The present invention relates to a simple process for preparation of tadalafil in high yield and high purity without any pH adjustment using an acid.
Tadalafil is chemically pyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione, 6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-,(6R,12aR)- of Formula I wherein R = CH3.

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Tadalafil is a potent, selective and reversible inhibitor of cyclic guanosine 3',5'-monophosphate specific phosphodiesterase type 5 enzyme (cGMP specific PDE5). The biochemical, physiological, and clinical effects of cyclic guanosine 3',5'-monophosphate specific phosphodiesterase (cGMP-specific PDE) inhibitors suggest their utility in a variety of disease states in which modulation of smooth muscle, renal, hemostatic, inflammatory, and/or endocrine function is desired. Type 5 cGMP-specific phosphodiesterase (PDE5) is the major cGMP hydrolyzing enzyme in vascular smooth muscle, and its expression in penile corpus cavernosum has been reported (Taher et al., J. Urol., 149:285A (1993). Thus, PDE5 is an attractive target in the treatment of sexual dysfunction (Murray, DN&P 6(3):150-156(1993).
U.S. Pat. No. 5,859,006 (herein after the '006 patent) discloses a class of p-carboline compounds, and pharmaceutical compositions containing the p-carbolines, which are useful in the treatment of conditions wherein inhibition of PDE5 is desired. The '006 patent discloses two synthetic pathways for preparation of tadalafil. Path (I) involves Pictet-Spengler reaction of D-tryptophan methyl ester with piperonal leading to formation of a mixture of cis- and trans-tetrahydro (3-carboline intermediates of Formula A and B respectively in a 3:2 ratio.
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The cis-intermediate of Formula A (herein after the cis intermediate) is then converted to tadalafil in two steps. However the reaction times are longer and the yield of the desired cis intermediate is poor and additionally it has to be separated from the corresponding trans-isomer of Formula B. The condensation step in path (I) is carried out in the presence of trifluoroacetic acid which is a highly corrosive and hazardous reagent. Path (II) starts with the reaction of D-tryptophan methyl ester with piperonoyi chloride in the presence of triethylamine. Though this a better yielding process but it is cumbersome as it involves many synthetic steps.
PCT Application No WO 2004/11463 (herein after the '463 PCT application) discloses a four-step modified Pictet-Spengler reaction for preparation of tadalafil wherein D-tryptophan methyl ester hydrochloride is reacted with piperonal in isopropanol as solvent to obtain the cis-intermediate as the hydrochloride salt. The cis-intermediate is converted a chloroacetyl derivative of Formula C (herein after the "chloroacetyl derivative"),
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which is subsequently converted to tadalafil of Formula I by treatment with methylamine. The reaction is carried out in THF as solvent and excess methylamine is neutralized by
adding 12 IVl hydrochloric acid to a pH of 2.0. Tadalafil is crystallized from isopropanol and to increase the purity it is further recrystallized from glacial acetic acid.
However the present inventors have found that the use of hydrochloric acid is not favoured as acidic medium generates impurities, which are difficult to separate and this affects the yield and purity of tadalafil.
The present inventors have found that tadalafil can be prepared by a simple process in high purity and high yield wherein the said process does not involve pH adjustment using an acid. The term "pure" as used herein signifies a purity of 99% or more as measured by HPLC.
A first aspect of the present invention provides a process for the preparation of a
compound of Formula I,
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wherein R represents C1-4 straight or branched chain alkyl and wherein the said process comprises of, a) dissolving a compound of Formula II wherein R1 represents C1-4 straight or branched
chain alkyl and X represents a halogen selected from chlorine, bromine or iodine, in a
polar solvent,
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b) treating the solution obtained in step a) with an amine of Formula III,
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wherein R is as described above,
c) isolating a compound of Formula I from the reaction mass thereof, wherein the said
process does not involve pH adjustment.
The compound of Formula II can be prepared by methods known in the art. The compound of Formula II is dissolved in a polar solvent wherein the polar solvent is characterized by the fact that it has appreciable solubility for compound of Formula II. The solution can be optionally warmed to effect dissolution. The above solution is treated with an amine of Formula III and the resulting mixture is stirred at a temperature of about 20-60°C for 1-10 hours. The organic solvent is optionally recovered from the reaction mixture and the resultant mass is cooled to ambient temperature. To the cooled mass isopropanol and deionized water are added and the resulting mixture is cooled to 5-10°C and stirred for 1-4 hours and filtered. The solid so obtained is washed with isopropanol and deionized water mixture (1:1) and dried under vacuum at about 60-100°C for 10-15 hours to obtain a compound of Formula I. The product is recrystallized from a polar aprotic solvent. Compound of Formula I obtained by the present process is found to have a purity of 99.9% or more as measured by HPLC.
The polar solvent can be selected for example from the group comprising C3-6 ethers, C3.5 ketones and the like or mixtures thereof. Preferably the ether is 1,4-dioxane.
The polar aprotic solvent can be selected from the group comprising of C3-6 ketones, nitriles, C3-6 ethers or mixtures thereof. Preferably the polar aprotic solvent is nitrile selected from acetonitrile, propanenitrile, butanenitrile and the like or mixtures thereof. Most preferably the polar aprotic solvent is acetonitrile.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE 1
PREPARATION OF TADALAFIL

