WO2005116030A1 - A process for the preparation of tadalafil - Google Patents
A process for the preparation of tadalafil Download PDFInfo
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- WO2005116030A1 WO2005116030A1 PCT/IN2005/000136 IN2005000136W WO2005116030A1 WO 2005116030 A1 WO2005116030 A1 WO 2005116030A1 IN 2005000136 W IN2005000136 W IN 2005000136W WO 2005116030 A1 WO2005116030 A1 WO 2005116030A1
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- tadalafil
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
Definitions
- the present invention relates to an optimized process for the preparation of pure (6R,12aR)-6-(l,3-Benzodioxol-5-yl)-2-methyl-l,2,3,4,6,7,12,12a-octahydropyrazino T , : 6, 1 ]pyrido [3 ,4-b] indole- 1 ,4-dione (Tadalafil) .
- Tadalafil namely (6R,12aR)-6-( 1,3 -Benzodioxol-5-yl)-2-methyl- 1,2,3 ,4,6,7, 12, 12a- octahydropyrazino[2',l':6,l]pyrido[3,4-b]indole-l,4- dione has the formula
- Tadalafil is a potent and selective inhibitor of cyclic guanosine S' ⁇ -monophosphate specific phosphodiesterase having a utility in a variety of therapeutic areas where such inhibition is thought to be beneficial including the treatment of cardiovascular disorders. Tadalafil and its similar compounds are reported in US Patent 5,859,006 (Equivalent to EP 740,668).
- solubility of Tadalafil in isopropanol is only less than 1% and herein any recrystallization process which involve very large volumes of the solvent isopropanol thereby making the process unwieldy and nonoperable.
- the main object of the present invention is to provide an optimized process for the preparation of Tadalafil.
- Another object of the invention is to provide a process for recrystallisation of Tadalafil without the usage of large volumes of solvents.
- Another object of the invention is to provide a process for the isolation of the Tadalafil from the reaction mass without involving the usage of large volumes of solvents, extensive workup like distillation of one solvent and dissolution in second solvent, removal of second solvent and crystallization from a third solvent.
- Another object of the invention is to provide a process for recrystallization of Tadalafil with reduced cycle times and minimizing loss of material.
- the present invention relates to a process for the preparation of Tadalafil from D-Tryptophan methyl ester through (6R, 12aR)-methyl l,2,3,4-tetrahydro-2- chloroacetyl-l-(3,4-methylene dioxyphenyl) - 9H - pyrido [3,4-b] indole-3-carboxylate (chloroacetyl intermediate) which on reaction with methylamine solution in short chain alcohol followed by cooling gives crude Tadalafil. Recrystallization is carried out by dissolution of crude Tadalafil in minimum volume of organic polar solvent followed by quenching the solution into water/water miscible solvents to give the pure Tadalafil in quantitative yields.
- Tadalafil Detailed description of the Invention: The preparation and recrystallization of Tadalafil from (6R, 12aR)-Methyl 1,2,3,4- tetrahydro-2-chloroacetyl-l-(3,4-methylenedioxyphenyl) - 9H-pyrido [3,4-b]indole-3- carboxylate comprises the following steps:
- the crude Tadalafil is recrystallized by dissolving it in about 2 to 12 volumes, preferably 4 to 8 volumes of a polar solvent selecting from DMF, 1,4-Dioxane and DMSO, followed by quenching the mass into 6 to 30 volumes of water/water miscible solvent such as methanol, ethanol, isopropanol, acetone or mixtures thereof over a period of 30 rnin to 2 hrs or water/water miscible solvent can be added to the solution of crude Tadalafil in a polar solvent.
- a polar solvent selecting from DMF, 1,4-Dioxane and DMSO
- Reaction mass is cooled and maintained at -10°C to 10°C preferably at -5°C to 5°C for 1 hr to 6 hrs followed by isolation, washing with acetone and drying gives the pure Tadalafil in quantitative yields of pharmaceutically acceptable quality.
- (6R, 12aR)-Methyl-l,2,3,4-tetrahydro-2-chloroacetyl-l-(3,4-methylene dioxy phenyl) - 9H-pyrido[3,4-b]indole-3-carboxylate (Chloroacetyl intermediate) is prepared as per the reported prior art methods.
