NO762723L - HYDROLYTICAL PROCEDURE FOR THE PREPARATION OF 6,11-DIHYDRODIBENZO- (B.E.) - THIEPIN-11-ONE-3-ACETIC ACID - Google Patents

Description

Hydrolysis method for the preparation of a* 6,11-dihydrodibenzo-(b.e)thiepin-11-one-3-acetic acid. The present invention relates to a process for the production of 6,11-dihydrodibenzo-(b.e)thiepin-11-one-3-acetic acid with the formula; ; and their alkali metal salts (ie sodium, potassium and lithium salts) by baée hydrolysis of the amides of the compound. These compounds are suitable as anti-inflammatory, antipyretic and analgesic agents, blood clot inhibitors, fibrinolytic agents and smooth muscle relaxants. They can be used both ■ prophylactically and therapeutically. Therefore, preparations containing these compounds are useful in the treatment of inflammation in it. musculoskeletal system, joints and other tissues, e.g. in the treatment of inflammatory conditions such as rheumatism, shock, excruciating wounds, arthritis, broken bones, post-traumatic conditions and gouty fever. In those cases where the above conditions include pain and fever as well as inflammation, the present compounds will be suitable for eliminating these conditions and the inflammation. The compound with formula A and their salts are also muscle relaxants on the smooth muscles of the uterus and are therefore . suitable for maintaining pregnancy in pregnant mammals for the benefit of both mother and/or fetus until the period of pregnancy is terminated from a medical point of view or is more beneficial to the mother or fetus. ;The present method can be illustrated by the following reaction core: ; where R denotes hydrogen or a lower alkyl group with 1-4 carbon atoms. In carrying out the above process, a starting material of formula I, i.e. 3-diazoacetyl-6,11-dihydro-dibenzo-(b.e.)thiepin-11-one is treated with an aqueous solution of ammonium hydroxide or lower alkyl primary amine in the presence of silver nitrate in a suitable water-miscible organic inert solvent with a high boiling point for the preparation of the corresponding amino or substituted amino derivative of formula (II). The reaction is carried out at 90-120°C during from 20 min. to 4 hours. ; The amount of reagents is not critical, however, it is generally preferred to use 3-10 molar equivalents of both ammonium hydroxide (or amine) and silver nitrate. Examples of suitable primary amines are methylamine, ethylamine, isopropylamine, n-butylamine, etc. Suitable organic solvents which are miscible with water are those with a boiling point within or higher than the above range, e.g. dioxane, diglyme, triglyme and the like. In a preferred embodiment, the reaction is carried out in aqueous dioxane at reflux temperature for about. 30 min. when using ammonium hydroxide and for 2-4 hours when using an amine. Base hydrolysis of an amide of formula II gives the desired 6,11-dihydrodibenzo-(b.e)thiepin-11-one-3-acetic acid (A) via its salt. The hydrolysis takes place with a strong base, e.g. an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, or lithium hydroxide in aqueous high-boiling inert ;. solvent such as ethylene glycol or propylene glycol.and at a temperature of 120-220°C, preferably at. reflux, over a period which can vary from 30 min. to 5 hours. The reaction gives the salt of the base used and this can easily be transferred to the free acid by treatment with a strong acid such as hydrochloric acid, sulfuric acid, phosphoric acid and the like. The starting material with formula I can be prepared as described, e.g. in the parallel US application no. 634,086/75 - from the same applicant. Briefly, the method consists in the esterification of nitroterephthalic acid with isopropanol in the presence of an acid catalyst to form diisopropylnitroterephthalate, followed by treatment with benzylmercaptan and sodium hydride in a suitable organic solvent for the production of iiisopropyl(benzylthio)terephthalate, which on alkaline hydrolysis gives (benzylthio)-terephthalic acid. • ;The latter compound is treated with thionyl chloride and the formed (benzylthio)-terephthalyl chloride is ring-closed again to 6,11-dihydrodi-benzo-(b . e . ) thiepine-ll-one-3-carbonyl chloride by treatment with nitromethane and aluminum chloride in suitable organic solvent. Reaction of this compound with ethereal diazomethane gives the desired 3-diazoacetyl-6,11-dihydrodibenzo-(b.e. )thiepin-ll-one (I). The following examples shall illustrate preferred embodiments of the invention but shall not limit its scope. Product yields may vary depending on reagents, conditions and work-up. In general, however, yields are in the range of 30-60%. ;Process 1 ;A solution of 200 g of nitroterephthalic acid in 1 liter of isopropanol is saturated with hydrogen chloride and refluxed for 3 days. (During this period, hydrogen chloride is added to the solution at intervals to maintain the concentration). The reaction solution is then cooled and the isopropanol is evaporated under reduced pressure, which gives a residue which is dissolved in 500 ml of methylene chloride. The resulting solution is washed with 10% aqueous sodium carbonate and the organic layer is dried over magnesium sulfate, after which the solvent is removed under reduced pressure, which gives 2^5 g (yield 87.5%) of diisopropyl nitroterephthalate, as a oil<*>I.R.: v^jb172<4,>1542, 1350 cm"<1.>N.M.R. «TMS<3>"3lj35(6H'd)'1>i|0(6H>d)'5>2k (1H'7 lines) > 5.27 (1HV 7 lines), 7.71 (1H, d), 8.24 (1H,.dd), 8.43 ppm (1H, d).

