CS262296B1 - Preparation of 10- (2-bromoethoxy) -2-chloro-10,11-dihydrodibenzo / b, f / thiepine - Google Patents

Abstract

The solution falls within the field of synthesis of new drugs. Its subject is a method for preparing a new 10-(2-bromomethoxy)-2-chloro-10,11- -dihydrodibenzo/b,f/thiepin (I), which is an intermediate in the synthesis of psychotropic and neuroleptically active drugs. The method for preparing substance I according to this solution consists in the reaction of 2-chloro-10,11-dihydrodibenzo/b,f/thiepin-10-ol with 2-bromoethanol in benzene or toluene in the presence of brominated trifluoride etherate. The process is carried out under moderate cooling, i.e. at 10 to 20 °C, preferably at 12 to 14 °C. A 95% oily product is obtained in high yield, which can be used further in this state and which can be purified by chromatography to a state of analytical purity.

Description

The present invention relates to a process for the preparation of 10- (2-bromoethoxy) -2-chloro-10,11-dihydrodibenzo [b, f] thiepine of the formula I

OCH ₂ CH ₂ Br ( _X ).

Said compound of formula I is novel and is an intermediate in the manufacture of psychotropic drugs with neuroleptic activity.

The process for the preparation of the compound of the formula I according to the invention consists in the reaction of the known 2-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-ol (Pelz K. et al., Collect. Czech. Chem. Commun.

33, 1952, 1968) with 2-bromoethanol in benzene in the presence of boron trifluoride etherate. The reaction proceeds rapidly under moderate cooling, i.e. at temperatures of 10 to 20 ° C, preferably 12 to 14 ° C.

Instead of benzene, toluene can also be used as an environment, which is more favorable from the point of view of occupational safety. The reaction mixture is quenched with water, the organic phase is washed with water, dried and evaporated.

The residue is a very viscous oil which contains approximately 95% of the desired 10- (2-bromoethoxy) -2-chloro-10,11-dihydrodibenzo [b, f] thiepine of formula I. The yield on the pure substance is 92%.

The 2-bromoethanol used must be carefully cleaned of hydrogen bromide, which it always contains during prolonged storage. 2a, allow to stand with anhydrous alkaline carbonate for 24 hours and distil after filtration. The content of the desired compound of formula I in the product can then be determined based on the bromine content. A completely homogeneous compound of formula I is obtained by chromatography of a sample of 95% of the product on silica gel. The chromatographed product then provides satisfactory elemental analysis and can be used to measure the NMR spectrum. The crude 95% product is pure enough for preparative use. Further details of the preparation of the compound of formula I according to the invention are given by way of example, but it is not intended to describe all the possibilities of the invention in a comprehensive manner.

Example

A solution of 6.0 g of 2-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-ol in 60 ml of benzene is cooled to 12-14 ° C and 4.5 g of pure 2-bromoethanol ( of colored hydrogen bromide on standing for 24 hours with anhydrous potassium carbonate and distilled, mp, 47 ° C / 1.33 kPa). With stirring, 3.4 g of freshly distilled boron trifluoride etherate (bp 126-129 ° C) is then added dropwise. Stirring was continued at 12-14 ° C for 1 h and the mixture was then quenched by the slow addition of 30 mL of water. After stirring for 15 min, the benzene layer was separated, washed with water, dried over calcium chloride and evaporated on a rotary evaporator under reduced pressure. The residue (8.2 g) is crude 10- (2-bromoethoxy) -2-chloro-10,11-dihydrodibenzo [b, f] thiepine which, according to analysis, contains 95% of the desired compound and is useful in this state for further preparative purposes. Thus, the yield on pure product is 7.8 g (92%).

A sample of this product is chromatographed on a column (20 times the weight of substance) of silica gel for complete purification. Elution with petroleum ether, which contains 10% benzene, removes less polar components. Elution with a 7: 3 mixture of petroleum ether and benzene gives a homogeneous oily substance of formula I. The residue obtained by completely evaporating the solvents under vacuum is analytically 1 2

Pure as confirmed by 1 H NMR spectrum (C HCl): δ 3.20 to 4.00 ra, 6 H (ArCH ₂ and

OCH-CH-Br)? 5.40 dd, 1H (Ar-Ch-O, J = 8.0-4.0 Hz); 6.90 to 7.60 m, 7H (7 ArH). Density, ^zz 20 d = 1.40? refractive index, n * - 1.625.

Claims (4)

SUBJECT OF THE INVENTION A process for the preparation of 10- (2-bromoethoxy) -2-chloro-10,11-dihydrodibenzo [b, f] thiepine of formula I OCH ₂ CH ₂ Br, characterized in that 2-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-ol is reacted with 2-bromoethanol in the presence of boron trifluoride etherate. 2. Process according to claim 1, characterized in that the reaction of said components is carried out in a lower aromatic hydrocarbon environment, preferably in benzene or toluene, under gentle cooling, i.e. at temperatures of 10 to 20 ° C, preferably at 12 to 14 °. C. 3. The process of claim 1 wherein the reaction mixture obtained is quenched with water, the organic phase is washed with water, dried and the volatiles are removed by evaporation in vacuo to give a 95% crude product which is suitable. for further processing. 4. A process according to any one of claims 1 to 3, characterized in that the crude product is purified by silica gel column chromatography for the purpose of perfect characterization, resulting in a homogeneous, analytically pure product.