Reivindicaciones
CLAIMS What is claimed is: . 1. A process for preparing 2-( 1 -benzylpiperidin-4-ylmethyliden)-5 ,6-dimethoxyindan- 1-one comprising reacting 5,6-dimethoxyindan-l-one with l-benzylpiperidine-4- carbaldehyde using an alkali metal hydroxide in a mixture of an organic solvent and water at a temperature between room temperature and 120[deg.] C. 2. The process of claim 1 , further comprising the use of a phase transfer catalyst. 3. The process of claim 1 , further comprising the step of isolating said 2-(l - benzylpiperidin-4-ylmethyliden)-5,6-dimethoxyindan-l-one. 4. The process of claim 3, wherein said step of isolating said 2-(l-benzylpiperidin-4- ylmethyliden)-5,6-dimethoxyindan-l-one comprises filtration from water after removing said organic solvent. 5. The process of claim 3, wherein said step of isolating said 2-(l-benzylpiperidin-4- ylmethyliden)-5,6-dimethoxyindan-l-one comprises filtration after cooling said mixture. 6. The process of claim 1, further comprising the step of purifying 2-(l- benzylpiperidin-4-ylmethyliden)-5,6-dimethoxyindan-l-one with at least one purifying solvent. 7. The process of claim 6, wherein said at least one purifying solvent is isopropyl alcohol. 8. The process of claim 6, wherein said at least one purifying solvent is water. 9. The process of claim 1 , wherein said alkali metal hydroxide is at least one of potassium hydroxide and sodium hydroxide. 10. The process of claim 9, wherein said alkali metal hydroxide is potassium hydroxide. 11. The process of claim 1, wherein said organic solvent is at least one of toluene, xylene, tetrahydrofuran and 2-methyltetrahydrofuran. 12. The process of claim 11, wherein said organic solvent is toluene. 13. The process of claim 11 , wherein said organic solvent is tetrahydrofuran. 14. The process of claim 2, wherein said phase transfer catalyst is at least one of benzyltriethyl ammonium chloride, benzyltriethylammonium bromide, tetraethylammonium chloride, tetraethylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium bromide, tributylmethylammonium chloride, tributylmethylammonium bromide, benzyltrimethyl ammonium chloride, benzyltrimethylammonium bromide, tetrahexylammonium chloride, tetrahexylammonium bromide, tetraoctylammonium chloride, tetraoctylammonium bromide, hexadecyltrimethylammonium chloride and hexadecyltrimethylammonium chloride. 15. The process of claim 14, wherein said phase transfer catalyst is benzyltriethylammonium chloride. 16. The process of claim 1, wherein said temperature is between approximately 90 and approximately 97[deg.] C. 17. The process of claim 1, wherein said temperature is at or near reflux. 18. The process of claim 1, further comprising converting said 2-(l-benzylpiperidin-4- ylmethyliden)-5,6-dimethoxyindan-l-one into donepezil hydrochloride. 19. The process of claim 18, wherein said step of converting said 2-(l-benzylpiperidin- 4-ylmethyliden)-5,6-dimethoxyindan-l-one into donepezil hydrochloride comprises hydrogenating said 2-(l-benzylpiperidin-4-ylmethyliden)-5,6-dimethoxyindan-l-one and treating the product thereof with hydrochloric acid or an equivalent thereof. 20. A polymorphic form of solid, crystalline 2-(l-benzylpiperidin-4-ylmethyliden)-5,6- dimethoxyindan-1-one, designated Form I, having an X-ray diffraction pattern (2[Theta]) substantially similar to that of Fig. 1. 21. The Form I polymorph of claim 20, wherein said solid, crystalline 2-(l - benzylpiperidin-4-ylmethyliden)-5,6-dimethoxyindan-l-one is prepared according to the process of claim 1. 