CS247593B1 - Process for the preparation of pure (E) -isomers of 2-cyano- and 9-cyanide of 11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzoMb, f) thiepine and their salts - Google Patents

Abstract

The solution falls into the field of synthetic drugs. Its subject is a method for preparing pure (E)-isomers of the 2-cyano- and 9-cyano-derivative of 11-(3-dimethylaminopropylidene)-6,11- -dihydrodibenzo(b,e)thiepine and their salts with pharmaceutically acceptable inorganic or organic acids. . The substances according to the invention have the property of selective inhibitors of serotonin reuptake in some brain structures and are useful in the therapy of mental depression. The essence of the process according to the invention is the reaction of pure (E)-isomers of the 2-bromo derivative of 11-(3-dimethylaminopropylidene) - 6,11-dihydrodibenzo (b,e)thiepine with copper cyanide in hexamethylphosphoric triamide at 150 °C.

Description

The present invention relates to a process for the preparation of the pure (E) -isomers of the 2-cyano- and 9-cyander derivative of 11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo (b, e) thiepine of formula I

wherein one of R ¹ and R ² is cyano and the other is hydrogen, and salts thereof with pharmaceutically acceptable inorganic or organic acids.

Reports of the 3-cyander derivative of the imipramine antidepressant (cyanopramine, Ro 11-2465) as a selective inhibitor of serotonin reuptake in some brain structures (Haefely W. et., 11th CINP Congress, Vienna, July 1987, summaries p. 96; Burkard WP,

Eur.J.Pharmacol. 61, 409, 1980) and in platelets (Lenehan T. et al., Arch.Int. Pharmacodyn. Ther. 249, 147, 1981) and in particular the first clinical report on its therapeutic effect in mental depression (Omer LMO et al. al., 13th CINP Congress, Jerusalem, June 1982, abstract page 545 (Hormazabal L. et al., Psychopharmacology £ 6, 205 (1985)) have elicited interest in analogous cyander derivatives of other tricyclic antidepressants, primarily prothiadene. Prothiadene, also referred to in the literature as dosulepin or 'dothiepine, is chemically (E) -11 (3-dimethylaaminopropylidene) -6,11-dihydrodibenzo (b, e) thiepine, used in the form of the hydrochloride in practice (No. 105,590Rajšner M et al., Collet.Czech.Chem.Commun 34, 1963, 1969; Vencovsky E., Peterova E., Cesk. Psychiat. 58, 327, 1962).

While the imipramine molecule is symmetrical, the prothiadene molecule is due to the sulfur in the middle ring - asymmetric, and thus cyanopramine corresponds to two prothiadene cyanoderivatives, represented by the general formula I, ie the 2-cyander derivative Ia (I, R ¹ = CN, R ² = H) and 9-cyano derivative Ib (I, ^R1 - H, ^R2 = CN). The extracyclic double bond in the prothiadene molecule makes the situation even more complicated, as it makes it possible for Ia and Ib to exist in two geometric isomers: (E) (= trans) and (Z) (= cis). Only the relative position of the sulfur atom and the basic substituent (branch chain) on the olefinic carbon is taken into account as a criterion for designating the geometric isomers (E) and (Z); thus, the position of the substituent, i.e. the cyano group on the nucleus, is intentionally omitted.

Interest in cyanderivatives of prothiadene Ia and Ib is documented by the European Patent Application. 101 234, where the preparation of both Ia and Ib is described, and both have the predicted property of selective serotonin reuptake inhibitors in the rat cortex and hence the potential of a novel novel antidepressant. The described method of preparation comprises reacting the 2- or 9-bromo derivatives of formula I Prothiaden (one of R ¹ and R ² is bromine and the other is hydrogen) with cuprous cyanide in refluxing DMF. The crude products obtained are chromatographed on alumina and eluted crude and uncharacterized. bases are converted to crystalline hydrobromides.

Citovaná Evr.pat.přihl. '101 234 represents an imperfect and incomplete solution to the problem of the synthesis of 2- and 9-cyander derivatives of prothiadene (Ia and Ib), in particular in two directions: (1). Although it is stated in the description that the invention encompasses both the geometric (E) and (Z) isomers of Ia, in fact this question is not solved at all, the products appear to be mixtures of both isomers and the problem of its separation seems not to be solved. Regarding Ib, this is not included in the present invention and its geometric isomers are not mentioned in the general part (21 -). No recovery is reported for the reaction of both isomeric 2- and 9-bromo derivatives of prothiadene with cuprous cyanide in boiling dimethylformamide. By reproducing the process described, it was found that this yield is very low and ranges between 10 and 15%.

