DD300169A7 - Process for the preparation of 5-chlorocarbonyl-5H-dibenz [b.f] -azepin - Google Patents

Abstract

The invention relates to a process for the preparation of * which is the precursor for the large-scale synthesis of *. The latter substance is used as a drug. The essential features of the invention are 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 addition of a aqueous base releases iminostilbene from the formed iminostilbene hydrochloride, the latter thus rendering the complete phosgenation accessible, while maintaining an acidic reaction milieu. After complete conversion of the iminostilbene, the reaction mixture is slowly heated to 80 ° -90 ° C. and detoxified with stirring by the hydrochloric acid formed. {Iminostilbene; phosgenation; aqueous auxiliary bases; *}

Description

For this 1 page formulas

Field of application of the invention

The invention relates to a technical process for the preparation of 5-chlorocarbonyl-5H-dibenz [b, f] azepine (II). This compound is the precursor for the large-scale synthesis of 5-carbamoyl-5H-dibenz | b, () azepine (III), which is used as a drug, preferably as an antiepileptic.

Characteristic of the known technical solutions

The synthesis of 5-chlorocarbonyl-5H-dibenz (b, f] azepine (II) from iminostilbene (I) (= 5H-dibenz [b, f] azepine) was described for the first time by W. SCHINDLER (DE-AS 1,136,707 , CH-PS 54.023).

According to this method, the iminostilbene (I) is suspended in toluene and phosgene is introduced into this suspension, the reaction mixture being heated to 70 ° 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 also DE-AS1,001,271, where the excess phosgene after the phosgenation of the 5H-10,11-dihydro-dibenz | b, f | azepine = iminodibenzyl likewise dry air is blown out).

The so nentgiftete reaction solution is worked up as usual, and the isolated by crystallization 5-chlorocarbonyl-5H-dibenz [b, f] azepine (II) in a known manner to 5-carbamoyl-5H-dibenz [b, f | azepine (III ) amidated. The processes described so far all work in inert anhydrous solvents at temperatures above 100X (for example in toluene, in chlorobenzene or in o-dichlorobenzene, see patents and reviews by B. RENFROE, C. HARRINGTON and GR PROCTOR in "Heterocyclic compounds", Vol.43, "Azepines", Part I, John Wiley & Sons, New York 1984, page 524, Table 118).

The dissociation of the always arising in the phosgenation iminostilbene hydrochloride in hydrogen chloride gas and free iminostilbene is thermally carried out in all industrial processes 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 a table in the HCUBEN-WEYL (Volume E4, page 46-50, 1983). The solvents used in the re Ή above all aromatic hydrocarbons such as benzene, toluene or chlorobenzene. However, methods have also been described in CHCl ₃ , in 1,4-dioxane and in ethyl acetate. If the reaction is carried out at low temperatures, only half of the amine is converted into the desired carbamoyl chloride upon introduction of phosgene into a solution of the secondary amine in an inert solvent, because the hydrogen chloride liberated in the reaction turns the other half of the amine into the hydrochloride transferred. The amine hydrochloride separates out in crystalline form, ie the yield of carbamoyl chloride can be only 50% in the most favorable case.

It has been known since the work of H. ERDMANN and P. HUTH (J. Prakt. Chem. [2] 56.7 [1887]) that m can be converted into the conversion when an inert anhydrous base such as pyridine in at least equimolecular Quantity added. According to HOUBEN-WEYL (see above), triethylamine and, of course, the amine to be reacted are suitable as inert bases except pyridine itself. Since it always requires at least equimolar amounts of inert base, the Kaltphosgenierur.g expensive, and the process is technologically complex, because the amine hydrochloride must be separated in any case, for the purpose of recovery of the inert base. For this reason, the cold phosgenation in the presence of inert auxiliary bases has only significance for the implementation of temperature-sensitive secondary amines, which tend increasingly at the high temperatures of the hot phosgenation to undesirable side reactions.

In the art, it is preferred to operate at temperatures above 100 ⁰ C. In HOUESN-WEYL (see above): "Advantageously, the reaction mixture is heated to more than 100 ⁰ C with further introduction of phosgene, the Arnin hydrochloride in the carbamoyl chloride "The HCI gas liberated from this thermal dissociation entrains considerable amounts of phosgene, which is why the exhaust gas in special exhaust systems must be detoxified and destroyed In the event of an accident, such a procedure can seriously endanger the environment Above all, the extreme toxicity of phosgene poses a danger to adjacent residential areas.)

