CS236550B1 - Method of esters preparation of piperazinoalkanoles of dibenzo(b,e)thiepine series and their salts with maleic acid - Google Patents

Abstract

The invention is within the scope of synthetic drugs. ' His subject is a method of preparation dibenzo piperazinoalkanol esters (b, e) thiepine series of formula I, wherein R represents a hydrogen atom or Chlorine and r 'is alkyl β 1 to 9 carbon atoms or 3,4,5-trimethoxyphenyl, and salts thereof with maleic acid. The compounds of formula 1 and their salts are intermediates preparation of psychotropic drugs. The process of the invention is based on the invention in the reaction of the respective (E) -1- (3 / 6,11-dihydrodibenzothi, e) thiepin-11-ylidene / propyl) -4- (2-hydroxyethyl) piperazines with chlorides or anhydrides of the corresponding acids at at 20 to 100 ° C in chloroform or acetic acid and subsequent neutralization obtained with maleic acid.

Description

(54) A process for the preparation of dibenzo (b, e) thiepine series piperazinoalkanol esters and their maleic acid salts

The invention is in the field of synthetic drugs. It relates to a process for the preparation of piperazinoalkanol esters of the dibenzo (b, e) thiepine series of formula I,

wherein R is hydrogen or chlorine and r 'is alkyl of 1 to 9 carbon atoms or 3,4,5-trimethoxyphenyl, and maleic acid salts thereof.

The compounds of formula 1 and their salts are intermediates in the preparation of psychotropic drugs. The process according to the invention consists in reacting the corresponding (E) -1- (3 / 6,11-dihydrodibenzotb, e) thiepin-11-ylidene / propyl) -4- (2-hydroxyethyl) piperazines with the chlorides or anhydrides of the corresponding acids at temperatures 20 DEG-100 DEG C. in chloroform or acetic acid and subsequent neutralization of the bases obtained with maleic acid.

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The invention relates to a process for the preparation of piperazinoalkanol esters of the dibenzo (b, e) thiepine series of the general formula I, oja (I), ¹ - 1 CH 3 NNCH 3 -C 1 JOCOR 'wherein R is hydrogen or fluorine and R ¹ is alkyl of 1 to 9 carbon atoms; 3,4,5-trimethoxyphenyl, and maleic acid salts thereof. As indicated in the formula, the (E) (trans) -line products are assigned.

The compounds of the invention of formula I and their salts with maleic acid are intermediates for the preparation of psychotropic medicaments and are also suitable in themselves for experiments in the field of the therapy of mental depression using depot injection forms. As such, the substances according to the invention are of low toxicity. For example, bis (hydrogen maleatate) of I, R = H,

R ¹ = 3,4,5-trimethoxyphenyl, in oral administration has a value LD ^ Q (acute toxicity in mice) greater than 2.5 g / kg. Similarly, they are non-toxic; bis (hydrogen maleate) of substance I, R 'Cl,

R @ ¹ = 3,4,5-trimethoxyphenyl. At oral doses of these agents greater than 300 mg / kg, the mice exhibit a mild central depressant discoordination effect. Some of the compounds of the invention have been found to have antimicrobial effects in in vitro assays. For example, for the bis (hydrogen maleate) compounds I, R = Cl, R ¹ = CH 2, the following activities have been observed (microorganisms and minimum inhibitory concentrations in µg / ml): Streptococcus p-haemolyticus 50, Streptococcus faecalis 100, Staphylococcus pyogenes aureus 00, Escherichia coli 50, Mycobacterium tuberculosis 50, Trichophyton mentagrophytes 25.

The process for the preparation of the esters of formula 1 according to the invention consists in the esterification of amino alcohols of formula II.

(II) wherein R denotes the same as in formula I, by the action of reactive acid derivatives of formula III,

R @ 4 COOH (III) in which r @ 1 is also the same as in formula I. The reactive derivatives of these acids are preferably chlorides or anhydrides and the reactions usually proceed at room temperature sufficiently quickly (they can be completed by heating the reaction mixtures to boiling). in suitable solvents, especially chloroform. In the case of esterified with acetic anhydride, acetic acid is suitable as the reaction medium. Of the starting materials of formula II, a substance with R = H is known (Dutch Patent Application 64/7758; Fr. Pat. 88 751, 3rd Amendment to Pat. 1,449,569).

