CS232340B1 - Process for the preparation of 11- (3-dimethylaminopropyl) -α, 11-dihydrodibenzo '(b, e) thiepin-11-ol - Google Patents

Abstract

The invention relates to a new process for the preparation of 11-(3-dimethylaminopropyl)-6,11-dihydrodibenzo(b,e)thlepin-11-ol of formula I, (I) which is an intermediate in the production of the antidepressant-active hydrochloride E-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenzo(b,e)thlepin. The new process for preparation uses the usual reaction of 3-dimethylaminopropylaluminium chloride with 6,11-dihydrodibenzo-(b,e)thlepin-11-one and subsequent decomposition with an aqueous solution of ammonium chloride, Isolation of the precipitated addition product of formula III CIMgO (CH2)3N(CH3)2 (III) and finally decomposition of a suspension of this addition product in pure toluene with an aqueous solution of ammonium chloride. The resulting toluene solution of product I is either used directly for further processing or processed into the pure substance of formula I.

Description

(54) Process for preparing 11-(3-dimethylaminopropyl)-e,11-dihydrodibenzo[b,e]thiepin-11-ol

The invention relates to a new process for the preparation of 11-(3-dimethylaminopropyl)-6,11-dihydrodibenzo(b,e)thlepin-11-ol of formula I,

(I) which is an intermediate in the production of the antidepressant-active hydrochloride E-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenzo(b,e)thlepin. The new preparation method uses the usual reaction of 3-dimethylaminopropylaluminium chloride with 6,11-dihydrodibenzo(b,e)thlepin-11-one and subsequent decomposition with aqueous ammonium chloride. Isolation of the precipitated addition product of formula III

CIMgO (CH ₂ ) ₃ N(CH ₃ ) ₂ ^(III) and finally decomposition of a suspension of this addition product in pure toluene with an aqueous solution of ammonium chloride. The resulting toluene solution of product I is either used directly for further processing or processed to give the pure substance of formula I.

The present invention relates to a process for the preparation of 11-(3-dimethylaminopropyl)-6,11-dihydrodibenzo(b,e)thlepin-1 1-ol of formula I.

^5,

HO( _CH2 ) _3N ( _CH3 ) ₂ (I)

The amino alcohol of formula I is an intermediate in the production of the antidepressant-active hydrochloride

E-11-(3-dimethyleminopropylidene)-6,11-dihydrodibenzo(b,e)thiepine, which is known under the generic names prothladen, dosulepin and dothlepin and is marketed in large parts of the world under the brand name Prothladen (M, Protiva, Advances in Pharmacy £, 73, 1980: J. A. Rees et al., Int. Pharmacopsychlat. ,0 (1), 54, 1975: Curr. Med. Res. Opin. 4 (6), 416, 1976: K. Néhunek, Acta Facult. Med. Univ. Brunensls 65, 15, 1979: J. Mendlewlcz et al., Brit. J. Psychiat. 136 (Feb.), 154, 1980).

The preparation of amino alcohol I was described by three working groups independently and almost simultaneously in 1962. M. Protiva, M. Rajěner et al. (Experientia 18. 326, 1962: íesk. Farm. ji, 404, 1962) prepared Orignard's reagent by reacting 3-dimethylaminopropyl chloride with magnesium in ether, to which they added a solution of 6,11-dlhydrodlbenzo(b,e)thlepln-11-one of formula II

(Π) in benzene and the reaction was completed by refluxing the reaction mixture. This apparently produced an edition compound of formula III,

GOO (ΠΙ)

CIMgO (CH ₂ ) ₃ N(CH ₃ ) ₂ which was decomposed directly in the reaction mixture with an aqueous solution of ammonium chloride and the liberated amino alcohol I was isolated in the usual manner.