The mode of operation of hot phosgenation has, in particular, the following serious disadvantages:

high exhaust gas emissions from released HCl gas, entrained ihosgene and entrained solvent vapors and the resulting environmental problems

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

- high onergy expenses 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 90 ° C increasingly occurring constriction of the seven-membered ring of iminostilbene to form undesirable 9-methylacridine.

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 achieve acceptable Rbaktionszeiten for industrial purposes.

The preferred variant of the division of the phosgenation into a phase of the cold phosgenation (conversion of the first hold, 50%) and a phase of the hot phosgenation (conversion of the second half) by SCHINDLER has clear advantages over the direct hot phosgenation, because, firstly, the yield in this way secondly, the side reactions above 90 ° C were suppressed and thirdly the quality and color were improved. Nevertheless, the disadvantages described in the second reaction stage - from the beginning of the heating to 90 ° C and during the thermal dissociation of the iminostilbene hydrochloride to the end point of the reaction - are retained. In order to make full use of the gentle heat conditions of the cold phosgenation phase, an excess of phosgene is introduced into the reaction mixture. If the reaction mixture is then heated for the thermal dissociation of the iminostilbene hydrochloride, the pressure surge can occur. This danger is also brought to our attention, HOUBEN-WEYL (Volume E 4, page 744,1983). In a burst of pressure, the spontaneously released amounts of HCI gas entrain considerable amounts of phosgene. Consequently, the exhaust gas annihilation plant must be large enough to avoid such a surge of phosgene into 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. At this reaction temperature, 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 already evident in the Tataache, that for the conversion of the first half iminostilbene in the phase of the 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. As a rule, the excess phosgene from the hot reaction solution is inflated with dry nitrogen, or some of the solvent is distilled off until the crude 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 iminostilbene (I), some methods for the synthesis of 5-chlorocarbonyi-5H-dibenz [b, f] azepine (II) have been described in the literature, which are derived from imino-dibenzyl (IV) (II). = 10,11 -dihydro-5H-dibemlb, f] azepine) (see in this regard 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, DD 234.863).

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 F-chlorocarbonyl-5H-10,11-dihydro-dibenz [b, f) azepine (V) is then reacted in an inert organic solvent with elemental bromine or a selective bromination reagent, the corresponding 10-monobromo- (VI, R = H) and / or 10,11-dibromo derivatives (VII, R = Br) are formed. Subsequently, the bromine compounds (VI and / or VII) are thermally dehydrobrominated and / or dabrominated. In this thermal process, a partial exchange (30-40%) of the chlorine atom of the B-chlorocarbonyl group takes place at the same time against a bromine atom. These drastic reaction conditions inevitably lead to uncontrollable side reactions (nuclear bromination, resinification, cracking, discoloration) due to the required high reaction temperatures (150 ° C-170 ° C) and the liberated bromine.

It follows that the synthesized via such a process S-chlorocarbonyl-5H-dibonz [b, f] azepine (II) in addition to numerous - especially bromine - by-products still greasy, tarry components and dyes containing the removal of which requires enormous effort.

There is no knowledge of the nature and structure of the by-products mentioned. The usual cleaning ancestors lead to considerable losses.

So far, there is no purification process that solves the problem of residual bromine content in an economically justifiable way. All this can be explained, then the HPLC-determined content of the thus synthesized 5-chlorocarbonyl-5H-dibenz [b, f] azepine (II) is on average 90%, d. H. the precursor for the final product carbamazepine contains about 10% impurities.

The invention aims to produce 5-chlorocarbonyl-5H-dibenz [b, f] azepine of the formula (II) under extremely mild and mild reaction conditions in quantitative yield with substantially improved quality from iminostilbene, the novel process having a substantially reduced reaction time and requires considerably less energy. With the invention, a significant improvement in environmental protection and noticeably reduced risk torques are also achieved wp'den.

Explanation of the essence of the invention

The present invention is based on the object, 5-chlorocarbonyl-5H-dibenz [b, f] azepine of the formula (II) with a shortened reaction time while avoiding the Heißphosgenierungsphase or elimination of the usual thermal dissociation of iminostilbene hydrochloride in quantitative yield and produce in much improved quality.

