NO753413L - - Google Patents

Description

The present invention relates to a method for the production of 2-(5H-dibenzo[a,djcyclohepten-5-on-2-yl)-propionic acid and its salts and esters. More specifically, the invention relates to a hydrogenation method for producing the aforementioned compounds from the corresponding acrylic acid, ester or salt.

The substituted propionic acid, esters and salts to which the invention applies have anti-inflammatory, analgesic and anti-pyretic properties. Accordingly, such compounds and preparations containing them are useful in the treatment of

inflammations such as inflammatory conditions in the muscle/skeletal system, skeletal joints and other tissues, e.g. in the treatment of inflammatory conditions such as rheumatism, tremors, sprains, arthritis, broken bones, post-traumatic conditions and true giEt. In those cases where the above conditions include pain and fever along with inflammation, the compounds of formula I are useful in alleviating these conditions along with the inflammation.

The compounds according to the invention are also relaxing agents for the smooth muscles in the uterus and they are therefore useful as agents for maintaining the pregnancy in pregnant mammals for the benefit of the mother and/or the fetus until, from a medical point of view, the termination of the pregnancy to be favorable or more favorable for the mother and/or the fetus.

The term "esters" of the present propionic acid or the acrylic acid that forms the starting point for it is used if the esters are formed from straight or branched alkanols having from 1 to 20 carbon atoms, such as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-amyl, n-hexyl, octyl,

decyl, dodecyl, hexadecyl and octadecyl esters and also about benzyl esters. A preferred subclass of esters are those formed from pharmaceutically acceptable, non-toxic alcohols.

"Salts" of the present propionic acid and acrylic acid which form the starting point for it relate to the salts which are prepared from inorganic and organic bases. -Salts formed from inorganic bases include alkali metal salts such as sodium, potassium and lithium; alkaline earth metal salts such as calcium and magnesium; and also ammonium and copper salts. The salts formed from organic bases include ethanolamine, diethylamine, tris(hydroxymethyl)aminomethane, choline, caffeine and lysine salts. A preferred uhdefc class of salts are those formed from pharmaceutically acceptable, non-toxic bases.

The method according to the present invention comprises hydrogenating 2-(5H-dibenzo(a,d)cyclohepten-5-on-2-yl)-acrylic acid or an ester or a salt. of this to produce the corresponding propionic acid, ester or salt.

The hydrogenation is carried out by bringing the acrylic acid, ester or salt into contact with hydrogen in the presence of a suitable hydrogenation catalyst in a suitable solvent. medium.

Suitable hydrogenation catalysts for this reaction include supported, unsupported or soluble metal catalysts such as e.g. palladium, plåtinum, rhodium, ruthenium, tris(triphenylphosphine)chlororhodium and the like.

Suitable catalyst supports include carbon, barium sulfate and the like.

The reaction is carried out in a suitable solvent such as e.g. a liquid alcohol such as methanol, ethanol and the like;

esters such as ethyl acetate; ethers such as diethyl ether or tetrahydrofuran; hydrocarbons such as benzene, toluene or xylene;

dimethylformamide or mixtures thereof with water.

The reaction temperature is not very critical. For example, the reaction can be carried out at temperatures from approx. .0°C

to the boiling point of the solvent in question (which can

is raised above its normal value depending on the pressure used).

The reaction is carried out until the hydrogenation is largely complete, i.e. until a molar equivalent of hydrogen has been absorbed, which usually takes from 15 minutes to approx. 48 hours. The pressure is not particularly critical and you can work from atmospheric pressure to approx. 10 atmospheres. • A preferred hydrogenation involves the use of palladium on charcoal catalyst at room temperature and normal pressure in a solvent such as dimethylformamide.

The hydrogenated product is usually isolated by conventional methods such as filtration to remove the hydrogenation catalyst, followed by evaporation of the solvent.

