DD298508A5 - PROCESS FOR THE PREPARATION OF 5-CARBAMOYL-5H-DIBENZ / B, F / AZEPIN - Google Patents

Abstract

The invention relates to a method for the direct production of * from * is used as a medicament. The essential feature of the invention is that it is introduced into a suspension of iminostilbene in an inert solvent at 20-60C phosgene until the iminostilbene is converted to a nearly equimolecular mixture of * and iminostilbene hydrochloride, followed by the addition of a liquid base releases iminostilbene from the iminostilbene hydrochloride formed, thus making the latter capable of complete phosgenation while maintaining an acidic reaction milieu. After complete conversion of the iminostilbene, the reaction solution is detoxified with stirring at 80-90 ° C and reacted with an amidating agent. {Iminostilbene; phosgenation; aqueous auxiliary bases; * Amidation; * Carbamazepine}

Description

For this 1 page formulas

Field of application of the invention

The invention relates to a technical process for the preparation of 5-carbamoyl-5H-dibenz / b, f / azepine (III), which is used as a medicament, preferably as an antiepileptic.

Characteristic of the known technical solutions

The synthesis of 5-carbamoyl-5H-dibenz / b, f / azepine (III ¹ "> iminostilbene (I) (= 5H-dibenz / b, f / azepine) was first described by W.SCHINDLER (DE-AS 1.136 .707, CH-PS 64.0ü3).

According to this method, the iminostilbene (I) is suspended in toluene, and phosgene is introduced into this suspension, wherein the reaction mixture is heated to 70 ⁰ C. Subsequently, the reaction mixture is heated to further reflux with further introduction of phosgene and boiled until the iminostilbene is completely reacted and the hydrogen chloride evolution is complete.

As soon as the reaction solution is free of iminostilbene, phosgene introduction is stopped. The excess phosgene is removed from the reaction mixture with dry nitrogen or dry air (see DE-AS 1,001,271, after which the excess phosgene after the phosgenation of 5H-10,11-dihydro-dibenz / b, f / azepine has ended Iminodibenzyl is also blown out with dry air). The reaction solution thus detoxified is worked up as usual, and the isolated by crystallization 5-chlorocarbonyl-SH-dibenz / b, f / azepine (II) is amidated in a known manner to 5-carbamoyl-5H-dibenz / bf / azepine (III) ,

The processes described so far all work in inert anhydrous solvents at temperatures above 100 ° C (for example in toluene, in chlorobenzene or in o-dichlorobenzene, see patents considered in this regard

and review articles by B. RENFROE, C. HARRINGTON and G.R. PROCTOR in "Heterocyclic compounds", Vol.43, "Azepiness", Part I, John Wiley & Sons, New York 1984, page 524. Table 118).

The dissociation of the always phased in the phosgenation iminostilbene hydrochloride in hydrogen chloride gas and free iminostilbene is made in all technical methods thei mix by heating the reaction mixture to the boiling point of the indifferent solvent and initiates phosgene under reflux.

The tests carried out according to the prior art Heißtemperaturphosgenierungen all work at 100 ⁰ C and higher in order to achieve a complete phosgenation of iminostilbene or iminodibenzyl.

The known processes for the preparation of carbamoyl chlorides from secondary amines are summarized in HOUBEN-WEYL (Volume E 4, page 46-50, 1983) in a table. The solvents used are generally aromatic hydrocarbons, such as benzene, toluene or chlorobenzene.

When working at low temperatures, when phosgene is introduced into a solution of the secondary amine in an inert solvent, only half of the amine is converted into the desired carbamoyl chloride, and the other half of the amine is dissolved in the hydrogen chloride liberated in the reaction Hydrochloride transferred. The amine hydrochloride precipitates in crystalline form, i. the yield of carbamoyl chloride can be only 50% in the most favorable case. Since the work of H. EDMANN and P. HUTH (J. Prakt. Chem. [2] 56,7 [1897]), it has been known that one can complete reactions by reacting an inert anhydrous base such as pyridine in at least According to HOUBEN-WEYL (see above) triethylamine and, of course, the amine to be reacted are suitable as inert bases, since always equimolecular Mengmi ε η inert base is required, the cold phosgenation becomes more expensive and the procedure becomes technologically complex, For this reason, cold phosgenation in the presence of inert auxiliary bases has only significance for the reaction of temperature-sensitive secondary amines, which are increasingly prone to undesirable Nebon reactions at the high temperatures of the hot phosgenation ,

