NO149387B - PROCEDURE FOR THE PREPARATION OF 6,11-DIHYDRO-11-OXODODIBENZE (B, E) -EXSEPINAL CANCER ACIDS - Google Patents

Abstract

Process for the preparation of 6,11-dihydro-11-oxodibenz (b, e) -oxepinalkanoic acids.

Description

The invention relates to a process for the production of 6,11-dihydro-ir-oxodibenz(b,e)-oxepinalkanoic acids with anti-inflammatory and analgesic activity.

The method according to the invention has not previously been discussed. In previous methods, side reactions, polymerization or products appeared in significantly lower yields. In an article by K. Stach and H. Springler, Mh. Chem., volume 93, 1962 and .BRD patent no. 1,279,682 mentions the cyclization of α-phenoxy-o-toluene acids under practical conditions, for example prolonged heating with thionyl chloride at an elevated temperature of approx. 160°C 6,11-dihydro-11-oxodibenz(b,e)-oxepines in substantially lower yields. The . the above-mentioned state of the art also mentions cyclization of monoacid chlorides with formula

wherein R is hydrogen, methyl, methoxy, chlorine or bromine at elevated temperatures, 130-220°C to give the corresponding oxepine. It is also known to cyclize a dicarboxylic acid of formula

by treatment with a dehydrating or condensing medium such as polyphosphoric acid, ethanol-phosphorus pentoxide, phosphoric acid anhydride, anhydrous trifluoroacetic acid or sulfuric acid with or without a solvent at a temperature of approx. 20-150°C. This cyclization is described in US Patent Application No. 459,774 and in Belgian Patent No. 818,055.

However, the state of the art does not include the present invention. The method according to the state of the art results either in low yields and large formation of by-products or polymerization and it is surprising that high yields are obtained with the method according to the invention. Exceptionally high yields approaching 100% achieved

under the conditions according to the invention is surprising.

According to the invention, a diacid halide is cyclized

and it is unusual and unexpected that under the reaction conditions according to the invention approximately only intramolecular cyclization is observed. The earlier and equally possible intermolecular Friedel-Crafts reaction does not occur. It is the absence of intermolecular reaction that enables the high yields obtained according to the invention.

Apart from the absence of intermolecular reaction, it is surprising that high yields are obtained by utilizing very small amounts of Lewis acid catalyst. Those skilled in the art would assume that the completion of a Friedel-Crafts reaction would necessitate a mole ratio of acyl group to catalyst of about 1:1. Consequently, it is very surprising that the high yields of the process according to the invention can be achieved by using as little as 1/10 mol of catalyst per moles of acyl group.

It is well known that the usual reason for poor yields in the Friedel-Crafts cyclization of acid chlorides is drastic reaction conditions, (Friedel-Crafts and Related Reactions, edited by George A. Olah, Interscience Publishers, New York (1964), page 912). This is shown by the lower yields mentioned in connection with the state of the art.

In addition, previous methods for preparing 6,11-dihydro-11-oxodibenz (b,e)-oxep'in-3-alkanoic acids have the disadvantage that both 3-alkane and 1-alkanoic acid isomers are formed. This is evident from example 6 in the above-mentioned Belgian patent. Although the method described there is not region-specific,<1>

the method according to the invention is surprising

found to be regiospecific and thus enables obtaining 3-alkanoic acid without simultaneous formation of 1-alkanoic acid. This is very surprising.

It has been found that treatment of a dicarboxylic acid with a sufficient amount of a substance such as thionyl halide or phosphorus pentahalide to form the diacid halide, followed by cyclization under specific Friedel-Crafts conditions, gives in very high yields 6,11-dihydro-II- oxodibenz-(b,e)-oxepinalkanoic acids according to the following equation:

1 2

in which R and R mean hydrogen or methyl, Y is alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, halogen or trifluoromethyl, n is 0, 1 or 2 and

R<1>

IN

The C-C09H group is in the 2- or 3-position of the phenyl ring. By

R

in the method according to the invention, a diacid halide is cyclized in contrast to a monoacid chloride discussed by Stach and Springler to form considerably higher yields than the known methods.

