CS202331B1 - Method of preparing novel trans-11-/3-amino-propylidene/-6,11-dihydrodibenzo/b,e/thiepine - Google Patents

Abstract

A process for the preparation of new trans-11- (3-aminopropylidene) -6,11-dihydrodibenzo (b, e) thiepine

Description

The present invention relates to a process for the preparation of the novel trans-11- (3-aminopropylidene) -6,11, -dihydrodibenzo (b, e) thiepine of the formula I

and its salts.

The compound of formula I is a preferred intermediate for the preparation of pharmacodynamically active substances, in particular antidepressant drugs of the anti-henene series.

The process for the preparation of the compound I according to the invention is based on the known dibenzo (b, e) thiepin-11 (6H) -one (Rajšner M. and Protiva M., Čes. Farm. 11, 404, 1962) and consists of a four-step synthesis. The first step is the reaction of said ketone with a Grignard reagent prepared from cyclopropyl bromide (Meek JS, Osuga DT: Org. Syn., Coll. Vol. 5, 126, 1973). The reaction is preferably carried out ^- in boiling tetrahydrofuran and the product is a 1 l-cyclopropyl-6,11-dihydro-dibenzo (b, e) thiepin-1 l-ol of formula II,

Next, the tertiary alcohol is treated with hydrogen bromide in acetic acid, preferably at 15 ° C. The cyclopropane ring is opened and dehydrated at the same time and the product results in 11- (3-bromopropyl) -6,11-dihydrodibenzo (b, e) -thiepine III

The CHj1Bp trans-configuration has been demonstrated using the infrared spectrum, which in the area of extra-plane vibration of C-H bonds of benzene nuclei appears to be similar to that observed with trans202331

Prothiadene (Rajsner M. et al., Collect. Czech. Chem. Commun. 34, 1963, 1969).

In the next step, the bromo derivative III is reacted with phthalimide, preferably in dimethylformamide, at temperatures of 50 to 100 ° C. Crystalline phthalimidoderivative IV is obtained as a product.

The last step is the hydrazinolysis of the phthalimidoderivative IV in boiling ethanol. The desired amine of formula (I) is formed, for which the trans-configuration has again been demonstrated by means of IR spectrum. The amine of formula I is a crystalline substance with 1.1. 78-81 ° C, crystallizing from a mixture of benzene and petroleum ether. Neutralization with acids gives crystalline salts, of which the hydrogen maleate which crystallizes from ethanol and melts at 178-181 ° C is preferred for characterization.

Further details of the preparation of the compound I according to the invention are evident from the exemplary embodiment, which, however, is merely illustrative of the possibilities of the invention and is not intended to fully describe all these possibilities. Example:

To a mixture of 29 g of magnesium and 300 ml of tetrahydrofuran was added a small portion of a solution of 165 g of cyclopropyl bromide in 300 ml of tetrahydrofuran, heated to reflux and, after starting the reaction, dropwise the rest of the cyclopropyl bromide solution dropwise. cooler. Boil for 1 hour and then allow to cool. A solution of 141 g of dibenzo (b, e) thiepin-11 (6H) -one in 350 ml of tetrahydrofuran is then added dropwise with stirring over 40 minutes. The mixture was refluxed for an additional 1 hour and, after cooling, quenched by the dropwise addition of 900 ml of saturated aqueous ammonium chloride solution. After filtration, the organic phase of the filtrate is separated and the aqueous is extracted with ether. The tetrahydrofuran and ether phases were combined, washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue provides crystallization from a mixture of benzene and petroleum ether I. Product (84 g) of 11-cyclopropyl-6,11-dihydrodibenzo (b, e) thiepin-11-ol (II), m.p. 104-106 ° C. Evaporation of the mother liquor and crystallization gave II. product (29 g) mp 105-108 ° C. A total of 113 g (68%) of almost pure product of formula II is thus obtained, the analytical sample of which is obtained by recrystallization from a mixture of benzene and petroleum ether, m.p. 105-106.5 ° C.