22. The Form I polymorph of claim 20 having an X-ray diffraction pattern (2[Theta]) having characteristic peaks at 5.28, 10.52, 11.54, 13.40, 17.51, 18.17, 19.24, 20.24, 20.95, 22.23, 23.15, 24.52, 25.64, 26.16 degrees. 23. The Form I polymorph of claim 20, wherein said solid, crystalline 2-(l - benzylpiperidin-4-ylmethyl iden)-5,6-dimethoxyindan-l-one is prepared by (i) reacting 5,6-dimethoxy indan-1-one with l-benzylpiperidine-4-carbaldehyde in a mixture of toluene and water and (ii) isolating said solid, crystalline 2-(l-benzylpiperidin-4-ylmethyliden)-5,6- dimethoxyindan-1-one by filtration after cooling said mixture of toluene and water. 24. A polymorphic form of solid, crystalline 2-(l-benzylpiperidin-4-ylmethyliden)-5,6- dimethoxyindan-1-one, designated Form II, having an X-ray diffraction pattern (2[Theta]) substantially similar to that of Fig. 2. 25. The Form II polymorph of claim 24, wherein said solid, crystalline 2-(l - benzylpiperidin-4-ylmethyliden)-5,6-dimethoxyindan-l-one is prepared according to the process of claim 1. 26. The Form II polymorph of claim 24 having an X-ray diffraction pattern (2[Theta]) having characteristic peaks at 8.17, 11.51, 14.87, 17.68, 19.29, 19.91, 21.09, 21.74, 24.75, 27.62 degrees. 27. The Form I polymorph of claim 20 having a purity higher than 95% as measured by high performance liquid chromatography. 28. The Form I polymorph of claim 20 having a purity higher than 98% as measured by high performance liquid chromatography. 29. The Form I polymorph of claim 20 having a purity higher than 98.9% as measured by high performance liquid chromatography. 30. The Form I polymorph of claim 20 having a content of 2-[(l-benzylpiperidin-4- yl)hydroxymethyl]-5,6-dimethoxyindan-l-one of less than 2.5% as measured by high performance liquid chromatography. 31. The Form I polymorph of claim 20 having a content of 2- [(I -benzylpiperidin-4- yl)hydroxymethyl]-5,6-dimethoxyindan-l-one of less than 1.0 % as measured by high performance liquid chromatography. 32. The Form I polymorph of claim 20 having a content of 2-[(l -benzylpiperidin-4- yl)hydroxymethyl]-5,6-dimethoxyindan-l-one of less than 0.5% as measured by high performance liquid chromatography. 33. The Form II polymorph of claim 24 having a purity higher than 95% as measured by high performance liquid chromatography. 34. The Form II polymorph of claim 24 having a purity higher than 98% as measured by high performance liquid chromatography. 35. The Form II polymorph of claim 24 having a purity higher than 98.9% as measured by high performance liquid chromatography. 36. The Form II polymorph of claim 24 having a content of 2- [( 1 -benzylpiperidin-4- yl)hydroxymethyl]-5,6-dimethoxyindan-l-one of less than 2.5% as measured by high performance liquid chromatography. 37. The Form II polymorph of claim 24 having a content of 2- [( 1 -benzylpiperidin-4- yl)hydroxymethyl]-5,6-dimethoxyindan-l-one of less than 1.0 % as measured by high performance liquid chromatography. 38. The Form II polymorph of claim 24 having a content of 2- [( 1 -benzylpiperidin-4- yl)hydroxymethyl]-5,6-dimethoxyindan-l-one of less than 0.5% as measured by high performance liquid chromatography. 39. A mixture comprising 2-(l-benzylpiperidin-4-ylmethyliden)-5,6-dimethoxyindan-l- one polymorph Form I and 2-(l-benzylpiperidin-4-ylmethyliden)-5,6-dimethoxyindan-l- one polymorph Form II. 40. The mixture of claim 39, wherein each of 2-(l-benzylpiperidin-4-ylmethyliden)-5,6- dimethoxyindan-1-one polymorph Form I and 2-(l-benzylpiperidin-4-ylmethyliden)-5,6- dimethoxyindan-1-one polymorph Form II has a purity higher than 95% as measured by high performance liquid chromatography. 