KR830002566B1 - 6,11-Dihydro-11-oxodibenz [b, e] preparation of oxepin-2-alkanoic acid - Google Patents

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Description

6,11-dihydro-11-oxodibenz [b, e] manufacturing method of oxepin-2-alkanoic acid

The present invention relates to a process for preparing 6, 11-dihydro-11-oxodibenz [b, e] oxepin-2-alkanoic acid of the following general formula (I), which is useful as an anti-inflammatory and analgesic agent.

In the general formula, R ₁ and R ₂ are hydrogen or methyl, Y is alkyl having 1 to 4 carbon atoms, alkoxy, halogen or trifluoromethyl having 1 to 4 carbon atoms, and n is 0, 1 or 2.

Until now, the manufacturing method of the present invention has not been described. According to the conventional method, a side reaction and a polymerization reaction occur or the yield is very low. The following documents disclose that 6-, 11-dihydro-11-oxodibenz [b] is closed by heating α-phenoxy-0-toluic acid with strong thionyl chloride for extended periods of time under elevated conditions such as 160 ° C. , e] A method for obtaining oxepin in very low yields is described. See M. K. Stach and H. Spingler. Chem., Bd. 93, 1962 and Stach and Spingler, German Patent No. 1,279,682]. The prior art also describes a process for the closing of monoacid chlorides of the general formula at the elevated temperature of 130 to 220 ° C. to produce the corresponding oxepins.

(Wherein R is hydrogen, methyl, methoxy, chlorine or bromine.) In addition, the dicarboxylic acid of the following structural formula is dehydrated at 50 to 125 ° C in the presence or absence of a solvent (e.g. polyhydric acid, ethanol-phosphorous pentoxide, or Sulfuric acid) is known to be closed by treatment for 15 minutes to 12 hours (US Patent Application Nos. 394,801 to Helsley, McFadden and Hoffman).

However, there is no mention of the method of the present invention in the prior art. Since the yields are low in the prior art, many by-products are produced and many polymerization reactions occur, those skilled in the art would not have expected that our method would be able to obtain the products in good yields. It was unexpected that it was obtained in exceptionally high yield according to the method of the invention. The present invention is to ring-close diacid halides, and it is rare and unexpected that intramolecular ring-closure reactions occur under the conditions of the present invention. No expected intermolecular Friedel-Crafts reaction occurred. It is possible to produce the pure product of the present invention in excellent yield because no intermolecular reaction has taken place.

We prepare diacid halides by treating the following dicarboxylic acids of general formula (II) with a sufficient amount of reagents (e.g., thionyl halides or phosphorus halides) to produce diacid halides, which are either standard Friedel-Craft conditions or modified Friedel-Craft conditions. It was found that 6, 11-dihydro-11-oxodibenz [b, e] oxepin-2-alkanoic acid (I) was obtained in exceptionally high yield by anti-closing and then hydrolyzing.

In the above formula

R ₁ and R ₂ are hydrogen or methyl, Y is alkyl of 1 to 4 carbon atoms, alkoxy, halogen or trifluoromethyl of 1 to 4 carbon atoms, and n is 0, 1 or 2.

According to the method of the present invention, unlike the mono acid halides described in the prior art of Stach and Spinger, a much higher yield was obtained by closing the diacid halides.

In particular, the diacid halide of formula (III), which is an intermediate, reacts the dicarboxylic acid of formula (II) with a sufficient amount of reagent (e.g., thionyl halide or phosphorus halide) at ambient temperature in the presence or absence of a solvent. Prepared by treatment for 15 minutes to 4 hours at the boiling point of the mixture.

In the general formula, Y, R ₁ , R ₂ and n are as described above, and X is chlorine, bromine or fluorine. Diacid halides can be closed by one of two methods.

A: Friedel-Craft Lung Reaction

The diacid halide is cyclized under standard Friedel-Craft conditions and then hydrolyzed to give 6, 11-dihydro-11-oxodibenz [b, e] oxepin-2-alkanoic acid of the general formula (I): .

