CS257340B1 - Process for the preparation of 6,11-dihydrodibenzo / b, N-thiepine-11-carbonitriles - Google Patents

Abstract

The solution falls into the field of intermediates for the synthesis of drugs. Its subject is a method for the preparation of 6,11-dihydrodibenzo(b,e)-thiepine-11-carbonitriles of the general formula I in which R denotes a hydrogen atom, a halogen atom or a methyl group. These substances are intermediates for the synthesis of pharmacodynamically active substances and potential drugs. , The preparation method consists in the reaction of the corresponding 11-chloro.6,11-dihydrodibenzo (b,e)-thiepines with trimethylsilyl cyanide in dichloromethane in the presence of tin tetrachloride.

Description

The invention relates to a process for the preparation of S,11-dihydrodibenzo(b,e)thiepine-11-carbonitriles of general formula I.

in which R represents a hydrogen atom, a halogen atom or a methyl group.

The substances of general formula I are intermediates in the preparation of pharmacodynamically active compounds, usable as drugs (see e.g. Šindelář K. et al., Collect. Czech. Chem. Commun, 48,

898, 1983), and as such are technically important.

Of the compounds of general formula I, only the basic compound of formula 1, R = H, has been described in the literature so far. It was obtained in low yield by the reaction of 11-chloro-6,11-dihydrodibenzo(b,e)thiepine with copper cyanide in boiling benzene (Seidlová V. et al., Monatsh. Chem. 96, 650, 1965), and by heating 6,11-dihydrodibenzo(b,e)thiepine-11-carboxaldehyde oxime with acetic anhydride.

(Rajšner M. et al., Collect. Czech. Chem. Commun. 44, 2,536, 1979) In the second way is a difficult-to-access starting material, so total yield of the desired nitrile from dibenzo(b,e) thiepin-11(6H)-one is very low. It has now been found that chlorinated derivatives of general formula II, see 1 (II) ^Cl wherein R has the same meaning as in formula I, can be brought to react with trimethylsilyl cyanide

(Hunig S., Wehner G., Synthesis 1979, 522; Rasmussen J.K., Heilmann S.M., Synthesis

1979, 523) in dichloromethane in the presence of tin tetrachloride and in this way to arrive at the desired nitriles of the general formula I. A similar method has so far been used only for the cyanation of tertiary alkyl chlorides, and it was found that primary alkyl chlorides do not react under the above conditions. Nothing has been known so far about a possible similar reaction of secondary alkyl chlorides and especially about the reaction of aralkyl chlorides of the benzhydryl chloride type, which is the case in question.

The essence of the method for preparing 6,11-dihydrodibenzo(b,e)thiepine-11-carbonitriles of the general formula I according to the present invention is therefore the reaction of chloroderivatives of the general formula XI with trimethylsilyl cyanide in dichloromethane in the presence of tin tetrachloride. Details of the procedure are described in the examples, which illustrate the possibilities of the invention. If the starting chlorides of the formula II are known, references to the relevant literature are given in the examples; if they are new, their preparation is also described in the examples. The identity of the new substances described in this invention was ensured by both analytical and physicochemical (spectral) methods.

Example 1

6,11-dihydrodibenzo(b,e)thiepine-ll-carbonitrile (I, R = H)

To a solution of 160 g of 11-chloro-6,11-dihydrodibenzo(b,e)thiepine (Seidlová V. et al., Monatsh. Chem. 96, 650, 1965) in dichloromethane, 80 g of trimethylsilyl cyanide are added and then, with stirring, 18 ml of tin tetrachloride are carefully added dropwise over 30 min (foaming may occur). The mixture is stirred for 4 h at room temperature and poured into 500 ml of water while stirring. After shaking, the organic phase is separated, washed with 500 ml of 5% sodium bicarbonate solution and dried.

with anhydrous potassium carbonate. Evaporation of the dichloromethane directly yields 135 g (87.7%) of the desired crystalline product, m.p. 133-135 °C. The substance forms two crystal modifications, with the conversion of the lower melting point to the higher melting point occurring at a temperature just below the stated final melting point.

Example 2 »

2-Methyl-6,11-dihydrodibenzo(b,e)thiepine-11-carbonitrile (I, R = CH^)

To a solution of 13.45 g of 11-chloro-2-methyl-6,11-dihydrodibenzo(B,e)thiepine in 80 ml of dichloromethane is added 6.35 g of trimethylsilyl cyanide and then very carefully added dropwise with stirring

1.5 ml of stannous chloride. After the first few drops of this reagent, a violent reaction accompanied by foaming occurs, the stirrer is stopped for a short time and after this violent reaction has subsided, it is started again and the rest of the reagent is slowly added dropwise.