-Chromatography and/or recrystallization of the end product from

a suitable solvent is usually useful to purify the final product.

When carrying out the hydrogenation reaction as described above, the acid which forms the starting material will give an acid product, a salt will give a salt product and an ester in the starting material will give an ester product.

The acrylic acid, esters and salts used as starting material can be prepared in the following way: - The starting material (i.e. 5-oxo-5H-dibenzo(a,d)cyclo-heptene-2-carboxylic acid) is prepared by esterifying 2-methylterephthalic acid with methanol - in the presence of an acid catalyst to provide it. corresponding dimethyl ester, which in turn reacts with N-bromosuccinimide to give 2-bromomethylterephthalic acid dimethyl ester. This diester is reacted with triphenylphosphine to give 2,5-bis(carbomethoxy)benzyltriphenylphosphonium bromide which is treated with benzaldehyde and the diazabicyclonone to give, after alkaline hydrolysis, cis and trans-stilbene 2,5-dicarboxylic acid. Hydrogenation of the latter compound with hydrogen over a 5 f°palladium on charcoal catalyst gives 2-(2-phenethyl)terephthalic acid. Treatment with polyphosphoric acid gives 5-°xo-5.H-dibenzo £a,d]cycloheptane-2-carboxylic acid which can be recrystallized from aqueous dimethylformamide.

5-oxo"5H-dibenzo-;zo (a,dj cycloheptene-2-carboxylic acid is prepared by subsequent treatment of 5-oxo-5H-dibenzo[a,dj-cycloheptane-2-carboxylic acid with diazomethane, N-bromosuccinimide and dimethylformamide/ the diazabicyclonone followed by base hydrolysis and acidification to provide 5-α-xo-5H-dibenzo(α,d)cycloheptene-2-carboxylic acid.

The carboxylic acid chain of the 2-carboxylic acid compound which is the starting material is extended to the acetic acid compound by carrying out a standard Arndt-Eistert reaction which comprises conversion of the carboxylic acid to its acid chloride with thionyl chloride, reaction of the acid chloride with diazomethane to form a diazo ketone and rearrangement of the diazo ketone by the action of a silver salt in the presence of an alcohol to give the corresponding 2-acetic acid ester which can be hydrolyzed to free acetic acid.

The acrylic acid ester can be prepared by reacting the acetic acid ester with an alkali metal dialkylamide such as lithium diisopropylamide in a solvent such as tetrahydrofuran, hexamethylphosphoramide and the like and then with formaldehyde. The acrylic acid ester can be hydrolyzed with a base to form the corresponding acrylic acid or a salt thereof.

The following examples illustrate preferred embodiments of the methods according to the invention. These examples must not be understood as limiting the scope or content of the invention in any way. The yields of the products vary, depending on the choice of starting material, reagents, reaction conditions and method. However, the yields are usually in the range from 10 to 70 percent .

Preparation 1

148 g of 2-methylterephthalic acid is refluxed for 24 hours in 750 ml of dry methanol containing 30 ml of sulfuric acid. The solution is cooled, poured into water and extracted with ether. The extract is washed, dried and evaporated to give dimethyl-2-methylterephthalate.

88 g of dimethyl-2-methylterephthalate in 1000 ml of carbon tetrachloride containing 89 g (1 eq.) of N-bromosuccinimide is refluxed for 3 hours using a hot lamp. The solution is cooled, filtered and evaporated to dryness and

gives dimethyl-2-bromomethylterephthalate.

25.7 g of dimethyl-2-bromomethyl terephthalate is refluxed in 250 ml of acetonitrile containing 26.2 g (1 eq.) of triphenylphosphine for 4 hours. The solution is cooled and diluted

with 1250 ml of ether, after which 2,5-bis(carbomethoxy)-benzyltriphenyl-phosphonium bromide is precipitated and filtered off and dried under vacuum.