In this novel process, optimum yields are obtained when running at low temperatures of about 5-10 ° C. using Lewis acids such as ammonium chloride. As the temperature rises, the yield decreases. At 80 ° C., better results are obtained by the “B” method described later.

B: thermal ring closure (modified Friedel-Craft reaction)

The diacid halide is heated at 80 to 125 ° C. for 10 minutes to 24 hours and then hydrolyzed to give 6, 11-dihydro-11-oxodibenz [b, e] oxepin-2-alkanoic acid. One skilled in the art recognizes that the yield depends on the reaction time, temperature and the particular derivative used.

The preferred method is method B, the preferred diacid halide is chloride, and among the compounds prepared by the method of the present invention, 6, 11-dihydro-11-oxodibenz [b, e] oxepin-2-acetic acid, 6 , 11-dihydro-α-methyl-11-oxodibenz [b, e] oxepin-2-acetic acid, and 8-chloro-6,11-oxodibenz [b, e] oxepin-2-acetic acid to be.

The following examples are intended to illustrate the method of the present invention in detail, which is not intended to limit the scope of the present invention.

Example 1

To 16 ml of thionyl chloride was added 28.6 g of 4- (2-carboxybenzyloxy) phenylacetic acid and the mixture was slowly heated to reflux and continued to reflux for 1 hour. Excess thionyl chloride is removed at 90 ° C. under reduced pressure to give an oily diacid halide. This oil is taken up in 160 ml of 1,2-dichloroethane and cooled to 5-10 ° C. 14.1 g of anhydrous aluminum chloride is added to the reaction material, the mixture is stirred at 5 to 10 ° C. for 90 minutes, poured into ice, stirred for 1 hour, extracted with chloroform, and chloroform is obtained to obtain an oily material. This oil is taken up in 15% sodium hydroxide solution and heated for 30 minutes. The solution is acidified and extracted with chloroform to give 25.6 g (95.5%) of 6, 11-dihydro-11-oxodibenz [b, e] oxepin-2-acetic acid. This compound was identified as a target compound by thin layer chromatography, nuclear magnetic resonance, and mixed melting point measurement.

Example 2

Diacid halides were prepared in the same manner as in Example 1 from 340 ml of thionyl chloride and 400 g of 4- (2-carboxybenzyloxy) phenylacetic acid. This diacid halide is heated at 110 to 120 ° C. under a nitrogen atmosphere for 2 hours. After the reaction mixture was cooled, 1500 ml of water was added thereto and heated to 65 ° C. to hydrolyze it. After completion of the hydrolysis, the oily product is dissolved in 20% sodium hydroxide solution at 50-55 ° C. and adjusted to pH 1 using 6N hydrochloric acid. After cooling the acidified solution to 10 ° C., the resulting precipitate was filtered, washed, collected and dried to give 362 g (96.5) of 6, 11-dihydro-11-oxo-dibenz [b, e] oxepin-2-acetic acid. %) Is obtained. This compound was found to be the target compound by thin layer chromatography, hex resonance and mixed melting point measurements.

The following compounds were also prepared in high yield by the methods of Examples 1 and 2:

6,11-dihydro-α-methyl-11-oxodibenz [b, e] oxepin-2-acetic acid

8-chloro-6, 11-dihydro-11-oxodibenz [b, e] oxepin-2-acetic acid

6, 11-dihydro-α, α-methyl-11-oxodibenz [b, e] oxepin-2-acetic acid

6,11-dihydro-9-trifluoromethyl-11-oxodibenz [b, e] oxepin-2-acetic acid

Claims (1)

Next, the diacid halide of general formula (III) is ring-closed at 5 to 125 ° C. for 20 minutes to obtain an oxepin alkanoyl halide of general formula (IV), which is hydrolyzed. 6, 11-dihydro-α-methyl-11-oxodibenz [b, e] oxepin-2-alkanoic acid.

Wherein R ₁ and R ₂ are hydrogen or methyl, X is chlorine, bromine or fluorine, Y is alkyl of 1 to 4 carbon atoms, alkoxy, halogen or trifluoromethyl of 1 to 4 carbon atoms, n is 0.1 Or two.