FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION (SECTION 10)
AN IMPROVED PROCESS FOR THE PREPARATION OF TADALAFIL
UNICHEM LABORATORIES LIMITED, A COMPANY REGISTERED
UNDER THE INDIAN COMPANY ACT, 1956, HAVING ITS REGISTERED
OFFICE LOCATED AT UNICHEM BHAVAN, PRABHAT ESTATE, OFF S.
V. ROAD, JOGESHWARI (WEST), MUMBAI - 400 102.
MAHARASTRA, INDIA
The following specification particularly describes the invention and the manner in which it is to be performed.

AN IMPROVED PROCESS FOR THE PREPARATION OF TADALAFIL
TECHNICAL FIELD
The present invention relates to an improved and efficient process for the preparation of Tadalafil, chemically known as (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2,l:6,l]pyrido[3,4-b]indole-l,4-dione with high pharmaceutical purity.
BACKGROUND OF THE INVENTION
Tadalafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP) specific
phosphodiesterase type 5 (PDE5) used for the treatment of erectile dysfunction (ED)
under the name Cialis, and under the name Adcirca for the treatment of pulmonary
arterial hypertension. Tadalafil was developed by the biotechnology company ICOS,
and then again developed and marketed world-wide by Lilly ICOS, LLC, the joint
venture of ICOS Corporation and Eli Lilly and Company. Tadalafil which is
chemically known as (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-methyl-6-(3,4-
methylenedioxyphenyl)-pyrazino[2,l:6,l]pyrido[3,4-b]indole-l,4-dione is
represented as Formula I.


US 5859006 (Alain Claude-Marie Daugman; et. al. 1999) disclosed the process for the preparation of Tadalafil by Pictet-Spengler cyclization between a D-tryptophan methyl ester or its salt and piperonal using trifluoroacetic acid in anhydrous methylene dichloride (MDC) to form methyl-l,2,3,4-tetrahydro-l-(3,4-methyIenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate, cis- and trans-isomers. The required cis-isomer was purified by flash chromatography and then reacted with chloroacetyl chloride using sodium bicarbonate in anhydrous chloroform. The chloroacetyl intermediate was further reacted with ethanolic methyl amine to obtain Tadalafil, which was purified by column chromatography to get pure product.
The process taught by US 5859006 suffers from several drawbacks
i) The Pictet-Spengler cyclization between a D-tryptophan methyl ester or
a salt and piperonal using trifluoroacetic acid in anhydrous methylene
dichloride (MDC) takes inordinately long duration at times exceeding 4
days to complete the reaction. Very low temperatures are required.
Trifluoroacetic acid is highly corrosive and toxic material. Epimerization
process is time consuming and requires volatile solvents.
ii) The purification of required cw-isomer of Methyl-l,2,3,4-tetrahydro-l-
(3,4-methylenedioxyphenyl)-9H-pyrido [3,4-b]indole-3-carboxylate
from the mixture of cis and trans requires column chromatography which is quite expensive and time consuming, iii) Use of excess (2.3 equivalent) trifluoroacetic acid leads to generation of inseparable mass, reduces yield and restricts commercial scale production. iv) The overall yield of the reaction is also very low.

Various other methods are also known in the literature for the synthesis of Tadalafil, few of them are described below.
US7223863 B2 (Pandurang B. Deshpande; et. al. 2006) described a process for the preparation of Tadalafil in which D-Tryptophan methyl ester hydrochloride and piperonal was condensed in the presence of a dehydrating agent like sodium sulphate and in the presence of high boiling solvent like DME (N,N-Dimethylacetamide), DMF (N,N-Dimethylformamide), DMSO (Dimethyl sulphoxide) etc. to obtain mixture of cis- and trans-isomtx of methyl-1,2,3.4-tetrahydro-l-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate, which was reacted with aqueous hydrochloric acid to get required c/s-isomer. The cis-isomer was then treated with chloro acetyl chloride followed by methyl amine to get Tadalafil of Formula I
The said process has some limitation due to the use of expensive high boiling solvent like DME (N,N-Dimethylacetamide), DMF (N,N- Dimethyl formamide), DMSO (Dimethyl sulphoxide); which is very difficult to recover on industrial scale. The industrial application of the process is therefore expensive.
US 20110124866 Al (Lukasz Kaczmarek; et. al. 2011) described a process for the synthesis of Tadalafil by reacting cis-isomer of methyl-l,2,3,4-tetrahydro-l-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate with acetyl chloride in presence of THF and triethylamine. The reaction is monitored by TLC and then 40% aqueous methyl amine solution was added to the reaction mixture to obtain crude Tadalafil, which was recrystallized from acetone. Use of excess volume (approx. 30 volume) of solvent during the final crystallization limits its commercial scale production.

