DESC:FILED OF INVENTION

The present invention provides a novel process for the preparation of Tadalafil.

BACKGROUND OF THE INVENTION

Tadalafil, chemically known as (6R-trans)-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-pyrazino[1',2':1,6] pyrido[3,4-b]indole-1,4-dione, Tadalafil is PDE5 inhibitor marketed in pill form for treating erectile dysfunction (ED) under the name Cialis, and under the name Adcirca for the treatment of pulmonary arterial hypertension.

Cialis was discovered by Glaxo Wellcome (now GlaxoSmithKline) under a partnership between Glaxo and ICOS to develop new drugs that began in August 1991. In 1993, the Bothell, Washington biotechnology company ICOS Corporation began studying compound IC351, a phosphodiesterase type 5 (PDE5) enzyme inhibitor.

Tadalafil is a selective inhibitor of cGMP specific Type V phosphodiesterase (PDE5) and it is used for treatment of erectile dysfunction (Clalis®). The pharmacological activity of Tadalafil is specifically attributable to (6R,12aR)-enantiomer and many syntheses have been developed to prepare the enantiomerically pure compound. Since Tadalafil possesses at C(12a)-atom R-configuration, corresponding to configuration of D-tryptophan, all published syntheses have been using exclusively the significantly more expensive D-tryptophan as the starting material

No synthesis of Tadalafil has ever been reported using either L- or rac.-tryptophan which are less expensive: L-tryptophan is less expensive because its industrial production is based on the fermentation of indole and serine using either wild-type or genetically modified bacteria. This conversion is catalyzed by the enzyme tryptophan synthase which cannot produce D-tryptophan. For the synthesis of Tadalafil the required, more expensive D-tryptophan has to be manufactured by a resolution of rac.-tryptophan prepared by chemical method. For cost efficient manufacture of Tadalafil there is a clear need for a new process in which the less expensive either L- or racemic tryptophan could be used.
(U.S. Pat. No. 6,140,329, U.S. Pat. No. 6,127,542, Synlett 2004, 8, 1428, OPPI Briefs 2005, 37, No. 1, Tetrahedron Asymmetry 2008, 19, 435-442, ibid. 2009, 20, 2090, ibid. 2009, 20, 430, Synth. Commun. 2008, 38, 4265 and Europ. J. Org. Chem. 2010, 1711.

US20120123124 describe process for preparing racemic or L-tryptophan the invention describes preparation of an enantiomerically pure compound making using chiral acid HX is (1R or 1S)-10-camphorsulfonic acid or (D or L)-tartaric acid or (D or L)-dibenzoyl tartaric acid, (1R or 1S)-3-bromocamphor-8-sulfonic acid, (±)-1,1'-binaphtyl-2,2'-diyl-hydrogenphosphate or (D or L)-mandelic acid.

WO2004011463 describe process for preparing compound formula(V) using a pictet-spengler reaction using organic solvent like toluene, benzene, xylene. Acetonitril, propionitrile, ethylene acetate, propanol, butanol, THF(tetrahydrofuran), MTBE(Methyl tertiary butyl ether), dioxane, hexane, heptane, acetic acid, only written in description but example only isopropyl alcohol; they provide crude product 92% purity, purification and seeding of process in isopropyl alcohol, other steps they are using THF as solvent which is expensive solvent disclosed steps having low yield and loss of purity.

US20110124866 process for preparation of tadalafil one pot process using cyclic ether or aliphatic ketone as solvent.

US2007/0004737 process for purification of crude tadalafil to pure tadalafil using solvent C2-C6- aliphatic alcohol, and mixtures of keton or nitriles with a hydroxylic solvent.

WO2005068464 process for the preparation of Tadalafil (I), heating a mixture of (1R, 3R)-methyl-1,2,3,4-tetrahydro-2-chloroacetyl-(3,4-methylenedioxyphenyl)-9H-pyrido[3, 4]indole-3-carboxylate (II), methylamine and a suitable solvent[methanol,ethanol, isopropyl alcohol] at 40-60 °C for 10-12 hrs.