The technique is preferably carried out at temperatures above 100 ° C. In Houben-Weyl (so) is carried out for this purpose: "Advantageously, heated the reaction mixture with continued introduction of phosgene at about 100 ⁰ C, the amine hydrochloride is in the carbamic acid chloride" The liberated during this thermal dissociation HCl gas tears considerable. For this reason, the exhaust gas in special exhaust systems must be detoxified and destroyed.In the event of an accident, such a procedure can lead to a serious risk to the environment. (Due to the extreme toxicity of the phosgene, there is a danger of bordering residential areas.) The mode of operation of hot phosgenation has, in particular, the following serious disadvantages:

- Exhaust gas emissions from released HCI gas, entrained phosgene and entrained l.ösungsmiueldämpfe and the resulting environmental problems

- Long reaction times over 18-24 hours with severe corrosive loads on the equipment

- high energy expenditure and

- A variety of side reactions and darkening of the reaction product, which ultimately lead to significant reductions in the quality of 5-carbamoyl-5H-dibenz / b, f / azepine and the

- Above 9O ⁰ C increasingly occurring constriction of the seven-membered ring of the iminostilbene, with the formation of unwanted 9-methyl acridine.

The iminostilbene belongs to the group of temperature-sensitive amines. For these reasons, the iminostilbene is advantageously phosgenated by the method of SCHINDLER (DE-AS 1,136,707).

The thermal dissociation of the iminostilbene hydrochloride into free iminostilbene and HCl gas occurs only at about 90 ° C sufficiently fast to reach akezptable reaction times for industrial purposes.

The preferred variant of the division of phosgenation into a phase of cold phosgenation (conversion of the first half, 50%) and a phase of hot phosgenation (conversion of the second half) by SCHINDLER has clear advantages over direct hot phosgenation, because, first, the yield was thus obtained secondly, the side reactions which occurred above 90 ° C were suppressed and, thirdly, the quality and the color were improved. Nevertheless, however, the disadvantages described in the second reaction stage - from the beginning of the heating to 9O ⁰ C and during the thermal dissociation of the iminostilbene hydrochloride to the end point of the reaction - obtained.

In order to fully exploit the gentle reaction conditions of the cold phosgenation phase, a phosgene excess is introduced into the reaction mixture. If the reaction mixture is subsequently heated for the thermal dissociation of the iminostilbene hydrochloride, a pressure surge may occur.

This danger is also brought to the attention of HOUBEN-WEYL (Volume E4, page 744,1983).

In a burst of pressure, the spontaneously released amounts of HCI gas entrain considerable amounts of phosgene. The AbgasVarnichtungsanlage or -Detgiftungsanlage must therefore be large enough to prevent such a pressure surge of the phosgene in the atmosphere.

In order to suppress the undesirable side reactions and the formation of 9-methylacridine, it is advantageous to operate at temperatures of 90-100 ⁰ C. In this reaction, although the phosgenation reaction proceeds sufficiently rapidly, but the vapor pressure of the phosgene is naturally increases considerably with respect to the phase of the cold phosgenation, so that it is unavoidable that the liberated hydrogen chloride constantly carries large amounts of phosgene. This is reflected in the fact that for the conversion of the first half of iminostilbene in the phase of cold phosgenation much less time is needed than for the conversion of the second half in the phase of hot phosgenation.

After complete conversion of the iminostilbene, the reaction solution must be detoxified. In general, the excess phosgene is blown out of the hot reaction solution with dry nitrogen, or it is distilled off a portion of the solvent until the reaction mixture is free of phosgene. These detoxification procedures have the disadvantage that phosgene can escape in the event of leakage due to the gas pressure prevailing in the system. Over longer periods of time, there is a risk that the environment may be contaminated by phosgene.

