HU176990B - Process for producing 2-square bracket-4-bracket-3-thienoyl-bracket closed-phenyl-square bracket closed-propionic acid - Google Patents

Abstract

The present invention concerns a process of preparation of a novel substituted propionic acid. This compound, which is the 2-¢4-(3-thenoyl)-phenoyl!-propionic acid, is obtained by the intermediary of the ethyl 2-methyl-2-¢4-(3-thenoyl)-phenyl! malonate and fluorophenylthenyl methanone. This compound is of particular interest as an analgesic anti-inflammatory agent and anti-aggregating agent for blood platelets.

Description

The present invention relates to a novel process for the preparation of 2- / 4- / 3-thienoyl-phenyl-propionic acid.

2- / 4- / 3-Thienoyl-phenyl-7-propionic acid corresponds to formula (1). This compound has an asymmetric carbon atom and can thus be separated into two optical isomers by methods well known in the art, for example in the form of crystals with an optically active organic base.

The preparation of salts with an organic or inorganic base is also within the scope of the present invention.

The acid of formula (1) is prepared by alkaline hydrolysis of 2-methyl-2- [4- (3-yenoyl) -phenyl] -ethyl malonate of formula (11) and decarboxylation of the resulting intermediate.

This new intermediate is also within the scope of the invention. Preferably, this compound is prepared live such that the fluorophenylthienyl methanone of formula (III) is 2-methyl ethyl malonate.

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- 2 176990 bowls in a proton-free dipolar solvent in the presence of a strong base.

Fluorophenylthienyl methanone (111) is a novel intermediate and is also within the scope of the invention. The chemical order is obtained by condensing 3-thienoyl chloride with fluorobenzene under Friedel-Crafts conditions.

2- / 4- / 3-Thienoyl / phenyl] -propionic acid is a particularly valuable compound because of its analgesic, anti-inflammatory and anticoagulant properties.

The analgesic effect was investigated in mice using acetic acid for the digestion of lka l / according to Siegmund's method modified by Koster, Anderson and Debeer /. At an active dose of 50 mg / kg, DA 4 is 2- / 4- / 3- 1, phenoyl / phenyl 7-propionic acid 9, aspirin / acetylsalicylic acid / 130, pyramidone / phenyldimethylaminodimethylpyrazolone / 32, and pethidine / l- methyl 4-phenylpiperidine-4-carboxylate hydrochloride / 17.

The anti-inflammatory activity was tested, inter alia, in the Edema and Carrageenan Test in rats / Winter et al., Proc. OOC. II: p. Biol. Med., 1972, III, 544-547, and found to be very favorable. At an active dose of 30 mg / kg, DA _{Crt is} expressed as tert-butyl t-3-thienoyl-phenyl-propionic acid 5, phenylbutazone / 1,2-allyl-3,5-dioxo-4. —N-butyl-pyrazolidine / 50-es pyramidone 82.

Inhibition of Inflammatory Redness in Guinea Pigs / ffxnter C.7. and lax, J., Burr, V., et al., Arch. Int. Pharm. / 1958 / 116-2617 2- / 4- / 3 "tenoyl / -phenyl7 ~ px ⁱ opionic acid proved to be 20 times more potent than aspirin. The animals have already been protected at a dose of 5 mg / kg and this is in the same order of magnitude as indomethacin / 3- / T- / 4-chlorobenzene 1 / -3 - ^^ 07 ^ - 3 176990

2-methyl-7-indolylacetic acid / or ketoprofen / ~ 2- (3 * ~ benzoyl) phenyl] p'ionsay7 ·

2- / 4 '/ 3-Thienoyl-phenyl-7-propionic acid is capable of inhibiting plasma clotting in rabbits, both in vitro and in vivo, preceded by 5-adenosine diphosphate (ADP) and collagen. 2 Pharmacological Properties Assays Based on Born's Method / Journal of Physiology 1953 / by using a lgeard BgeF regometer »The result is expressed as a coefficient representing the lowest effective concentration of the standard (micromolar) and the lowest effective concentration of the product is the quotient. / An effective concentration is defined as a concentration greater than or equal to 50%. inhibits aggregation to a significant degree.

The results are presented below » ADP collagen aspirin fenergan (10- (2-dimethylaminopropyl) phenothiazine 2- / 4- / 3-Thienyl] -phenyl7-prop ion- 1 1 acid 4 60 Those pharmaceutical preparations, which a invention

Formulations of the compounds of the present invention, either in base form or in the form of an organic or inorganic salt, may be formulated as tablets, capsules, gels, dragees, aqueous suspensions, injectable solutions, aerosols, syrups and the like. The tablets may optionally be coated with cellulose lacquer to provide a sustained action when administered to the digestive tract.