Thus, the process of the cited application is preparatively very disadvantageous and explicitly unsuitable for larger scale work.

The present invention solves both drawbacks cited by European Patent Application. 101 234.

(1) The preparation of the pure (E) -isomers of the 2-cyano- and 9-cyander-derivatives of the counterhiadene (1a and 1b) is based on the pure (E) -isomers of the 2-bromo- and 9-bromo derivative of the counterhiadene. Thus, the separation of the geometric isomers was shifted to the stage of the immediate precursors of the fines and was carried out by salt crystallization. In the case of both end products (Ta and 1b), bases were also in the crystalline state of preparation, allowing their spectral characterization; attributed E-configuration based on NMR spectra - in part using Eu (FOD) - - d27 tris (1,1,1,2,2,

3,3, -heptafluoro-7,7-dimethyloctane-4,6-dionato) europium-d ₂ 7 · (E) -Isomers are predominantly a component of mixtures resulting in acid-catalyzed dehydration of 2- and 9-bromo-11- ( 3-dimethylaminopropyl) -6,11-dihydrodibenzo (b, e) thiepin-11-ol. The (E) -isomers of the end products 1a and 1b correspond to the double bond configuration of the therapeutically proven and commercially disclosed counterhiadene (i.e., dothiepine). * (2) The problem of low recovery of conversion of bromo derivatives to cyander derivatives by reaction with copper (I) cyanide, which is a fundamental drawback of the European patent application. 101,234, was solved using hexamethylphosphoric triamide as reaction medium instead of dimethylforraamide. Conversion yields increased to 80-95%, making the process technically feasible. The reaction temperature is 150 ° C.

The details of the procedure for the preparation of the pure (E) -isomers of 2-cyano and 9-cyander derivative of 11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo [b, e) thiepine and their salts are further demonstrated in the examples to illustrate the possibilities of carrying out the process. according to the invention, but not exhaustively.

Example 1 (E) -2-Cyano-11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo (b, e) thiepine (1a)

According to the literature (Protiva M. et al., Experientia 18, 326 (1962), Rajšner M. et al., Czech Pharm. 11, 451 (1962)) gives 2-bromo dibenzo (b, e) by reaction with 91.6 g. thiepin-11 (6H) -one with excess 3-dimethylaminopropylmagnesium chloride in tetrahydrofuran 103 g (88%) of crude 4-bromo-11- (3-dimethylaminopropyl) -6,11-dihydrodibenzo (b, e) thiepin-11-ol . This was also dehydrated according to the literature for 40 minutes by boiling with 1 liter of 20% sulfuric acid and treating the mixtures to give an oily mixture of (E) - and (Z) -2-bromo-11- (3-dimethylaminopropylidene) -6,11-dihydro »Dibenzo (b, e) thiepine. This mixture (91.3 g) was dissolved in ethanol and a solution of hydrogen chloride in ether precipitated crude hydrochloride (72.5 g), which is also a mixture of (E) - and (Z) -isomers.

Crystallization from ethanol / ether followed by evaporation of the mother liquors and crystallization of the 2nd and 3rd product from ethanol / ether yielded a total of 55.5 g (62%) of virtually pure (E) -isomer of 2-bromo-11- ( 3-dimethylaminopropylidene-6,11-dihydrodibenzo (b, e.) Thiepine, melting at 260 DEG-261 DEG C. Evaporation of the mother liquor after product 3 and crystallization of the residue from ethanol gave 1.84 g (2.5%). (Z) -isomer of 2-bromo-11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo (b, e) thiepine hydrochloride, melting at 215 DEG-222 DEG C. Decomposition of pure (E) -isomer hydrochloride with aqueous ammonia; extraction with ether gives pure crystalline base (E) -2-bromo-11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo (b, e) thiepine, which crystallizes from a mixture of cyclohexane and petroleum ether and melts at 64-68 ° C Similarly, decomposition of (Z) -2-bromo-11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo (b, e) thiepine hydrochloride affords the corresponding (Z) -base, which in the if it is oily. Comparison of NMR spectra showed the (E) -configuration for the minor isomer.