- Methyl amine solution (25% in methanol, 163 ml) is added to a suspension of (6R,12aR) - Methyl 1,2,3,4 -tetrahydro-2 - chloroacetyl -l-(3,4 -methylenedioxy phenyl) -9H- pyrido[3,4-b]indole-3-carboxylate (Chloro acetyl intermediate) (79 g) in methanol (790 ml). Temperature of the reaction mass is raised and maintained at 50°C to 55°C for 6 hrs. The reaction mass is then cooled and maintained at 25°C to 30°C for 1 hr, filtered, washed with methanol (50 ml) and dried at 45°C to 50°C.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The present invention discloses an optimized process for the preparation of Tadalafil starting from (6R, 12aR)-Methyl 1,2,3,4-tetrahydro - 2 - chloroacetyl-1-(3,4-methylenedioxy phenyl)- 9H -pyrido [3,4-b] indole-3-carboxylate (Chloro acetyl intermediate) without using large volumes of solvents, distillation, extraction, evaporation of solvents, Crude Tadalafil is isolated by cooling and recrystallizing from polar solvents such as DMF, 1,4-Dioxane, DMSO followed by addition of the reaction mass into water/water miscible solvent followed by cooling and maintaining at low temperature.
Description
"A process for the preparation of Tadalafil"
The present invention relates to an optimized process for the preparation of pure (6R,12aR)-6-(l,3-Benzodioxol-5-yl)-2-methyl-l,2,3,4,6,7,12,12a-octahydropyrazino T , : 6, 1 ]pyrido [3 ,4-b] indole- 1 ,4-dione (Tadalafil) .
Background of the Invention:
Tadalafil namely (6R,12aR)-6-( 1,3 -Benzodioxol-5-yl)-2-methyl- 1,2,3 ,4,6,7, 12, 12a- octahydropyrazino[2',l':6,l]pyrido[3,4-b]indole-l,4- dione has the formula
Tadalafil is a potent and selective inhibitor of cyclic guanosine S'^-monophosphate specific phosphodiesterase having a utility in a variety of therapeutic areas where such inhibition is thought to be beneficial including the treatment of cardiovascular disorders. Tadalafil and its similar compounds are reported in US Patent 5,859,006 (Equivalent to EP 740,668).
US Patents 5,859,006, 6,025,494, 6,127,542, 6,369,059 and US Patent application US 2002/0,119,976 discloses the process for the preparation of Tadalafil starting from the D- tryptophan methyl ester through the intermediate (6R,12aR)-Methyl 1,2,3,4-tetrahydro- 2-chloroacetyl-l-(354-methylene dioxy phenyl) - 9H-pyrido[3,4-b] indole-3-carboxylate.
The disclosed process for preparation of Tadalafil in the above prior art comprises the following steps:
- Suspending (6R, 12aR)-Methyl 1 ,2,3 ,4-tetrahydro-2-chloroacetyl- 1 -(3 ,4- methylenedioxy phenyl) -9H-pyrido [3 ,4-b]indole-3 -carboxylate (chloroacetyl derivative) in about 32 -50 volumes of methanol
- Adding methylamine solution (33 % in ethanol)
- Maintaining at 50°C for about 14 hrs
- Removing the solvent by distillation under reduced pressure - Dissolving of the resultant residue in 80 - 135 volumes of Methylene chloride
- Washing the organic layer with water and drying over sodium sulphate
- Evaporating the solvent till dryness to obtain white solid
- Recrystallizing the solid from isopropanol
It may be noted that the solubility of Tadalafil in isopropanol is only less than 1% and herein any recrystallization process which involve very large volumes of the solvent isopropanol thereby making the process unwieldy and nonoperable.
Further the process disclosed in the prior art teaches the preparation involving large volumes of solvents such as 32 volumes to 50 volumes of methanol, 80 volumes to about 135 volumes of methylene chloride for isolation of crude and about 100 volumes of isopropanol for recrystallization of Tadalafil resulting material loss, extended cycle times thereby making this commercially not feasible.
There is a long-standing need to provide a process for the preparation of Tadalafil by avoiding the handling of large volumes of materials with reduced cycle times and optimized process steps.
Summary of the invention:
The main object of the present invention is to provide an optimized process for the preparation of Tadalafil.
Another object of the invention is to provide a process for recrystallisation of Tadalafil without the usage of large volumes of solvents.
Another object of the invention is to provide a process for the isolation of the Tadalafil from the reaction mass without involving the usage of large volumes of solvents, extensive workup like distillation of one solvent and dissolution in second solvent, removal of second solvent and crystallization from a third solvent.
Another object of the invention is to provide a process for recrystallization of Tadalafil with reduced cycle times and minimizing loss of material.
Accordingly, the present invention relates to a process for the preparation of Tadalafil from D-Tryptophan methyl ester through (6R, 12aR)-methyl l,2,3,4-tetrahydro-2- chloroacetyl-l-(3,4-methylene dioxyphenyl) - 9H - pyrido [3,4-b] indole-3-carboxylate (chloroacetyl intermediate) which on reaction with methylamine solution in short chain alcohol followed by cooling gives crude Tadalafil. Recrystallization is carried out by dissolution of crude Tadalafil in minimum volume of organic polar solvent followed by quenching the solution into water/water miscible solvents to give the pure Tadalafil in quantitative yields.