In addition, the reaction is to eliminate the phosgene emission and to ensure self-detoxification of the reaction solution.

According to the present invention, this is achieved in that in a suspension of iminostilbene (I) in an inert solvent at 20-6O ⁰ C initiates phosgene or allowed to run in a solution of phosgene in the same solvent until the iminostilbene to a nearly equimolecular mixture from 5-chlorocarbonyl-5H-dibenz [b, f | azepine (II) and iminostilbene hydrochloride is reacted, whereupon iminostilbene is liberated from the formed iminostilbene.hydrochloride by addition of an inorganic aqueous base and accessible to complete phosgenation while maintaining an acid reaction medium makes.

Preferably, the work is carried out in the temperature range of 35-5O ⁰ C. After dom about 50% conversion of the iminostilbene to the desired carbamoyl chloride (II) begins with continuous further introduction of phosgene either with the feed of a dilute solution of an alkali metal hydroxide or dilute ammonia water or an aqueous solution of an alkali carbonate or bicarbonate or an aqueous Solution of a salt which reacts alkaline as a result of hydrolysis (for example sodium acetate).

During the feed of the aqueous base, the temperature is maintained at 35-5O ⁰ C.

After the feed of the aqueous base, the introduction of the phosgene is continued until 100% conversion of the iminostilbene, wherein the specified temperature limits are met. The complete conversion of the iminostilbene is determined by thin-layer chromatography.

In the final phase of the phosgenation, the temperature is maintained at about 40-60 ⁰ C, so that the formed 5-chloronarbonyl-5H-dibenz [b, f] azepine (II) does not crystallize. 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. Thereafter, the strongly acidic reaction mixture (which has the pH of 1) is slowly heated to 80-90 ° C, so that the excess phosgene is hydrolyzed by the present in the aqueous phase hydrochloric acid. In this way, the reaction mixture is detoxified in a much shorter time and easier than after the Ausblasverfahren the carried out excluding 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 inorganic base or present at the end of the phosgenation hydrochloric aqueous phase be noticeably decomposed in any way.

Phosgene is detoxified, for example, with 15-20% sodium hydroxide solution (see, "Organikum", 6th edition, page 630, 1967).

The 5-chlorocarbonyl-5H-dibenz [b, f] azepine (II) is as alkali-sensitive carbamoyl chloride also in the presence of aqueous alkali solutions immediately spontaneously on the sodium salt of the carbamic acid in question with decarboxylation back in

the iminostilbene transferred. .

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

In contrast, it is known that primary amines (RNH)) in a two-phase system with phosgene and alkali (see HOUBEN-WEYL, Volume E 4, page 746) can be converted to the corresponding isocyanates (R-NCO). This isocyanate synthesis gives only satisfactory yields when the R group push electrons towards the N atom. The yield is about 75%. In addition, you must work at very low temperatures, so that the isocyanate formed is not decomposed by the existing water to the starting amine (via the corresponding carbamic acid due to decarboxylation).

According to the example described in HOUBEN-WEYL (Volume E 4, page 746) for the phosgenation of tert-butylamine, exactly 2 moles of NaOH are used per mole of phosgene, ie. that is, the amount of HCI theoretically expected from the phosgene is neutralized.

It is therefore worked as close as possible to the neutral point. The phosgenation of primary amines leads to the carbamoyl chloride R-NH-COCl. Due to the electron-withdrawing effect of the COCI group, the proton on the N atom is strongly acidified. This is ultimately based on the implementation of this carbamoyl chloride with NaOH to the isocyanate:

R-NH-COCl + ΟΗ ^Θ -Ü! I RN ^e -COCl - ^ - »RN = C = O.

In the acidic or alkaline pH range, even the more stable isocyanate would be decomposed. At the end, in the acidic pH range, only tert-butylamine hydrochloride would be present (based on the example given, with continuous further phosgene introduction in order to attempt a 100% conversion).

It follows that one can not compare the method for the phosgenation of iminostilbene according to the inventive method described above with the isocyanate method.