41. The mixture of claim 39, wherein each of 2-(l-benzylpiperidin-4-ylmethyliden)-5,6- dimethoxyindan-1-one polymorph Form I and 2-(l-benzylpiperidin-4-ylmethyliden)-5,6- dimethoxyindan-1-one polymorph Form II has a purity higher than 98% as measured by high performance liquid chromatography. 42. The mixture of claim 39, wherein each of 2-(l-benzylpiperidin-4-ylmethyliden)-5,6- dimethoxyindan-1-one polymorph Form I and 2-(l-benzylpiperidin-4-ylmethyliden)-5,6- dimethoxyindan-1-one polymorph Form II has a purity higher than 98.9% as measured by high performance liquid chromatography. 43. The mixture of claim 39 having a content of 2- [( 1 -benzylpiperidin-4- yl)hydroxymethyl]-5,6-dimethoxyindan-l-one of less than 2.5% as measured by high performance liquid chromatography. 44. The mixture of claim 39 having a content of 2-[(l -benzylpiperidin-4- yl)hydroxymethyl]-5,6-dimethoxyindan-l-one of less than 1.0% as measured by high performance liquid chromatography. 45. The mixture of claim 39 having a content of 2- [( 1 -benzylpiperidin-4- yl)hydroxymethyl]-5,6-dimethoxyindan-l-one of less than 0.5% as measured by high performance liquid chromatography, 46. A process for preparing donepezil hydrochloride comprising converting at least one compound of 2-( 1 -benzylpiperidin-4-ylmethyliden)-5 ,6-dimethoxyindan- 1 -one polymorph Form I, 2-(l-benzylpiperidin-4-ylmethyliden)-5,6-dimethoxyindan-l-one polymorph Form II and mixtures thereof into donepezil hydrochloride. 47. The process of claim 46, wherein said at least one compound is 2-(l- benzylpiperidin-4-ylmethyliden)-5,6-dimethoxyindan-l-one polymorph Form I. 48. The process of claim 46, wherein said at least one compound is 2-(l- benzylpiperidin-4-ylmethyliden)-5,6-dimethoxyindan-l-one polymorph Form II. 49. The process of claim 46, wherein said at least one compound is a mixture of 2-(l- benzylpiperidin-4-ylmethyliden)-5,6-dimethoxyindan-l-one polymorph Form I and 2-(l- benzylpiperidin-4-ylmethyliden)-5,6-dimethoxyindan-l-one polymorph Form II. 50. Donepezil hydrochloride prepared according to the process of claim 46. 51. Donepezil hydrochloride prepared according to the process of claim 47. 52. Donepezil hydrochloride prepared according to the process of claim 48. 53. Donepezil hydrochloride prepared according to the process of claim 49. 54. A process for preparing 2-(l -benzylpiperidin-4-ylmethyliden)-5,6-dimethoxyindan- 1-one comprising reacting 5,6-dimethoxyindan-l-one with l-benzylpiperidine-4- carbaldehyde using potassium hydroxide in a mixture of toluene and water at reflux temperature. 55. The process of claim 54, further comprising the use of a phase transfer catalyst. 56. 56.. The process of claim 54, further comprising the step of isolating said 2-(l- benzylpiperidin-4-ylmethyliden)-5,6-dimethoxyindan- 1 -one. 57. The process of claim 56, wherein said step of isolating said 2-(l-benzylpiperidin-4- ylmethyliden)-5,6-dimethoxyindan-l-one comprises filtration from water after removing said toluene. 58. The process of claim 56, wherein said step of isolating said 2-(l-benzylpiperidin-4- ylmethyliden)-5,6-dimethoxyindan-l-one comprises filtration after cooling said mixture. 59. The process of claim 54, further comprising the step of purifying 2-(l- benzylpiperidin-4-ylmethyliden)-5,6-dimethoxyindan-l-one with at least one purifying solvent. 60. The process of claim 59, wherein said at least one purifying solvent is isopropyl alcohol. 61. The process of claim 59, wherein said at least one purifying solvent is water.
