DD264115A3 - PROCESS FOR THE PREPARATION OF 5-CARBAMINOYL-IMINOSTILS - Google Patents

Abstract

The invention includes a process for the preparation of 5-carbaminoyl-iminostilbene by allowing 5-halocarbonyl-iminostilbene or a mixture thereof to run into an amidating agent in the presence of an aprotic nonpolar aromatic hydrocarbon, advantageously in the presence of a surfactant. The target product is a valuable pharmaceutical substance used as a psychotropic drug.

Description

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Title of the invention

Process for the preparation of 5-CaFbaminoyl-iminostilbene

Field of application of the invention

The invention relates to a process for the preparation of 5-carbaminoyl-iminostilbene (carbamazepine). This compound has gained significance in human medicine for the treatment of both epileptic and psychological disorders.

Characteristic of the known state of the art

Economically significant production process of 5-carbaminoyl-iminostilbene are based in principle on 5-halocarbonyl-iminostilbene of the general formula I, wherein these compounds are reacted with amidating agents such as ammonia, ammonium salts or polyamides to the target compound. This reaction is preferably carried out in alcohols (CH-PS 366 541, DD-PS 82 719, DD-PS 102 150, DE-PS 1 001 271) at elevated temperature. DD-PS 126 329 this reaction is described in heterogeneous phase in the presence of water and carboxylic acid esters of monohydric or polyhydric aliphatic alcohols or their Halbis or in the presence of higher alcohols. All amidation processes of the prior art, the procedure is the same that the starting compounds of the formula I in one of the abovementioned solvents

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submitted (dissolved) and the respective amidating agent is then added, which is not advantageous for reasons described below.

Decisive disadvantage of the known process for the preparation of Oarbamazepin from the compounds of formula I is also the insufficient selectivity of the reaction course in the sense of the exclusive formation of 5-carbaminoyl-iminostilbene as the target product. As a result, one inevitably obtains by-products which are difficult to separate from the main product and thus lead to economic losses in cleaning operations. The reasons for the non-selective course of the reaction are complex. On the one hand, the solvents used according to the prior art for the amidation reaction are not sufficiently inert to the starting materials of the formula I by either - in the case of the use of alcohols - directly with 5-halocarbonyl-iminostilbene to the corresponding 5-Carbalkoxi-iminostilbenen can react the general formula II or - in the case of the use of carboxylic acid esters as solvent - enter into the undesirable side reaction to the compounds of formula II with the DD-PS 126 329 indirectly by hydrolytic cleavage of the esters resulting alcohols according to the following scheme:

+ RAW

- HX = C - X (HH ₄ X) 0 = C - OR

In particular, under technical conditions, in the case of circulation of the solvent, the reactive alcohols accumulate in the carboxylic acid esters used in each case and lead to increased side reactions in accordance Scheme shown above.

It is therefore not surprising that by procedures of DD-PS 126 329, Examples 1 and 2, up to 0.05% 5-Carbbutoxi-iminostilbene be found in the target product as an impurity. Even with reworking of DD-PS 102 150 is analogous to the corresponding methyl ester of iminostilbene-5-carboxylic acid, among other impurities unknown constitution. This last finding is also understandable, since in the cited patent in continuous work, starting from 5-chlorocarbonyl-iminodibenzyl to 5-carbaminoyliminostilbene on the halogenated in 10,11-position compounds, a partially non-selective bromination is described. Thus, in the case of such a preparation of 5-halocarbonyl-iminostilbene or 5-carbaminoyliminostilbene, one must always expect the occurrence of several reactive halogen compounds which can yield a multiplicity of secondary products, in particular in the case of nucleophilic attack of the following amidation reaction by, for example, alcohols, water or ammonia. what by og The facts can be recognized by analytical investigations of final products according to the valid quality guidelines (pharmacopoeias). This circumstance is also already indicated in DD-PS 133 052, which was attempted according to this patent by additions of organic dicarboxylic acids in the bromination / dehydrobromination to reduce the bromine content of the final products.

In addition to the described solvent influence is another cause for the insufficient selectivity of the amidation reaction of compounds of formula I to 5-carbaminoyl-iminostilbene in an additional reaction possibility of the amidation product itself justified. While 5-halocarbonyl-iminostilbene reacts preferentially with the amidating agent to give the 5-ocarbaminoyl-iminostilbene as desired under the reaction conditions, there are also possible reactions of the target compound with the starting materials of the formula I to form further by-products.

These side reactions are preferably carried out at low ammonia supply, which is why a metered addition or addition of the respective amidating agent to the compounds of formula I is unfavorable (eg., Secondary substitution of the amide nitrogen).

Impurities - even in the smallest amounts - significantly reduce the use value of carbamazepine, because in a long-term medication in humans must be paid to the highest purity of the final product. Cleaning operations - such. B, crystallization or sorption do not result due to low solubility or polarity differences of the substances to be separated or are associated with high economic costs and loss of substance, so that advantageously already in the synthesis must be tried to limit the formation of by-products or to exclude.

