IPC분류정보
국가/구분 |
United States(US) Patent
공개
|
국제특허분류(IPC7판) |
|
출원번호 |
US-0389358
(2010-08-09)
|
공개번호 |
US-0190849
(2012-07-26)
|
우선권정보 |
IN-1650/DEL/2009 (2009-08-07) |
국제출원번호 |
PCT/IB10/53594
(2010-08-09)
|
§371/§102 date |
20120330
(20120330)
|
발명자
/ 주소 |
- Mittal, Anu
- Khanna, Mahavir Singh
- Thaper, Rajesh Kumar
- Prasad, Mohan
|
출원인 / 주소 |
- RANBAXY LABORATORIES LIMITED
|
인용정보 |
피인용 횟수 :
0 인용 특허 :
0 |
초록
The present invention provides processes for the preparation of vardenafil, its pharmaceutically acceptable salts, hydrates and intermediates.
대표청구항
▼
1. A process for the preparation of vardenafil of Formula I, its pharmaceutically acceptable salts and hydrates, comprising: i) hydrogenating 2-ethoxy-N-hydroxy-5-[(4-ethylpiperazin-1-yl)sulfonyl]benzene carboximidamidine of Formula II to obtain 2-ethoxy-5-[(4-ethyl-1-piperazinyl)sulfonyl]benzamidi
1. A process for the preparation of vardenafil of Formula I, its pharmaceutically acceptable salts and hydrates, comprising: i) hydrogenating 2-ethoxy-N-hydroxy-5-[(4-ethylpiperazin-1-yl)sulfonyl]benzene carboximidamidine of Formula II to obtain 2-ethoxy-5-[(4-ethyl-1-piperazinyl)sulfonyl]benzamidine of Formula III or its salt;ii) converting the 2-ethoxy-5-[(4-ethyl-1-piperazinyl)sulfonyl]benzamidine of Formula III or its salt to vardenafil of Formula I; andiii) optionally converting the vardenafil of Formula I to its pharmaceutically acceptable salts or hydrates. 2. The process of claim 1, wherein the hydrogenation of the compound of Formula II to obtain the compound of Formula III or its salt is carried out using a transition metal catalyst. 3. The process of claim 1, wherein the hydrogenation of the compound of Formula II to obtain the compound of Formula III or its salt is carried out in a solvent comprising straight and branched chain alcohols, cyclic alcohols, aromatic alcohols, carboxylic acids or a mixture thereof. 4. The process of claim 3, wherein the straight and branched chain alcohols comprise methanol, ethanol, n-propanol or iso-propanol. 5. The process of claim 3, wherein the cyclic alcohols comprise cyclopentanol or cyclohexanol. 6. The process of claim 3, wherein the aromatic alcohol comprises benzyl alcohol. 7. The process of claim 3, wherein the carboxylic acids comprise formic acid or acetic acid. 8. A process for the preparation of vardenafil of Formula I its pharmaceutically acceptable salts and hydrates, comprising: i) treating 2-ethoxy-5-[(4-ethyl-1-piperazinyl)sulfonyl]benzonitrile of Formula V with hydroxylamine hydrochloride to obtain 2-ethoxy-N-hydroxy-5-[(4-ethylpiperazin-1-yl)sulfonyl]benzene carboximidamidine of Formula II; ii) hydrogenating the 2-ethoxy-N-hydroxy-5-[(4-ethylpiperazin-1-yl)sulfonyl]benzene carboximidamidine of Formula II to obtain 2-ethoxy-5-[(4-ethyl-1-piperazinyl)sulfonyl]benzamidine of Formula III or its salt;iii) treating the 2-ethoxy-5-[(4-ethyl-1-piperazinyl)sulfonyl]benzamidine of Formula III or its salt with hydrazine hydrate to obtain 2-ethoxy-5-[(4-ethyl-1-piperazinyl)sulfonyl]benzene carboximido hydrazide of Formula VI; iv) reacting the 2-ethoxy-5-[(4-ethyl-1-piperazinyl)sulfonyl]benzene carboximido hydrazide of Formula VI with ethyl-3-(butanoylamino)-2-oxobutanoate of Formula VII; to obtain N-{1-[3-{2-ethoxy-5-[(4-ethylpiperazin-1-yl)sulfonyl]phenyl}-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}butanamide of Formula IV v) cyclizing the N-{1-[3-{2-ethoxy-5-[(4-ethylpiperazin-1-yl)sulfonyl]phenyl}-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}butanamide of Formula IV to obtain the vardenafil of Formula I; andvi) optionally converting the vardenafil of Formula I to its pharmaceutically acceptable salts or hydrates. 9. (canceled) 10. (canceled) 11. (canceled) 12. (canceled) 13. (canceled) 14. (canceled) 15. (canceled) 16. (canceled) 17. The process of claim 8, wherein the reaction of the compound of Formula V with hydroxylamine hydrochloride to obtain the compound of Formula II is carried out in the presence of a base. 18. The process of claim 9, wherein the base comprises an organic base or an inorganic base. 19. The process of claim 10, wherein the organic base comprises triethylamine, diisopropylethylamine or 4-methyl morpholine. 20. The process of claim 10, wherein the inorganic base comprises potassium carbonate, sodium carbonate, sodium bicarbonate, lithium hydroxide monohydrate or lithium carbonate. 