Circulation 100 copies Price: PLN 3,000