WO2007052283 process for the preparation of tadalafil(I), D-Tryptophan methyl ester hydrochloride, added Piperonal in high boiling solvent is selected from N, N-Dimethyl acetamide, Dimethyl sulfoxide, N, N-dimethyl formamide, N-methyl pyrrolidine or mixture.

WO200904557 patent describe process for the preparation of tadalafil(I), D-Tryptophan methyl ester compound formula (III), added compound formula(IV) in salfolane solvent.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide an improved process for the preparation of Tadalafil having grater than 99.5%.

Yet another objective of the present invention is to provide an improved process, which having high purity grater than 99.0% of (1R,3R)-methyl 1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate hydrochloride of compound formula(V).

Yet another objective of the present invention is to provide a simple and environmentally friendly process for the preparation of tadalafil, which avoids use of hazardous and expensive reagents.

Yet another objective of the present invention is to provide a process with a good yield and high purity grater than 99.5%.

Yet another objective of the present invention is to provide an improved process for tadalafil, which is simple and industrially applicable.
SUMMARY OF INVENTION

The present invention relates to a novel improved process for the preparation of Tadalatil of Formula (I) having grater than 99.5%.

I
which comprises:
a) (R)-2-amino-3-(1H-indol-3-yl)propanoic acid of compound formula(II)

II
treating with thionyl chloride in methanol to give (R)-methyl 2-amino-3-(1H-indol-3-yl)propanoate hydrochloride of compound formula(III)

III

b) (R)-methyl-2-amino-3-(1H-indol-3-yl)propanoate hydrochloride of compound formula(III)

III
react with benzo[d][1,3]dioxole-5-carbaldehyde of compound formula (IV)

IV
in n-butanol solvent with out any catalyst to given to (1R,3R)-methyl 1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate hydrochloride of compound formula(V).

V
c) reacting (1R,3R)-methyl 1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido [3,4-b]indole-3-carboxylate hydrochloride of Formula (V)

V
React with chloroacetylchloride in methanol solvent to uncyclis compound formula (VI)

VI

which is react with 40% of aqueous solution of methylamine in methanol to give title compound formula (I).
d) Compound formula (I) treated with dichloro methan solvent and methanol solvent.

DETAILED DESCRIPTION OF THE INVENTION

A first object of the present invention to provide an improved process for the preparation of tadalafil of Formula (I) having grater than 99.5%,

I

Thus, preparation of (1R,3R)-methyl 1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido [3,4-b]indole-3-carboxylate hydrochloride of Formula (V)

V

using (R)-methyl 2-amino-3-(1H-indol-3-yl)propanoate hydrochloride of compound formula(III)

III

react with benzo[d][1,3]dioxole-5-carbaldehyde of compound formula (IV)

IV

in alcohol solvent with out any catalyst to given to (1R,3R)-methyl 1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate hydrochloride of compound formula(V).

Another embodiment of present invention is mole ratio of (R)-methyl 2-amino-3-(1H-indol-3-yl)propanoate hydrochloride of compound formula(III) and benzo[d][1,3]dioxole-5-carbaldehyde of compound formula (IV) is 1 to 1.2 mole. But preferably mole 1.05 mole.

Another embodiment of present invention is wherein the reaction carried out in solvent is alcohol solvent selected from group is n-butanol, tert-butanol preferably n-butanol.

Another embordiment of present invention is the reaction is carried temperature range 110ºC to 130ºC and most preferably temperature range 120ºC-125ºC.

Another embodiment of present invention is wherein heat the reaction mass to 120º-125ºC, reaction completes in 4 to 6 hrs. during the reaction obtain water is removing in reaction mixture using the dean stark apparatus.

Another embodiment of present invention is not carried out with out any catalyst. In prior art reference using base as catalyst. In prior art reference using reaction carryout less temperature and having more time to maintained, not achieved yield and purity.