21. The process of claim 8, wherein the reaction of the compound of Formula V with hydroxylamine hydrochloride to obtain the compound of Formula II is carried out in a solvent comprising ethers, chlorinated hydrocarbons, ketones, esters, alcohols or a mixture thereof 22. The process of claim 21, wherein the ethers comprise diethyl ether, diisopropyl ether, or tetrahydrofuran. 23. The process of claim 21, wherein the chlorinated hydrocarbons comprise chloroform, dichloromethane, or 1,2-dichloroethane. 24. The process of claim 21, wherein the ketones comprise acetone, methyl ethyl ketone or methyl isobutyl ketone. 25. The process of claim 21, wherein the esters comprise methyl acetate, ethyl acetate, propyl acetate, or butyl acetate. 26. The process of claim 21, wherein the alcohols comprise methanol, ethanol, n-propanol, or iso-propanol. 27. The process of claim 8, wherein the hydrogenation of the compound of Formula II to obtain the compound of Formula III or its salt is carried out using a transition metal catalyst. 28. The process of claim 8, wherein the hydrogenation of the compound of Formula II to obtain the compound of Formula III or its salt is carried out in a solvent comprising straight and branched chain alcohols, cyclic alcohols, aromatic alcohols, carboxylic acids or a mixture thereof. 29. The process of claim 28, wherein the straight and branched chain alcohols comprise methanol, ethanol, n-propanol or iso-propanol. 30. The process of claim 28, wherein the cyclic alcohols comprise cyclopentanol or cyclohexanol. 31. The process of claim 28, wherein the aromatic alcohol comprises benzyl alcohol. 32. The process of claim 28, wherein the carboxylic acids comprise formic acid or acetic acid. 33. The process of claim 8, wherein the treatment of the compound of Formula III or its salt with hydrazine hydrate to obtain the compound of Formula VI is carried out in a solvent comprising ethers, chlorinated hydrocarbons, ketones, esters, alcohols or a mixture thereof. 34. The process of claim 33, wherein the ethers comprise diethyl ether, diisopropyl ether, or tetrahydrofuran. 35. The process of claim 33, wherein the chlorinated hydrocarbons comprise chloroform, dichloromethane, or 1,2-dichloroethane. 36. The process of claim 33, wherein the ketones comprise acetone, methyl ethyl ketone or methyl isobutyl ketone. 37. The process of claim 33, wherein the esters comprise methyl acetate, ethyl acetate, propyl acetate, or butyl acetate. 38. The process of claim 33, wherein the alcohols comprise methanol, ethanol, n-propanol, or iso-propanol. 39. The process of claim 8, wherein the reaction of the compound of Formula VI with the compound of Formula VII to obtain the compound of Formula IV is carried out in a solvent comprising ethers, chlorinated hydrocarbons, ketones, esters, alcohols or a mixture thereof 40. The process of claim 39, wherein the ethers comprise diethyl ether, diisopropyl ether, or tetrahydrofuran. 41. The process of claim 39, wherein the chlorinated hydrocarbons comprise chloroform, dichloromethane, or 1,2-dichloroethane. 42. The process of claim 39, wherein the ketones comprise acetone, methyl ethyl ketone or methyl isobutyl ketone. 43. The process of claim 39, wherein the esters comprise methyl acetate, ethyl acetate, propyl acetate, or butyl acetate. 44. The process of claim 39, wherein the alcohols comprise methanol, ethanol, n-propanol, or iso-propanol. 45. (canceled) 46. (canceled) 47. (canceled) 48. (canceled) 49. (canceled) 50. (canceled) 51. (canceled) 52. (canceled) 53. (canceled) 54. The process of claim 8, wherein the cyclization of the compound of Formula IV to obtain the vardenafil of Formula I is carried out in the presence of a cyclizing agent comprising phosphorus oxychloride, oxalyl chloride or acetyl chloride. 55. The process of claim 8, wherein the cyclization of the compound of Formula IV to obtain the vardenafil of Formula I is carried out in a solvent comprising ethers, chlorinated hydrocarbons, ketones, esters, alcohols or a mixture thereof. 56. The process of claim 55, wherein the ethers comprise diethyl ether, diisopropyl ether, or tetrahydrofuran. 57. The process of claim 55, wherein the chlorinated hydrocarbons comprise chloroform, dichloromethane, or 1,2-dichloroethane. 58. The process of claim 55, wherein the ketones comprise acetone, methyl ethyl ketone or methyl isobutyl ketone. 59. The process of claim 55, wherein the esters comprise methyl acetate, ethyl acetate, propyl acetate, or butyl acetate. 60. The process of claim 55, wherein the alcohols comprise methanol, ethanol, n-propanol, or iso-propanol.
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