Patent EA-004938-B1 (EA)
Title: Method for producing 6-(4-chlorophyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1h-pyrrolizine-5-yl acetic acid
Inventor: KAMMERMEIER THOMAS
IPC: A61P29/00
Filed: 2001-01-26
Abstract: 1. Process for the preparation of the compound of the formula I where the compound of the formula III is reacted with oxalyl chloride and the product obtained is treated with hydrazine and an alkali metal hydroxide in the aqueous phase at a temperature between 120-180 degree C in the presence of one or two atom alcohol having the boiling temperature of at least 140 degree C after treatment is complete a three-phase system is produced by addition of an ether and the compound of the formula I is obtained by acidifying the middle phase. 2. Process according to Claim 1, the ether used being diethyl ether, methyl t-butyl ether or tetrahydrofuran. 3. Process according to Claim 1 or 2, the treatment with hydrazine and the alkali metal hydroxide being carried out in the presence of ethylene glycol, ethylene glycol monomethyl ether or diethylene glycol. 4. Process according to Claim 3, the treatment with hydrazine and the alkali metal hydroxide being carried out in the presence of diethylene glycol. 5. Process according to one of the preceding Claims, the product obtained by the reaction with oxalyl chloride being treated first with hydrazine and then with the alkali metal hydroxide. 6. Process according to Claim 5, the treatment with the alkali metal hydroxide being carried out at a temperature in the range from 120 to 180 degree C. 7. Process according to Claim 6, the constituents which are volatile at the treatment temperature being removed at least partially during the treatment. 8. Process according to one of the preceding Claims, the middle phase being treated with a mixture of water and a water-immiscible ether before acidification. 9. Process according to Claim 8, the desired product being obtained from the ether phase by adding to the ether phase an aliphatic or cycloaliphatic hydrocarbon which has a higher boiling point than the ether. 10. Process according to Claim 8 or 9, the ether being at least partially distilled off to obtain the desired product. 11. Process according to one of the preceding Claims, where, for the preparation of the compound of the formula III, 2-benzyl-4,4-dimethyl-1-pyrroline is reacted with an omega-halogen-4-chloroacetophenone in a polar organic solvent in the presence of an alkali metal hydrogencarbonate and/or of an alkali metal carbonate in solid form. 12. Process according to Claim 11, the polar organic solvent used being methanol. 13. Process according to Claim 11 or 12, the reaction being carried out in the presence of solid sodium hydrogencarbonate. 14. Compound of the formula II 15. Compound of the formula I in crystalline form having a single endotherm in the DSC diagram, which is in the range from 155 to 170 degree C. 16. Compound according to Claim 15, which has the following significant peaks in the IR spectrum (wavenumber, cm<-1>): 1706; 1601; 1536; 1487; 1463; 1450; 1441; 1413; 1395; 1383; 1369; 1293; 1219; 1177; 1099; 1013; 836; 765; 698. 17. Compound according to Claim 15 or 16 essentially having the IR spectrum shown in fig. 2. 18. Compound according to one of Claims 15 to 17 having the following characteristic d values (lattice distance) in the X-ray diffraction diagram: 11.9; 4.2; 40. 19. Compound according to Claim 18 having the following d values: 11.9; 8.2; 7.9; 6.4; 5.9; 5.8; 5.6; 5.3; 5.0; 4.9; 4.7; 4.5; 4.4; 4.3; 4.2; 4.05; 4.0; 3.9; 3.7; 3.6; 3.55; 3.5; 3.4; 3.3; 3.25; 3.2; 3.1; 2.95; 2.9; 2.85; 2.8; 2.75; 2.7; 2.65; 2.6. 20. Pharmaceutical composition comprising the compound as claimed in one of Claims 15 to 19, if appropriate together with customary excipients. 21. Use of the compounds as claimed in one of Claims 15 to 19 for the production of a pharmaceutical composition for the treatment of disorders of the rheumatic type.