The reaction scheme is given below:
- Suspending (6R, 12aR)-Methyll, 2,3,4-tetrahydro-2-chloroacetyl -l-(3,4- methylenedioxyphenyl)-9H-pyrido[3,4-b] indole-3-carboxylate in minimum volume of short chain alcohol
- Addition of methyl amine solution
- Maintaining the reaction mass at temperature of 40°C to 60°C for about 4 hrs to 10 hrs
- Cooling the reaction mass - Isolating and drying the crude product
- Dissolving the obtained crude Tadalafil in minimum volumes of polar organic solvent
- Quenching the clear solution into water/ water miscible solvent
- Cooling and maintaining the reaction mass at low temperature
- Isolating, washing and drying the pure product
Suspending (6R, 12aR)-Methyl l,2,3,4-tetrahydro-2-chloroacetyl-l-(3,4-methylenedioxy phenyl) - 9H-pyrido[3,4-b]indole-3-carboxylate (Chloro acetyl intermediate) in 5 to 20 volumes preferably 6 to 12 volumes of a short chain alcohol selected from methanol, ethanol is treated with methyl amine solution ( about 20% to 30 % in methanol , ethanol) at 40°C to 60°C for 4 to 10 hrs preferably 5 to 8 hrs followed by cooling and maintaining the reaction mass to 10°C - 30°C preferably to 20°C - 30°C. The precipitated product on isolation and drying gives the crude Tadalafil.
The crude Tadalafil is recrystallized by dissolving it in about 2 to 12 volumes, preferably 4 to 8 volumes of a polar solvent selecting from DMF, 1,4-Dioxane and DMSO, followed by quenching the mass into 6 to 30 volumes of water/water miscible solvent such as methanol, ethanol, isopropanol, acetone or mixtures thereof over a period of 30 rnin to 2 hrs or water/water miscible solvent can be added to the solution of crude Tadalafil in a
polar solvent. Reaction mass is cooled and maintained at -10°C to 10°C preferably at -5°C to 5°C for 1 hr to 6 hrs followed by isolation, washing with acetone and drying gives the pure Tadalafil in quantitative yields of pharmaceutically acceptable quality. (6R, 12aR)-Methyl-l,2,3,4-tetrahydro-2-chloroacetyl-l-(3,4-methylene dioxy phenyl) - 9H-pyrido[3,4-b]indole-3-carboxylate (Chloroacetyl intermediate) is prepared as per the reported prior art methods.
The invention is now illustrated with the following example.
Example: Preparation of Tadalafil
Methyl amine solution (25% in methanol, 163 ml) is added to a suspension of (6R,12aR) - Methyl 1,2,3,4 -tetrahydro-2 - chloroacetyl -l-(3,4 -methylenedioxy phenyl) -9H- pyrido[3,4-b]indole-3-carboxylate (Chloro acetyl intermediate) (79 g) in methanol (790 ml). Temperature of the reaction mass is raised and maintained at 50°C to 55°C for 6 hrs. The reaction mass is then cooled and maintained at 25°C to 30°C for 1 hr, filtered, washed with methanol (50 ml) and dried at 45°C to 50°C.
Dry wt of the crude Tadalafil is 67 g (92.5 % yield)
Crude Tadalafil (67 g) is dissolved in DMF (330 ml,) at room temperature, treated with activated carbon for 30 min at 25°C to 30°C. The reaction mass is filtered and the filtered mass is quenched into methanol (2010 ml) over lhr at 25°C to 30°C under mixing. The reaction mass is cooled and maintained at 0°C to 5°C for 2hrs. The precipitated product is filtered, washed with methanol (50 ml) and dried at 50°C to 55°C.
Dry wt of the pure Tadalafil is: 50 g (74.6 % yield)
Claims
1. A process for the preparation of Tadalafil from (6R, 12aR) - Methyl -1,2,3,4 - tetrahydro - 2-chloroacetyl -l-(3,4-methylenedioxy phenyl) - 9H - pyrido [3,4- b] indole-3-carboxylate comprising of
Suspending (6R,12aR)-Methyl-l,2,3,4-tetrahydro-2-chloro acetyl-l-(3,4- methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate in a short chain alcohol followed by addition of methyl amine solution Heating the reaction mass to about 40°C and maintaining the reaction mass at 40°C to 60°C for about 4 hrs Cooling and maintaining the reaction mass at room temperature Isolating and drying the crude Tadalafil at about 65°C - Dissolving the obtained crude Tadalafil in a polar organic solvent selected from DMF, DMSO and Dioxan Quenching the above solution into 6 to 30 volumes of water/ water miscible solvent Cooling and maintaining the reaction mass at -10°C to 10°C for 2 to 3 hrs - Isolating, washing and drying the product at about 50°C
2. A process as claimed in claim 1, wherein the volume of short chain alcohol is 5 volumes to 20 volumes, preferably 6 to 12 volumes with respect to (6R,12aR)- Methyl 1 ,2,3 ,4-tetrahydro-2-chloroacetyl- 1 -(3 ,4-methylene dioxyphenyl) - 9H-pyrido [3,4-b]indole-3-carboxylate