To a solution of 10.8 g of cyclopropylcarbinol of formula II in 160 ml of acetic acid, with stirring at 13-15 ° C, was added dropwise 80 ml of a 15% solution of hydrogen bromide in acetic acid over 30 minutes. The mixture was stirred at 15 ° C for an additional 30 minutes, then quenched with 500 mL of ice water and the product isolated by extraction with benzene. The extract was washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue (10.8 g, 81%) crystallized and melted at 144-148 ° C. It is almost pure trans-11- (3-bromopropyl) -6,11-dihydrodibenzo (b, e) thiepine (III). Crystallization from cyclohexane gave a pure material with a melting point of 145-150 ° C.

To a mixture of 10.8 g of the bromo derivative of formula III and 65 ml of dimethylformamide was added 6.5 g of phthalimide potassium and the mixture was stirred at room temperature for 20 minutes, then at 65-70 ° C for 1 hour. An additional 6.5 g of phthalimide potassium was added and heated at 65-70 ° C for a further 2 hours. After standing overnight, it is diluted with 100 ml of chloroform, washed with water, 5% sodium hydroxide solution and again with water, dried over potassium carbonate, filtered with carboraffin and evaporated under reduced pressure. The residue is stirred with a small amount of ether, filtered off with suction and dried in vacuo. 6.4 g (49%) of trans 11- (3-phthalimidopropylidene) -6,11-dihydrodibenzo (b, e) thiepine (IV) of m.p. 172-175 C are obtained. Recrystallization from a mixture of benzene and petroleum ether gives the analytical product mp 175-177 ° C.

A mixture of 6.4 g of the preceding phthalimide derivative of the formula IV, 175 ml of ethanol and 1.2 g of 80% hydrazine hydrate was refluxed for 6 hours. The ethanol was then evaporated under reduced pressure. The residue is mixed with 150 ml of water, acidified to pH 4.5 by addition of 2N-HCl, stirred for 1 hour at room temperature and 15 minutes at 80 ° C. After cooling, it is filtered, the filtrate is basified with aqueous ammonia and the liberated basic product is isolated by extraction with ether. After the extract was dried with potassium carbonate, the ether was evaporated. 3.9 g (91%) of crude 1- (3-aminopropylidene) -6,11-dihydrodibenzo (b, e) thiepine (I) were obtained. This was neutralized with 2.0 g of maleic acid in 50 ml of ethanol; Upon standing for the next day, 4.3 g of crystalline hydrogen maleate, m.p. 178 DEG-182 DEG C., precipitated. Its decomposition with sodium hydroxide solution and extraction with ether gives a crystalline base of formula I, m.p. 78 DEG-81 DEG C. (benzene-petroleum ether), which is a pure trans form.

Claims (5)

Subject A process for the preparation of a novel trans-11- (3-aminopropylidene) -6,11-dihydrodibenzo (b, e) thiepine of the formula I and its salts, characterized in that dibenzo (be) thiepin-11 (6H) - he treated with cyclopropyl magnesium bromide, the obtained 11-cyclopropyl-6,11-dihydrodibenzo (b, e) thiepin-11-ol is treated with hydrogen bromide in acetic acid to form trans-11- (3-bromopropyl) -6,11 -dihydrodibenzo (b, e) thiepine is converted by reaction with phthalimidoalkyl to trans-11- (3-phthalimidopropylpropyl) -YL) -6,11-dihydrodibenzo (b, e) thiepine, which is subjected to hydrazinolysis, wherein the base of formula I obtained is optionally is converted into salts by neutralization with inorganic or organic acids. 2. The process of claim 1 wherein the reaction of dibenzo (b, e) thiepin-11 (6H) -one with cyclopropylmagnesium bromide is carried out in tetrahydrofuran and the primary product is quenched with aqueous ammonium chloride solution. 3. The process of claim 1, wherein the reaction of 11-cyclopropyl-6,11-dihydrodibenzo (b, e) thiepin-11-ol with hydrogen bromide in acetic acid is carried out at 15 ° C. 4. The process of claim 1, wherein the reaction of trans-11- (3-bromopropyl) -6,11-dihydrodibenzo (b, e) thiepine with phthalimide is performed in dimethylformamide at 50-100 ° C. 5. The process of claim 1 wherein the hydrazinolysis of trans-11- (3-phthalimidopropylidene) -6,11-dihydrodibenzo (b, e) thiepine is carried out in boiling ethanol.