SI8810141A - PROCEDURE FOR THE PREPARATION OF N, N- (DIBENZOHEXATRIENYLENE) UREA - Google Patents

Abstract

N,N - (dibenzohexatrienylene) ureas can be prepared in a straightforward one-step reaction by reacting the corresponding N,N - (dibenzohexatrienylene)amine with cyanuric acid.

Description

CIBA-GEIGY AG

Process for the preparation of N, N- (dibenzohexatrienylene) urea

The invention relates to a process for the preparation of N, N- (dibenzohexatrienylene) urea, in particular 1,5-dibenz / b, f / azepine-5-carboxamide, characterized in that the corresponding N, N- (dibenzohexatrienylene) amine, in particular 1,5-dibenz / b, f / azepine (iminostilbene), is reacted with cyanic acid.

1,5-dibenz / b, f / azepine-5-carboxamide, commonly known as carbamazepine as a drug substance, is prepared according to US-PS 2 948 718, usually by metabolizing iminostilbene with phosgene to chloride 1,5-dibenz / b, f / azepine-5-carboxylic acid and its further metabolism with ammonia. In a new process according to DE-A1 2307174, iminostilbene is metabolised with acyl isocyanate and the resulting 1,5-dibenz / b, f / azepine-5- (N-acyl) carboxamide is hydrolyzed basicly. Known methods have explicit drawbacks.

Thus, two separate reaction steps should always be carried out, without the use of an equimolar amount of highly toxic phosgene for the first step of the US-PS process.

Therefore, the invention is based on a hitherto unsolved task, to develop a method of preparation that leads in one step directly to 1,5-dibenz / b, f / azepine-5-carboxamide.

According to the invention, the proposed solution is surprising in that it is known that iminostilbene with alkyl isocyanates does not react to the corresponding 1,5-dibenz / b, f / azepine-5- (N-alkyl) carboxamides (DE-A1 2307174), and the metabolism of Ν, Ν-diarylamines with sodium cyanate and trifluoroacetic acid in benzene cannot be transferred to the N, N- (benzobutadienylene) - and N, N- (dibenzobutadienylene) amines, such as indole and the like. carbazole (Chem. and Ind. 1965, p. 1428-9).

The cyanic acid used in the invention for the introduction of the 5-carbamyl group is usually prepared by pyrolysis of cyanuric acid, oxidation of formamide with oxygen at silver or copper contact, or treatment of a solution and / or suspension of one of its salts, preferably sodium or potassium cyanate, with acid. Free cyanic acid is not stable. It enters into numerous polymerization and autocondensation reactions and additionally easily admixtures with water, alcohols, amines and the like.

However, its solutions in suitable organic solvents are sufficiently stable for the purpose of the invention.

The metabolism of the invention is therefore preferably carried out in an organic solution, i.e. in an organic solvent or solvent mixture, whereby cyanic acid is preferably sucked into the reaction system in a gaseous state, preferably diluted with an inert gas such as nitrogen or argon, or released by treatment of a solution and / or suspension of one of its salts, preferably sodium or potassium cyanate, with acid.

Suitable organic solvents are those which react with isocyanic acid not only or so slowly that they do not adversely affect the reaction of the invention by the formation of undesirable intermediates. They are suitable e.g. aromatic or. araliphatic hydrocarbons such as benzene or toluene; halogenoaliphates such as

1,2-dichloroethane, aliphatic carboxylic acids and their aliphatic esters, such as lower alkanecarboxylic acids, e.g. acetic acid, or lower alkyl esters of lower alkanecarboxylic acids, e.g. acetic acid ethyl ester, further aliphatic ethers such as diethyl ether, dioxane, tetrahydrofuran and the like, and mixtures thereof.

Because cyanic acid enters with water, alcohols, amines, etc. to undesirable side reactions, the metabolism of the invention is advantageously carried out under far-reaching aprotic conditions, i.e. in an organic solution far-reaching free of water, alcohols and amines, and excluding water vapor. However, these precautions are completely unnecessary when processing the reaction mixture and isolating the resulting additive product.

The metabolite of the invention requires an amount of cyanic acid that is at least equimolar to the N, N- (dibenzohexatrienylene) amine used. In order to achieve better metabolism, about 1.05 molar to about 2.5 molar, preferably about 1.25 molar to about 2.25 molar, e.g. around

1.3 molar to about twice the molar amount of cyanic acid, i.e. about 5% to about 150%, preferably about 25% to about 125%, e.g. about 30% to about 100% excess cyanic acid.