B. To a cooled (-20°C) solution of 23.5 ml of benzyl mercaptan in 100 ml of dimethylformamide, slowly add 5.1 g of sodium hydride. The resulting solution is cooled to -30°C and 53 g of diisopropyl nitroterephthalate in 100 ml of dimethylformamide are added. After one hour at -30°C and 2 hours at 0°C, the reaction mixture is poured into water, the precipitate is filtered off, washed with water and dried to give 77-92% crude diisopropyl-(benzylthio)-terephthalate which melts on recrystallization from pentane at 70-7.1°C. C. The crude diisopropyl-(berylthio)terephthalate prepared under part B is refluxed with 500 ml of methanol, 25 g of potassium hydroxide and 50 ml of water for 2 hours. The reaction mixture is then concentrated to a small volume, cooled, diluted with water and filtered through diatomaceous earth (celite). The filtrate is acidified with 4N hydrochloric acid and the formed precipitate is filtered off and dried in an oven at 90-100°C and give? 45 g (87%) of (benzylthio)-terephthalic acid with m.p. 299-300°C.

D. A mixture of 10 g of (benzylthio)terephthalic acid and 10 ml of thionyl chloride is refluxed for 4 hours. "After removing excess thionyl chloride in vacuo, the evaporation residue is slurried with hexane and the solid is filtered off to give 10.2 g (92%)

(benzylthio)-terephthalyl chloride with m.p. 158°C.

E. A solution of 10.2 g of (benzylthio)-terephthalyl chloride in 100 ml of methylene chloride is added to a solution of 14.75 g of aluminum chloride in 100 ml of methylene chloride containing 10.51 nil of nitromethane. After 5 hours at 25°C, 16.5 ml of saturated aqueous sodium chloride are added with vigorous stirring. The inorganic salts that precipitate are filtered off and the filtrate is evaporated to a solid residue which is slurried with ether. The ether slurry is filtered to give 7.0 g (70.7%) of 6,11-dihydrodibenzo(b.e.)thiepin-11-one-3-carbonyl chloride of m.p. 119-120°C.

F. A solution of 11 g of 6,11-dihydrodibenzo(b.e.)-thiepin-1-one-3-k-carbonyl chloride in 100 ml of methylene chloride is added slowly to an excess of diazomethane (prepared from 20 g of N-nitroso-N-methylurea ) in 200 ml ether solution. After 2 hours, the reaction mixture is concentrated to approx. 50 ml by boiling off the solvent and the mixture is cooled. The cooled reaction mixture is filtered and gives a residue of 9.5 g (85%) of 3-diazo-acetyl-6,11-dihydrodibenzo(b.e.)-thiepin-11-one with m.p. at 153°C (decomp.).