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The acid of the invention is an active ingredient and a physiologically acceptable solid or liquid drug. Pharmaceutical compositions containing _the carriers which got diluent or allow the drug to be administered in an amount of from 20 mg to 1000 mg per day.

The following example illustrates the various steps of the process of the present invention which result in the novel acid

Example

1st step

4-Fluorophenyl-3-thienylmethanone / Compound III / Ο- ^ ΗγΡΟδ Molecular Weight = 206.17

To a solution of 42.5 g (0.29 mol) of 3-thiophenecarbonyl chloride in 315 ml of fluorobenzene was added 57 g / 0.42 mol of anhydrous aluminum chloride in small portions with stirring and cooling in an ice bath. The reaction is slightly exothermic and the temperature rises to 10 ° C. The reaction mixture was then heated at 60 ° C for 45 minutes and under reflux for 15 minutes. The mixture was cooled and poured into ice water, followed by extraction with chloroform. The organic layer was washed with a 5% sodium numbohydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was distilled under reduced pressure to give 18.3 g of the above product. Yield 30%.

^ 0.25 mm ⁼ ? 25-13 0 0 °?) 74 ° C / hexane.

IR _ 0 3-660 cm ~

- Step 5 of 2.

2-methyl-2- / 4- / 3-thienoyl / phenyl ^ -dietilmalonát / II compound / formula ^C 19 ^H 2 O 5 ^S MW = 360.35 g / 0.083 mole / of sodium hydride in 83 ml of freshly distilled 50% hexametilfoszfortriamiddal 14.4 g (0.083 mol) of 2-methyl diethyl malonate are added dropwise at room temperature. The reaction is slightly exothermic. The mixture was added in small portions mole / of 4-phenyl-3-tienilmetanont ₀ The mixture was heated at 100 ° C ~ C for 10 hours 17.1 g / 0.083, quenched with 300 ml of diluted with benzene, washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a pale yellow oil.

Kit yield 12.1 g, corresponding to a yield of 40.6. ^ • 0.4 m = ^190-200 ° ^C

1660 cm ^- ^ / ketone /

1750 cm -1 / ester / proton at 1.25 / triplet J = 7 op / proton at 1.95 / singlet / proton at 4.3 / quartet J = .7 op / proton at 7.3 to 8 to / shoulder /

3 · step

2 - ^ - /> t ^ oil / -phen ± 27propionic acid / compound of formula 1 / here < weight > 260.30 - · ^r c = 0

9 <j = 0 MR / CC1 ₄ / / ppm /:

- 6 176990

12.1 g / 3.3 x 10 ^"2 mole / of 2-methyl-2-2j- / 3-thienoyl / -fenil7dietilmalonátot and 80 ml of an aqueous sodium carbonate solution is heated with 5% for 6 hours under reflux. The solution is cooled, washed with benzene and the aqueous phase is acidified with dilute hydrochloric acid 1/2. The resulting oil was extracted with chloroform and dried over anhydrous sodium sulfate and the solvent was evaporated. This gave 9 g of a viscous, dense oil which crystallized to give 3.4 g of a white solid. Mp = 99-105 ° C - 0 -

Yield = 39.5%

IR ϊ SJq _ o 1650 cm * · ¹ · / ketone / ^ 0 = 0 cm · * · / sav /

Claims (2)

A process for the preparation of 2-N- (3-thienoyl) -phenyl-7-propionic acid (1) comprising condensing 3-thienoyl chloride with fluorobenzene under Friedel-Crafts reaction conditions to yield the fluorophenylthienyl methanone (111) in a proton-free dipolar alkylated with 2-methyl ethyl malonate in the presence of a strong base in solvent and the resulting 2-methyl-2- [3- (3-thienoyl) -phenyl] -ethyl malonate (II) is basically hydrolyzed and then decarboxylated. 2. The process of claim 1 for the manufacture of a medicament for the treatment of analgesic, anti-inflammatory and anticoagulant drugs, wherein the 2- / 4- / 3-thienoyl-phenyl-7-propionic acid is a potent. 7 quantities are mixed with excipients and / or excipients conventionally used in the preparation of pharmaceuticals and converted into pharmaceutical compositions.