For the release of cyanic acid from one of its salts, which is a particularly preferred embodiment of the invention, generally all protic acids whose strength is sufficient to displace cyanic acid from its salts are suitable. They are suitable e.g. mineral acids, e.g. hydrochloric acid or sulfuric acid, organic sulfonic acids such as, C 1 -C 4 -alkanals optionally with halogen or -C 1 -alkyl substituted benzenesulfonic acid, e.g. methane, ethane, benzene, p-toluenals p-bromobenzenesulfonic acid, or organic carboxylic acids, the strength of which in the solvent used practically corresponds to at least the strength of formic acid, such as 2-mono-, 2,2-di- or

2,2,2-trihalogen-C2-Cy-alkanoic acids, e.g. trichloroacetic acid.

The reaction of the N, N- (dibenzohexatrienylene) amine component with cyanoic acid is spontaneous and slightly exothermic. Reaction parameters are not critical. A claim can be made e.g.

- 5 in the temperature range from about 0 ° C to about 120 ° C and homogeneous or preferably heterogeneous. However, metabolism and metabolic rate can be accelerated by gentle heating and / or the presence of an acidic agent. The metabolism is therefore preferably carried out in a temperature range from room temperature, i.e. about 20 ° C to about 100 ° C as well as in the presence of an acidic agent. Since these reactions are only catalytically involved, catalytic amounts of acid are sufficient in principle. In general, about 0.01 to about 0.15 are completely sufficient, e.g. about 0.04 to about 0.05 equivalents of acidic agent per mole of N, N- (dibenzohexatrienylene) amine. Only with the use of multibasic acids with distinctly different levels of acidity should the heterogeneous conduct of the reaction be taken into account to allow acidic salts to be eliminated, thereby blocking some of the acid used. When using sulfuric acid, for example, therefore, for a mol of N, N- (dibenzohexatrienylene) amine up to 1.5, e.g. about 1.05 to about 1.4 molar equivalents, corresponding to about 0.525 to about 0.7 moles, i.e. about 5% to about 40% excess by using a variant in which cyanic acid is liberated from one of its salts and the reaction is heterogeneous. Of course, the acid catalytic agent may be present or may also be added in the form of the corresponding N, N- (dibenzohexatrienylene) ammonium salt.

For example, as an acidic agent, e.g. the protic acids listed above as being suitable for the release of cyanic acid, further aliphatic carboxylic acids, such as C 1-6 alkanoic acids, e.g. acetic acid, especially when used as a solvent. If a variant is used in which cyanic acid is released from one of its salts in situ, it is advantageous to use a generally small, i.e. about 0.5% to about 10%, e.g. about 1% to about 5%, and when using sulfuric acid, for the reasons given, about 5% to about 40%, e.g. about 32% excess acid used to release cyanic acid.

In a preferred embodiment, a suspension of N, N (dibenzohexatrienylene) amine, in particular iminostilbene, and at least equimolar, in particular about 1.75 to about 2.25 molar, e.g. twice the molar amount of sodium cyanate in toluene at about 20 ° C to about 30 ° C, e.g. at room temperature to about 25 ° C, per mole of sodium cyanate about 1.005 to about 1.05, e.g. 1.02 moles, i.e. about 0.5% to about 5%, e.g. about 2% excess trichloroacetic acid and, if necessary, heated to about 40 ° C to about 80 ° C, e.g. at about 50 ° C to 65 ° C, or a suspension of N, N- (dibenzohexatrienylene) amine, especially iminostilbene, in acetic acid about 1.05 to about 1.40 molar equivalents is added, corresponding to about 0.525 to about 0.7 the pier, ie about 5% to about 40% excess sulfuric acid and then an amount of sodium cyanate which is at least equimolar to the amount of N, N- (dibenzohexatrienylene) amine used is added, e.g. per mole of amine about 1.25 to about 1.75, e.g. about 1.6 moles of sodium cyanate, e.g. at about 10 ° C to about 120 ° C, or introduced into the suspension of sodium isocyanate in acetic acid ethyl ester about 1.02 to 1.40, e.g. about 1.05, i.e. 1.04 to about 1.06 molar amount, i.e. small, preferably about 2% to about 10%, e.g. about 5% -en, i.e. 4% to 6% excess hydrogen chloride and then add the amount of N, N- (dibenzohexatrienylene) amine, which is at most equimolar to the amount of sodium cyanate used, e.g. about 5% to about 50% molar deficit, e.g., per mole of sodium cyanate about 0.6 to about 0.9, e.g. about 0.75 mol iminostilbene, preferably operating at about 0 ° C to about 80 ° C, and after addition of the amine component is heated e.g. at about 40 ° C to 70 ° C.