From 10.1 g of (E) -2-bromo-1,1- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo (b, e) thiepine hydrochloride, aqueous ammonia was released and the base was isolated by extraction with benzene. After evaporation of the benzene, the (E) -base is dissolved in 20 ml of hexamethylphosphorothiamide, 5.0 g of copper cyanide is added and the mixture is heated to 150 ° C under stirring under nitrogen for 14 h. Partition by shaking between 15% aqueous ammonia and a 1: 1 mixture of benzene and ether, filtered, the organic phase washed with water, dried over potassium carbonate and evaporated. The remaining crude base was dissolved in ether and converted into the hydrochloride with ethereal hydrogen chloride solution. 8.3 g (95%) of (E) -2-cyano-11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo (b, e) thiepine (Ia) hydrochloride are obtained, which is pure and melts after a single crystallization from ethanol. at 256-258.5 ° C. Decomposition of 20% sodium hydroxide solution and extraction with ether gave pure, crystalline (E) -base Ia melting at 87.5-88.5 ° C (cyclohexane-petroleum ether). This base provides additional salts: hydrochloride hemihydrate, mp 250-255 ° C with decomposition; hydrobromide, m.p. 255-256 ° C (cited in European Patent Application No. 101 234, discloses for hydrobromide m.p. 213-215 ° C with decomposition; it is therefore a mixture of geometric isomers); hydrogenenoxalate modification 1, mp 210-213 ° C (ethanol ether); hydrogen oxalate modification II, mp 229.5-230.5 ° C (aqueous ethanol).

Example 2 (E) -9-Cyano-11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzole (b, e) thiepine (Ib)

By reaction of 3.4 g of magnesium with 17.1 g of 3-dimethylaminopropyl chloride in 45 ml of boiling tetrahydrofuran, a solution of Grigriard's reagent is prepared (the reaction is started with a grain of iodine and 0.3 ml of 1,2-dibromoethane). under reflux, during which all the magnesium enters the solution). After cooling the reagent solution to 10 ° C, a solution of 28.3 g of 9-bromo-dibenzo (b, e) thiepin-11 (6H) -one in 125 ml of tetrahydrofuran is added dropwise with stirring over 30 minutes. the temperature is maintained at 10-15 ° C and stirred dropwise at room temperature for 30 min. It is then recooled and quenched with stirring with a solution of 29 g of ammonium chloride in 110 ml of water. The organic layer was separated, the aqueous was extracted three times with 150 mL of ether and the organics were combined and evaporated. 250 ml of 20% sulfuric acid are added to the residue, the neutral part is removed from the suspension by extraction with ether and the aqueous phase with sulfate is refluxed for 40 minutes with stirring. After cooling, it is made alkaline with a 40% sodium hydroxide solution and the crude base is isolated by extraction with chloroform. The extract was dried over potassium carbonate and evaporated. The residue (23.8 g) is an oily mixture of (E) - and (Z) -base 9-bromo-11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo (b, e) thiepine, which is dissolved in 140 ml. of ether and treatment with an excess of a solution of hydrogen chloride in ether gave a non-fading hydrochloride (28.6 g, mp 132-174 ° C), which is again a mixture of the (E) - and the (Z) -isomer. Crystallization twice from ethanol-ether yielded 6.5 g of the pure (E) -isomer of 9-bromo-11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo (b, e) thiepine hydrochloride, mp 182.5-185 5 ° C. The combined mother liquors were evaporated to dryness in vacuo, the base was liberated with aqueous ammonia and isolated by extraction with chloroform. Evaporation gave 18.1 g of a base mixture which was dissolved in 50 ml of acetone and the solution was neutralized by addition of a solution of 6.1 g of oxalic acid dihydrate in 25 ml of acetone.

On standing, 20.5 g of oxalate (m.p. 198-203 ° C), which is again a mixture of the (E) - and (Z) -isomer, precipitated. Crystallization twice from a mixture of 80% aqueous ethanol gives 13.2 g of homogeneous (E) -9-bromo-11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo (b, e) thiepine hydrogen oxalate, mp 109-211.5 Deň: 32 ° C. The combined mother liquors were again evaporated in vacuo to dryness, the aqueous ammonia liberated the base mixture and isolated by extraction with ether. The dried and concentrated extract is neutralized with a solution of maleic acid in ether. The excreted maleate is initially oily? the ether phase was removed by decantation and the residual oil crystallized upon addition of acetone. 2.8 g of practically homogeneous (E) -9-bromo-11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo- (b, e) thiepine hydrogen maleate precipitate, which is completely pure after recrystallization from ethanol and melts at 186 ° C. to 189 ° C. Evaporation of the acetone mother liquor yielded 2.3 g of glassy hydrogen maleate which was crystallized from ethanol to give 0.62 g of homogeneous (Z) -9-bromo-11- (3-dimethylamino-propylidene) -6,11-dihydrodibenzo (b) e) thiepine. It melts at 152.5 to 154 ° C. The bases released from both pure isomeric hydrogen maleate are oily, but their ¹ H NMR spectra confirm homogeneity and for the predominant product of the (E) -configuration and for the monorite (Z) -configuration.