Since this substance is only characterized in the cited literature by stilts *, it is included in the example in its preparation. The compound of formula II, R = Cl, is novel and its preparation is also described in the example. Since the preparation of amino alcohols of the formula II is based on the corresponding 11- (3-bromopropylpropylidene) -1H, 11-dihydrodibenzo (b, e) thiepines, for which the trans (E) -configuration at the double bond has been determined by IR spectrum, this configuration is attributed to all products prepared from them, ie esters of formula I. For some of them, the accuracy of this attribution was verified by a detailed measurement of the spectra in the area of extra-plane vibration of aromatic CH bonds at 700 to 900 cm ^-1 . All novel compounds described in this invention, both end products and intermediates, were confirmed in identity and by means of analyzes and spectra.

Further details of the process for the preparation of the compounds of formula I according to the invention are given in the examples, which are of course only illustrative of the possibility of the invention, but are not intended to limit the invention to the conditions set forth therein.

Example, (E) -1- (3- / 6,11-Dihydrodibenzo (b, e) thiepin-11-ylidene / propyl) -4- (2-acetoxyethyl) piperazine

A mixture of 5.0 g of (E) -1- (3- / 6,11-dihydrodibenzo (b, e) thiepin-11-ylidene / propyl) -4- (2-hydroxyethyl) piperazine, 7.0 ml acetic anhydride and 50 g ml of acetic acid was allowed to stand at room temperature for 24 h. The reaction mixture was then diluted with water, basified with aqueous ammonia and extracted with benzene. The extract is dried over potassium carbonate, evaporated under reduced pressure. The residue is dissolved in 25 ml of ethanol and neutralized with a solution of 3.2 g of maleic acid in 10 ml of ethanol. After standing overnight, 8.2 g (95 96) of crystalline bis (hydrogen maleate) melting at 176-178 ° C are obtained by suction. The analytically pure material was obtained by crystallization from ethanol, m.p. Mp 182-183 ° C.

Although the starting amino alcohol has been described (cited) in the literature, it is preferable to proceed in the following manner in its preparation:

A mixture of 25.0 g of (E) -1- (3-bromopropyl) -6,11-dihydrodibenzo (b, e) thiepine (Bajner M. et al., Collect. Czech. Chem. Commun. 44. 2536, 1979) . 34.0 g of 1- (2-hydroxyethyl) piperazine and 65 ml of chloroform are stirred and refluxed for 3 hours. The mixture is diluted with 100 ml of chloroform, filtered with charcoal, the filtrate is washed with water and the bases are extracted by shaking into a solution of 25 ml of hydrochloric acid in 175 ml of water. The aqueous layer was again filtered with charcoal, the filtrate basified with aqueous ammonia, and the product was extracted with dichloromethane. The extract was dried over potassium carbonate and evaporated. The oily residue representing crude (E) -1- (3H / 6,11-dihydrodibenzo (b, e) thiepin-11-ylidene / propyl-4- (2-hydroxyethyl) piperazine) was dissolved in 150 ml of ethanol and the solution 6.8 g of maleic acid in 60 ml of ethanol is crystallized by standing and cooling, 28.2 g of (96.9) bis (hydrogen maleate) melting at 154 DEG-155 DEG C. crystallize by standing and cooling. An analytical sample is obtained by recrystallization from ethanol, m.p. Mp 55 DEG -156 DEG C. Pure oily bases are prepared in theoretical yield by decomposition of the salt with aqueous ammonia, extraction with ether and evaporation of the extract.

Example 2 (E) -1- (3- / 2-Chloro-6,11-dihydrodibenzo (b, e) thiepin-11-ylidene) propyl-4- (2-ethoxyethyl) plperazine

A mixture of 4.2 g of (E) -1- (3- / 2-chloro-6,11-dihydrodibenzo (b, e) thien-11-ylidene / propyl) -4- (2-hydroxyethylpiperazine), 5.0 ml of acetic anhydride and 15 ml of acetic acid are allowed to stand at room temperature for 48 h and then heated at 100 DEG C. for 2 h. A similar treatment as in Example 1 yields 5.6 g (80%) of bis (hydrogen maleate) melting at 190 DEG. 92 DEG C. An analytical sample was obtained by recrystallization from ethanol, mp 192 DEG -93 DEG C. The pure oily base was obtained by decomposition of the salt with aqueous ammonia, extraction with ether and evaporation of the extract.