Another embodiment of the present invention reaction compound formula(V) is desire form (1R, 3R) achieved with out any purification.

Another embodiment of the present invention is compound formula(V) purity achieved 98-99% other isomer less than 1%.

Another embodiment of the present invention is compound formula(V) co-distillation solvent is aromatic solvent.

Another embodiment of present invention reaction workup process using aromatic solvent like toluene, xylene, hexeane but preferably solvent toluene.

Another embodiment of the present invention is distilled approx 150ml n-butanol. Charge 50ml toluene and co-distilled n-butanol below 100°C. Charge 250ml toluene and Maintain for 1hr at 25º-35ºC and filter, wash with toluene, Suck dry.

Another embodiment of present invention reacting (1R,3R)-methyl 1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido [3,4-b]indole-3-carboxylate hydrochloride of Formula (V)

V

react with chloroacetyl chloride in alcoholic solvent to uncyclise compound formula (VI)

VI

which is react with aqueous solution of methylamine to give title compound formula (I) .
d) compound formula (I) treated with chlorinated solvent and alcoholic solvent.

(1R,3R)-methyl 1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido [3,4-b]indole-3-carboxylate hydrochloride of Formula (V) converted to free base using inorganic salt.

Another embodiment of present invention is wherein the reaction carried out in chlorinated solvent, chlorinated solvent is dichloro methane, ethylene dichloro but preferably solvent is dichloro methane.

Another embordiment of present invention is the reaction using inorganic salt is alkali carbonate like sodium carbonate, pottasium carbonate but preferably sodium carbonate using as solution in water.

Another embordiment of present invention is the reaction is 8 to 10% solution of sodium carbonate in water.

Another embordiment of present invention is the reaction is carried temperature range 15ºC to 35ºC and most preferably temperature range 20ºC-30ºC.

Another embordiment of present invention dichloro methane solvent extration using treating with sodium chloride solution and dry with sodiumsulfate solid.

Another embordiment of present invention dichloro methane solvent treated with sodium chloride solution is using 10-20% of solution using neutrlizing solvent.

Another embodiment of present invention is mole ratio of (1R,3R)-methyl 1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido [3,4-b]indole-3-carboxylate hydrochloride of Formula (V) and base is 1 to 5 mole. But preferably mole 1: 2.3 mole.

Another best mode of doing reaction (1R,3R)-methyl 1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido [3,4-b]indole-3-carboxylate hydrochloride(65gm, 1 mole) to the assembly at temperature 20º–30ºC, Charge Dichloromethane(650ml) at temperature 20º–30ºC. Charge 8% aqueous sodium carbonate solution(600ml) at temperature 20º–30ºC, Stirred the reaction mass for 20–30 minutes, stop stirring and allowing settling for layer separation. Check out pH NLT(not less than) 8, if Emulsion occur filter through hi flow bed Separated lower Dichloromethane layer and keep aside, Back extract aqueous layer with Dichloromethane Combined Dichloromethane layer and wash with 10% aqueous sodium chloride solution (650ml). Take clear Dichloromethane layer and dried over anhydrous sodium sulfate for 1hr Check moisture content NMT(not more than) 0.5%. Filter Dichloromethane layer and wash with 65ml Dichloromethane.

(1R,3R)-methyl 1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido [3,4-b]indole-3-carboxylate hydrochloride of Formula (V) free base treated with chloroacetylchloride.

Another embodiment of present invention is wherein the reaction carried out in chlorinated solvent, chlorinated solvent is dichloromethane, ethylene dichloro but preferably solvent is dichloro methane.

Another embodiment of present invention is wherein heat the reaction mass to -5º to 10ºC, reaction completes in 1 to 4 hrs. but preferable temperature is 0º to 5ºC and 1 to 3hrs.

Another embodiment of present invention is mole ratio of (1R,3R)-methyl 1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido [3,4-b]indole-3-carboxylate hydrochloride of Formula (V) and chloroacetylchloride is 2 to 3 mole. But preferably mole 2.5 mole.

