IE56385B1

IE56385B1 - Dihydropyridine intermediate

Info

Publication number: IE56385B1
Application number: IE2240/85A
Authority: IE
Original assignee: Pfizer Ltd
Priority date: 1983-12-20
Filing date: 1983-12-20
Publication date: 1991-07-17

Description

Preparation of 2-(2-aminoethoxymethyl)-4-(2-chloro’-3-trifluorogiethylphenyl)-3-ethoxycarbonyl-5-methoxycarbony3-6-methyl-l ,4- The phthalimido compound from Preparation 1 (2.8 g) was added to aqueous methylamine (14 ml of 40Z) and stirred at room temperature for 17 hours· The resultant solid was filtered, redissolved In chloroform (50 ml), dried (MgSO*), filtered and evaporated to give a yellow solid. Crystallisation from hexane gave the title compound, yield 1.0 g, m.p. 122°.

Analysis:Found: C.53.25; H.4.9; N.5.75 Calculated fron c2l^24C1F3V2°5: C,52.9; H.5.1; N.5.9.

Exacrcle 2 --Preparation of 2-i2-Amlnoethpxymet.hyl]-4-(2-chloro-3-trifluorpme thylpheny 1)-3-e t hoxycarbony 1-5-me thoxy car bony 3-6-methyl 1,4-dlhydropyridine The title compound was prepared by the catalytic hydrogenation of the azido compound of Preparation 2 by the method described In Preparation 1 of Patent Specification No.

This compound was confirmed by n.m.r. and l.r. analysis 5 to be Identical to the product of Example 1 above.

The following preparations describe the preparation of certain starting materials.

PREPARATION I The following compound, m.p. 179%, was prepared similarly to 10 Preparation 5 of the said Patent Specification No. 30/0^3 but using 2-chloro-3-trifluoromethylbenzaJdehyde In stage (11). The Analysis: Found: C.57.2; H.4.45; N.4.8%; Calculated for C^H^ClF^Oy.· C.57.4; H.4.3; N.4.6%.

PREPARATION 2 Preparation of 2-(2-azidoethoxyiBethyl)-4-(2-chloro-3-trlfluoronethylpheny l)-3-ethoxycarbonyl-5-methoxycarbonyl-6-Bethyl-l ,4dl hydropyridine The title compound, m.p. 143-145°C, was prepared similarly to the method described In Preparation 3 of the said Patent Specification No. but using 2-chloro-3-trifluoromethylbenzaldehyde. The reaction time was the same;10 Analysis:Found: Calculated for c2iH22ClF3N4°5: C,50.2; H,4.4; N,11.3%; 0,50.15; H.4.4; N,ll.l%.

PREPARATION 3 Preparation of 2-chloro-3-trlfluoromethylbenzaldehyde 15 2-Chloro-l-trifluoromethylbenzene (54.15 g) was dissolved In dry tetrahydrofuran (500 ml) and stirred while cooling to -68° C under a stream of dry nitrogen. (The whole reaction Is carried out under dry nitrogen until the addition of distilled water.) -To this vas added n-butyl lithium (180 ml of 1.6 M solution in hexane) dropwlse keeping the temperature below -60°C. After stirring at-68°c for a further 2 hours, a solution of dimethylformamide (22 ml) in dry tetrahydrofuran (100 al) vas added dropwise keeping the temperature below -60° C. The reaction mixture was allowed to warm to room temperature slowly over 17 hours and distilled water (200 ml) was then added. The organic phase vas separated off and the aqueous liquors were extracted with ether (100 ml). The combined ether extracts plus the organic phase were washed with saturated brine, dried filtered and evaporated to give 61.5 g of an orange oil, being the crude title compound.

This oil vas then added to an aqueous sodiua bisulphite solution (65 g in 600 ml distilled water) and heated at 60° C for 0.5 hours. The solution was extracted with methylene chloride (3 x 100ml) and, after acidification of the aqueous phase with concentrated sulphuric acid to pH<=-|, was heated at 100°C for a further 0.5 hours. The resultant aqueous solution was extracted with methylene, chloride (3 x 200 al) and the combined organic extracts were dried (MgSO*), filtered and evaporated to give 42 g of a colourless solid which was crystallised from hexane to give the title compound, m.p. 43-44°C.

Analysis: Found: C.45.9; H,2.0%; Calculated for CgH^ClO: C.46.1; H,2.0%.

Claims

CLAIMS 3 . 3. 4. 4.
2-(2-Aninoethoxymethyl)-4-(2-chloro-
3-trifluorone thy Iphenyl) -3-ethoxycarbonyl-5-nethoxycarbonyl-6-Bethyl-i .4dihydropyridine. A pharmaceutical composition comprising the compound as claimed in Claim 1 in association with a pharmaceutically acceptable carrier or diluent therefor. A process for the preparation of 2-(2-aminoethoxymethyl)
4- (2-ch2 oro-3-trif luoromethylphenyl) -3-ethoxycarbcnyl
5- methoxycarbonyl -
6-methy 1-1,4-dihydropyridine, substantially ashereinbefore described and exemplified. 2. - (2-Aminoethoxymethyl) -4- (2-chloro-3-trif luoromethylphenvl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl1,4-dihydropyridine whenever prepared by the process claimed in Claim 3.