In addition to the described process for the direct phosgenation of the iminostilbene (I), some methods for the synthesis of the 5-carbamoyl-5H-dibenz / b, f / azepine (III) described by iminodibenzyl (IV) (= 10 , 11-dihydro-5H-dibenz / b, f / azepine) go out (see patent specifications: GB 1,246,606, DD 82,719, DD 100,948, DD 101.671, DD 102.149, DD 102.150, DD 102.151, DD 108,535, DD 133,052, DD 234,862 A1, DD 234,863 A1).

According to these processes, iminodibenzyl (IV) is reacted with phosgene in a boiling inert aromatic solvent, preferably toluene or chlorobenzene, with the phosgene being introduced into the reflux. It is therefore again a hot phosgenation with all its disadvantages. The resulting 5-chlorocarbonyl-5H-10,11-dihydro-dibenz / b, f / -azepine (V) is then reacted in an inert organic solvent with an ethereal bromine or a selective brominating reagent, whereby the corresponding ⁰ ". VI, R = H) and / or 10,11-dibromo derivatives (VII, R = ure) The bromine compounds (VI and / or VII) are then thermally dehydrobromated and / or debrominated in this thermal process at the same time a partial exchange (30-40%) of the chlorine atom of the 5-chlorocarbonyl group against a bromine atom.

These drastic reaction conditions inevitably result due to the required high reaction temperatures

(150-170 ⁰ C) and the released bromine to nk · it manageable side reactions (Kernbromierungen, resin,

Discoloration, cracking). It follows that the 5-chlorocarbonyl-5H-dibenz / b, f / azepine (II) synthesized by such processes except numerous -

contains all greasy by-products still greasy, tarry components and dyes whose removal is a tremendous

Expenditure requires or, if working continuously on 5-carbamoyl-5H-dibenz / b, f / azepine (III) inevitably too Quality loss leads to the final product. There is no knowledge of the nature and structure of the by-products mentioned. The usual cleaning procedures

lead to considerable losses.

So far, there is no purification process that solves the problem of residual bromine content in an economically justifiable way. The

all can be explained because the HPLC-determined content of the thus synthesized 5-chlorocarbonyl-5H-dibenz / b, f / -azepins (II) is on average 90%, i. the preliminary product - for the final product carbamazepine contains approx. 10%

Impurities. Object of the invention

The invention aims to produce 5-carbamoyl-5H-dibenz / b, f / -azepine of formula (III) under extremely mild and mild reaction conditions in quantitative yield with substantially improved quality from iminostilbene (I), the novel process with significantly reduced reaction time and requires considerably less energy. The invention should also be achieved a significant improvement in environmental protection and noticeably reduced risk moments.

Explanation of the essence of the invention The present invention is based on the object, 5-carbamoyl-5H-dibenz / b, f / azepine of the formula (III) in a truncated Reaction time while avoiding the Heißphosgenierungsphase or under elimination of the usual thermal Dissociation of iminostilbene hydrochloride in quantitative yield and to produce much improved quality. In addition, the reaction must eliminate phosgene emissions and allow for self-detoxification of the reaction solution

guarantee. Widening should the final product of the formula (IM) without substantial isolation of the very skin toxic 5

Chlorocarbonyl-5H-dibenz / b, f / azepins of the formula (II) can be obtained in a continuous process. According to the present invention, this is achieved in that in a suspension of iminostilbene (I) in a

inert solvent at 20-60 ⁰ C initiates phosgene or allowed to run in a solution of phosgene in the same solvent, bisdas iminostilbene to a nearly equimolecular mixture of 5-chlorocarbonyl-5H-dibenz / b, f / azepine (II) and Iminostilben-

Hydrochloride is reacted, followed by addition of an aqueous base of the formed iminostilbene hydrochloride Iminostilbene releases and thus accessible to the complete phosgenation while maintaining an acidic reaction milieu

makes.

Preferably, the phosgenation is carried out in the temperature range of 35-50 ° C. After about 50% sales of the Iminostilbene to the desired carbamoyl chloride (II) is begun with continuous further introduction of phosgene

either with the feed of a dilute solution of an alkali hydroxide or of dilute ammonia water or an aqueous solution of an alkali carbonate or bicarbonate or an aqueous solution of a hydrolysis alkaline salt (for example, sodium acetate).