The starting alcohol is a novel substance which can be prepared by the following procedure from the known 2-chlorodibenzo (b, e) thiepin-11 (6H) -one (Rajsner M. et al., Czech Fara. H,

451, 12 (12);

A solution of Grignard reagent is prepared by reacting 4.7 g of magnesium with 25.0 g of cyclopropyl bromide (Meek JS, Osuga DT, Org. Syn., Coll. Vol. 2, 126, 1973) in 100 ml of tetrahydrofuran (see Rajsner U. et. al., Collefct. Czech. Commun. 44, 2536 (1979). The reagent solution was cooled to room temperature and a warm solution of 25.0 g of 2-chlorodibenzo (b, e) thiepin-11 (6H) -one in 100 ml of tetrahydrofuran was added dropwise over 1 hour to the stirring solution. The mixture was refluxed for 1 h, cooled in an ice bath, and quenched with slow addition of 135 mL of saturated ammonium chloride solution with stirring.

The mixture was extracted, the extract was washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. Upon standing the residue crystallized overnight to give 26.7 g (92%) of crystalline 2-chloro-11-cyclopropyl-6,11-dihydrodibenzo (b, e) thiepin-11-ol melting at 124-127 ° C. Recrystallization of the sample from a mixture of benzene and petroleum ether gave an analytically pure material, melting at 129-131 ° C.

To a stirred solution of 10.0 g of the preceding alcohol in 170 ml of acetic acid was added dropwise over 30 minutes at 10-15 ° C 85 ml of a 15% solution of hydrogen bromide in acetic acid. The mixture is left at room temperature for 24 h, filtered with charcoal, the filtrate is diluted with 200 ml of water and extracted with benzene. The extract was washed with water, dried (MgSO4) and evaporated. The residue crystallizes upon dilution with cyclohexane. 9.0 g (75%) of crude (E) -11 (3-bromopropyl) -2-chloro-6,11-dihydrodibenzo (b, e) thiepine are obtained, which is recrystallized from a mixture of cyclohexane and hexane and is then obtained in the pure state as a substance melting at 109-111 ° C.

A mixture of 5.0 g of the above bromo derivative, 6.0 g of 1- (2-hydroxyethyl) piperazine and 10 ml of chloroform was stirred and refluxed for 3 h. The mixture was then diluted with 50 ml of chloroform, filtered with charcoal, the filtrate was washed with water and then extracted with a solution of hydrochloric acid (10 ml) in 60 ml of water. The aqueous layer was filtered with charcoal, the filtrate basified with aqueous ammonia, and the product was extracted with dichloromethane. The extract was dried over potassium carbonate and evaporated. The oily residue is dissolved in 50 ml of ethanol and neutralized with a solution of a calculated amount of maleic acid in ethanol. Standing and cooling results in crystallization to give 5.2 g (59%) of bis (hydrogen maleate) (E) - .- (3- / 2-chloro-6,11-dihydrodibenzo (b, e) thlepin) -1-ylidene / propyl) -4- (2-hydroxyethylpiperazine) mp, 63-165 ° C.

Crystallization from ethanol / ether gives a pure salt, m.p. 65-166 ° C. Decomposition of this salt with aqueous ammonia and extraction with chloroform gave a crystalline base melting at 12 to 122 ° C (benzene-petroleum ether). By neutralizing this base with methanesulfonic acid in ethanol, crystalline dimethane sulfonate melting at 206-208 ° C (ethanol-ether) can be prepared.

