Title of Invention

A PROCESS FOR THE PREPARATION OF TADALAFIL

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.

Full Text

Field of the Invention: The present invention relates to a novel optimized process for the preparation and crystallization of (6R,12aR)-6-(l,3-Benzodioxol-5-yl)-2-methyl-l,2,3,4, 6, 7,12,12a-octahydropyrazino[2\r :6,l]pyrido[3,4-b]indole-l,4-dione (Tadalafil). Background of the Invention: Tadalafil namely (6R,12aR)-6-(l,3-Benzodioxol-5-yl)-2-methyl-l,2,3, 4,6,7,125l2a-octahydropyrazino[2%r:6,l]pyrido[3,4-b]indole-l,4-dione has the formula Tadalafil is a potent and selective inhibitor of cyclic guanosine 3\ 5'-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 558595OO6 (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 l,2,3,4-tetrahydro-2-chloroacetyl-l-(3,4-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 l,2,3,4-tetrahydrO"2-chloroacetyl-l-(3,4 -methylenedioxy phenyl) -9H-pyrido[3,4-b]indole-3-carboxylate (chloroacetyl derivative) in about 32 volumes to 50 volumes of methanol - Adding of methylamine solution (33 % in ethanol) - Maintaining at 50^C for about 14 hrs - Removing of solvent by distillation under reduced pressure - Dissolving of the resultant residue in 80 volumes to 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 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: Detail description of the Invention: The preparation and recrystallization of Tadalafil from (6R5 12aR)-Methyl l,2,3,4-tetrahydro-2-chloroacetyl"l-(3,4-methylenedioxyphenyl) - 9H-pyrido [3,4-b]indole-3"Carboxylate comprises of the following steps: - Suspending (6R, 12aR)-Methyll, 2,3,4-tetrahydro-2-chloroacetyl -1- (3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate in minimum volume of short chain alcohol - Addition of methyl amine solution - Heating and maintaining the reaction mass at temperature 40*^C to eO^'C for about 4 hrs to 10 hrs - Cooling the reaction mass - Isolation and drying of the solid - Dissolution of the obtained crude Tadalafil in minimum volumes of polar organic solvent - Addition of the clear solution into a water/ water miscible solvent - Cooling and maintaining the reaction mass at low temperature - Isolating, washing and drying the product Suspension of (6R, 12aR)-Methyl U2,3,4-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 temperature of lO^C to 40*^C preferably to 20^C to 30^C, directly precipitating the Tadalafil. The precipitated Tadalafil on isolation and drying gives the crude Tadalafil. The crude Tadalafil is recrystallized by dissolving it in about 2 to 12 volumes of a polar solvents preferably DMF, l,4-Dioxane5 DMSO and followed by transferring the filtrate to 6 volumes to 30 volumes of water/water miscible solvent such as methanol, ethanol, isopropanol, acetone or mixture thereof over a period of 30 min to 2 hrs. In another embodiment water/water miscible solvent can be added to the solution of Tadalafil crude in polar solvent. Reaction mass is cooled and the temperature is maintained -lO^C to 10°C preferably to -5°C to 5°C for 1 hr to 6 hrs followed by isolating, washing with acetone and drying gives the pure Tadalafil in quantitative yields of pharmaceutically acceptable quality. The (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) is prepared as per the reported prior art methods. The invention is now illustrated with a few non-limiting examples. 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 - 1 - (3,4 -methylenedioxy phenyl) -9H-pyrido[3,4-b]indole-3-carboxylate (Chloro acetyl intermediate) (79 g) in methanol (790 ml).Temperature of reaction mass is raised and mai ntained 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 RT, treated with activated carbon for 30 min. at 25^C o 30^C followed by filtration and addition to methanol (2010 ml) over Ihr at 25^C to 30*^C under mixing. The mass is cooled and maintained at O^C to 5^C for 2hrs. The 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) We claim: 1. A process for the preparation and recrystallization 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- 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 Heating and maintaining the reaction mass at temperature 40*^C to 60°C for about 4 hrs to 10 hrs Cooling and maintaining the reaction mass to 10°C to 40^C Isolating and drying the solid Dissolving the obtained crude Tadalafil in polar organic solvent Transferring the solution into water/ water miscible solvent or adding water/water miscible solvent to the solution of Tadalafil in organic polar solvent Cooling and maintaining the reaction mass for 1 hr to 6 hrs Isolating, washing and drying the product Without involving the large volumes of solvents, operations of distillation, extraction and evaporation of solvents 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-l- (3,4-methylene dioxyphenyl) - 9H-pyrido[3,4-b]indole"3-carboxylate 3. A process as claimed in claiml, wherein the short chain alcohol is methanol, ethanol and mixtures thereof 4. A process as claimed in claim 1, wherein the organic polar solvent is DMF, 1,4-dioxane, DMSO 5. A process as claimed in claim 1, wherein the volume of organic polar solvent is 2 volumes to 12 volumes w.r.t crude Tadalafil 6. A process as claimed in claim 1, wherein the water miscible solvent is methanol, ethanol, isopropanol, acetone and mixtures thereof 7. A process as claimed in claiml, wherein the product is dried at 35°C - 75"C

Documents:

491-che-2004 correspondence others 12-04-2011.pdf

491-che-2004 form-1 12-04-2011.pdf

491-CHE-2004 FORM-13 30-11-2010.pdf

491-che-2004-abstract.pdf

491-che-2004-claims duplicate.pdf

491-che-2004-claims original.pdf

491-che-2004-correspondnece-others.pdf

491-che-2004-correspondnece-po.pdf

491-che-2004-description(complete) duplicate.pdf

491-che-2004-description(complete) original.pdf

491-che-2004-form 1.pdf

491-che-2004-form 19.pdf

491-che-2004-form 3.pdf