During the feed of the aqueous base, the temperature is maintained at 35-50 ° C. After the feed of the aqueous base, the introduction of the phosgene is continued until 100% conversion of the iminostilbene,

the specified temperature limits are met. The complete conversion of iminostilbene is determined by thin layer chromatography.

In the final phase of the phosgenation, the temperature is kept at about 40-50 ° C, so that the formed ö-chlorocarbonyl-SH-aibenz /

b, f / azepine (II) not crystallized. Temperature deviations up or down by a few degrees have no meaning.

As soon as iminostilbene is no longer detectable in the reaction solution, the introduction of phosgene is terminated. After that, the

strongly acidic reaction mixture (which has the pH value 1) is slowly heated to 80-90 ⁰ C, so that the excess phosgene is hydrolyzed by the hydrochloric acid present in the aqueous phase. In this way, the reaction mixture is detoxified much shorter and easier than after the Ausblasverfahren carried out in the absence of water

Hot phosgenation. It is extremely surprising that according to the process of the invention neither the already formed 5-chlorocarbonyl

5H-dibenz / b, f / azepine (II) nor the phosgene introduced by the added aqueous base or towards the end of the

Phosgenation present hydrochloric acid aqueous phase can be significantly decomposed in any form. Phosgene is detoxified, for example, with 15-20% sodium hydroxide solution (see "Organikum", 6th edition, page 630, 1967). The ö-chlorocarbonyl-öH-dibenz / b ^ / azepine (II) is also used as alkali-sensitive carbamoyl chloride in the presence of

aqueous alkali solutions immediately spontaneously transferred via the sodium salt of the carbamic acid in question with decarboxylation again in the iminostilbene.

These are the reasons why amines are not normally reacted with phosgene in the presence of aqueous-alkaline solutions

can. In a totally unexpected way, the phosgenation of iminostilbene under the conditions described also proceeds much faster and under much milder, gentler conditions. The reaction time is shortened by half according to the inventive method. The formation of the by-products is also suppressed. Surprisingly, very little 9-methyl acridine is formed under the reaction conditions described. This undesirable

By-product is obtained by the process according to the invention in a very elegant way voi teilhafterweise according to the

Removed "self-detoxification" during phase separation.

The detoxified hot reaction solution remains for a period of time to phase separation at 80-9O ⁰ C. The lower aqueous, strongly acidic phase is separated and discarded. In this aqueous phase are - except for the respective salt - about 0.2% of the original amount of iminostilbene used in the form of various by-products. Of this, an estimated FiO% is accounted for by the 9-methylacridine present as the hydrochloride.

The detoxification of the reaction solution by the formed 7-10% hydrochloric acid thus still has a positive effect by extracting basic amine-like by-products in Forin their hydrochlorides from the organic phase, i. the aqueous acid phase acts with respect to the end product 5-carbamoyl-5H-dibenz / b, f / azepine (III) (= Caj & amazepin) in the sense of a

Pre-cleaning. · "*

If desired, the reaction mixture may be extracted once more with dilute hydrochloric acid for further purification and treated after the phase separation with adsorbents such as activated carbon and / or alumina. The organic phase is then converted in a manner known per se to 5-carbamoyl-5H-dibenz / b, f / azepine (III). This is achieved by reacting the solution of 5-chlorocarbonyl-5H-dibenz / b, f / azepine in the respective inert solvent at elevated temperature with an amidating agent. As such serve aqueous ammonia with a content of 15-25% or aqueous solutions of ammonium salts. As an advantageous temperature range for the reaction have 0-100 ⁰ C, preferably 40-80 ⁰ C proved. To avoid losses of amidating agent, it may be appropriate to carry out the reaction under pressure, depending on the solvent or amidating agent used pressures between 1 χ 10 ⁵ Pa to 3 χ 10 ⁶ Pa arise. The amidation reaction may also be advantageously carried out in the presence of surfactants, such as quaternary aryl-alkyl-ammonium salts or non-ionic surfactants, which are conveniently added in amounts of 0.01-10 Ma%. After completion of the reaction - the content of 5-chlorocarbonyl-5H-dibenz / b, f / -azepin must be less than 0.2 wt .-% - the reaction mixture is cooled to room temperature and the precipitated 5-carbamoyl-5H-dibenz / b , f / azepine (III) aspirated. The crude product already has a high purity. A (one-time) crystallization from methanol or methanol-water yields a 5-carbamoyl-5H-dibenz / b, f / azepine (III) (- carbamazepine) of excellent pharmaceutical quality (single impurity at most 0.01%).

