Patent EA-003248-B1 (EA)
Title: Method of manufacturing septindole
Inventor: BECH SOMMER MICHAEL
IPC: C07D401/04
Filed: 1998-05-07
Abstract: 1. A process for the preparation of N-(4-fluorophenyl)-N-(2-carboxy-4-chlorophe-nyl)-glycine comprising a copper catalysed arylation of 2,5-dichlorobenzoic acid with N-(4-fluorophenyl)glycine in which alkalimetal salts of 2,5-dichlorobenzoic acid and N-(4-fluorophenyl)glycine are employed in an aqueous, alkaline environment in the presence of a copper catalyst according to the reaction scheme: wherein M1 and M2 are alkali metal ions. 2. A process according to Claim 1, characterised in that the reaction is carried out at an elevated temperature, preferably at a temperature between 80 degree C and the reflux temperature of the medium, in particular at about the reflux temperature. 3. A process according to Claim 1 or 2, characterised in that the reaction medium is water or water to which a cosolvent is added, wherein the cosolvent is a protone cosolvent, such as ethylene glycol. 4. A process according to Claim 3, characterised in that water is used as solvent. 5. A process according to Claim 3 or 4, characterised in the amount of water is less than 10 mL/g 2,5-dichlorobenzoic acid, preferably less than 5 mL/g. 6. A process according to Claim 5, characterised in the amount of water is less than 3.5 mL/g, preferably less than 2.5 mL/g 2,5-dichlorobenzoic acid. 7. A process according to any of Claims 1 to 6, characterised in that the alkalimetal salts used are the lithium, sodium or potassium salts. 8. A process according to Claim 7, characterised in that the same salt of the reactants are used, preferably the potassium salts. 9. A process according to any of Claims 1 to 8, characterised in that the base is an alkalimetal carbonate, preferably Li2CO3, Na2CO3 or K2CO3. 10. A process according to any of Claim 9, characterised in that the alkalimetal of the alkali metal carbonate is the same as the alkalimetal of the reactants. 11. A process according to any of Claims 1 to 8 characterised in that the base is potassium carbonate. 12. A process according to any of Claims 1 to 11 characterised in that the amount of base is larger than the stoechiometric amount of 2,5-dichlorobenzoic acid. 13. A process according to any of Claims 1 to 12 characterised in that the catalyst is copper-bronze. 14. A process according to any of Claims 1 to 13 characterised in that the ratio between the amounts of the alkalimetal salt of N-(4-fluorophenyl)glycine and the alkali metal salt of 2,5-dichlorobenzoic acid is from 0.5 to 3.0, preferably 1.0 to 2.5, in particular 2.0 to 2.3 mol/mol. 15. A process for preparing 5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)indole comprising reaction of 5-chloro-1-(4-fluorophenyl)indole with 4-piperidone in a mixture of a mineral acid and acetic acid. 16. Process according to Claim 15, characterised in that the 4-piperidone is used in the form of 4-piperidone-hydrate, hydrochloride. 17. Process according to Claim 15 or 16, characterised in that the mineral acid used is phosphoric acid, nitric acid, sulfuric acid or hydrochloric acid. 18. Process according to Claim 17, characterised in that the mineral acid used is concentrated hydrochloric acid. 19. Process according to Claim 15 or 16, characterised in that at least 1.5 equivalents of 4-piperidone is used pr. equivalent 5-chloro-1-(4-fluorophenyl)indole. 20. Process according to Claim 19, characterised in that at least 1.75 equivalents of 4-piperidone is used pr. equivalent 5-chloro-1-(4-fluorophenyl)indole. 21. Process according to Claim 20, characterised in that at least 2.0 equivalents of 4-piperidone is used pr. equivalent 5-chloro-1-(4-fluorophenyl)indole. 22. Process according to Claim 18, characterised in that hydrochloric acid is used in an amount of at least 2.5 mL concentrated HCl pr. g 5-chloro-1-(4-fluorophenyl)indole. 23. Process according to Claim 15 or 16, characterised in that at least 8 mL acetic acid pr. g 5-chloro-1-(4-fluorophenyl)indole is used. 24. Process according to Claim 23, characterised in that at least 10 mL acetic acid is used pr. g 5-chloro-1-(4-fluorophenyl)indole. 25. Process according to Claim 24, characterised in that 10 - 14 mL acetic acid is used pr. g 5-chloro-1-(4-fluorophenyl)indole. 26. Process according to Claim 22, characterised in that the ratio is 3.5 to 5 mL concentrated HCl pr. g 5-chloro-1-(4-fluorophenyl)indole. 27. Process according to Claim 18, characterised in that the ratio between acetic acid and concentrated HCl is 2:1 to 4:1 (vol/vol). 28. A process of manufacturing sertindole comprising: a) preparation according to any of claims 1-14 of N-(4-fluorophenyl)-N-(2-carboxy-4-chlorophenyl)glycine, by reacting an alkalimetal salt of 2,5-dichlorobenzoic acid with an alkalimetal salt of N-(4-fluorophenyl)glycine in an aqueous, alkaline environment in the presence of a copper catalyst; b) cyclisation of N-(4-fluorophenyl)-N-(2-carboxy-4-chlorophenyl)glycine to the corresponding 3-acetoxy-indole using acetic anhydride/alkalimetal acetate, preferably sodium acetate; c) reduction of the 3-acetoxy-indole and subsequent d) elimination of H2O thereby obtaining 5-chloro-1-(4-fluorophenyl)indole; e) reaction of 5-chloro-1-(4-fluorophenyl)indole with 4-piperidone according to any of claims 15-27 in a mixture of an acetic acid and concentrated HCl f) reduction of the resulting 5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyri din-4-yl)indole in order to obtain 5-chloro-1-(4-fluorophenyl)-3-(piperidin-4-yl)indole g) reaction of the product of f) with 1-(2-chloroethyl)-2-imidazolidinon, or h) reaction of 5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)indole with 1-(2-chloroethyl)-2-imidazolidinon followed by reduction of the product, thereby obtaining sertindole.