More particularly, a diacid halide intermediate of formula is prepared

1 2 in which Y, R , R and n have the above meaning and X means chlorine, bromine or fluorine by treating a dicarboxylic acid of formula with a sufficient amount of a substance such as thionyl halide or a phosphorus pentahalide in the presence or absence of a solvent by' a temperature from room temperature to the boiling point of the reaction mixture from 15 minutes to 4 hours. The diacid halide is reacted under special Friedel-Crafts conditions and then hydrolyzed by a method known per se to provide a 6,11-dihydro-11-oxodibenz(b,e)-oxepin-2- or -3-alkanoic acid of formula

In this new method, the specific Friedel-Crafts conditions require the presence of a Lewis acid catalyst such as aluminum chloride, stannous chloride, ferric chloride or other Lewis acids known to be suitable in Friedel-Crafts reactions and the reaction is carried out at low temperatures of approx. . 0°C to ambient temperatures in the presence of a suitable solvent, preferably 1,2-dichloroethane.• In addition, each mole of the diacid chloride cyclized in the reaction requires as little as 0.1-1.0 mole of Lewis acid. A preferred Lewis acid catalyst is aluminum chloride and optimum yields are obtained at a temperature between 5 and 15°C.

The invention therefore relates to a method for the production of a 6,11-dihydro-11-oxodibenz(b,e)-oxepinalkanoic acid

1 2 in which R and R mean hydrogen or methyl, Y is alkyl with from 1-4 carbon atoms, alkoxy with from 1-4 carbon atoms, halogen or trifluoromethyl, n means 0, 1 or 2, and the group is bonded in 2- or 3 -position in the phenyl ring, as forward-; the procedure is characterized by cyclizing 1 mol of a diacid halide with formula II

1 2

wherein R , R , Y and n have the above meaning, and X means bromine, chlorine or fluorine, in the presence of a solvent • and 0.1-1.0 mol of a Lewis acid at a temperature from 0°C to ambient temperature and hydrolyzing the oxepin7 alkanoyl halide formed.

It is clear to those skilled in the art that the yields depend on the reaction time and temperature and especially the derivatives involved.

Preferred diacid halides are chlorides and preferred compounds produced by the method according to the invention are 6,11-dihydro-11-oxodibenz(b,e)-oxepine-2-acetic acid, 6,11-dihydro-11-oxodibenz(b,e)-oxepine -3-acetic acid.

Other very good compounds are 6,11-dihydro-α-methyl-11-oxodibenz(b,e)-oxepine-2-acetic acid, 6,11-dihydro-α-methyl-11-oxodibenz(b,e)-oxepine -3-acetic acid and 8-chloro-6,11-oxodibenz-(b,e)-oxepin-2-acetic acid.

The invention will be explained in more detail with the help of some examples.

Example_el_l_

28.6 g of 4-(2-carboxybenzyloxy)phenylacetic acid are added to 16 ml of thionyl chloride and the mixture is slowly heated to reflux and refluxed for one hour. Excess thionyl chloride is removed under reduced pressure at 90°C to form

a diacid chloride as an oil. The oil is dissolved in 160 ml of 1,2-dichloroethane and cooled at a temperature of 5-10°C. 14.1 g of anhydrous aluminum chloride are added to the reaction mixture and the mixture is stirred for 90 minutes at 5-10°C. The mixture is poured onto ice and stirred for one hour, extracted

with chloroform and the chloroform is removed to provide

an oil. The oil is absorbed in a 15% sodium hydroxide solution

ning and heated for 30 minutes. The solution is acidified

and extracted with chloroform to give 25.6 g of 6,11-dihydro-11-oxodibenz (b,e)-oxepin-2-acetic acid (95.5%).