Example 3 (E) -1- (3- / 6,11-Dihydrodibenzo (b, e) thiepin-11-ylidene (propyl) -4- (2-decanoyloxyethyl) piperazine

A mixture of 5.0 g of (E) -1- (3- / 6,11-dihydrodibenzo (b, e) thiepin-11-ylidene / propyl) -4- (2-hydroxyethylpiperazine (see Example 1), 5.1 g) decanoyl chloride (Fierz-David DavidE., Kuster W., Helv, Ghim.Acta 22, 82, 1939) 8 ml of chloroform and 25 ml of benzene are allowed to stand at room temperature for 24 hours and then refluxed for 3 hours. After cooling, it was partitioned by shaking between dilute aqueous ammonia and benzene, the benzene layer was dried over potassium carbonate and evaporated under reduced pressure, and the residue was neutralized with 3.2 g maleic acid in 35 ml ethanol to give 8.9 g (88 g). %) of crystalline bis (hydrogen maleate), mp

68 DEG-169 DEG C. (ethanol).

Homogeneous oily bases are obtained by decomposing the salt with aqueous ammonia, extracting with ether and evaporating the extract.

EXAMPLE 4 4 (E) -1- (3- / 2-Chloro-6,11-dihydrodibenzo (b, e) thiepin-11-ylidene / propyl) -4- (2-decanoyloxyethyl) piperazine

A mixture of 4.2 g of (B) -1- (3- / 2-chloro-6,11-dihydrodibenzo (b, e) thiepin-11-ylidene / propyl) -4- (2-hydroxyethyl) piperazine (see Example 1), 3.9 g of decanoyl chloride (cited), 6 ml of chloroform and 20 ml of benzene were treated as in Example 3. 6.5 g (80%) of bis (hydro-maleate), m.p. 178 DEG-179 DEG C. (ethanol). A homogeneous plywood base is obtained by decomposing this salt with aqueous ammonia, extracting with ether and evaporating the extract.

Example (E) -i- (3- / 6,11-Difaydrodibenzo (b, e) thiepin-11-ylidene / propyl) -4- (2- / 3,4,5-trimethoxybenzoyloxy / ethyl) piperazine

A mixture of 5.0 g of (E) -1- (3- / 6,11-dihydrodibenzo (b, e) thlepin-11-yllden / propyl) -4- (2-hydroxyethyl) piperazine (see Example 1), 6, 1 g of 3,4,5-trimethoxybenzoyl chloride (Marsh JT, Stephen H., J. Chem. Soc. 127. 1635, 1925). 25 ml of benzene and 10 ml of chloroform were left to stand at room temperature for 36 hours and then partitioned by shaking between dilute aqueous ammonia and benzene. The benzene layer was washed with saturated ammonium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue was neutralized with 3.2 g of maleic acid in 35 ml of hot ethanol. Crystallization yielded 9.5 g (90%) of bis (hydrogen maleate) melting at 149-151 ° C. Recrystallization from ethanol gave the pure product, m.p. 153-154 ° C.

Example 6 (E) -1- (3- / 2-Chloro-6,11-dihydrodibenzo (b, e) thiepine-11-ylidene / propyl) -4- (2- (3,4,5-trimethoxybenzoyloxy)) ethyl) piperazine

A mixture of 3.1 g of 3,4,5-trimethoxybenzoic acid (Mautnner r., Org. Syn., Coll. Vol. 1, 537, 12W, 25 ml of benzene and 3.0 ml of thionyl chloride is refluxed for 6 hours and The residue (acid chloride) is diluted with 30 ml of benzene and the evaporation is repeated and then 3.0 g of (E) -1- (3- / 2-chloro-6,11-dihydrodibenzo (b, e) are added. (thiepin-11-ylidene / propyl) -4- (2-hydroxyethyl) piperazine (see Example 2), 15 ml of benzene and 5 ml of chloroform, and the mixture was treated as in Example 5. 4.7 g (80 SS) of bis were obtained. (hydrene maleate) melting at 166-169 ° C (ethanol).

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of piperazinoalkanol esters of the dibenzo (b, e) thiepine series of formula I, -SR (I) wherein R is hydrogen or chlorine and R ¹ is alkyl of 1 to 9 carbon atoms or 3,4,5-trimethoxyphenyl, and their maleic acid salts, characterized in that the amino alcohols of formula 11 (11) wherein R is the same as in Formula I is treated with reactive acid derivatives of Formula III, R ¹ COOH (III), wherein R ¹ also denotes the same as in formula I, preferably the chlorides or anhydrides of these acids, at temperatures of 20 to 100 ° C in suitable solvents, preferably chloroform or acetic acid, and the base of the formula I obtained are neutralized with maleic acid.