Patent EA-003468-B1 (EA)
Title: A process for preparation of morpholine
Inventor: COTTRELL IAN FRANK
IPC: C07D249/02
Filed: 1999-06-10
Abstract: 1. A process for the preparation of a compound of formula (I) wherein R<2> and R<3> are independently selected from the group consisting of: (1) hydrogen, (2) C1-6alkyl, (3) C2-6alkenyl, and (4) phenyl, R<6>, R<7> and R<8> are independently selected from the group consisting of: (1) hydrogen, (2) C1-6alkyl, (3) fluoro, (4) chloro, (5) bromo, (6) iodo, and (7) -CF3; R<11>, R<12> and R<13> are independently selected from the group consisting of: (1) hydrogen, (2) C1-6alkyl, (3) fluoro, (4) chloro, (5) bromo, (6) iodo, and (7) -CF<3>; and Z is C1-4alkyl, which comprises: (i) reacting a compound of formula (II) or a salt thereof, wherein R<2>, R<3>, R<6>, R<7>, R<8>, R<11>, R<12>, R<13> and Z are as previously defined, with a compound of formula (III) wherein LG is a leaving group selected from halogen (e.g. bromo, chloro or iodo) or an alkyl- or arylsulfonate group (e.g. mesylate or tosylate), in an organic solvent and in the presence of a base; and (ii) collecting the resultant crystalline compound of formula (I). 2. A process for the preparation of the compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine which comprises: (i) reacting 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl) morpholine or a salt thereof, with a compound of formula (III) as defined in Claim 1, in an organic solvent and in the presence of a base; and (ii) collecting the resultant crystalline 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine. 3. A process according to Claim 1 or Claim 2 wherein the leaving group LG is chloro. 4. A process according to Claim 1 or Claim 2 wherein the base is an organic base. 5. A process according to Claim 4 wherein the organic base is selected from diisopropylethylamine or triethylamine. 6. A process according to Claim 1 or Claim 2 wherein the base is an inorganic base. 7. A process according to Claim 6 wherein the inorganic base is selected from sodium hydride or potassium carbonate. 8. A process according to any one of Claims 1 to 5 wherein the organic solvent is acetonitrile. 9. A process according to any one of Claims 1 to 3, 6 or 7 wherein the organic solvent is dimethylformamide. 10. A process according to Claim 1 or Claim 2 wherein step (i) is effected in dimethylformamide in the presence of potassium carbonate. 11. A process according to any one of Claims 1 to 10 wherein the reaction is effected at room temperature. 12. A process according to any one of Claims 2 to 11 wherein the 2-(R)-( 1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine of use in step (i) is in the form of its free base or its (R)-camphor sulfonic acid salt or its para-toluenesulfonic acid salt. 13. A process for the preparation of 3-chloromethyl-1,2,4-triazolin-5-one which comprises: (i) treatment of semicarbazide hydrochloride with benyloxyacetyl chloride under Schotten-Baumann conditions to give benzyloxyacetylsemicarbazide; (ii) cyclization of the product of step (i) under basic conditions to give 3-benyloxymethyl-1,2,4-triazolin-5-one; (iii) hydrogenation of the product of step (ii) to give 3hydroxymethyl-1,2,4-triazolin-5-one; and (iv) treatment of the product of step (iii) with a chlorinating agent to give 3-chloromethyl-1,2,4-triazolin-5-one. 14. A process according to Claim 13 wherein, in step (i), the Schotten-Baumann conditions involve use of aqueous alkali in an ether, at a reduced temperature. 15. A process according to Claim 14 wherein the aqueous alkali is aqueous sodium hydroxide. 16. A process according to Claim 14 or 15 wherein the ether is tetrahydrofuran. 17. A process according to any one of Claims 14 to 16 wherein the Schotten-Baumann reaction is effected between -10 degree C and +10 degree C. 18. A process according to Claim 13 wherein, in step (ii), cyclization is effected in the presence of a base at an elevated temperature. 19. A process according to Claim 18 wherein the base is an alkali metal hydroxide. 20. A process according to Claim 19 wherein the alkali metal hydroxide is sodium hydroxide. 21. A process according to any one of Claims 18 to 20 wherein the reaction is effected at reflux. 22. A process according to Claim 13 wherein, in step (iii), hydrogenation is effected by catalytic hydrogenation using hydrogen in an organic solvent, and in the presence of a noble metal catalyst on a support. 23. A process according to Claim 22 wherein the organic solvent is an alcohol. 24. A process according to Claim 23 wherein the alcohol is methanol. 25. A process according to any one of Claims 22 to 24 wherein the noble metal catalyst is palladium or platinum or an oxide thereof. 26. A process according to any one of Claims 22 to 25 wherein the support is charcoal. 27. A process according to any one of Claims 22 to 26 wherein the reaction is effected at room temperature and pressure. 28. A process according to Claim 13 wherein, in step (iii), hydrogenation is effected by transfer hydrogenation in a organic solvent using a hydrogenation catalyst in the presence of a hydrogen donor. 29. A process according to Claim 28 wherein the organic solvent is an alcohol. 30. A process according to Claim 29 wherein the alcohol is methanol. 31. A process according to any one of Claims 28 to 30 wherein the hydrogenation catalyst is palladium on charcoal. 32. A process according to any one of Claims 28 to 31 wherein the hydrogen donor is selected from sodium hypophosphite, triethylammonium formate, potassium formate, ammonium formate and cyclohexene. 33. A process according to Claim 32 wherein the hydrogen donor is ammonium formate in water. 34. A process according to any one of Claims 28 to 33 wherein the transfer hydrogenation is effected at an elevated temperature. 35. A process according to Claim 34 wherein the reaction is effected at a temperature between 50 degree C and 70 degree C. 36. A process according to Claim 12 wherein, in step (iv), the chlorinating agent is an inorganic acid chloride. 37. A process according to Claim 36 wherein the inorganic acid chloride is selected from SOCI2, PCI5, PCI3 and POCI3. 38. A process according to Claims 36 or 37 wherein the reaction is preferably effected in an organic solvent. 39. A process according to Claim 38 wherein the organic solvent is acetonitrile. 40. A process according to any one of Claims 36 to 39 wherein the reaction is effected at room temperature and pressure.