'which is identical to an authentic sample by thin layer chromatography, nuclear magnetic resonance and mixed melting point.

Example_el_2

20 g of 4-(2-carboxybenzyloxy)-phenylacetic acid are added to 20 ml of thionyl chloride and the mixture is slowly heated to reflux and refluxed for 2 hours. Excess thionyl chloride is removed under reduced pressure at 90°C to give a diacid chloride as an oil. The oil is dissolved in 75 ml of 1,2-dichloroethane, cooled to ambient temperature and 1.82 g of stannous chloride is added to the cooled solution. The reaction mixture is stirred

for 4 hours at ambient temperature and then poured on

35 g of ice. The resulting mixture is stirred for 1 hour and the biphasic mixture is separated. The organic phase is collected

and then concentrated under pressure to give an oily

solid which is poured onto 200 ml of water and the aqueous mixture is heated to 60°C, which hydrolyzes the monoacid chloride to free acid. The acid is neutralized with caustic soda, treated with 0.4 g of charcoal and 0.4 g of celite and filtered. The clear filtrate is solidified by addition of 12 N hydrochloric acid and the solid precipitate is collected by filtration, washed with water and dried under reduced pressure to give 17.2 g of 6,11-dihydro-11-oxodibenz (b,e)-oxepin- 2-acetic acid (91.4%).

Example_3

80 g of 4-(2-carboxybenzyloxy)-phenylacetic acid is added to 80 ml of thionyl chloride and the mixture is slowly heated to reflux over the course of 2 hours and refluxed for a further 2 hours. Excess thionyl chloride is removed under reduced pressure at 90°C to give the diacid chloride. The diacid chloride is dissolved in 250 ml of 1,2-dichloroethane, cooled to 10°C and 3.73 g of aluminum chloride are added to the cooled solution. The reaction mixture is stirred at 10°C for 4 hours and then poured onto 250 g of ice. The resulting mixture is stirred for 1 hour and separates the biphasic mixture. The organic phase is collected and then concentrated under reduced pressure to give an oily solid which is poured into 500 ml of water and the aqueous mixture is heated to 60°C which hydrolyzes the monoacid chloride to free acid. The acid is neutralized by adding caustic soda and this solution is treated with 2.4 g of charcoal and 2.4 g of celite and filtered. The clear filtrate is solidified by the addition of 12 N hydrochloric acid and the solid precipitate formed is washed with water and dried under reduced pressure to give 72.5 g of 6,11-dihydro-11-oxodibenz-(b,e)-oxepin-2- acetic acid (96%).

Example_4

5.1 g of 3-(2-carboxybenzyloxy)phenylacetic acid is added to 10 ml of thionyl chloride and the mixture is slowly heated to reflux and refluxed for 2 hours. Excess thionyl chloride is removed under reduced pressure at 90°C to give the diacid chloride. The diacid chloride is dissolved in 25 ml of 1,2-dichloroethane, cooled to between 10 and 15°C and 0.2 g of aluminum chloride is added to the cooled solution. The reaction mixture is stirred between 10 and 15°C for 4 hours and then poured onto 25 g of ice.

The resulting mixture is stirred and thereby a two-phase mixture is separated. The organic phase is collected and concentrated under reduced pressure to form the monoacid chloride. The acid chloride is poured into water and heated to 60°C, which hydrolyzes the acid chloride into the free acid. The acid is neutralized with caustic soda and the solution is clarified by treatment with 0.15 g of charcoal and 0.15 g of celite. Acidification of the clear solution again with 12 N hydrochloric acid causes a solid precipitate which is collected by filtration, washed with water and dried under reduced pressure to form a white crystalline product. Nuclear magnetic resonance spectra and thin-layer chromatography confirm the presence of the desired 6,11-dihydro-11-oxodibenz (b , e )-oxepin-3-acetic acid and the absence of the less desirable 6,11-dihydro-11-oxodibenz(b,e )-oxepin-1-acetic acid.