The mother liquor of the amidation reaction contains two phases, which are separated for workup. The aqueous phase is discarded while the organic phase is distilled to recover the solvent. Also a multiple use of this phase is possible if desired.

Suitable inert solvents are the aromatic hydrocarbons benzene, toluene or chlorobenzene.

The bases used are preferably dilute alkali solutions or dilute ammonia water. The use of these bases - as a preferred variant - guarantees an exhaust-free polymerisation process until almost complete conversion of the iminostilbene, that is, only shortly before the end of the reaction begins a slight decomposition of the introduced phosgene, which manifests itself in a evolution of carbon dioxide. The escaping carbon dioxide carries small amounts of phosgene in the absorption template. Compared to the previously practiced hot phosgenation, however, this is only a few percent of the otherwise expelled and to be detoxified phosgene and HCI-containing exhaust gases.

In the process of the present invention, an equimolecular portion of the liberated hydrogen chloride is chemically bound by the added base while the residue is dissolved in the aqueous phase.

The use of aqueous solutions of alkali metal carbonates or bicarbonates is possible in principle. In this particular case, however, a carbon dioxide evolution begins immediately with the beginning of the feed of these solutions to the reaction mixture, so that phosgene reaches the exhaust gas at the latest after the 50% conversion. Although less phosgene is discharged here than after the hot phosgenation process, the use of alkali lye or ammonia water is the preferred process variant.

However, the use of the latter bases is possible from the beginning of the reaction, because under alkaline conditions - d. H. in the presence of excess aqueous base solutions - the phosgene is immediately decomposed.

Sparingly nearly neutral reacting carbonates such as calcium carbonate can be used as an aqueous suspension as an acid scavenger already at the beginning of the phosgenation. But in this case, the CO ₂ evolution - and thus the expulsion of phosgene - substantially more early than when the feed of an aqueous alkali carbonate solution after the approx.

50% conversion of iminostilbene.

The aqueous solutions of alkali metal carbonates or the aqueous suspensions of alkali metal bicarbonates or alkaline earth metal carbonates are therefore not particularly suitable for large-scale phosgenations (batch size up to 600 kg iminostilbene).

A special embodiment of the invention, however, is that after the approximately 50% conversion of iminostilbene an aqueous suspension of an alkaline earth metal oxide - preferably CaO or MgO - or alkaline earth metal hydroxide let run.

For one equivalent of iminostilbene, one uses 0.55-1.00 equivalents of base, but preferably only 0.55-0.75 equivalents of base.

For example, one mole of iminostilbene requires 0.55-0.75 moles of NaOH, KOH or NH _3, or 0.28-0.38 moles of CaO.

Another particular embodiment of the method according to the invention consists in the fact that after only about

10-20% conversion of the iminostilbene with the feed of the aqueous base solution begins, wherein the rate of introduction of the phosgene and the feed rate of the aqueous base is controlled so that the pH of the reaction mixture never slides into the alkaline range.

embodiments

example 1

160 g of iminostilbene (I) (0.835 mol) are suspended in 800 ml of toluene. This suspension is heated to 35-40 ° C. Phosgene is introduced into the stirred suspension. The reaction is slightly exothermic. The temperature of the reaction mixture rises to about 5O ⁰ C. In large-scale approaches, the temperature of the reaction mixture by cooling at 40-5O ⁰ C is maintained.

After the 50% conversion (about 1.5 hours reaction time) of the iminostilbene to the 5-chlorocarbonyl-5H-dibenz / b, f / azepine (II), the temperature of the reaction mixture no longer increases, and the iminostilbene color is disappeared. With continuous further introduction of phosgene, the slow addition of dilute sodium hydroxide solution (20 g NaOH = 0.50 mol, dissolved in 150 ml water) is started at this point.