Two other groups (K. Stech and F. Blckelhaupt, Liona tah. Chem. £2, Θ96, 1962: F. Gadlant and appel., Helv. Chim. Acta AŽ, 1 860, 1962) prepared 3-dimethylaminopropyl magnesium chloride by reacting 3-dimethylaminopropyl magnesium chloride with magnesium in tetrahydrofuran and in the same boiling solvent they carried out the reaction of the Grignard reagent with ketone II. The resulting addition compound of formula HI was again decomposed directly in the reaction mixture with an aqueous solution of ammonium chloride and the isolation of the amino alcohol I was carried out in the usual way.

Common features of the described methods for the preparation of the amino alcohol of formula I are a) work in ethereal solvents (diethyl ether, tetrahydrofuran), which are very inconvenient for industrial scale for safety reasons, b) use of the Grignard reagent, i.e. 3-dimethylaminopropylmagnesium chloride (calculated on the starting 3-dimethylaminopropyl chloride and magnesium) in a relatively high excess (up to 100%) with respect to the amount of ketone II used, c) decomposition of the additive compound III with ammonium chloride solution is carried out directly in the reaction mixture, i.e. in the presence of all by-products formed both during the preparation of the Grignard reagent and during its reaction with ketone II; this circumstance causes the obtained crude amino alcohol I to be contaminated with these by-products and its purification is then relatively difficult.

The new method of preparing amino alcohol I, which is the subject of this invention, differs fundamentally from the previous and mentioned methods of preparation in all points e) to c).

First of all, the reaction of 3-dimethylaminopropylmagnesium chloride, which is used in a highly pure form, with ketone II is carried out in mixtures of aliphatic and aromatic hydrocarbons, preferably in a mixture of petroleum ether and toluene, i.e. without the presence of ethereal solvents. The high purity of the 3-dimethylaminopropylmagnesium chloride used, the preparation of which is described in the example, allows the use of a much lower excess of this reagent than is usual.

It is sufficient to use a 20 to 40% excess, preferably a 30% excess, which results in significant savings in the preparation of aminoalcohol I.

The main benefit of this invention, however, is the discovery that it is possible and expedient to isolate the ediate compound of formula III. This is of such consistency in the medium used that it can be isolated by suction filtration or centrifugation. In doing so, it is washed with a pure solvent, preferably again with a hydrocarbon, e.g. toluene, then suspended in a pure solvent, preferably again in toluene, and only then is it decomposed with an aqueous solution of ammonium chloride.

In this process, by-products and impurities remain in the mother liquor during filtration and washing of the addition compound III. By means of thin-layer chromatography on silica gel, the presence of eight foreign substances was detected in this mother liquor, which in itself provides evidence of the high cleaning effect of the solvent exchange carried out. For this reason, the above decomposition of the suspension of the washed addition compound IH with ammonium chloride solution releases very pure amino alcohol I, which can be used for a longer time either directly in the form of the obtained toluene solution, or it can be isolated in pure form by evaporating the toluene solution. Highly pure carbinol is thus obtained in a yield of over 90%. Further details of the process for preparing amino alcohol I according to the present invention are given in the following example:

A solution of 41.2 g of pure sodium hydroxide in 80 ml of water is added to a mixture of 150 g of 3-dimethylaminopropyl chloride hydrochloride (0.95 mol) with 70 ml of water in a separatory funnel, and the liberated base of 3-dimethylaminopropyl chloride is shaken into 280 ml of petroleum ether (b. v. 40 to 60 °C). After separation of the aqueous layer, the organic phase is washed three times with water and dried by refluxing for 45 minutes using an attachment for separating water volatile with petroleum ether in the form of an azeotropic mixture.

Then the mixture is cooled to 30 °C, 23.0 g of powdered magnesium (0.95 tsol) and 100 ml of toluene are added, the mixture is heated to reflux and the stirrer is started. After 30 min from the start of boiling, petroleum ether is slowly distilled from the reaction mixture and this is continued until the temperature of the reaction mixture reaches 62 °C and the total volume of distillate is 100 ml. Once the distillation is complete, stirring and refluxing of the mixture are continued for 3 to 3.5 h.

