The preparation of 5-chlorocarbonyl-5H-dibenz[b,f]azepine (CCDA) (I) from iminostilbene or 5H-dibenz[b,f]azepine of formula (III) ##STR3## was described for the first time by W. Schindler in German DAS No. 1,136,707, and in Swiss patent No. 54,023.
According to this method, the iminostilbene of formula (III) is suspended in toluene. Phosgene is introduced into the suspension while heating the reaction mixture to 70.degree. C. Then the reaction mixture is refluxed during the further addition of phosgene, and is kept at boiling until the iminostilbene completely reacted and the evolution of hydrogen chloride has ceased. The introduction of phosgene is discontinued as soon as the reaction solution is free of iminostilbene. Excess phosgene is removed from the reaction mixture with dry nitrogen or dry air, such as is described in German DAS No. 1,001,271, in which the excess phosgene is blown out with dry air at the end of the phosgenation of 5H-10,11-dihydro-dibenz[b,f]azepine, or iminodibenzyl.
The so detoxified reaction solution, is worked up in a manner known per se and then the CCDA of formula (I) is recovered by crystallization is amidized in a manner known per se to the carbamazepine of formula (II). The known methods all use an inert, anhydrous solvent such as toluene, chlorobenzene or o-dichlorobenzene at temperatures above 100.degree. C. See, for example, the patents referred to in the survey article by B. Renfroe, C. Harrington and G. R. Proctor in "Heterocyclic Compounds", Vol. 43, "Azepines", part I, published by John Wiley & Sons, NY, 1984, page 524, Table 118.
In all known industrial methods the iminostilbene hydrochloride formed by the phosgenation is thermally dissociated into hydrogen chloride gas and free iminostilbene. This is carried out by heating the reaction mixture to the boiling point in an inert solvent, and introducting phosgene under reflux conditions.
The known high temperature phosgenations are all carried out at 100.degree. C. and higher temperatures, to achieve a complete phosgenation of the iminostilbene, or the iminodibenzyl.
The known methods of synthesizing carbamic acid chlorides from secondary amines are summarized in a table in the Houben-Weyl organic chemistry methodology mannual (vol. E 4pages 46-50, Georg Thieme Verlag, Stuttgart, N.Y., Publisher, 1983). Usually especially aromatic hydrocarbons, such as benzene, toluene or chlorobenzene are used as solvent. Methods have also been described, in which the reaction is carried out in chloroform, 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 carbamic acid chloride when the phosgene is passed into a solution of the secondary amine in an inert solvent. This is because the hydrogen chloride liberated during the reaction, converts the other half of the amine into the hydrochloride. The amine hydrochloride precipitates in crystalline form. Therefore, the yield of the carbamic acid chloride can even in the most favorable case amount only to 50%.
Since the work of H. Erdmann and P. Huth (J. Prakt. Chem. (2) 56, 7, 1897), it is known that the conversion can be completed if an inert, anhydrous base, such as pyridine, is used in an at least equimolar amount.
According to Houben-Weyl (see above) in addition to pyridine, triethylamine and of course, the amine itself that is to be reacted are suitable as inert bases. The cold phosgenation becomes more costly since at least equimolar amounts of inert base are always required. The process is costly because the amine hydrochloride has to be separated out for recovering the inert base. Therefore, the cold phosgenation in the presence of inert auxiliary bases is of importance only for the reaction of temperature sensitive, secondary amines, which increasingly tend to undergo undersirable side reactions at the high temperatures of the hot phosgenation.
In industry, the reaction is preferably carried out at temperatures above 100.degree. C. In this connection Houben-Weyl (see above) states that "[A]dvantageously, the reaction mixture is heated to temperatures above 100.degree. C. while further phosgene is introduced, and the entire amine chloride is converted into the carbamic acid chloride." In this thermal dissociation the hydrogen chloride gas carries along appreciable amounts of phosgene. Therefore, the off-gas decontamination must be detoxified and destroyed in special off-gas equipment. Such a procedure can seriously endanger the environment in the case of an accident, because of the danger presented by the extremely poisonous nature of phosgene which is a gas under ambient conditions.
The procedure of high temperature phosgenation has, the following more significant serious disadvantages:
the burden of having to deal with large amounts of liberated hydrogen chloride off-gas, including phosgene, and the entrained solvent vapors, and the resulting environmental protection problems; PA0 long reaction times of more than 18-24 hours in contact with highly corrosive media; PA0 a number of side reactions, and the dark coloration of the reaction product resulting in a low quality of the carbamazepine end product; and PA0 increasing formation of unwanted 9-methylacridine byproduct temperatures above 90.degree. C. represents a contraction of the 7-membered ring of the iminostilbene.