The feed of the liquor is completed after 30-45 minutes. The iminostilbene hydrochloride goes into solution. Phosgene is further introduced until no more iminostilbene is detectable. There are then added 100ml of water.

Then heated the reaction mixture having pH 1, slowly from 50 ⁰ C to 80-90 C to ^0. Excess phosgene is rapidly hydrolytically decomposed under these conditions.

Once the reaction mixture is phosgene, the lower aqueous acidic phae are separated and discarded.

The organic phase is allowed to run now at 40-80'C in 260 ml of aqueous 25% ammonia (laboratory autoclave). The vessel is sealed and the reaction mixture is stirred 2 hrs. At 80-90 ⁰ C. After cooling and addition of 150 ml of water, the 5-carbamoyl-5H-dibenz / b, f / azepine (III) is filtered off with suction and dried.

Yield: 188-193 g carbamazepine (III), 96-98% of theory F. 189-192 ° C.

The crystallization from methanol-water with the addition of activated carbon yields a product in pharmaceutical purity (individual contamination below 0.01%).

Example 2

160g of iminostilbene are suspended in 800ml toluene. In this suspension is introduced according to Example 1 at 35-40 ° C phosgene. After the 50% conversion of the iminostilbene, the slow feed of 70 ml of 12.7% ammonia water (density = 0.95 g / cm ³ at 15 ° C., 0.50 mol of NH ₃ ) is begun, the phosgene introduction being continued continuously , The diluted ammonia water is added dropwise in about 1 hour.

Subsequently, the Phosgeneinleilung is continued until complete conversion of iminostilbene. Thereafter, the reaction solution is slowly heated from about 50 ⁰ C to 80-9O ⁰ C and stirred at this temperature until no more phosgene is detectable (duration of the detoxification about 1 hr.). The detoxified reaction mixture is mixed with 100 ml of water to dissolve the ammonium chloride.

Thereafter, 4 g of activated carbon zugegetu, i. The mixture is stirred for a further hour at 80-90 ⁰ C and then filtered.

The charcoal is washed with 50ml of hot Toiuen. From the filtrate, the acidic aqueous phase is separated and discarded. The Toluenian solution is treated according to Example 1.

Yield: 190-193g carbamazepine (III), 97-98% d. Th. F. 189-192 ⁰ C.

Example 3

160g iminostilbene are suspended in 800ml chlorobenzene. This suspension is treated according to Example 1 with phosgene, After the 50% conversion of iminostilbene begins with the addition of dilute potassium hydroxide solution (30 g KOH = 0.55 mol, dissolved in 170 ml of water). The liquor is added dropwise with further phosgene introduction in about 45 minutes. During phosgenation, the temperature is maintained at 35-45 ° C, preferably at 34-4O ⁰ C. Due to the better solubility of the 5-chlorocarbonyl-5H-dibenz / b, f / azepine (II) in chlorobenzene can (compared with toluene) be worked at about 40 ° C, without the reaction product begins to crystallize. In toluene below 4O ⁰ C and the crystallization of the Chlorcarbonyliminostilbens (II) must be gerechnot. After complete conversion of the iminostilbene, the reaction mixture is detoxified as in Example 1 or 2.

In order to keep the formed KCl in solution, 80 ml of water are added.

The reaction mixture is then vercetzt with 4g of activated carbon, stirred for 1 hour at 80-9O ⁰ C and then filtered. The charcoal is washed with 50 ml of hot chlorobenzene. The aqueous phase is separated off at 80-90 "C (possibly with the addition of a surfactant for refraction of the emulsion layer) and discarded.

The chlorobenzene phase is amidated according to Example 1.

Yield: 190-193 g carbamazepine (III), 97-98% of theory F. 189-191 ⁰ C.

BelspleU

160 g of iminostilbene are suspended in 800 ml of chlorobenzene and treated at 35-5O ⁰ C with phosgene until the iminostilbene color has disappeared. To the approximately equimolar mixture of S-chlorocarbonyl-SH-dibenz / bf / azepine (II) and iminostilbene hydrochloride is added dropwise with further phosgene within 1 hr. A solution of 41 g (0.50 mol) of sodium acetate in 150 ml of water, wherein the temperature of the reaction mixture may drop to 40 ⁰ C.

