RU2007395C1 - Method of 5h-dibenz[b, fiazepines synthesis - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: method involves rearrangement of 1-arylindole of the general formula (1) given in description, where R₁, R₃ - hydrogen, lower alkyl, R₂ - hydrogen, chlorine, lower alkyl; R₄ - hydrogen, lower alkyl. Process is carried out at heating in polyphosphoric acid, and obtained, where R₁, R₃ - hydrogen, lower alkyl, R₂ - hydrogen, chlorine, lower alkyl. Yield is 25- 43,5% . EFFECT: improved method of synthesis.

Description

(I) где R₁ и R₃ - Е или низший алкил; R₂ - Н, Сl или низший алкил, которые могут быть использованы в синтезе лекарственных препаратов.The invention relates to organic chemistry, and in particular to a new method for producing 5H-dibenz [b, f] azepine and its derivatives of the general formula I,

(I) where R ₁ and R ₃ are E or lower alkyl; R ₂ is H, Cl or lower alkyl, which can be used in the synthesis of drugs.

 Derivatives of 5H-dibenz [b, f] azepine have diverse physiological activity and are used in medicine as drugs. For example, the anticonvulsant carbamazepine, which is 5-carbamoyl-5H-dibenz [b, f] azepine, is well known (1).

 Other derivatives of dibenzazepine also exhibit anesthetic, antiallergic, sedative and other types of physiological activity [2-5].

 Known methods for producing dibenzazepines, based on the closure of the azepine ring either on the nitrogen atom, or by the relationship between positions 10 and 11, with the formation of an ethylene bridge.

_{___________→}

Для синтеза замещенных дибензазепинов получают замещенные 2,2'-динитродибензилы V конденсацией замещенных о-нитротолуолов VI под действием амилнитрита и этилата натрия. В дальнейшем процесс ведут аналогично вышеописанному, лишь стадию дегидрирования проводят в газовой фазе, возгоняя дигидродибензазепин IV через колонку, заполненную палладием на угле [7] :

В случае замыкания азепинового цикла этиленовой цепочкой используют 2,2'-дизамещенные дифениламины VII и IX. Так, 2,2'-] . бисгидроксиметильное производное дифениламина VII переводят в дибромид VIII, пропуская HBr в кипящий толуольный раствор. Под действием большого избытка фениллития образовавшийся дибромид затем циклизуют в дибензазепин [8]

Другой метод основан на циклизации 2,2'-диформилдифениламина IX под действием гидразина. Диальдегид IX получают, исходя из 2,2'-дикарбоксидифениламина Х, который переводят в соответствующий хлорангидрид XI и далее гидрируют над палладием на сульфате бария [9]
_{____→}

_{_____→}

Недостатком перечисленных способов является использование труднодоступных исходных соединений либо многостадийность процесса. Среди этих методов нет общего метода, позволяющего целенаправленно получать определенным образом замещенные дибензазепины. Особые трудности вызывает синтез несимметрично замещенных дибензазепинов.In the first case, 2,2'-dinitro derivatives of stilbene II are used as starting materials, which are hydrogenated over Raney nickel to 2,2'-diaminodibenzyl III. Thermal cyclization is then carried out at 280 ^C. digidrodibenzazepin 10,11-IV, which is further dehydrogenated over palladium at reflux in diethyl dibenzazepine [6]:

_{___________ →}

For the synthesis of substituted dibenzazepines, substituted 2,2'-dinitrodibenzyls V are obtained by condensation of substituted o-nitrotoluenes VI under the action of amyl nitrite and sodium ethylate. In the future, the process is carried out similarly to the above, only the dehydrogenation stage is carried out in the gas phase, sublimating dihydrodibenzazepine IV through a column filled with palladium on coal [7]:

When the azepine ring is closed with an ethylene chain, 2,2'-disubstituted diphenylamines VII and IX are used. So, 2,2'-]. the bishydroxymethyl derivative of diphenylamine VII is converted to dibromide VIII by passing HBr into a boiling toluene solution. Under the influence of a large excess of phenyl lithium, the resulting dibromide is then cyclized to dibenzazepine [8]

Another method is based on cyclization of 2,2'-diformyldiphenylamine IX under the action of hydrazine. Dialdehyde IX is prepared starting from 2,2'-dicarboxydiphenylamine X, which is converted to the corresponding acid chloride XI and then hydrogenated over palladium on barium sulfate [9]
_{____ →}

_{_____ →}

The disadvantage of these methods is the use of inaccessible starting compounds or a multi-stage process. Among these methods, there is no general method for purposefully producing substituted dibenzazepines in a specific way. Of particular difficulty is the synthesis of asymmetrically substituted dibenzazepines.

 Closest to the technical nature of the claimed invention is a method for producing dibenzazepines, based on rearrangement, accompanied by the expansion of a nitrogen-containing heterocycle. So, for the synthesis of 2-methyl-5H-dibenz [b, f] azepine XII, a seven-stage method was proposed, the last stage of which was a rearrangement of 2-methyl-9,10-dihydro-9-acridinemethanol XIII when heated in polyphosphoric acid - PFC [10] .