The suspension of very pure 3-dimethyleminopropylmagnesium chloride thus obtained is cooled to +5 °C and, while stirring, a solution of 165 g of 6,11-dihydrodibenzo(b,e)thiepin-11-one (its preparation is described in the cited works) in 500 ml of toluene is added very slowly dropwise to it so that the temperature gradually increases during the reaction and reaches approximately 20 °C at the end of the operation. Towards the end, it is possible to increase the rate of addition of the ketone solution. The addition takes 2.5 to 3 h. The dropping funnel through which the toluene solution of the ketone was added is rinsed three times with 15 ml of toluene, the mixture is heated to 30 to 40 °C and maintained at this temperature for 1 h. This completes the phase of preparation of the addition compound III.

The suspension of the addition product is now filtered using a Buehner funnel and a suction filter, the solid filter cake is washed eight times with 30 ml of toluene, the wet filter cake is returned to the reaction vessel and the substance is stirred in 450 ml of pure toluene. The resulting suspension is cooled to .0 °C and at a temperature of 10 to 20 °C a solution of 220 g of ammonium chloride in 600 ml of water is slowly added with stirring. After the entire amount has been added, the mixture is heated to 60 °C and maintained at this temperature for 15 min. The aqueous phase is then separated in a separatory funnel and the organic layer is washed three times with 250 ml of water heated to 70 °C. After the last remaining water has been separated, 5.4 g of activated carbon is added to the toluene solution, after a few minutes of stirring it is filtered off with suction and washed with a small amount of toluene. The filtrate obtained is a toluene solution containing pure amino alcohol I in an approximate yield of 95%, which can be used directly for the preparation of prothiaden hydrochloride.

In the preparation of the fifth hundredth substance of amino alcohol I, the filtrate obtained is evaporated under reduced pressure almost to dryness, 300 ml of methanol is added to the resulting crystalline precipitate and the mixture is stirred for 2 to 3 h at a temperature of 0 °C. Then the first crystalline portion is filtered off with suction, washed ten times with 15 ml of methanol and dried. 190 g of pure product with a melting point of 134 to 135.5 °C is obtained. The mother liquors are combined with the washing solutions and evaporated under reduced pressure to dryness. The residue is crystallized from a fourfold amount of a mixture of toluene and methanol 1 : 3. In this way, a second crystalline portion is obtained in a yield of 20.5 g, melting at the same temperature as the main portion. The total yield is therefore 210.5 g, i.e. 92% of theory.

Claims (3)

P fi B D Μ £ T OF THE INVENTION A process for the preparation of 11- (3-dimethylaminopropyl) -6,11-dihydrodibenzo (b, e) thiepin-11-ol of formula I (I) by reacting 6,11-dihydrodibenzo (b, e) thiepin-11-one of formula II O with 3-dimethylaminopropylmagnesium chloride and subsequent decomposition with aqueous ammonium chloride solution, characterized in that ketone II in solid form or its mixture is added to a suspension of 3-dimethylaminopropylmagnesium chloride in an aliphatic hydrocarbon or in a mixture of an aliphatic and aromatic hydrocarbon, preferably a mixture of petroleum ether and toluene. a solution in an aromatic hydrocarbon, preferably toluene, after completion of the reaction, the precipitated addition product of formula III is aspirated CIMgO (CH ₂ ) ₃ N (CH ₃ ) ₂ (III) which is quenched with an aqueous solution of ammonium chloride from the presence of a non-water-miscible organic solvent, preferably toluene, after which a pure ammonium alcohol solution of formula I is obtained, 2. A process according to claim 1 for obtaining the alcohol of formula I in pure crystalline form, characterized in that the solution is concentrated by evaporation to crystallize. 3. The process according to claim 1, wherein the Grlgnerd reagent is used in only 20 to 40%, preferably 30%, excess of the amount of ketone II used.