KR830002203B1 - Method for preparing isopropyl 4, 10-dihydro-10-oxothieno [3, 2-c] [1] benzoxepin-8-acetate - Google Patents

Abstract

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Description

Method for preparing isopropyl 4, 10-dihydro-10-oxothieno [3, 2-c] [1] benzoxepin-8-acetate

The present invention relates to a process for the synthesis of isopropyl 4,10-dihydro-10-oxothieno [3,2-c] [1] -benzoxepin-8-acetate.

The compounds having the following general formula are known to have anti-inflammatory and analgesic effects (US Pat. No. 4,025,640 to McFadden, filed Aug. 26, 1975).

In the above general formula

R represents hydrogen or lower alkyl group. This compound is also described in Japanese Patent Application No. 61 607 1975 filed on May 23, 1975 by Dakawa et al. And published on November 26, 1976. Compounds such as McFadden and Dakkawa are prepared as two different synthetic routes, including, but not limited to, each compound described herein.

In Schemes 1 and 2 above, intermediate compound (V) is separated and esterification is subsequently carried out in each step. Compound VI), i.e., a study to increase the total yield of lower alkyl 4,10-dihydro-10-oxo thieno [3,2-c] [1] -benzoxepin-8-acetate, an intermediate compound ( It has been found that several unexpected advantages can be obtained by performing in a multistage reaction system (Scheme 3) involved in the synthesis of the compound without going through the formation and separation steps of V). Thus, according to the process of the present invention, the starting compound (II) is first converted into an acyl halide using a suitable reagent (e.g. SOCl ₂ or SOBR ₂ ), and then a Friedel craft catalyst (especially aluminum chloride or bromide) is added to the reactor After ring closure, lower alcohol is added to the reactor without hydrolysis to form intermediate compound (V). This operation can be carried out in a suitable solvent, preferably in a halogen solvent (eg methylene or 1,2-dichloroethane) within the range of about 0-25 ° C., preferably about 5 ° C.-15 ° C. In order to promote esterification, it is not necessary to add a catalyst such as sulfuric acid. It should be noted that the esterification takes place on acyl halides, not on the free carboxylic acid (V), and the aluminum chloride or bromide is converted to the corresponding aluminum-lower-alkoxide. The term "lower" described above refers to having up to 5 carbon atoms.

An advantage of the process of the present invention is that it is significantly increased over the known schemes as described above as well as the scheme 1 described above of the total yield of the final compound (VI) obtained from the starting compound (II). Unexpected performance was achieved by continuously performing three reactions in the same reactor, in which large amounts of by-products and side reactions could occur in each reaction.

Another advantage of the process of the present invention is that it is simpler than known Schemes 1 and 2 because all the reaction steps are carried out continuously in the same reactor without going through the formation and separation of intermediate compound (V).

Another advantage of the process of the present invention is that the aluminum catalyst can be recovered to the aluminum lower alkoxide side by simple filtration followed by washing with a suitable solvent. This simple recovery of aluminum alkoxides also has significant advantages in economic and environmental aspects, whereby aluminum salts are removed to reduce the total process cost for wastewater treatment. Moreover, when isopropyl alcohol is used, the aluminum catalyst is recovered as a valuable and in demand aluminum isopropoxide used for various chemical applications, in particular for synthetic purposes (e.g., by reduction of Merbain pondorf-worm).

The following examples illustrate the advantages of the present invention and the prior art in more detail.

EXAMPLE

292.3 g of 4- (2-carboxy-3-thiethyl-methoxy) -phenylacetic acid, methylene chloride or 500 ml of 1, 2-dichloroethane, 182.3 ml of dionyl chloride and 5 ml of N, N-dimethylformamide Heated to 28-30 ° C. over 15 minutes with stirring and left at the same temperature for 5 1/2 hours. The reaction mixture is refluxed (vessel temperature 40 ° C.) for 1 hour and left at room temperature for 16 hours.

500 ml of methylene chloride or 1,2-dichloroethane are added to the impure fluoride solution. The solution is cooled to 9-10 ° C. in a cold water bath and 160 g of aluminum chloride is added in small portions to maintain the temperature of the reaction mixture at 10-15 ° C. After addition the mixture is stirred at 10-12 ° C. for 2 1/2 hours and then cooled to 0-5 ° C. 1 L of isopropyl alcohol is slowly added over 1 1/4 hour while maintaining the temperature below 15 ° C. All of this phophophil alcohol is added and the mixture is warmed to 20 ° C. over 50 minutes. The resulting aluminum isopropoxide is filtered off and washed with 500 ml of methylene chloride. The filtrate is extracted successively with a mixture of 1N cold hydrochloric acid (0-5 ° C.), 5% titanium bicarbonate solution and 5% sodium chloride solution and then with 5% sodium chloride solution. The organic layer is dried over 50 g of anhydrous magnesium sulfate and filtered.

Magnesium sulfate is washed with 120 ml of methylene chloride. The combined filtrates were evaporated under reduced pressure and the residue was recrystallized from cyclohexane to give isopropyl 4,10-dihydro-10-oxothieno [3,2-c] [1] -benzoxepin-8 having a melting point of 92 to 94 캜. 221 g (70% yield) of acetate are obtained.

Elemental Analysis: C ₁₇ H ₁₆ SO ₄

Calculated C 64.54% H 5.10%

Found C 64.42% H 5.17%

In contrast, 4,10-dihydro-10-oxothieno [3,2, -c] [1] -benzoxepin-8-acetic acid crystal preparation and separation (yield 40%) and subsequent esterification with isopropyl ester In the practice of US Pat. No. 4,025,640 to obtain (yield 30%) in the methods 1b and 3, the total yield of the desired product was only 12%.

Claims (1)

Diacid halides obtained by halogenating 4- (2-carboxy-3-thienylmethoxy) phenyl acetic acid were treated with aluminum halide to give 4,10-dihydro-10-oxothieno [3,2-c] [1] Isopropyl 4, 10-dihydro-10-oxothieno [3,2-c] [1] benz, characterized by forming benzoxepin-8-acetylhalide and treating this acetyl halide with isopropyl alcohol. A process for synthesizing oxepin-8-acetate in the same reactor.