51.9 g of 2,5-bis(carbomethoxy)-benzyltriphenylphosphonium bromide and 10.6 g of benzaldehyde are stirred in ^ 00 ml of acetonitrile and

12.4 g of the diazabicyclonon are added. The mixture is heated briefly to reflux, after which it is cooled and evaporated to an oil. The oil is dissolved in ethyl acetate and the solution is washed with dilute hydrochloric acid, dried and evaporated. The residue is refluxed for 12 hours in a solution of 20 g of potassium hydroxide in 200 ml of water and 50 ml of methanol. The solution is cooled and extracted with chloroform. The aqueous solution is acidified with dilute hydrochloric acid and the precipitated cis and trans stilbene-2,5-dicarboxylic acid is filtered off and dried.

23.6 g of cis and trans -stilbene-2,5-dicarboxylic acid are dissolved in 100 ml of dimethylformamide containing 500 mg of 5% palladium on charcoal and hydrogenated for 2 hours. The solution is filtered and evaporated to dryness and gives an impure product which, after recrystallization from aqueous ethanol, gives 2-(2-phenethyl)-terephthalic acid.

23.8. g of 2-(2-phenethyl)terephthalic acid is dissolved in 200 ml of sulfolane at 130°C and 150 ml of polyphosphoric acid is added while stirring. The mixture is stirred at 130°C for 4 hours, and then poured into 1000 ml of water. The product is filtered off and recrystallized from aqueous dimethylformamide to give 5-ox°-5H-dibenzo-(a,djcycloheptane-2-carboxylic acid (melting point 203- 204<G>C).

Preparation 2

5.0 g of 5-oxo-5H-dibenzo(a,d)cycloheptane-2-carboxylic acid (prepared in preparation 1 above) is suspended in 50 ml of dioxane, added to an excess of diazomethane dissolved in ether and stirred until the solution is complete.. The solution is evaporated to dryness and gives 2-carbomethoxy-5-oxo-5H-dibenzo(a,dJcycloheptane.

The solution irradiated with a 100 watt incandescent lamp. After 2 hours the solution is cooled, filtered and evaporated to dryness. The residue is dissolved in JO ml, dimethylformamide and 2.48 g (1 eq.)

1,5-diazabicyclo-(3>4>OJnonene-5) is added. The mixture is heated briefly to 60°C, and water and ethyl acetate are added. The organic layer is washed with dilute hydrochloric acid and water, and dried and evaporated to give 2-carbomethoxy- 5-pxo-5H-dibenzo(a,d)cycloheptene Hydro-

bright. in 8 to 1 aqueous methanol: 5$ potassium hydroxide, followed by acidification with dilute hydrochloric acid gives 5-oxo-5H-dibenzo(a,dJ-cycloheptene-2-carboxylic acid (m.p. 26l-262°C).

. Preparation

22 g of 5-oxo-5H-dibenzopha.,dj cycloheptene-2-carboxylic acid is stirred in 200 ml of chloroform, ^0 ml of thionyl chloride and 1 ml of dimethylformamide for 8 hours. The mixture is evaporated to dryness and the residue is recrystallized from acetonitrile to give 2-chloro-formyl-5-oxo-5H-dibenzo(a,d)cycloheptene. This dissolves in

200 ml of chloroform and added to a 3-fold excess of diazomethane in ether at 0°C. The mixture is left at 0°C for 12

hours and evaporated to dryness. The residue is recrystallized from acetonitrile and gives 2-diazoacetyl-5-oxo-5H-dibenzo(a,d)cycloheptene. The diazoketone is heated to reflux in 250 ml of ethanol and a saturated triethylamine solution of 2 g of silver benzoate is added. slowly until gas development ceases. The solution is cooled, filtered and evaporated to give ethyl (5-oxo-5H-dibenzo(a,djcyclo-hepten-2-yl)acetate. This ester is refluxed in 5 f° aqueous potassium hydroxide for 12 hours. The solution is cooled, acid- is done with dilute hydrochloric acid and extracted with ether. The ether extract is dried and evaporated and gives (5-oxo-5H-dibenzo(a,d)-cyclohepten-2-yl)acetic acid which can be recrystallized from acetone-hexane (melting point. 148-149?5°C).

