CS254742B1 - Process for preparing (E) -N, N-dimethyl-3- (6,11-dihydrodibenzo / b, e-thiepin-11-ylidene) -propylamine - Google Patents

Abstract

The solution falls into the field of synthetic drugs. Its subject is a method for preparing antidepressant-active (E)-N,N-dimethyl- -3-(6,11-dihydrodibenzo/b,e/thiepin-11- -ylidene)propylamine of formula I by reducing the novel (E)-N,N-dimethyl-3-(6,11- -dihydrodibenzo/b,e/thiepin-11- -ylidene)propionamide with lithium aluminum hydride in boiling ether.

Description

The present invention relates to a process for the preparation of (E) -N, N-dimethyl-3- (6,11-dihydrodibenzo [b, e] thiepin-11-ylidene) propylamine of formula I (I)

I.e., the antidepressant active trans-isomer of prothiadene, which is used in hydrochloride therapy (Rajsner et al., Protiva et al., Czech Farm. 11, 404, 1962; Metysova J. et al., Arzneim. Forsch. 13, 1039 (1963); Vencovsky E. et al., Cfesk. Psychiat. 60, 416 (1964).

The preparation of the compound of formula I has so far been described in two ways. The first consists in repeated crystallization of the hydrochloride of a mixture of (E) - and (Z) -isomers of N, N-dimethyl-3- (6,11-dihydrodibenzo [b, e] thiepin-11-ylidene) propylamine, which is obtained by acid catalyzed dehydration 11- (3-dimethylaminopropyl) -6-11-dihydrodibenzo [b, e] thiepine-11-ol (West German Laid-Open 1,199,278).

A second compound of formula (I) is prepared from the pure (E) -isomers of N-methyl-3- (6,11-dihydrodibenzo [b, e] thiepin-11-ylidene) propylamine by N-formylation with chloral followed by reduction of the N-formyl derivative with lithium aluminum hydride in tetrahydrofuran (Rajšner M. et al., Collect. Czech.

Chem. Commun. 34, 1963, 1969). In the first process, repeated and lossy crystallization is required which leads to the desired removal of the (Z) -isomers present. In the latter case, the preparation of the starting material is already difficult and its two-stage transformation into the desired compound of the formula I is preparatively demanding and time-consuming.

It has now been found that the preparation of the compound of formula (I) is essentially based on a novel process, which in a key step consists in reducing the hitherto unwritten pure (E) isomers of N, N-dimethyl-3- (6,11-dihydrodibenzo / b, (thiepin-11-ylidene) propionamide of formula II

lithium aluminum hydride in boiling ether. This process is an object of the present invention. Details of the reduction of the amide of formula II to the compound of formula I are given in the example, where the preparation of the starting amide of formula II is also described. The process of the invention yields crystalline hydrochloride which melts at 227-229 ° C after a single crystallization from ethanol-ether. The liberated base is crystalline and melts at 52-54 ° C. According to gas chromatography, this substance contains at least 99.5% of the desired (E) -isomer I.

To a stirred suspension of lithium aluminum hydride (5.0 g) in ether (200 ml) was added dropwise a solution of (E) -N, N-dimethyl-3- (6,11-dihydrodibenzo [b, e] thiepin-11- ylidene) propionamide (II) in 150 ml of ether. The mixture is refluxed for 4 h and, after cooling, is quenched by the dropwise addition (with stirring) of 5 ml of water, 5 ml of 15% sodium hydroxide solution and 15 ml of water.

The precipitated solid was filtered off, washed with ether, the filtrate was dried and evaporated.

The residue (25 g, practically 100%) was dissolved in 250 ml of ethanol, the solution was acidified slowly with a solution of hydrogen chloride in ether and ether was added to form a clear base. After standing overnight, the precipitated hydrochloride is filtered, washed with ether and dried in vacuo. 24 g (86%) of hydrochloride are obtained, which melts at 224-227 ° C. A single crystallization from ethanol / ether yields m.p. to 227-229 ° C.

The literature (Rajšner et al, quoted) discloses pure (E) -I m.p. 226 až

227 ° C. Decomposition of the hydrochloride sample with aqueous ammonia, extraction with dichloromethane, and work-up of the extract gave a crystalline base melting at 52-54 ° C. The literature (Rajšner M. et al., Cited) provides for pure (E) -I m.p. Mp 53-54 ° C.

(E) -N, N-dimethyl-3- (6,11-dihydrodibenzo [b, e] thiepin-11-ylidene) propionamide (II) not previously described in the literature can be prepared, for example, from the known dibenzo [b], e] thiepine -ll (6H) -one (Rajšner Μ., Protiva Μ., cited) as follows:

The magnesium (23.9 g) was overlaid with 30 mL of tetrahydrofuran and activated with an iodine bead and 1.5 mL of 1,2-dibromoethane. When the reaction has started, a 10% solution of 104 g of vinyl bromide in 400 ml of tetrahydrofuran under nitrogen is added under a reflux condenser equipped with a freeze capsule filled with ethanol and solid carbon dioxide. The reaction is quickly started and the remaining portion of the vinyl bromide solution is added dropwise so quickly that the reaction temperature is maintained at 58 to 62 ° C. Addition takes about 1.5 h and mixture; The mixture was then refluxed in a 65 ° C bath for 30 min.

