HU192812B - New process for production of 6,11-dihydro-dibenzo/b,e/oxepin - Google Patents

Abstract

6,11-dihydro dibenzo-(b,e)-oxepin-11-one is obtd. by cyclisation of 2-phenoxy-methyl-benzoyl-chloride produced in the reaction of 2-phenoxy-methyl benzoic-acid with thionyl-chloride in an aromatic hydrocarbon at 60-120 deg.C. in the presence of catalytic amts. of metals or oxides of metals belonging to the iron or earth gps. of elements in the periodic table. - The target cpd. of formula I is the starting material in the synthesis of pharmaceutically valuable Dopexin of formula II.

Description

The present invention relates to a novel process for the preparation of 6,11-dihydro-dibenzo (b, e) oxepin-11-one of formula (I). This compound is the starting material for the synthesis of doxepin (II), a well-established drug for the treatment of depression, anxiety and, more recently, gastric ulcer.

Several processes are known in the literature for the preparation of the product of formula (I).

According to one method (J. Org. Chem. 27, 230 (1962)), 2-phenoxymethylbenzoic acid is treated with a large excess of polyphosphoric acid for 9 hours at 170 ° C and extracted from the resulting mixture (I). The disadvantage of this method is the high reaction time, the high temperature and the strong tariness due to the vigorous treatment of polyphosphoric acid.The tar is highly contaminated with the reaction mixture, which requires distillation under high vacuum to obtain the pure product, followed by crystallization. All of these circumstances make the industrial scale implementation of the process difficult and costly.

In another method (German Patent No. 1 279 682), a ketone of formula (I) is prepared by cyclization of 2-phenoxymethylbenzoic acid with ethyl polyphosphoric acid at 100 ° C for 30 minutes. Although the yield of the process is 85% relative to the crude product, the product obtained must be recrystallized several times in order to obtain an appropriate degree of purity, thereby reducing the yield of the pure product to below 60%. According to another method disclosed herein, the ring closure is carried out starting from 2-phenoxymethylbenzoyl chloride by melting at high temperature under a nitrogen atmosphere. Due to the significant amount of by-products, the yield is also low at about 61%, and this crude product also needs to be recrystallized. According to a variant of this method described in the same specification, the cyclization is carried out by boiling in xylene instead of melting to obtain the crude product of formula (I) in 80% yield. However, to obtain a pure product, the resulting crude product must be distilled at a pressure of 6.7 Pa.

A further process for the preparation of the ketone of formula (I) is disclosed in U.S. Patent No. 3,420,851. According to this, 2-phenoxymethylbenzoic acid is cyclized with trifluoroacetic anhydride. The yield is then 75%, and no vacuum fractionation is required. The industrial utilization of the process is hindered by the large amount of expensive ring sealing reagent.

Finally, the compound of formula (I) may also be prepared by cyclization of 2-phenoxymethylbenzoyl chloride with sublimed aluminum chloride (1950, Bér. 83, 367; J. Am. Soc. 73, 1673). Yield 65-73% based on 2- (phenoxymethyl) benzoic acid The commercial realization of this process is complicated by the use of highly flammable and explosive toxic carbon disulphide as a solvent.

It is an object of the present invention to provide a process for the preparation of a ketone of formula (I) easily, with good yields and inexpensive chemicals, on an industrial scale.

Surprisingly, it has been found that the conversion of the crude 2-phenoxymethylbenzoyl chloride to the compound of formula (I) is more advantageous than the methods known hitherto by the use of catalytic amounts of ferrous or earth metals or of oxides of these groups.

Accordingly, the present invention provides a novel process for the preparation of 6,11-dihydro-dibenzo (b, e) oxepin-11-one of formula (I) by reacting crude 2-phenoxymethylbenzoic acid with thionyl chloride. - cyclization of (phenoxy-20-methyl) -benzoyl chloride which results in the cyclization of 2-phenoxymethylbenzoyl chloride in an aromatic hydrocarbon at a temperature of 70 ° C to 90 ° C in the presence of a catalytic amount of iron powder or alumina carried out.

According to the invention, it is advantageous to react the 2- (phenoxymethyl) benzoic acid in a benzene solution with thionyl chloride and to obtain the crude acid chloride obtained after evaporation of the solvent and the thionyl chloride in the presence of iron powder as a catalyst, cyclizing when heated.

Another advantageous embodiment of the present invention is the use of alumina sites as catalysts for iron powder.

The process according to the present invention has several advantages over the prior art processes: neither a large amount of expensive reagents nor high temperatures are required for the ring closure reaction; the acid chloride may be used as a crude distillation residue for the ring closure reaction; small amount of cheap catalyst used for ring sealing is unnecessary to regenerate; the reaction time is short, the formation of by-products is small and therefore purification of the crude product can be carried out without distillation by crystallization.

Accordingly, the process is suitable for industrial kiwifruit.

The following examples illustrate the process of the invention in more detail.

Example 1

To a mixture of 6.84 kg (30 mol) of 2-phenoxymethylbenzoic acid and 10 L of benzene is added 8.85 kg (74 mol) of thionyl chloride at 30-40 ° C and the temperature is maintained for about 20 minutes. under 70-80 [deg.] C., and after stirring at 85-90 [deg.] C. for one hour. The solvent and excess thionyl chloride were evaporated in vacuo. The acid chloride remaining in the oily form

192812 (which crystallizes upon cooling) are dissolved in 20 L of benzene and 70 g of hydrogen-reduced iron powder are added. The mixture is heated with stirring to an internal temperature of 70-75 ° C for 210 minutes, at which time gas evolution begins. After half an hour, the temperature was raised to 80-85 ° C and at this temperature the mixture was stirred for 2 hours. After cooling, the reaction mixture was poured into 50 L of water, after separation the aqueous phase was extracted with 3 x 20 L of benzene, the organic phases were combined and the solution clarified with 500 g of charcoal. After filtration, the solution was concentrated in vacuo, the residue was recrystallized from 50 L of methanol, and the crystalline precipitate was filtered off and dried. This gives 5.23 kg of product. Yield: 83%, m.p. 70-73 ° C.

Example 2

All of the procedures described in Example 1 were followed except that aluminum oxide was used instead of iron powder. 5.91 kg of product of formula I are obtained. Yield: 94%, m.p. 72-74 ° C.

Claims (2)

A process for the preparation of 6,11-dihydro-10-dibenzo (b, e) oxepin-11-one of formula (I) by reacting crude 2- (phenoxymethyl) 2- (phenoxymethyl) benzoic acid with thionyl chloride. ) by cyclization of benzoyl chloride, characterized in that the cyclization of 2- (phenoxymethyl) besoyl15 chloride is carried out in an aromatic hydrocarbon at a temperature between 70 ° C and 90 ° C in the presence of a catalytic amount of iron powder or alumina. The method of claim 1, wherein 20 characterized in that benzene is used as a diluent for the ring closure reaction.