Object of the invention

It is the object of the invention, in procedurally simple and economically favorable manner, to enable the production of 5-carbaminoyl-iminostilbene from 5-halocarbonyl-iminostilbenes of the formula I in high purity, in particular excluding the formation of 5-carbalkoxi-iminostilbenen II , In particular, provision should be made for a high ammonia supply even at the beginning of the reaction in order to suppress the formation tendency of further by-products and to obtain a final product in pharmaceutical purity without increased expenditure compared with the prior art.

Explanation of the essence of the invention

The object of the invention is to produce 5-carbaminoyl-iminostilbene from 5-halocarbonyl-iminostilbene I in a process-wise simple manner, in particular without obtaining 5-carbalkoxy-iminostilbene II.

According to the invention, this is achieved by allowing 5-halocarbonyl-iminostilbene I, which are preferably used as a melt, to run into an amidating agent in the presence of an aprotic-nonpolar aromatic solvent. Β Suitable solvents, if appropriate also used as a mixture, are aromatic hydrocarbons or haloaromatics, such as. B · benzene, toluene, monochlorobenzene or bromobenzene. The amidation agent used is ammonia with a content of preferably 15 to 25 % or ammonium salts in aqueous form.

Since the starting compounds of the formula I according to a preferred embodiment of the invention in high-energy form, namely as a melt, are metered into the amidating agent, the desired reaction proceeds virtually instantaneously and quantitatively. Such an advantageous variant is obtained, for example, when the compounds of formula I are obtained as melts by procedures of DD-PS 102 I50, 102 15I, 108 535, 101 671 and 100 94-8 and so directly in the amidation according to the invention Method to be used ·

The amidation reaction can also be advantageously carried out in the presence of surfactants, such as. For example, quaternary aryl Alkylammpnium salts or nonionic surfactants, which are suitably added in amounts of 0.01 to 10 Mas'se-%, performed. Thereby According to the invention one proceeds ^ is left that run in a melt of 5-halocarbonyl iminostilbenen of 130 to 180 ⁰ O in an aqueous solution of amidating agent to the surfactant mixture with the aprotic, non-polar aromatic hydrocarbon. As an advantageous temperature range have for the reaction 0 to 100 ⁰ G, preferably 40 to 60 ⁰ C, proven, wherein the reaction mixture may be heated by the energy content of the melt of the compounds of formula I and the reaction enthalpy of the amidation and cooled if necessary can. Since this reaction is practically instantaneous at the inlet of the

Runs melt, control of the desired temperature range by regulating the feed rate of the compounds of formula I is possible without difficulty.

The reaction mixture is cooled to tree temperature and the precipitated 5-carbaminoyl-iminostilbene is filtered off with suction. The mother liquor contains 2 phases, which are separated. The saline, aqueous upper phase is discarded, while the deep dark colored organic lower phase for Bückgewinnung the aprotic nonpolar hydrocarbon is redistilled.

Although the aprotic nonpolar aromatic hydrocarbons used for the reaction have practically no dissolving power for water or the polar amidating agents, the desired reaction proceeds smoothly and quantitatively. This result is surprising, since so far according to the prior art-such as DD-PS 126 329 for this synthesis step, only polar solvents having at least a conditional water miscibility, have found use.

A decisive advantage of the process according to the invention is the selectivity of the reaction in the sense of the desired formation of 5-carbaminoyl-iminostilbene, since the aprotic-nonpolar aromatic hydrocarbons used according to the invention are absolutely indifferent to the reactant and side reactions with the starting compounds of the formula I become 5 -Carbalkoxiverbindungen of formula II or with the aqueous amidating agents are safe to exclude. Even with repeated reuse of the aromatic solvents, if necessary after redistillation, consistently good results are achieved. The high selectivity of the process according to the invention represents a further element of surprise, because the first-time use of melts of the compounds of the formula I for the amidation reaction naturally results in a course of the reaction with increased secondary activity.

expect product formation ·

Since the compounds of the formula I according to the procedures of DD-PS 102 150, 102 I5I, 108,535, 101 671 and 100 948 incurred anyway primarily as melts, thus resulting in a favorable linkage possibility of preparing the compounds of formula I with the amidation according to the invention for the preparation of 5-carbaminoyl-iminostilbene. This results in a significant economic advantage, which is particularly effective in the industrial production of carbamazepine.

embodiments

example 1

A 160 ⁰ G hot melt of 128 g of 5- ^ ΒΐθΓθ3 ^ οη3Ί-ΐΐΐιίηο stilbene is allowed to run within one hour in a stirred mixture of 400 ml of monochlorobenzene and 200 ml of 25% aqueous ammonia, wherein the reaction mixture to about 40 heated to 50 ⁰ C. One adds 25 ml of ammonia, stirred for 1 hour at 80 ⁰ C and then 15Ο ml of hot water. When cooled to Eaumtemperatur crystallization of 5-carbaminoyl-iminostilbene, which is filtered off with suction and washed abundantly with hot water.