In another preferred embodiment, the N, N- (dibenzohexatrienylene) amine, especially iminostilbene, is introduced into the suspension in acetic acid at least equimolar, e.g. about 1.25 molar to about 1.75 molar, preferably about 1.4 molar to about 1.6 molar amount, i.e. e.g. about 25% to about 75%, preferably about 40% to about 60% excess cyanic acid and, if necessary, heated to about 25 ° C to about 50 ° C or introduced into the N, N- ( dibenzohexatrienylene) amines, in particular iminostilbene, in toluene, xylene, 1,2-dichloroethane or acetic acid ethyl ester, first about 0.01 molar to about 0.15 molar, e.g. 0.01 molar to about 0.12 molar amount, i.e. about 1 to about 15 mol%, e.g. about 1 to about 12 mol% of hydrogen chloride and then less equimolar, e.g. about 1.25 molar

-δύο about 1.75 molar, preferably about 1.4 molar to about 1.6 molar, i.e. e.g. about 25% to about 75%, preferably about 40% to about 60% excess cyanic acid and, if necessary, heated to about 50 ° C to about 125 ° C, e.g. at about 75 ° C to about 100 ° C. In changing this variant, a mixture of N, N- (dibenzohexatrienylene) amine and one of its acid addition salts is introduced into the suspension. about 0.8 to about 0.96, preferably about 0.85 to about 0.95 molar parts of iminostilbene hydrochloride (about 0.95 to about 0.2, preferably about 0.05 to about 0.15 molar parts of iminostilbene hydrochloride (sum molar parts = 1), at least equimolar, e.g. about 1.25 molar to about 1.75 molar, preferably about

1.4 molar to about 1.6 molar amount, i.e. e.g. about 25% to about 75%, preferably about 40% to about 60% cyanic acid excess and, if necessary, heated to about 60 ° C to about 100 ° C.

The invention is further described in the following embodiments. Temperatures are given in degrees Celsius.

EXAMPLE 1

723 g of trichloroacetic acid were dissolved in 600 ml of toluene and 407 g of iminostilbene and 290 g of sodium cyanate in 600 ml of toluene were added to the suspension for 1 1/2 hours, maintained at cooling ^: 25 ° C.

Allow to react for 1/2 hour at 25 ° C and 1 hour at 50 ° C and then slowly add 1300 ml of water. It is then cooled to 20 ° C and the product is filtered off. Wash with toluene and water and dry at 85 to 90 ° C in vacuo. Yield: 475 g of carbamazepine.

EXAMPLE 2 g of iminostilbene is suspended in 180 ml of acetic acid and 14 g of 96% sulfuric acid are slowly added. At 30 ° C, 13.5 g of sodium cyanate is added portionwise after good stirring.

It was stirred for 3 hours at 30 ° C, the product was filtered off and washed with acetic acid and then with water.

After drying at 80 ° C in vacuo, 29.5 g of carbamazepine are obtained.

EXAMPLE 3 g of sodium cyanate was suspended in 1000 ml of acetic acid ethyl ester and 40 g of hydrogen chloride was introduced at room temperature while stirring. After 4 hours, the resulting sodium chloride was filtered off and 155 g iminostilbene was added to the clear filtrate. The reaction mixture was maintained for 4 to 5 hours at

50 ° C, cooled to 0 ° C and the product filtered off. Washing with a little acetic acid ethyl ester and drying at 80 ° C in vacuo gave 177 g of carbamazepine.

EXAMPLE 4

17.4 g of iminostilbene and 2.3 g of iminostilbene hydrochloride are suspended in 250 ml of toluene. Heat to 80 ° C and introduce 6.5 g of monomeric cyanic acid for 1 1/2 hours in a stream of nitrogen and then heat to 100 ° C for 1/2 hour.

After cooling to 5 °, it is filtered off, washed four times with cold toluene and dried at 60 ° in vacuo. 18.5 g of carbamazepine are obtained.

EXAMPLE 5

17.4 g of iminostilbene and 2.3 g of iminostilbene hydrochloride were suspended in 250 ml of xylene (mixture of isomers). At 20 ° C, 6.5 g of monomeric cyanic acid are introduced into the nitrogen stream and allowed to react for another 4 hours at 30 °.

It was then cooled to 0 °, filtered and washed with xylene. Drying at 80 ° in vacuo gave 22.1 g of carbamazepine.

EXAMPLE 6

19.3 g of iminostilbene are suspended in 200 ml of 1,2-dichloroethane. At 25 °, 4.5 g of hydrogen chloride is introduced first and then

6.5 g of cyanic acid in gaseous form (nitrogen stream).