Only at temperatures of about 90.degree. C. does the thermal dissociation of the iminostilbene hydrochloride into free iminostilbene and hydrogen chloride gas proceed sufficiently rapidly to achieve reaction times, which are acceptable for industrial purposes. However, iminostilbene is a temperature sensitive amine. Therefore, iminostilbene is suitably phosgenated by the method of Schnidler described in the aforementioned German DAS No. 1,136,707.
The process variant preferred by Schindler is dividing the phosgenation into two stages, a cold phosgenation stage resulting in an about 50% conversion in the first phase, and a hot phosgenating stage. Conversion carried out in a second stage has clear advantages over a direct single stage hot phosgenation, because the yields are appreciably increased in this manner, the side reactions that take place above 90.degree. C. are suppressed, and the quality and color of the end product are improved. Nevertheless, the aforementioned disadvantages continue to exist in the second stage of the reaction, i.e. from the start of the heating to 90.degree. C. and during the thermal dissociation of the iminostilbene hydrochloride until the end of the reaction.
An excess of phosgene is introduced into the reaction mixture to utilize the gentle reaction conditions of the first, the cold phosgenating stage as much as possible. A pressure surge can occur if the reaction mixture is heated subsequently to dissociate thermally the iminostilbene hydrochloride. This dangerous possibility is also mentioned in Houben-Weyl (volume E 4, page 744).
When a pressure surge occurs, the spontaneously released hydrogen chloride gas also carries along appreciable amounts of phosgene. Therefore, the apparatus for destroying or detoxifying the off-gases must be sufficiently large to avoid the release of phosgene into the atmosphere.
The reaction is advisably carried out at temperatures of between 90.degree. C. and 100.degree. C. to suppress the unwanted side reactions and the formation of the methylacridine byproduct. The phosgenation proceeds sufficiently rapidly at this temperature. However, the partial pressure of the phosgene is appreciably increased at the higher temperature, compared to that of the cold phosgenation, therefore it is not possible to prevent the steady escape of large quantities of phosgene being carried along by the liberated hydrogen chloride. This can, of course, be also realized from the fact that appreciably less time is required for the conversion of the first half of the iminostilbene in the cold phosgenation stage, than for the conversion of the second half in the hot phosgenation stage.
The reaciton solution has to be detoxified after the complete conversion of the iminostilbene. The excess phosgene is blown out of the reaction solution with dry nitrogen as a rule, or a portion of the solvent is distilled off until the reaction mixture is free of phosgene. This detoxification method has the disadvantage that phosgene can leak into the atmosphere if there are any leaks due to the high gas pressure in the apparatus. Therefore, in the long run there is a constant danger of atmospheric contamination by the escaping phosgene.
Other methods are also known for preparing CCDA. These other methods start from 10,11-dihydro-5H-dibenz[b,f]azepine, or iminodibenzyl of formula (IV) ##STR4## In this connection see British patent No. 1,246,606 and East German patents Nos. 82,719; 100,948; 101,671; 102,149; 102,150; 102,151; 108,535; 133,052; 234,862 Al: and 234,863 Al. According to the methods described in these references, iminodibenzyl is reacted with phosgene in a boiling, inert, aromatic solvent, preferably toluene, or chlorobenzene. Phosgene is introduced into the refluxing material. Thus these methods also employ hot phosgenation with all of its attendant disadvantages.
The resulting 5-chlorocarbonyl-5H-10,11-dibenz[b,f]-azepine of formula (V) ##STR5## is reacted in an inert organic solvent with elemental bromine, or is otherwise subjected to selective bromination and the corresponding 10-monobromo derivative formula (VI) ##STR6## and/or the 10,11-dibromo-derivative formula (VII) ##STR7## is formed.
The bromo compounds (VI) and/or (VII) are subsequently dehydrobrominated and/or are thermally debrominated. A partial exchange (30-40%) of the chlorine atom of the 5-chlorocarbonyl group for a bromine atom takes place during such a thermal process. Due to the required high reaction temperatures (150.degree. C.-170.degree. C.) and because of the liberated bromine, these drastic reaction conditions necessarily lead to uncontrollable side reactions, such as bromination of the ring, resinification, cracking, and discoloration.
Thus the CCDA prepared by these processes contains, in addition to numerous, particularly bromine-containing, byproducts also some greasy, tarry, colored contaminants, the removal of which requires an undue effort.
The nature and structure of these byproducts is not known. The customary purification methods lead to appreciable losses.
No purification method was known until now, which can economically solve the problem of the residual bromine content. Thus, as determinedly high pressure liquid chromatography, the CCDA so prepared is present the average in an amount of 90%, and the precursor for the carbamazepine end product, contains about 10% impurities.