By the method according to examples 1-4, the following compound can be prepared in good yield: 6,11-dihydro-α-methyl-11-oxodibenz(b,e)-oxepin-3-acetic acid.

Example_el_5

36 g of 4-(2-carboxybenzyloxy)-α-methylphenylacetic acid is added to 19 ml of thionyl chloride and the product formed is reacted according to example 1 to give the corresponding dicarboxylic acid chloride, the latter being dissolved in 175 ml of 1,2,dichloroethane, cooled to 10°C and eventually 1.3 g of aluminum chloride is added. The reaction mixture is stirred for 4 hours at 10°C and poured onto 150 g of ice. The resulting mixture is stirred for a further 1 hour and extracted with chloroform. Removal of chloroform leaves an oil which is taken up in a

15% sodium hydroxide solution and the mixture is stirred

another 30 minutes. The resulting solution is acidified and extracted with chloroform, whereupon 32.3 g of 6,11-dihydro-α-methyl-11-oxodibenz(b,e)-oxepin-2-acetic acid (94.5%) are obtained in the form of an oil.

NMR: 61.50(d,3 protons, I = 7.5 Hz), 3.73 g(q,1 proton,

I = 7.5 Hz), 5.12 (s, 2 protons) in CDC13-

Example_6

4.5 g of 4-(2-carboxy-5-chlorobenzyloxy)-phenylacetic acid is added to 10 ml of thionyl chloride and the product is reacted according to example 1 to give the corresponding dicarboxylic acid chloride, the latter is dissolved in 25 ml of 1,2-dichloroethane, cooled to 10°C and 0.2 g of aluminum chloride is added. The reaction mixture is stirred for 4 hours at 10°C and poured onto 25 g of ice. The resulting mixture is stirred for a further 1 hour, after which the organic phase is separated. Concentration in vacuo leaves a solid which is taken up in 50 ml of water. The aqueous mixture is heated to 60°C, the monocarboxylic acid chloride being hydrolysed to give an acid. The acid is neutralized by adding caustic soda, the resulting solution is treated with 0.15 g of activated carbon and 0.15 g of celite and filtered. A solid is formed after the addition of 12 N hydrochloric acid. The resulting solid residue is washed with water and dried in vacuo to give 4.1 g of 6,11-dihydro-8-chloro-11-oxodibenz(b,e)-oxepin-2-acetic acid (95.6%) as colorless crystalline product with a melting point of 188-190°C.

Analysis: Calculated for C^H^CIO^ C 63.48%, H 3.66%

Found C 63.25%, H 3.67%

Example_7

6.5 g of 4-(2-carboxy-4-trifluoromethylbenzyloxy)-phenyl-acetic acid is reacted with thionyl chloride according to example 1

and gives the corresponding dicarboxylic acid chloride which is cyclized with 0.2 g of aluminum chloride according to example. 7. That

cyclized product is worked up as indicated in example 7 and gives 5.85 g of 6,11-dihydro-9-trifluoromethyl-11-oxodibenz-(b,e)-oxepin-2-acetic acid (94%) with a melting point of 152-155 °C.

Analysis:, Calculated for ci7H]_iF3°4: c 60.72%, H 3.30%

Found C 60.66%, H 3.35%

Claims (1)

Process for the preparation of a 6,11-dihydro-11-oxodibenz (b,e)-oxepinalkanoic acid of formula I 1 2 in which R and R mean hydrogen or methyl, Y is alkyl with from 1-4 carbon atoms, alkoxy with from 1-4 carbon atoms, halogen or trifluoromethyl, n means 0, 1 or 2, and the group is bound in the 2- or 3-position in the phenyl ring, characterized by cyclizing 1 mol of a diacid halide with formula II 1 2 wherein R , R , Y and n have the above meaning, and X is bromine, chlorine or fluorine, in the presence of a solvent and 0.1-1.0 mol of a Lewis acid at a temperature from 0°C to ambient temperature and hydrolyze the oxepinal alkanoyl halide formed.