Deployment takes place over 5 hours in several installments. The reaction was allowed to proceed for 1 hour, filtered off and washed with 1,2-dichloroethane and then with water.

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

In the same way, the resulting nozzle was evaporated after completion of the reaction, the residue was cold-digested with toluene and filtered off. Washing with toluene and water and drying in vacuo at 60 ° afforded 22.5 g of carbamazepine.

EXAMPLE 7

Suspend 29.0 g of iminostilbene at 20 ° in 150 ml of acetic acid ethyl ester. First, 0.6 g of hydrochloric acid is introduced and then 9.7 g of cyanic acid in gaseous form (in a stream of nitrogen).

After stirring for 20 hours at 20 °, it was filtered off, washed with acetic acid ethyl ester and then dried at 60 ° in vacuo. 32.0 carbamazepine is obtained. i

An analogous experiment at a reaction temperature of 50 ° yielded 29.4 g of carbamazepine.

EXAMPLE 8

Suspend 19.3 g of iminostilbene in 200 ml of acetic acid ethyl ester and add 1.0 ml of sulfuric acid (98%)

At 25 ° C, 6.5 g of monomeric cyanic acid (in a stream of nitrogen) is introduced. Let stand overnight, then evaporate to dryness in vacuo and take up the residue with toluene. After filtration, washing with toluene and water and drying at 80 [deg.] In vacuo, it is obtained

19.7 g of carbamazepine.

EXAMPLE 9

Heat 19.3 g of iminostilbene with 100 ml of acetic acid at 45 °. Introduce 6.5 g of monomeric cyanic acid (in a stream of nitrogen) for 1 1/2 hours and allow to react for another 12 hours at 40 °.

After cooling to 15 ° C, it was filtered, washed with cold with acetic acid and dried in vacuo at 60 °.

The crude product obtained was recrystallized from methanol / water (7: 3) to give 19.1 g of carbamazepine.

EXAMPLE 10

Heat 29.0 g of iminostilbene in 150 ml of acetic acid at 45 °. During 1 1/2 hours, 9.7 g of monomeric cyanic acid (in a stream of nitrogen) are introduced and allowed to react for another 2 hours at 40 ° and 12 hours at 20 °.

After addition of 15 ml of water, cool to 0 ° and filter after one hour. Wash with twice 15 ml of acetic acid and water to give the crude product, which after recrystallization from methanol / water (7: 3) 29.1 g of carbamazepine.

Claims (27)