While a primary carbamoyl chloride reacts with the added lye to the isocyanate (there is no attack on the carbonyl group, but it is first the proton detached from the N atom, then stabilizes the intermediately formed

Anion with the chloride ion escaping to the isocyanate), a secondary carbamoyl chloride is immediately decomposed by the added dropwise liquor under direct attack on the carbonyl group via the intermediate carbamic acid (with spontaneous decarboxylation) to the starting amine

 These are completely different reaction mechanisms and classes of compounds.

In the process described by us, the phosgenation of the iminostilbene after the 50% conversion by adding a minor amount of aqueous inorganic base (with respect to the amount of phosgene introduced, preferably only 0.55-0.7 equivalents of base to 1.0 equivalent Iminostilbene) and, after addition of base under strongly acidic pH conditions, surprisingly led to quantitative conversion.

In a completely 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 the process according to the invention to half.

The formation of the by-products is also suppressed. Amazingly, very little 9-methyl acridine is formed under the reaction conditions described. This undesirable by-product is removed by the process of the invention in a very elegant manner, advantageously after self-detoxification in the phase separation The detoxified 3 hot reaction mixture remains standing at 80-90 ° C. for a period of time for the phase separation The lower aqueous, strongly acidic phase In this aqueous phase, apart from the particular salt, about 0.2% of the amount of iminostilbene originally used is present in the form of the most varied by-products, of which about 50% is attributable to the 9-methyl-acridine present as the hydrochloride. Iminostilbene is present in an extremely small amount in the acidic aqueous solution, and the detoxification of the reaction solution by the formed 7-10% hydrochloric acid thus has a positive effect of extracting basic amine-like by-products in the form of their hydrochlorides from the organic phase, i. h "the aqueous acidic phase acts in be train on the end product carbamazepine in the sense of a pre-cleaning. Suitable inert solvents are both the aromatic hydrocarbons benzene, toluene or chlorobenzene and the aliphatic chlorinated hydrocarbons chloroform or carbon tetrachloride, preferably toluene or chlorobenzene are used.

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 phosgenation process until almost complete conversion of the iminostilbene, d. that is, just before the end of the reaction, a slight decomposition of the phosgene introduced, which manifests itself in a carbon dioxide evolution, begins. 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 gilled hydrogen chloride is chemically bound by the added base while the remainder 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 enters the exhaust gas at the latest after the 5% conversion. Although less phosgene is discharged here, according to the hot phosgenation process, the use of alkali lauric or ammonia water is the preferred process variant.

However, the use of the latter bases is not possible from the beginning of the reaction, because under alkaline conditions - c '. 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-is much more timely than the addition of an aqueous alkali carbonate solution after about 50% conversion of iminostilbene.

The aqueous solutions of the alkali metal carbonates or the aqueous suspensions of the alkali metal bicarbonates or alkaline earth metal carbonates are 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 can run. For one equivalent of iminostilbene, 0.55-1.00 equivalents of base are used, but preferably only 0.55-0.75 equivalents of base. For example, for 1 mol of iminostilbene, 0.55-0.75 mol of NaOH, KOH or NH ₃ or 0.28-0.38 mol of CaO are required. Another particular embodiment of the method according to the invention consists in the fact that it starts already after about 10-20% conversion of the iminostilbene with the feed of the aqueous base solution, 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.

Ausführungsbelsplele example 1

160 g of iminostilbene (I) (0.835 mol) are suspended in 800 ml of toluene. This suspension is heated to 35-40 ⁰ C. Into the stirred suspension is introduced phosgene. The reaction is slightly exothermic. The temperature of the reaction mixture rises to about 50 ° C. For large scale runs, the temperature of the reaction mixture is maintained at 40-50 ° C by cooling.

After the 50% conversion (about 1.5 hours reaction time) of iminostilbene to 5-chlorocarbonyl-5H-dibenz [b, f] jazepine (II) increases Temperature of the reaction mixture is no longer on, and the iminostilbene color has disappeared. Constantly further Initiation of phosgene begins at this point with the slow addition of dilute sodium hydroxide (20g NaOH = 0.50 mol, dissolved in 150 ml of water). The feed of the liquor is after 30-50min. completed. The iminostilbene hydrochloride goes into solution. It will continue phosgene

initiated.