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1 -Benzo[1,3]dioxol-5-yl-2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1 H-p-carboline-3-carboxylic acid methyl ester (100g, 0.2344 mol) was added to 1,4-dioxane (500 ml) and the resulting mixture was heated to 35-45°C under stirring. To the above solution 40% methylamine (0.9375 mol, 81 ml) solution in water was added at 35-45°C and the reaction mixture was stirred at a temperature 40-53°C for 3-5 hours. 1,4-Dioxane (300-350ml) was recovered by distillation at 55-75°C under vacuum. To the resultant mass isopropanol (600 ml) and deionized water (500 ml) were added at 25-30°C and the resultant mixture cooled to 5°C and stirred at 5-10°C for 2 hours and filtered. The solid product obtained was washed with mixture of isopropanol (50 ml) and deionized water (50 ml) and dried under vacuum at 80-90°C for 12 hours to afford the title compound.
Yield: 90 g (98%)
Tadalafil (100gm) was dissolved in acetonitrile (4400ml) at 80-82°C. The solution was filtered and acetonitrile (3300 ml) was recovered at 80-82°C. The resultant mass was cooled to 5°C and stirred at 5-10°C for 2-5 hours. The solid obtained was filtered, washed with acetonitrile (200 ml) and dried under vacuum at 80-90°C for 12 hours to obtain pure tadalafil.
Yield: 92 g (92%)
Purity: 100% by HPLC.

WE CLAIM:
1. A process for the preparation of a compound of Formula I,
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wherein R represents C1-4 straight or branched chain alkyl and wherein the said process comprises of,
a) dissolving a compound of Formula II wherein R1 represents C1-4 straight or branched chain alkyl and X represents a halogen selected from chlorine, bromine or iodine, in a polar solvent,
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b) treating the solution obtained in step a) with an amine of Formula III,
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wherein R is as described above
c) isolating a compound of Formula I from the reaction mass thereof, wherein the said
process does not involve pH adjustment.
2. A process according to claim 1 wherein the polar solvent is selected from the group comprising of C3-6 ethers, C3.5 ketones or mixtures thereof.
3. A process according to claim 2 wherein the ether is 1,4-dioxane.
4. A process according to claim 1 wherein the amine used in step b) is methylamine.
5. A process according to claim 1 further comprising recrystallization of compound of Formula I from a polar aprotic solvent.
6. A process according to claim 5 wherein the polar aprotic solvent is selected from the group comprising of C3-6 ketones, nitriles, C3-6 ethers or mixtures thereof.
7. A process according to claim 6 wherein the compound of Formula I obtained has a purity of 99.9% or more.