3. A process as claimed in claim 1, wherein the short chain alcohol is methanol, ethanol and mixtures thereof
4. A process as claimed in claim 1, wherein the preferred solvent for the dissolution of crude Tadalafil is DMF .
5. A process as claimed in claim 1, wherein the volume of organic polar solvent is 2 to 12 volumes with respect to crude Tadalafil
6. A process as claimed in claim 1 , wherein the water miscible solvent is selected from methanol, ethanol, isopropanol, acetone and mixtures thereof
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN491/CHE/2004 | 2004-05-31 | ||
| IN491CH2004 | 2004-05-31 |
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| Publication Number | Publication Date |
|---|---|
| WO2005116030A1 true WO2005116030A1 (en) | 2005-12-08 |
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| Application Number | Title | Priority Date | Filing Date |
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| PCT/IN2005/000136 Ceased WO2005116030A1 (en) | 2004-05-31 | 2005-05-02 | A process for the preparation of tadalafil |
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| WO (1) | WO2005116030A1 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006091975A1 (en) * | 2005-02-25 | 2006-08-31 | Teva Pharmaceutical Industries Ltd. | Process of synthesizing tadalafil |
| US7417044B2 (en) | 2005-02-25 | 2008-08-26 | Teva Pharmaceutical Industries Ltd. | Tadalafil having a large particle size and a process for preparation thereof |
| EP2238979A1 (en) * | 2009-04-06 | 2010-10-13 | LEK Pharmaceuticals d.d. | Active pharmaceutical ingredient adsorbed on solid support |
| US8063214B2 (en) * | 2004-10-28 | 2011-11-22 | Dr. Reddy's Laboratories Limited | Polymorphic forms of tadalafil |
| CN104262340A (en) * | 2014-09-19 | 2015-01-07 | 济南诚汇双达化工有限公司 | Method for preparing Tadalafil |
| CN116574102A (en) * | 2023-04-11 | 2023-08-11 | 广东九明制药有限公司 | A kind of preparation method of tadalafil |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5859006A (en) * | 1994-01-21 | 1999-01-12 | Icos Corporation | Tetracyclic derivatives; process of preparation and use |
| WO2002036593A1 (en) * | 2000-11-06 | 2002-05-10 | Lilly Icos Llc | Indole derivatives as pde5-inhibitors |
| WO2004011463A1 (en) * | 2002-07-31 | 2004-02-05 | Lilly Icos, Llc. | Modified pictet-spengler reaction and products prepared therefrom |
-
2005
- 2005-05-02 WO PCT/IN2005/000136 patent/WO2005116030A1/en not_active Ceased
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5859006A (en) * | 1994-01-21 | 1999-01-12 | Icos Corporation | Tetracyclic derivatives; process of preparation and use |
| WO2002036593A1 (en) * | 2000-11-06 | 2002-05-10 | Lilly Icos Llc | Indole derivatives as pde5-inhibitors |
| WO2004011463A1 (en) * | 2002-07-31 | 2004-02-05 | Lilly Icos, Llc. | Modified pictet-spengler reaction and products prepared therefrom |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8063214B2 (en) * | 2004-10-28 | 2011-11-22 | Dr. Reddy's Laboratories Limited | Polymorphic forms of tadalafil |
| WO2006091975A1 (en) * | 2005-02-25 | 2006-08-31 | Teva Pharmaceutical Industries Ltd. | Process of synthesizing tadalafil |
| US7417044B2 (en) | 2005-02-25 | 2008-08-26 | Teva Pharmaceutical Industries Ltd. | Tadalafil having a large particle size and a process for preparation thereof |
| EP2238979A1 (en) * | 2009-04-06 | 2010-10-13 | LEK Pharmaceuticals d.d. | Active pharmaceutical ingredient adsorbed on solid support |
| CN104262340A (en) * | 2014-09-19 | 2015-01-07 | 济南诚汇双达化工有限公司 | Method for preparing Tadalafil |
| CN104262340B (en) * | 2014-09-19 | 2016-08-31 | 济南诚汇双达化工有限公司 | A kind of preparation method of Tadalafei |
| CN116574102A (en) * | 2023-04-11 | 2023-08-11 | 广东九明制药有限公司 | A kind of preparation method of tadalafil |
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