The reaction solution becomes progressively lighter in color as the reaction progresses. Towards the end of the reaction, the color goes

of the foam of the reaction solution from yellow-brown over yellow to white. This white foam on the stirred

Reaction solution and incipient CCV development Shortly before the end of the reaction are important clues to the

complete conversion of iminostilbene.

Towards the end of the reaction, the temperature is kept at almost 50 ^° C., so that the chlorocarbonyl-iminostilbene formed does not

crystallized. The introduction of phosgene is terminated when no more iminostilbene is detectable in the reaction solution. 100 ml of water are added to keep the formed NaCl in solution.

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 free of phosgene, the lower aqueous acidic phase is separated and discarded. This watery Phase has a purifying effect on the formed 5-chlorocarbonyl-5H-dibenz [b, f] azepine (II), since it contains several amines By-products (0.2-0.3g) in the form of their hydrochlorides, especially 9-methyl acridine. From the aqueous phase, the

amine-like by-products are released with NaOH.

The Toluenic phase can be extracted with dilute hydrochloric acid and washed with water if necessary

is. After renewed phase separation, the toluene solution of the chlorocarbonyl-iminostilbene (II) is distilled. After

Removal of the solvent precipitates the remaining melt of the chlorocarbonyl-iminostilbene in methanol. The

methanolic suspension is cooled, and the crystallized chlorocarbonyl-iminostilbene is filtered off with suction and dried.

Yield: 197-20Og 5-Chlorocarbonyl-5H-dibenz [b, f] azepine (II) 93-94% of the total F .: 157-158 ⁰ C Content It. HPLC: 99.8 to 100% strength Salary It. DC: 99.7 to 99.9% pure

The 5-chlorocarbonyl-5H-dibenz [b, f] azepine (II) thus obtained is prepared according to those described in the patent literature Amidation process a crude carbamazepine, which is already formed after a single recrystallization from methanol-water Pure carbamncine yields that meets all the requirements of international pharmacopoeias (max Single contamination S0.01%). From the methanolic precipitation mother liquor, after concentration, a further 5-1Og 5-chlorocarbonyl-5H-

dibenz [b, f] azepine (II).

The total yield is thus 205-207 g, that is 96.5-97.6% of theory. The obtained from the methanolic mother liquor chlorocarbonyl-iminostilbene (II) is collected and separated

processed.

Example 2

160g of iminostilbene are suspended in 800ml toluene. Phosgene is introduced into this suspension according to Example 1 at 35-40 ° C. After the 50% conversion of iminostilbene one begins with dom slow inflow of 70 ml of 12.7%

Ammonia water (density = 0.95 g / cm ³ at 15 ⁰ C, 0.50 mol NH ₃ ), wherein the phosgene introduction is continued. The

Diluted ammonia water is added dropwise in about 1 hour.

Subsequently, the phosgene is continued until complete conversion of the iminostilbene. After that, the Reaction solution slowly heated from about 50 ° C to 80-90 ⁰ C and stirred at this temperature until no more phosgene

is detectable (duration of the detoxification about 1 hour). The detoxified reaction mixture is mixed with 100 ml of water to the

To dissolve ammonium chloride. Afterwards 4g activated charcoal are added. The mixture is stirred for a further hour at 80-90 ⁰ C and then filtered. The coal is washed with 50ml of hot toluene. From the filtrate, the acidic aqueous phase is separated and discarded. The

Toluenische solution is treated according to Example 1. '

Yield: 195-205 g of 5-chlorocarbonyl-5H-dibenz- | b, f] azepine (II)

92.0-96.5% of theory F .: 157-158 ⁰ C

Content It. HPLC: 99.8-100% pure From the methanolic iillbadmutterlauge obtained after distillation, a further 3-1Og chlorocarbonyl-iminostilbene (II). Example 3

160 g of iminostilbene are suspended in 800 ml of chlorobenzene. This suspension is treated according to Example 1 with phosgene.

After the 50% conversion of the iminostilbene, the feed of dilute potassium hydroxide solution (30 g KOH = 0.55 mol,

dissolved in 170 ml of water). The liquor is added dropwise uniformly with further phosgene introduction in about 45 minutes.