Another embordiment of present invention is the reaction carryout in presence of base using base is inorganic salt is alkali carbonate like sodium carbonate, pottasium carbonate but preferably sodium carbonate

Another embodiment of present invention is mole ratio of (1R,3R)-methyl 1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido [3,4-b]indole-3-carboxylate hydrochloride of Formula (V) and sodium carbonate is 2 to 3 mole. But preferably mole 1.5 mole.

Another best mode of doing reaction take dichloromethane layer in clean Round bottom flask,charge 19.5 gm (1.5 mole)anhydrous sodium carbonate and cool the reaction mass to 0–5ºC. Add 38ml (2.5 mol) Chloroacetylchloride slowly from addition funnel by maintaining at 0–5ºC during period of 40–60 minutes Stir the reaction mass at 0–5ºC for 1– 3 hours and monitor the progress of reaction by HPLC limit stating material not more than 1.0%, After completion of reaction dilute the reaction mass with 650ml dichloromethane than Add 650 ml of DM water, Separate the dichloromethane layer and Back extract Aqueous layer with 130 ml dichloromethane combined both the organic layers and wash twice with 8% sodium carbonate solution (2X650 ml), Again wash the lower organic layer with of 650ml DM water distilled out dichloromethane under vacuum at 35–40ºC completely.

The present invention relates to improved process for the preparation of tadalafil of formula (I)having purity grater than 99.5%, uncyclise compound formula (VI)

VI

which is react with aqueous solution of methylamine to give title compound formula (I) .
Then after Crude compound formula (I) treated with chlorinated solvent and alcoholic solvent.

Another embodiment of present invention is wherein the reaction carried out in methanol, ethanol, isopropanol, n-butanol, tert-butanol preferably methanol

Another embodiment of present invention is wherein heat the reaction mass to 45ºC to 65ºC, reaction completes in 1 to 4 hrs. but preferable temperature is 55ºC to 60ºC and 1 to 3hrs.

Another embodiment of present invention is compound formula(VI) and 40% solution of aqueous methyl amine solution.

Another embodiment of the present invention is using solvent chlorinated solvent, chlorinated solvent is dichloro methane, ethylene dichloro but preferably solvent is dichloro methane.

Another embodiment of the present invention is anti solvent is alcohol solvent selected from group is methanol, ethanol, isopropanol, n-butanol, tert-butanol preferably methanol.

Another embodiment of the present invention is purification solvent is alcohol solvent selected from group is methanol, ethanol, isopropanol, n-butanol, tert-butanol preferably methanol.

Another embodiment of the present invention is purification carried out at temperature range about 20ºC to 50ºC, but preferably temperature is 40ºC to 45ºC.

Another embodiment of the present invention making compound formula(I) having HPLC purity achieved 99.5%.

Another best mode of doing reaction take 130ml methanol and distilled out under vacuum at below 55ºC Charge 650ml methanol in the above residual mass, stir the reaction mass for 10–20 minutes. Add 88ml aqueous Methylamine solution (40% in water) in 30–45 minutes at 5–15ºC and stir reaction mass for 30–45 minutes. Heat the reaction mass to 55– 60ºC and maintain at this temperature till the completion of reaction and monitor the progress of reaction by HPLC. Starting material not more than 1.0%, After completion of reaction cooled to 45-50ºC, add 845 ml Dichloromethane (3gm) charge carbon filter and and wash with 100ml dichloromethane collect clear ml and distilled completely, add 100ml methanol cool to 25-30ºC maintain 1 hr, Filter the solids and wash the wet cake with methanol, Wet Weight 58 to 68gm.

Another best mode of doing reaction take100ml Methanol at 25-30ºC, Charge above crude Tadalafil (58gm to 68gm) to the assembly at 25-30ºC, Stir the reaction mass at 40 – 45ºC for 20– 40 minutes Cool to 25-30°C and maintained for 60min,Filter the solids and wash the cake with methanol, Dry the material in vacuum oven at 60– 70ºC till Loss on drying less than 0.3%. 40–45 grams 80–90% Yield: 50-60 grams
Chromatographic Purity (by HPLC): =99.5 (% area).