PATENT APPLICATIONS A process for the preparation of N, N- (dibenzohexatrienylene) urea, characterized in that the corresponding N, N- (dibenzohexatrienylene) amine is reacted with cyanic acid. Process according to claim 1, characterized in that the reaction is carried out in an organic solvent or solvent mixture and in the presence of an acidic agent. Process according to Claim 2, characterized in that the organic solvent used is aliphatic carboxylic acid or its aliphatic ester, aromatic or. araliphatic hydrocarbon, halogenoaliphate or aliphatic ether. Process according to one of Claims 2 and 3, characterized in that toluene, xylene, 1,2-dichloroethane, acetic acid or acetic acid ethyl ester are used as the organic solvent. Process according to one of Claims 1 and 4, characterized in that cyanic acid is liberated by acid treatment of a solution and / or suspension of cyanic acid salt in an organic solvent and used without isolation. Process according to one of Claims 2 and 3, characterized in that cyanic acid is liberated by acid treatment of a solution and / or suspension of cyanic acid salt in an organic solvent and used without isolation. Process according to one of Claims 2, 3 and 6, characterized in that acetic acid, acetic acid ethyl ester or toluene are used as the organic solvent. Process according to one of Claims 2 to 4, characterized in that a mineral acid, an organic sulfonic acid, an aliphatic carboxylic acid or 2-mono-, is used as the acidic agent. 2,2-di- or 2,2,2-trihalogenC ₂ -C 4 -alkanoic acid. Process according to one of Claims 2 to 5, characterized in that mineral acid, organic sulfonic acid or 2-mono-, 2,2-di- or 2,2,2-trihalogen-C ₂ - is used as the acidic agent. C 1-6 alkanoic acid. Process according to one of claims 2, 3, 6 and 7, characterized in that the mineral acid is used as an acidic agent. Process according to one of Claims 4, 5, 8 and 9, characterized in that trichloroacetic acid, hydrochloric acid or sulfuric acid is used as the acidic agent. Process according to one of Claims 2, 3, 6 and 7, characterized in that hydrochloric acid or sulfuric acid is used as an acidic agent. Process according to one of claims 2, 3, 6 and 7, characterized in that trichloroacetic acid is used as an acidic agent. Process according to one of Claims 2 to 4 and 8, characterized in that it is used as an acidic agent and at the same time as a solvent acetic acid. Process according to one of claims 1, 4, 5, 8, 9, 11 and 14, characterized in that it is operated in a temperature range from about 0 ° C to about 120 ° C. A method according to any one of claims 2, 3, 6, 7, 10, 12 and 13 ", characterized in that it is operated in a temperature range from about 0 ° C to about 120 ° C. Process according to one of Claims 1 to 7 and 9 to 13, characterized in that a suspension of N, N- (dibenzohexatrienylene) amine and about 1.75 to about 2.25 molar amounts of sodium cyanate in toluene are added at about 20 ° C to about 30 ° C about 0.5% to about 5% excess trichloroacetic acid and heated to about 40 ° C to about 80 ° C. Process according to one of claims 2, 3, 6, 7, 10, 12 and 13 for the preparation of 1,5-dibenzo / b, f / carboxamide, characterized in that a suspension of iminostilbene and about twice the molar amount of sodium cyanate in toluene at room temperature to about 25 ° C about 2% excess trichloroacetic acid and then heated to about 50 ° C to about 65 ° C. Process according to one of claims 2, 3, 6, 7, 10 - 'and 12 for the preparation of 1,5-dibenzo / b, f / carboxamide, characterized in that a small amount of acetic acid ethyl ester is introduced into the suspension of sodium cyanate an excess of hydrogen chloride and then the amount of iminostilbene that is at most equimolar to the amount of sodium cyanate used is added. Process according to one of Claims 1 to 7 and 9 to 12, characterized in that about 2% to about 10% excess hydrogen chloride is introduced into the suspension of sodium isocyanate in acetic acid ethyl ester, then about 0.6 is added. to about 0.9 molar amount of N, N- (dibenzohexatrienylene) amine, calculated on the amount of sodium cyanate used, and heated to about 40 ° C to about 70 ° C. Process according to one of claims 2, 3, 6, 7, 10 and 12 for the preparation of 1,5-dibenzo / b, f / azepine-5-carboxamide, characterized in that it is introduced at about 0 ° C to +80 ° C to a suspension of sodium isocyanate in acetic acid ethyl ester about 5% excess hydrochloric acid and then add the amount of iminostilbene which is at most equimolar to the amount of sodium cyanate used Process according to one of claims 2, 3, 6, 7, 10 and 12 for the preparation of 1,5-dibenzo / b, f / azepine-5-carboxamide, characterized in that it is added at about + 10 ° C to about + 120 ° C to a suspension of iminostilbene in acetic acid of about 5% to about 40% excess sulfuric acid, and then an amount of sodium isocyanate at least equimolar to the amount of iminostilbene used is added. Process according to one of Claims 1 to 7 and 9 to .12, characterized in that a suspension of N, N- (dibenzohexatrienylene) amine in acetic acid is added about 5% to about 40% excess sulfuric acid and then about 1.25 to about 1.75 moles of sodium isocyanate are added per mole of amine. Process according to one of claims 2, 3, 6, 7, 10 and 12 for the preparation of 1,5-dibenzo / b, f / azepine-5-carboxamide, characterized in that at about + 10 ° C to about + 120 ° C was added to the suspension of iminostilbene in acetic acid about 5% to about 40% excess sulfuric acid, and then about 1.6 moles of sodium isocyanate was added per mole of iminostilbene. Process according to one of Claims 1 to 4, 7, 8 and 14, characterized in that about 25% to about 75% cyanic acid is introduced into the suspension of N, N- (dibenzohexatrienylene) amine in acetic acid. . 26. A process according to any one of claims 1 to 4 and 7 to 12, characterized in that about 1 of the acetic acid ethyl ester in toluene, xylene, 1,2-dichloroethane or ethyl ester is first introduced into a suspension of N, N- (dibenzohexatrienylene) amine. about 15 mol% hydrochloric acid and then about 25% to about 75% excess cyanic acid. Process according to one of Claims 1 to 4 and 7 to 12, characterized in that about 0.8 to about 0.96 mole moiety of N, N- (dibenzohexatrienylene) arain and about 0.04 to about 0 are added to the suspension of the mixture. , 2 molar parts of iminostilben hydrochloride (sum of molar parts = 1) in the araliphatic hydrocarbon are introduced about 25% to about 75% excess cyanic acid.