Example 1

A. A solution of 500 mg of 3-diazoacetyl-6,11-dihydro-dibenzo-(b.e.)thiepin-ll-one in 20 ml of distilled dioxane is treated with 7 ml of aqueous ammonia solution (p.v. 0.880) and 5 ml of 10 % aqueous silver nitrate solution. The reaction mixture is refluxed for 30 min., cooled, diluted with 30 ml of saturated sodium chloride solution and extracted with ethyl acetate (2 x 50 ml). The combined extracts are washed with saturated sodium chloride solution, dried on anhydrous sodium sulfate and evaporated to dryness under reduced pressure, which gives a solid which, on recrystallization from methylene chloride-hexane, gives 380 mg of 3-acetamido-6,11 -dihydrodibenzo ( b . e .) thiepin-ll-one (II, R=H), with m.p. 162°C.

B. One_. solution of 170 mg of 3-acetamido-6,11-dihydrodi-benzo-(b.e.)thiepin-11-one in 10 ml of ethylene glycol is treated with one solution of 50 mg of potassium hydroxide in 10 ml of water. The reaction mixture is refluxed for 1 hour, cooled, acidified with 10% aqueous hydrochloric acid, diluted with 50 ml of water and extracted with ethyl acetate (2 x 50 ml). The combined extracts are washed with water and extracted with 10 ml of 10% aqueous potassium carbonate. Acidification of the basic aqueous extract with 10% hydrochloric acid gives a precipitate which is filtered off and air-dried. In this way, 117 mg of 6,11-dihydrodibenzo-(b.e.)thiepin-1-one-3-acetic acid is obtained

(A) with m.p. 152-153°C, identical to an authentic sample.

Similarly, other strong bases such as sodium hydroxide and other strong acids such as sulfuric acid can be used during step B above.

Example 2

A solution of 200 mg of 3-diazoacetyl-6,11-dihydro-dibenzo-( b . e .) tiepin-ll-one in 8 ml of distilled dioxane is treated with 5.6 ml of 40 #ig aqueous methylamine solution and 2.0 ml of 10 #ig aqueous silver nitrate solution. The reaction mixture is boiled at reflux for 3 hours, cooled, diluted with water and extracted with ethyl acetate. The combined extracts are washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The oil residue is chromatographed on 5.0 g of silica gel, eluted with chloroform. Evaporation of the eluate and crystallization of the residue from chloroform -hexane gives 130 mg of N-methyl-6,11-dihydrodibenzo-(b.e..)-thiepin-11-one-3-acetamide (II, R = Me), with mp 163-165°C.

B. A solution of 50 mg of N-methyl-6,11-dihydrodibenzo-(b.e.)thiepin-11-one-3-acetamide in 3 nil of ethylene glycol is refluxed for 1 hour with 140 mg of potassium hydroxide in 3 nil of water. The reaction mixture is cooled, diluted with saturated sodium chloride solution, acidified with dilute aqueous hydrochloric acid and extracted with ethyl acetate (2 x 25 ml). The combined extracts are washed with water and extracted with 10% aqueous potassium carbonate solution. The aqueous basic extract is acidified with dilute hydrochloric acid and the precipitate is filtered off, air-dried and crystallized from methanol-water to give 28 mg of 6,11-dihydrodibenzo-(b.e.)-thiepin-11-one-3-acetic acid (A) with m.p. . 152-153°C, identical to an authentic sample.

One can use ethylamine 9in or isopropylamine instead of methylamine in part Ai of this example, giving similar yields of 6,11-dihydrodibenzo-(b.e.)thiepin-11-one-3-acetic acid.

In a similar way, you can use other strong bases such as potassium hydroxide and other strong acids such as sulfuric acid and phosphoric acid under step B above.

Claims (5)

1. Process for the production of 6,11-dihydro-dibenzo-(b.e.)thiepin-1-one-3-acetic acid, characterized by hydrolyzing a compound with the formula: where R denotes hydrogen or a lower alkyl group of 1-4 carbon atoms, with a strong base, followed by treatment with a strong acid. 2. Method as stated in claim 1, characterized in that the base hydrolysis is carried out at 120-220°C. 3. Method as stated in claim 1, characterized in that the strong base is an alkali metal hydroxide. 4. Method as stated in claim 3, characterized in that the alkali metal hydroxide is potassium hydroxide. 5. Method as stated in claim 35, characterized in that the strong acid is hydrochloric acid.