Alcohol XIII was obtained according to the following scheme. Condensation of p-toluidine with o-chlorobenzoic acid in the presence of potash, copper and copper oxide in 84% yield gives N- (p-tolyl) anthranilic acid XIV, which is decarboxylated by heating with copper carbonate. Resulting in a yield of 52% p-tolilfenilamin XV is cyclized at ²²⁰ ° C with acetic acid and zinc chloride in 2,9-dimethylacridine XVI (yield 56%) which upon reaction with N, N-dimethyl-4- nitrosoaniline gave a mixture of nitrone XVII and anil XVIII. This mixture is then transferred without separation into a mixture of hydrochlorides and then hydrolyzed to 2-methyl-9-formyl acridine XIX (yield 56%). Upon reduction of the aldehyde XIX with lithium aluminum hydride in 63% yield, 9,10-dihydro-9-acridinemethanol is obtained, which, with a 76% yield, is rearranged to dibenzazepine XII.

+

_____→

+

____→

Недостатками этого метода является его многостадийность/ низкий суммарный выход конечного продукта (6,5% ), а также нестабильность промежуточного спирта XIII/ который на воздухе полностью разлагается за 24 ч.

+

_____ →

+

____ →

The disadvantages of this method are its multi-stage / low total yield of the final product (6.5%), as well as the instability of intermediate alcohol XIII / which completely decomposes in air in 24 hours.

 The purpose of the invention is to simplify the synthesis process and increase the yield of 5H-dibenz [b / f] azepines / as well as expanding their assortment.

This goal is achieved by the fact that in the quality of the nitrogen-containing heterocyclic compounds / undergoing rearrangement / use 1-arylindoles XX. The rearrangement is carried out in PFC with heating / for example at 75-120 ^° C / for 50-150 hours

. где R₁, R₂, R₃ - указаны выше;
R₄ - водород, низший алкил.The conversion of arylindoles XX to 5H-dibenz [b / f] azepines 1 proceeds according to the scheme below:

. where R ₁ , R ₂ , R ₃ - above;
R ₄ is hydrogen, lower alkyl.

 From the above examples it is seen that when using the proposed method, the preparation of dibenzazepines is carried out in one stage, which makes it possible to significantly simplify the synthesis process and increase the yield of dibenzazepines. The proposed method can be obtained both unsubstituted and substituted dibenzazepine with a substituent, in almost any position except the nitrogen atom. This allows you to significantly expand the range of this important group of physiologically active compounds (4-methyl-5H-dibenz [b, f] azepine obtained for the first time). Since the formation of the symmetric structure of dibenzazepine comes from an asymmetric arylindole molecule, the proposed method is especially advantageous for producing asymmetrically substituted dibenzazepines (see examples 2-6) and, in addition, in some cases the same dibenzazepine can be obtained from different arylindoles (see examples 3 and 4), which makes it possible to choose a more acceptable synthesis route.

 The synthesis of dibenzazepines I is illustrated in examples 1-6 (table. 1) and is carried out according to the following General method.

A mixture of 200 mg arylindole XX and 2.5-7.0 ml of polyphosphoric acid (PPA) was heated in an oil bath at 75-120 ^{° C} for 50-150 hours, stirring periodically. The reaction mixture is cooled, decomposed with ice water and extracted with chloroform (3x15 ml). The organic extracts were combined, dried with MgSO ₄ and the solvent was evaporated in vacuo. The residue was purified by chromatography on a column (17x1.2 cm) with silica gel (100-250 μm), eluting with a petroleum ether - benzene 2: 1 system. The specific conditions for the syntheses are given in table. 1, constants and characteristics confirming the structure of the obtained compounds are given in table. 2
Thus, the proposed method allows to simplify the preparation of compounds I, increase the yield of target products to 25-43% and expand their range. (56) 1. Mashkovsky M. D. Medicines, Medicine. M., 1972, v. 1, p. 117.

 2. UK patent N 849032, CL 2 (3), 1963.

 3. British patent N 862297, 2 (3), 1963.

 4. UK patent N 820476, CL 2 (3), 1962.

 5. US patent N 2948718, 250-231, 1960.

 6. Huisgen R., Lasschuvka E., Bayerlein F., Chem. Ber. 1960, B. 93, s. 392.

 7. UK patent N 854553, class. (23), 1963.

 8. Bergmann E. D., Aizenshtat Z., Shahak I., Israel. J. Chem. ., 1968, v. 6, N 4, p. 507.

 9. Sinka A. K. - Agarwal P. K., Nizamuddin S., Indian J. Chem. Sec. B., 1982, vol. 21 B, N 3, p. 237.

 10. Patton I. R., Dunley K. H., J. Heter. Chem. 1979, v. 16, N 2, p. 257.

Claims (1)

METHOD FOR PRODUCING 5H-DIBENZES [b, f] AZEPINS of the general formula

where R ₁ , R _{3 is} hydrogen or lower alkyl;
R ₂ is hydrogen, chlorine, lower alkyl,
by rearrangement with the extension of the cycle of a nitrogen-containing heterocyclic compound when heated in polyphosphoric acid, characterized in that 1-arylindole of the general formula is used as a heterocyclic compound

where R ₁ , R ₂ and R ₃ have the indicated meanings;
R ₄ is hydrogen or lower alkyl.

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