After cooling to 40 ° C, the solid carbon dioxide cooler is replaced with a normal reflux condenser and a solution of 113 g dibenzo / b, e / thiepin-11 (6H) on in 400 ml tetrahydrofuran (30-35 ° C) is added dropwise with stirring. C). The mixture was allowed to stand overnight at +4 ° C and then quenched by the slow addition of a solution of 100 g of ammonium chloride in 500 ml of water under external cooling (ice with salt). 500 ml of benzene are added, the mixture is filtered, the aqueous phase is extracted with benzene and the benzene solutions are combined, dried and evaporated. The residue was crystallized from a mixture of 230 ml of benzene and 500 ml of petroleum ether. 116 g (91%) (including the product obtained from the mother liquor), 11-vinyl-6,11-dihydrodibenzo [b, e] thiepine-11-ol, m.p. Mp 129-132 ° C. An analytically pure sample was obtained by recrystallization from a mixture of benzene and hexane, m.p.

Mp 130-132 ° C.

To a stirred suspension of 31.8 g of the preceding vinylcarbinol in 370 ml of acetic acid at 15 ° C is added dropwise 240 ml of a 15% solution of hydrogen bromide in acetic acid over 30 minutes. With gentle cooling, the mixture is stirred for 30 min, evaporated under reduced pressure and the acetic acid residue is removed by adding 100 ml of xylene and evaporating it under vacuum, which is repeated once more.

The residue was then crystallized from a mixture of 30 ml of benzene and 70 ml of hexane. Yield 37.2 g (94%).

11- (2-bromoethylidene) -6,11-dihydrodibenzo [b, e] thiepine (the second product obtained by treating the mother liquor is included in the yield), m.p. Mp 109-111 ° C. Analytical sample, m.p.

Mp 112-113 ° C.

A solution of 11.8 g of potassium cyanide in 20 ml of water is added dropwise to a stirred solution of 38.2 g of the preceding bromoethylidene compound in a mixture of 110 ml of tetrahydrofuran and 80 ml of ethanol. The temperature of the mixture rose spontaneously to 40 ° C and the mixture was stirred at room temperature for 1.5 h. It is evaporated under reduced pressure, the residue is diluted with 200 ml of water and the mixture is extracted with dichloromethane.

The extract was washed with water, dried and evaporated. The crude product was dissolved in 150 ml of benzene, filtered through a pad of 30 g of silica gel, which was then washed with 100 ml of benzene. The filtrate was evaporated and the residue was crystallized from a mixture of 25 ml of benzene and 40 ml of hexane; 25.4 g (80%)

3- (6,11-dihydrodibenzo [b, e] thiepin-11-ylidene) propionitrile, m.p. Mp 118-120 ° C. Analytical sample, m.p. M.p. 120-121 ° C (benzene-hexane). The IR spectrum of the substance indicates that it is predominantly the (E) -isomer.

To a suspension of 26.8 g of the previous nitrile in 80 ml of ethanol was added a solution of 28 g of potassium hydroxide in 28 ml of water, and the mixture was refluxed for 3.5 hours. After cooling, it is diluted with 350 ml of water and washed with benzene. The aqueous solution was acidified with 150 ml of 15% hydrochloric acid and extracted with dichloromethane, the extract was dried and evaporated. The residue was crystallized from 95 ml of benzene; 22.0 g (78%) of (E) -a (Z) -3- (6,11-dihydrodibenzo [b, e] thiepin-llylidene) propionic acid mixture, m.p. Mp 150-170 ° C.

The other two crystallizations from benzene gave 11.5 g (41%) of the continuously melting (E) -isomer, m.p. Mp 174-175 ° C. Configuration is provided by IR and NMR spectra.

To a stirred suspension of 28.5 g of the preceding (E) -acid in 100 ml of benzene was added dropwise a solution of 15 g of thionyl chloride in 20 ml of benzene over 10 minutes. The mixture was refluxed for 3 h and evaporated under reduced pressure. The residue was dissolved in a boiling mixture of 10 ml of benzene and 30 ml of hexane. After standing overnight in the cold, 29 g (97%) of (E) -3- (6,11-dihydrodibenzo [b, e] thiepin-11-ylidene) propionyl chloride crystallized, m.p. Mp 72-76 ° C.

A solution of 29 g of the preceding chloride in 100 ml of benzene is added dropwise to a cooled solution (0 to 5 ° C) of 45 g of dimethylamine in 200 ml of benzene over 10 minutes with stirring. The mixture was stirred for 10 minutes, refluxed for 10 minutes, washed three times with 150 ml of water, 100 ml of 2% hydrochloric acid, 100 ml of 2% sodium bicarbonate solution and again with water, dried and evaporated. The oily residue (32 kg) was chromatographed on a column of 250 g of silica gel. Benzene eluted with a small amount of impurities and eluted with chloroform 3.0 g (100%) of the desired homogeneous (E) -N, N-dimethyl-3- (6,11-dihydrodibenzo [b, e] thiepin-11-ylidene) propionamide. , which is used as the oil to the final stage.

Claims (1)

A process for the preparation of (E) -N, N-dimethyl-3- (6,11-dihydrodibenzo [b, e] thiepin-11-ylidene) propylamine of formula I, characterized in that (E) -N, N-dimethyl- The 3- (6,11-dihydrodibenzo [b, e] thiepin-11-ylidene) propionamide of formula II is reduced with lithium aluminum hydride, preferably in boiling ether.