After the addition of the acetate solution at 40-45 ⁰ C further phosgene is introduced until the complete conversion of iminostilbene.

Subsequently, the reaction solution is heated to 80-9O ⁰ C and detoxified. The phosgene-free reaction mixture is transferred to a separatory funnel. After separation of the acetic acid-smelling aqueous phase, the chlorobenzene solution is amidated as described in Examples 1 to 3.

Yield: 192-194g carbamazepine (III), 98-99% of theory. F. 188-190 ⁰ C.

Examples

160 g of iminostilbene are suspended in 800 ml of toluene and reacted according to Example 1 with phosgene. After the 50% conversion of the iminostilbene is begun at about 4O ⁰ C with further phosgene introduction with the slow addition of 14 g (0.25 mol) of CaO in 170 ml of water (this suspension is stirred to keep it homogeneous). The CaO-water suspension is added in about 45 minutes.

Subsequently, further phosgene is introduced up to the total iminostilbene conversion, where possible at 40-45 ⁰ C is used. The reaction mixture is detoxified as described and then amidated as described in Example 1.

Yield: 195-196g carbamazepine (III), 99-1004d.Th. F. 189-191 ⁰ C.

Example β

160g of iminostilbene are suspended in 800ml toluene. At about 4O ⁰ C to start with the introduction of the phosgene. After approx.

10-20% conversion of the iminostilbene takes place the slow addition of dilute sodium hydroxide solution (24 g NaOH = 0.60 mol, dissolved in 200 ml of water). The rate of phosgenation and the metered amount of dilute sodium hydroxide solution are adjusted to one another such that the pH of the reaction mixture during alkaline addition never in the alkaline

Area slides off. The phosgenation is carried out at 40-50 ° C. After the complete conversion of the iminostilbene is added to Example 1 with the addition of 1.5 g of benzyl-octyl-dimethyl

ammonium chloride amidated, with a complete conversion is achieved after 1 hr. Reaction time.

Yield: 192-194g carbamazepine (III), 98% of theory! ^: . 189-192 ⁰ C.

298 50

equation

-7-

Formula I Formula II /.

Formula II Formula IJi.

C-NH,

Claims (6)

1. A process for the preparation of 5-carbamoyl-5H-dibenz / b, f / -azepin by successive reaction of iminostilbene with phosgene and an amidating agent in an anhydrous aromatic solvent, characterized in that one iminostilbene in an inert solvent at temperatures of 20 -60 ⁰ C is reacted with phosgene, from which in addition to the 5-chlorocarbonyl-5H-dibenz / b, i / -azepin forming iminostilbene hydrochloride by the addition of suitable aqueous bases liberates ivrinostilbene, this phosgenated constantly while maintaining acidic reaction conditions, and Subsequently, the ö-chlorocarbonyl-öH-dibenz / b, f / azepine in this solution immediately reacted in a conventional manner with an amidating agent. 2. The method according to claim 1, characterized in that initially in the heated to 20-60 ⁰ C, preferably 35-5O ⁰ C, suspension of iminostilbene in an inert solvent so many phosgene initiates until a nearly equimolecular mixture of 5- Chlorocarbonyl-5H-dibenz / b, f / azepine and iminostilbene hydrochloride is formed. 3. The method according to claim 1 and 2, characterized in that are used as aqueous bases solutions of alkali metal hydroxides, aqueous ammonia solution, aqueous solutions of alkaline salts due to hydrolysis or aqueous suspensions of alkaline earth metal hydroxides or oxides. 4. The method according to claim 1 to 3, characterized in that are used for 1 equivalent of iminostilbene 0.5-1.0 equivalents, preferably 0.55-0.75 equivalents of alkali or base. 5. The method according to claim 1 to 4, characterized in that are used as the inert solvent aromatics or haloaromatics such as toluene or chlorobenzene. 6. The method according to claim 1 to 5, characterized in that the organic phase is reacted immediately after completion of phosgenation and phase separation with an amidating agent.