The mixture is stirred for 5.5 h at room temperature, after standing overnight it is poured into 100 ml of water, diluted with 250 ml of dichloromethane and shaken thoroughly. The organic phase is separated, washed with 100 ml of 5% sodium bicarbonate solution and dried over magnesium sulfate. The substance obtained by evaporation of dichloromethane (13.1 g) is dissolved in 170 ml of benzene and the solution is chromatographed on a column of 150 g of silica gel. 11.76 g (93%) of the homogeneous desired product are eluted with benzene, which crystallizes from ethanol and melts in the pure state at 180-180.5 °C.

The starting material used, 11-chloro-2-methyl-6,11-dihydrodibenzo(b,e)thiepin (II. R - CH^) has not yet been described in the literature. It can be prepared from the known 2-methyl-6,11-dihydrodibenzo(b,e)thiepin-11~ol (Rajšner M. et al., Collect. Czech. Chem. Commun. 21' 1 021, 1969) by the following procedure:

To a solution of 24.2 g of 2-methyl-6,11-dihydrodibenzo(b,e)thiepin-11-ol in 50 ml of benzene, 24.0 g of thionyl chloride are added dropwise with stirring and the mixture is refluxed for 20 min.

Then the benzene with excess thionyl chloride is evaporated in vacuo, 70 ml of benzene is added to the residue, which is evaporated again, which is repeated twice more. The residue is recrystallized from 100 ml of cyclohexane. 22.6 g (87%) of pure 11-chloro-2-methyl-6,11-dihydrodibenzo(b,e)thiepine is obtained, melting at 116-118 °C.

Example 3

2-chloro-6,11-dihydrodibenzo(b,e)thiepine-11-carbonitrile (I, R = Cl)

To a solution of 10.0 g of 2,11-dichloro-6,11-dihydrodibenzo(b,e)thiepine (West German Offenlegungsschrift (Ger. Offen. 2 065 636) in 55 ml of dichloromethane are added 4.4 g of trimethylsilyl cyanide and then very carefully - similarly to the previous examples - 1.02 ml of tin tetrachloride are added dropwise. The resulting thick reaction mixture is diluted with 15 ml of dichloromethane and the mixture is stirred for 5 h at room temperature. It is then shaken with 75 ml of water and extracted with 300 ml of dichloromethane. The organic phase is separated, washed with 100 ml of 5% sodium bicarbonate solution and dried with magnesium sulfate. Evaporation gives 9.6 g (99%) of the practically pure desired nitrile, which melts at 191-192 °C. By crystallization from benzene it is obtained in nicely developed crystals, but the melting point no longer increases.

Example 4

2-Bromo-6,11-dihydrodibenzo(b,e)thiepine-ll-carbonitrile (I, R - Br)

To a solution of 16.1 g of 2-bromo-11-chloro-6,11-dihydrodibenzo(b,e)thiepine in 80 ml of dichloromethane was added 6.45 g of trimethylsilyl cyanide and then 1.5 ml of tin tetrachloride was carefully added dropwise with stirring. After dilution with 20 ml of dichloromethane, the mixture was stirred for 5.5 h at room temperature. Working up as in the previous examples gave 15.2 g (97%) of the desired product, which crystallized from a mixture of benzene and ethanol and melted at 195-196, ^° C.

The starting material used, 2-bromo-11-chloro-6,11-dihydrodibenzo(b,e)thiepin (XI, R = Br) is a new substance, which is prepared from the known 2-bromodibenzo(b,e)thiepin-11(6H)-one (Rajšner M. et al., Cesk. Farm. 11, 451, 1962) by the following procedure:

A solution of 5.0 g of sodium borohydride in 20 ml of water containing 2 drops of 20% sodium hydroxide solution was added dropwise to a solution of 50 g of 2-bromodibenzo(e,b)thiepin-11(6H)-one in ethanol at 70 °C with stirring over a period of 20 min. The mixture was refluxed for 2 h, the ethanol was evaporated in vacuo and the residue was crystallized from benzene. 50.0 g (almost theoretical yield) of 2-bromo-6,11-dihydrodibenzo(b,e)thiepin-11-ol was obtained, mp 166.5 to 167 °C.

A mixture of 19.5 g of the previous alcohol and 40 ml of thionyl chloride is boiled under reflux for 1.5 h, a small amount of the separated high-melting substance is filtered off while hot and the filtrate is evaporated in vacuo. The residues of thionyl chloride are removed by adding 60 ml of benzene and repeatedly evaporating the volatile components in vacuo. The residue is dissolved in 50 ml of cyclohexane and the desired 2-bromo-11-chloro-6,11-dihydrodibenzo(b,e)thiepine is induced to crystallize by adding 40 ml of petroleum ether; 16.1 g (78%), m.p. 114 to 119 °C.

Claims (1)

A process for the preparation of 6,11-dihydrodibenzo (b, e) thiepine-11-carbonitriles of the general formula I in which R represents a hydrogen atom, a halogen atom or a methyl group, characterized in that 11-chloro-6,11-dihydrodibenzo (b) e) thiepines of formula II in which R is the same as in formula I, are reacted with trimethylsilyl cyanide in dichloromethane in the presence of tin (II) chloride.