Present invention provides (R)-methyl 2-amino-3-(1H-indol-3-yl)propanoate hydrochloride of compound formula (III)

III

comprising
(R)-2-amino-3-(1H-indol-3-yl)propanoic acid of compound formula(II)

II
treating with acid chloride in alcoholic solvent to give (R)-methyl 2-amino-3-(1H-indol-3-yl)propanoate hydrochloride of compound formula(III)
Another embodiment of present invention reaction carried out in alcoholic solvent where in alcohol solvent selected from group is methanol, ethanol, isopropanol, n-butanol, tert-butanol preferably methanol.

Process using the reaction carried out in acid chloride compound is define as thionyl chloride, phosphorus chloride preferably thionyl chloride, wherein the reaction carryout temperature range 50ºC to 80ºC and most preferably temperature range 65ºC-70ºC reaction completes in 2 to 4 hrs., wherein the reaction workup process using aromatic solvent like toluene, xylene, hexane but preferably solvent toluene.

Another embodiment of present invention reaction carried out in solvent is alcohol solvent selected from group is methanol, ethanol, isopropanol, n-butanol, tert-butanol preferably methanol.

Another embodiment of present invention reaction carried out in acid choride compound is define as thionyl chloride, phosphorus chloride preferably thionyl chloride.

Another embodiment of present invention reaction carryout temperature range 50ºC to 80ºC and most preferably temperature range 65ºC-70ºC.

Another embodiment of present invention reaction workup process using aromatic solvent like toluene, xylene, hexeane but preferably solvent toluene.

Throughout the description and claims the word "comprise" and variations of the word are not intended to exclude other technical features, additives, components, or steps. The content of the abstract of the present application is incorporated herein as reference. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples are provided by way of illustration, and is not intended to be limiting of the present invention.

Example – 1
Preparation of D-Tryptophan methyl ester hydro chloride[(R)-methyl 2-amino-3-(1H-indol-3-yl)propanoate hydrochloride of compound formula (III)]
Arrange four neck two liter round bottom flask with stopper, thermometer pocket,condenser with nitrogen purger, Charge 1000 ml of methanol under nitrogen atmosphere, Add 134.0 grams ( 2.3 Mole) of thionyl chloride drop wise from addition funnel at 10º– 30ºC. Cool the reaction mass to 10º– 20ºC and then add 100 grams (1 Mole) of D-Tryptophan [(R)-2-amino-3-(1H-indol-3-yl)propanoic acid of compound formula(II)] in lot wise in 20–40 minutes at 10º– 20ºC. Stir the reaction mass at 10º– 20ºC for 40–60 minutes. Reflux the reaction mass at 65º–70ºC. under nitrogen atmosphere for 2–4 hours and monitor the progress of reaction by HPLC. After completion of reaction distilled out methanol under vacuum at below 50ºC. Charge 100 ml of Toluene and distilled out solvents under vacuum at temperature below 65ºC. Charge 500 ml of toluene and 100 ml of methanol and reflux the reaction mass at 65º– 70OC for 20–40 minutes and then cool the reaction mass to 0º–5ºC. Stir the reaction mass at 0º–5ºC for 45– 60 minutes Filter the solids and wash the cake with toluene (2X100 ml). Dry the material at 65º– 70ºC till constant weight not more than 2.0% LOD (Loss on dying) Yield: 106 to 118 grams (85 – 95%).