Yield: 110 g of dry product, corresponding to 92% of theory. Th. Pp .: 189 - 191 ⁰ C

Example 2

A melt, bestberd from 1QO g 5-Chlorcarbonyliminostilben and 33 g of 5-bromocarbon; yl-iminostilbene, obtained according to a procedure of DD-PS 102 15Ο »is within 2 hours in a 40 to 50 ⁰ C warm, stirred mixture of 400 ml Monocblorbenzen and 200 ml of 25% aqueous ammonia run.

One adds 25 ml of ammonia and stirred for 1 hour

80 ⁰ C to. After adding 15O ml of hot water is cooled and sucks off the 5-garbaminoyl-iminostilbene. After washing with hot water and drying to obtain 105 to 11Og product with a mp. From 189 to 190 ⁰ C. Recrystallization from methanol provides a Eeinprodukt for pharmaceutical purposes (2nd AB of the GDR).

Example 3

A 120 ⁰ C hot mixture consisting of 77 g of 5-chlorocarbonyl-iminostilbene and 61 g of 5-bromocarbonyl-iminostilbene and 25 g of monochlorobenzene is allowed to run for 1 hour in a stirred mixture of 350 ml of monochlorobenzene and 15O ml of aqueous ammonia, so that one

Temperature of 50 ⁰ C is not exceeded.

One adds 25 ml of ammonia and stirred for 1 hour at 80 ⁰ C after. After ^such ugabe of 15O ml of hot water is cooled and sucks the failed 5-Carbaminoyl-iminostilbene from.

After washing with hot water and drying to obtain 108 g of crude product having a Pp. From 189 to I90 ⁰ C.

Example 4

A melt of 77 g of 5-chlorocarbonyl-iminostilbene and 61 g of 5-bromocarbonyl-iminostilbene is allowed to run at 130 to 140 ⁰ C in a stirred, 40 to 50 ⁰ O warm mixture of 100 ml of 25% aqueous ammonia and 300 ml of toluene , The inflow time is 30 minutes.

Another 100 ml of ammonia are added and the mixture is stirred at 80 ^° C. for a further 1 hour. After addition of 150 ml of hot water is cooled and the precipitated 5-carbaminoyl-iminostilbene isolated. After washing and drying, 112 g of product with a mp. From I90 to I91 ⁰ O.

Example 5

A melt of 77 g of 5-chlorocarbonyl-iminostilbene and 61 g of 5-bromocarbonyl-iminostilbene is run in 250 ml of toluene. This solution is at 80 ⁰ G with

5> g activated charcoal and filtered blank. At 40 to 50 ⁰ O this filtered solution is poured into a stirred mixture consisting of 100 ml of toluene and I50 ml of 25% aqueous ammonia and 5-octyl-S benzyl dimethyl ammonium chloride, allowed to shrink. One adds 25 ml of ammonia and stirred for 1 hour at 80 ⁰ O after. After addition of 150 ml of hot water is cooled, filtered with suction and the product washed with hot water.

Yield: 112 g of crude product, which can be sucked off well. The recrystallization from methanol provides a Eeinprodukt for pharmaceutical use (2nd AB of the GDR).

Claims (9)

10 claims 1. A process for preparing 5-carbaminoyl-iminostilbene from 5-halocarbonyl-iminostilbene and an amidating agent, characterized in that 5-halocarbonyl-iminostilbene of the general formula I or a mixture thereof in the presence of an aprotic-nonpolar aromatic solvent in an amidating agent can run in. 2. The method according to claim 1, characterized in that one uses 5-halocarbonyl-iminostilbene as a melt. 3 · Process according to claims 1 and 2, characterized in that supplying a 130 to 180 C hot melt of the 5-halocarbonyl-iminostilbene the amidating agent. 4. The method according to claim 1, characterized in that hydrocarbons such as benzene or toluene, but preferably haloaromatics such as chlorobenzene or bromobenzene are used as the solvent or solvent mixture · 5 · Process according to Claim 1, characterized in that ammonia having a content of 15 to 25% or ammonium salts in aqueous form is used as the amidating agent. 6. Process according to claims 1 to 5 », characterized in that the amidation agent during the reaction at a temperature of 0 to 100 ⁰ C, preferably from 40 to 60 ⁰ C, holds. 7 · Process according to claims 1 to 6, characterized in that the reaction mixture is optionally heated to the boiling point during the amidation. 8. Process according to claims 1 to 7t, characterized in that the reaction in the presence of surfactants, for example quaternary aryl-alkyl-ammonium salts or nicbtionogenen surfactants added in amounts of 0.01 to 10% by mass,
performs · 9. Process according to claims 1 to 8, characterized in that the solvent is redistilled from the organic lower phase. M η r ZtA Ί 6 tiU for Me / L