During phosgenation, the temperature is maintained at 35-45 ° C, preferably better Due to the at 34-40 ⁰ C. Solubility of 5-chlorocarbonyl-5H-dibenz [b, f] azepine (II) in chlorobenzene (vs. toluene) may be estimated at ca. 4O ⁰ C worked

be without the reaction product begins to crystallize. In toluene has to below 4O ⁰ C and the crystallization of the

Chlorocarbonyl-iminostilbene (II) are calculated. After complete conversion of iminostilbene, the Reaction mixture as in Example 1 or 2 detoxifies. In order to keep the formed KCl in solution, 80 ml of water are added. The reaction mixture is then mixed with ⁴ g of activated carbon, stirred for 1 hour at 80-90 ⁰ C and then filtered. The charcoal is washed with 50 ml of hot chlorobenzene. The aqueous phase is at 80-9O ⁰ C (possibly uniar addition of a

surfactant for refraction of the emulsion layer) separated and discarded.

The chlorobenzene phase is worked up according to Example 1.

Yield: 190-193 g5-Chlorocarbonyl-5H-dibenz [b, f] azepine (II) 90 to 91.5% d.Th. F .: 157-158 ⁰ C Content It. HPLC: 99.75 to 100% strength

From the methanolic precipitation bath mother liquor, a further 10-15 g of chlorocarbonyl-iminostilbene (II) is obtained. Example 4

160g iminostilbene are suspended in 800 ml of chlorobenzene and treated at 35-50 ⁰ C with phosgene until the iminostilbene is color Ever disappeared. To the approximately equimolecular mixture of 5-chlorocarbonyl-5H-dibenz [b, f) 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, the temperature of the reaction mixture may drop to 40 ° C.

After the addition of the Acatatlösung further phosgene is introduced at 40-45'C until the complete conversion of iminostilbene. Subsequently, the reaction solution is heated to 80-90 ⁰ C and detoxified. The phosgene-free reaction mixture is in a Transfer funnel. After separation of the acetic acid-smelling aqueous phase, the chlorobenzene solution

worked up as described in Example 1 to 3.

Yield: 192-194 g of 5-chlorocarbonyl-5H-dibenz (b, f) azepine (II)

90.5-91.5% d. Theory F .: 156-158 ° C

Example 5

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 one starts at about 40 "C with further phosgene introduction with the slow addition of 14 g (0.25 mol)

CaO in 170 ml of water (this suspension is stirred to keep it homogeneous). The addition of the CaO-water suspension

takes about 45 minutes.

Subsequently, further phosgene is introduced up to the total iminostilbene conversion, where possible at 40-45 ⁰ C.

is working. The reaction mixture is detoxified as usual and then worked up as described in Example 1.

Yield: 197-201 g5-chlorocarbonyl-5H-dibenz [b, f] azepine (II) 93-94.5% of theory. theory

The work-up of the methanolic precipitation bath mother liquor gives a further 5-1Og of chlorocarbonyl-iminostilbene (II). Example 6

160g iminos beets 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 phosgene introduction and the metered amount of dilute sodium hydroxide are adjusted to each other so that the pH of the reaction mixture during the addition of alkali never in the alkaline

Area slides off. The phosgenation is carried out at 40-5O ⁰ C. After the complete conversion of the iminostilbene is worked up according to Example 1. Yield: 197-20Og 5-chlorocarbonyl-5H-dibenz [b, f] azepine (II)

93-94% d. Theory F .: 157-158 ⁰ C

Formula scheme 30011.3

Formula I formula

Formula II Formula IJI

G-NH,

Il

Claims (3)

A process for the preparation of 5-chlorocarbonyl-5H-dibenz [b, f] jazepine by reacting iminostilbene with phosgene in a two-phase solvent system using chlorobenzene or toluene and an inorganic aqueous base, characterized in that one in 20-60 ⁰ C heated suspension of iminostilbene in the organic solvent is first introduced phosgene to its 10 to 50% conversion and then with further phosgene introduction and maintaining an acidic pH, the aqueous inorganic base in an amount of 0.5 to 1.0 Equivalents per equivalent of iminostilbene is added to the reaction mixture. 2. The method according to claim 1, characterized in that luf 1 equivalent of iminostilbene preferably 0.55 to 0.75 equivalents of alkali or base are used. 3. The method according to claim 1 and 2, characterized in that is preferably used as the aqueous inorganic base dilute alkali metal hydroxide.