Example – 2
Preparation of (1R,3R)-methyl 1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate hydrochloride
In a 1.0 liter 4 neck round bottom flask with condenser and deanstark assembly charge 200 ml of n-Butanol, Charge 50 grams (1 Mole) of D-Tryptophan methyl ester HCl (Example 1 as per (R)-methyl 2-amino-3-(1H-indol-3-yl)propanoate hydrochloride of compound formula (III)]) and stir the mass for 5– 10 minutes. Charge 31 grams (1.05 Mole) of Piperonal [benzo[d][1,3]dioxole-5-carbaldehyde of compound formula (IV)] at 25º– 35ºC stir the reaction mass for 15–30 minutes Heat the reaction mass to 117º– 120ºC and monitor the progress of reaction by TLC(Thin Layer chromatography) till the reaction completes (Reaction completes in 4–6 hours). Distilled approx 150ml n-butanol. Charge 50ml toluene and co-distilled n-butanol below 100°C. Charge 250ml toluene and Maintain for 1hr at 25º-35ºC and filter, wash with toluene, Suck dry and unload wet wt=65-68 gm; dry weight-66gm.
Chromatographic Purity (by HPLC): =98 (% area).

Example – 3
Preparation of (1R,3R)-methyl 1-(benzo[d][1,3]dioxol-5-yl)-2-(2-chloroacetyl)- 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate
Charge 65gm (1 Mole) (1R,3R)-methyl 1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate hydrochloride to the assembly at 20º–30ºC, Charge Dichloromethane (650ml) at 20º–30ºC. Charge (600ml) (2.3 mole) 8% aqueos sodium carbonate solution at 20º– 30ºC,Stir the reaction mass for 20–30 minutes, stop stirring and allowing settling for layer separation. Check pH not less than 8, if Emulsion occur filter through hi flow bed Separated lower Dichloromethane layer and keep aside
Back extract aqueous layer with Dichloromethane Combined Dichloromethane layer and wash with (650ml) 10% aqueous sodium chloride solution. Take clear Dichloromethane layer and dried over 20 gm anhydrous sodium sulfate for 1hr Check moisture content Not more than 0.5%, Filter Dichloromethane layer and wash with 65ml Dichloromethane. Take Dichloromethane layer in clean Round bottom flask,charge 19.5 gm (1.5 mole)anhydrous sodium carbonate and cool the reaction mass to 0–5ºC. Add 38ml (2.5 mol) Chloroacetylchloride slowly from addition funnel by maintaining at 0–5ºC during period of 40–60 minutes Stir the reaction mass at 0–5ºC for 1– 3 hours and monitor the progress of reaction by HPLC limit stating material not more than 1.0%, After completion of reaction dilute the reaction mass with 650ml Dichloromethane than Add 650 ml of DM water, Separate the Dichloromethane layer and Back extract Aqueous layer with 130 ml Dichloromethane combined both the organic layers and wash twice with 8% sodium carbonate solution (2X650 ml), Again wash the lower organic layer with of 650ml DM water Distilled out dichloromethane under vacuum at 35–40ºC completely, Charge 130ml methanol and distilled out under vacuum at below 55ºC Charge 650ml methanol in the above residual mass, stir the reaction mass for 10–20 minutes. Add 88ml aqueous Methylamine solution (40% in water) in 30–45 minutes at 5–15ºC and stir reaction mass for 30–45 minutes. Heat the reaction mass to 55– 60ºC and maintain at this temperature till the completion of reaction and monitor the progress of reaction by HPLC. Starting material not more than 1.0%, After completion of reaction cooled to 45-50ºC, add 845 ml Dichloromethane (3gm) charge carbon filter and and wash with 100ml dichloromethane collect clear ml and distilled completely, add 100ml methanol cool to 25-30ºC maintain 1 hr, Filter the solids and wash the wet cake with methanol, Wet Weight 58 to 68gm.
100ml charge Methanol at 25-30ºC, Charge above crude Tadalafil (58gm to 68gm) to the assembly at 25-30ºC, Stir the reaction mass at 40 – 45ºC for 20– 40 minutes Cool to 25-30°C and maintained for 60min,Filter the solids and wash the cake with methanol, Dry the material in vacuum oven at 60– 70ºC till Loss on drying less than 0.3%. 40–45 grams 80–90% Yield: 50-60 grams
Chromatographic Purity (by HPLC): =99.5 (% area).
,CLAIMS:1. An improved process for the preparation of Tadalafil of formula (I) having purity 99.5%,

I
which comprises:
a) (R)-methyl 2-amino-3-(1H-indol-3-yl)propanoate hydrochloride of compound formula(III)

III
reacted with benzo[d][1,3]dioxole-5-carbaldehyde of compound formula (IV)

IV

in alcoholic solvent with out any catalyst to give (1R,3R)-methyl 1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate hydrochloride of compound formula(V).