The methyl ester is produced by treating the free acid in dioxane with an excess of diazomethane in ether.

Preparation. 4

1.25 ml of 1.6 molar n-butyllithium in hexane is added

to a solution of 0.280 ml of diisopropylamine in 30 ml of tetrahydrofuran. -The solution is cooled to -80°C and 0.55 g of methyl(5-0x0-5H-dibenzo(a,djcyclohepten-2-yl)acetate is added. After 10 minutes, 0.38 ml of hexamethylphosphoric acid triamide is added. -The cooling bath is removed and formaldehyde vapor , entrained by a stream of nitrogen, is passed over the solution until it becomes colorless. Water and ether are added and the organic layer is washed with dilute hydrochloric acid, saturated sodium chloride solution, then dried and evaporated. The residue is chromatographed on 10 g of silica gel, eluting with hexane:ethyl acetate (5^ 1) to isolate methyl 2-(5-oxo-5H-dibenzopha,d]cyclo-hepten-2-yl)acrylate (melting point 153-156°C). 0.02 g of this

compound is refluxed under nitrogen in 5 ml of water,

2 ml ethanol and 0.5 ml saturated sodium carbonate solution for 4 hours. The mixture is cooled, washed with ether and acidified with dilute hydrochloric acid, after which it is extracted with ethyl acetate and the extract is dried and evaporated to give 2-(5-oxo-5H-dibenzo(a,d)cyclohepten-2-yl)acrylic acid (melting point 232- 235°C).

This can be converted to the sodium salt by reaction with an equivalent of sodium bicarbonate in water, evaporation of the solvent and recrystallization.

Example 1

1.38 g of 2-(5H-dibenzo(a,djcyclohepten-5-on-2-yl)-acrylic acid is dissolved in 25 ml of dimethylformamide containing 0.05 S 5 fo palladium on charcoal catalyst. The mixture is stirred in a hydrogen atmosphere at 26°C and jSf mm Hg pressure' until 60 ml (1 molar equivalent) has been absorbed. The solution is filtered and evaporated to dryness. The residue is chromatographed on 50 g of silica gel, eluting with 60:40:1 hexane:ethyl acetate:formic acid,

so that a 40 f° yield of 2-(5H-dibenzopha,djcyclohepten-5-on-2-yl)propionic acid is obtained, melting point (chloroform-hexane) 138-139°C; melting point (acetone-hexane) 113-115°C.

Use of methyl 2-(5H-dibenzo[a,dJcyclohepten-5-on-2-yl)acrylate gives a similar yield of methyl 2-(5H-dibenzo[a,dJcyclohepten-5-on-2-yl)propionate which an oil that crystallizes slowly with a melting point of 37-39°C"

Use of sodium 2-(5H-dibenzo(a,dJcyclohepten-5-on-2-yl)acrylate gives a corresponding yield of sodium 2-(5H-dibenzopha,djcyclohepten-5-on-2-yl)propionate, melting point 145 -148°C.

Claims (2)

.1. Process for the production of 2-(5H-dibenzo-{a,djcyclohepten-5-on-2-yl)propionic acid or an ester or a salt thereof, characterized by hydrogenating 2-(5H-dibenzofa,d)cyclohepten-5 -on-2-yl)acrylic acid or an ester or salt thereof with hydrogen in the presence of a hydrogenation catalyst. 2. Process according to claim 1, characterized in that the starting material is 2-(5H-dibenzo(a,d)cyclo-hepten-5-on-2-yl)acrylic acid and that the product is 2-(^H-dibenzo-.(a ,d]cyclohepten-5-on-2-yl)propionic acid.