The overall yield on the (E) -isomer is 52% and on the (Z) -isomer is 1.5%.

A mixture of 5.65 g of pure (E) -base 9-bromo-11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo (b, e) thiepine, copper (I) cyanide and 15 ml of hexamethylphosphoric triamide is heated under stirring for 14h in nitrogen atmosphere to 150 ° C (bath temperature). After cooling, the mixture is diluted with 200 ml of a 1: 1 mixture of benzene and ether and shaken with 100 ml of dilute aqueous ammonia. After filtration of the mixture, the organic phase is washed with water, dried over potassium carbonate and evaporated. The residue (3.9 g ie.

% (practically pure oily (E) -base) is dissolved in ether and 4.95 g of homogeneous (E) -9-cyano-11 (3-dimethylaminopropylidene) -hydrogen oxalate (E) -9-cyano-11 (3-dimethylaminopropylidene) is added by addition of a solution of 1.7 g of oxalic acid dihydrate in acetone. 6,11-dihydrodibenzo (b, e) thiepine, which crystallizes from a mixture of aqueous ethanol and ether as the monohydrate and melts at 99.5-101.5 ° C.

Decomposition with aqueous ammonia and extraction with ether gave the crystalline base (E) -9-cyano-11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo (b, e) thiepine (Ib), which crystallized from cyclohexane and melted at 117.5 Its NMR spectrum confirms the (E) -configuration.

The starting O-bromo dibenzo (b, e) thiepin-11 (6H) -one used was described in the European patent cited. prihl. 101,234, however, the inventors used somewhat different conditions and found somewhat different properties for intermediates, and therefore the preparation of said ketone from the known 6-bromophthalide (Teppema T., Rec. Trav. Chim. Pays-Bas 42, 47, 1923; 46, 665 (1927) is further described:

Dissolve 3.45 g of sodium metal in 50 mL of ethanol to prepare a sodium ethoxide solution, cool to 40 ° C, and add 16.5 g of thiophenol dropwise with stirring (over 5 min). 31.9 g of 6-bromophthalide are then added and the mixture is refluxed for 4 hours. After standing overnight, 100 ml of water are added to dissolve the precipitated sodium salt of the product, the solution is cooled and slowly acidified with the dropwise addition of 14 ml of hydrochloric acid under stirring. After standing for 2 h, it is obtained, washed with water and recrystallized from a mixture of 75 ml of ethanol and 10 ml of water. There was obtained 38.2 g (79%) of practically pure 5-bromo-2- (phenylthiomethyl) benzoic acid, m.p. 141-146 ° C. A single crystallization of the sample from aqueous ethanol yields a completely pure melting point at 145-148 ° C.

Polyphosphoric acid is prepared from 115 g of phosphoric pentoxide and 75 ml of phosphoric acid (heating at 120 ° C for 4 h), 37.4 g of the preceding acid are added and the mixture is stirred at 120 ° C for 2 h. After partial cooling, it is decomposed by pouring into 650 g of ice-water and the product is extracted twice with 250 ml of benzene. The extract was washed with 5% sodium hydroxide solution, dried over magnesium sulfate and evaporated. The residue, which slowly crystallizes, is recrystallized from ethanol. A total of 28.6 g (81%) of pure 9-bromo-dibenzo (b.e) thiepin-11 (6H) -one melting at 97-99 ° C was obtained by this treatment and treatment of the mother liquor.

Claims (2)

Process for preparing the pure (E) -isomer of 2-cyano- and 9-cyander derivative of 11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo (b, e) thiepine of formula I Ί on in which one of R and R ^z is cyano and the other is hydrogen, and their salts with pharmaceutically acceptable inorganic or organic acids, reactions 247593 6 2-bromo- and 9-bromo derivative of 11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo (b, e) thiepine with a copper cyanide, characterized in that the pure (E) -isomers of 2-bromo- and the 9-bromo derivative of 11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo (b, e) thiepine and the reactions are carried out in hexamethylphosphoric triamide at 150 ° C, whereupon the obtained pure (E) -base of formula I is converted by acid neutralization to salts .