V

b) reacting (1R,3R)-methyl 1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido [3,4-b]indole-3-carboxylate hydrochloride of Formula (V)

V
with chloroacetylchloride in alcoholic solvent to uncyclise compound formula (VI)

VI

which is reacted with aqueous solution of methylamine to give title compound formula (I) .
c) compound formula (I) treated with chlorinated solvent and alcoholic solvent.

2) The process according to claim 1 step-(a), where in the reaction is carried temperature range 110ºC to 130ºC and most preferably temperature range 120ºC-125ºC.

3) The process according to claim 1 step-(a), wherein the reaction carried out in solvent is
alcohol solvent selected from group is methanol, ethanol, isopropanol, n-butanol, tert-butanol preferably n-butanol.

4) The process according to claim 1 step-(a), wherein reaction mixture removing water using the dean stark apparatus.

5) The process according to claim 1 step-(b), wherein the chlorinated solvent, chlorinated solvent is dichloro methane, ethylene dichloro but preferably solvent is dichloro methane.

6) The process according to claim 1 step-(b), wherein the reaction is carried temperature range -10ºC to 10ºC and most preferably temperature range 0ºC-5ºC.

7) The process according to claim 1 step-(b), wherein compound formula (IV) is reacted with aqueous methylamine solution, aqueous solution % of methylamine in water is up to 40%.

8) The process according to claim 1 step-(b), wherein compound formula (IV) is reacted with aqueous methylamine solution, reaction is carried temperature range 45ºC to 65ºC and most preferably temperature range 55ºC-60ºC.

9) The process according to claim 1 step-(b), wherein reaction carried out in solvent is
alcohol solvent selected from group is methanol, ethanol, isopropanol, n-butanol, tert-butanol preferably methanol.

10) The process according to claim 1 step-(c), wherein purification solvent is alcohol solvent selected from group is methanol, ethanol, isopropanol, n-butanol, tert-butanol preferably methanol.

11) A process wherein, (R)-methyl 2-amino-3-(1H-indol-3-yl)propanoate hydrochloride of compound formula(III) reacted with benzo[d][1,3]dioxole-5-carbaldehyde of compound formula (IV) in n-butanol solvent with out any catalyst to give (1R,3R)-methyl 1-(benzo[d] [1,3] dioxol-5-yl)-2,3,4,9-tetrahydro-1 H-pyrido[3,4-b] indole-3-carboxylate hydrochloride of compound formula(V).

12) An improved process for the preparation of Tadalafil of formula (I) having purity
99.5% which comprising

a) (R)-2-amino-3-(1H-indol-3-yl)propanoic acid of compound formula(II)

II
treated with thionyl chloride in methanol solvent to give (R)-methyl 2-amino-3-(1H-indol-3-yl)propanoate hydrochloride of compound formula(III) a reaction carryout at temperature range 65ºC to 70ºC, isolation in toluene

III
b) reacting to product of step(a) with as per the claim no.1.

13) A process for the preparation of compound of formula (V) having purity 98%,

V
which comprises (R)-methyl 2-amino-3-(1H-indol-3-yl)propanoate hydrochloride of compound formula(III)

III
reacted with benzo[d][1,3]dioxole-5-carbaldehyde of compound formula (IV)

IV
in n-butanol with out any catalyst to given to title compound.
14) A process for the preparation of tadalafil substantially as herein described with reference to the examples.