US 20120123124 Al (Milan Soukup; et. al. 2012) disclosed a process for the synthesis of Tadalafil. In the said process piperonal and L-tryptophan methyl ester was condensed in presence of magnesium sulfate in acetonitrile solvent. The required cis-isomer was then separated by forming a diastereomer with (1R) -10-camphorsulfonic acid (CSA) followed by crystallization. The cis CSA salt was added upon an aqueous saturated sodium bicarbonate solution to obtain cis-isomer of methyl-l,2,3,4-tetrahydro-l-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate. After that the cis product was reacted with chloroacetyl chloride followed by methyl amine to obtain Tadalafil.
The use of expensive (1R) -10-camphorsulfonic acid (CSA), for the separation of cis-isomer from the mixture of cis- and trans-isomer limits its commercial scale production.
WO2005068464 discloses process to prepare Tadalafil in which trifluoroacetic acid is used. It is highly toxic and corrosive reagent.
WO2004011463 (Orme, Mark, W. et. al. 2004) disclosed a process for the synthesis of Tadalafil using D-Tryptophan methyl ester hydrochloride and piperonal in anhydrous IPA to obtain hydrochloride of methyl-l,2,3,4-tetrahydro-l-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate. The product was then reacted with chloroacetyl chloride and then with methyl amine to get Tadalafil (I). This process requires 0.1% of anhydrous IPA which limits its commercial production. The patent is silent whether reaction can proceed without isolation of intermediates formed.
WO2004011463 is directed to a method of preparing a desired diastereomer of a tetrahydro-p-carboline compound utilizing a modified Pictet-Spengler cyclization reaction wherein the reaction is performed using a solvent in which only one of the diastereomers is soluble. It teaches a process in which the desired diastereomer is insoluble in the solvent, and undesired diastereomer is soluble. Another aspect of the

invention was to increase the yield of the desired diastereomer by allowing the undesired diastereomer to equilibrate in solution to provide additional desired diastereomer that precipitates from solution. WO2004011463 states "increase the yield of the desired diastereomer at the expense of the undesired diastereomer". Accordingly, since cis-isorner was less soluble in isopropyl alcohol, it was thrown out of the solution resulting in a concentration differential in the reaction mixture. The outcome of the concentration differential was conversion of trans-isomer to cis-isomer in the solution.
Inventive aspect of the present invention resides in that the desired isomer remains soluble and not thrown out of solution at the expenses of undesired isomer as in case of WO2004011463. It differs from the WO2004011463 in that present invention is devoid of selective solubility of only one isomer.
The Pictet-Spengler reaction is a chemical reaction in which a β-arylethylamine such as tryptamine undergoes ring closure after condensation with an aldehyde or ketone. Usually an acidic catalyst is employed and the reaction mixture heated, but some reactive compounds give good yields even at ambient conditions. The reaction was discovered in 1911 by Ame Pictet and Theodor Spengler.
In the year 1979, Cook and his co worker reported a synthetic route in the Journal of Organic Chemistry, Vol. 44, No. 4, Page. 535-545, for the condensation of an aldehyde and an amine to form an imine, which undergoes ring closer in presence of organic solvents such as Toluene in the presence of an acid to get the cyclized product. Paper describes use of various solvents. The paper reports surprising results obtained in aprotic solvents.
Neither the patent literature nor the paper referred above provides any hint or direction, nor it provides any criteria for selection of combination of solvents so as to produce the required isomer as main product. Inventive step of the present invention

resides in combining two solvents for the process of cyclization when use of same solvents individually produces discouraging results.
The processes taught by prior art have several drawbacks namely non-specificity, expensive, not suitable for scale up at plant level, energy intensive, difficult, giving lower yields, use of corrosive acids, longer duration of corrosive reactions and less user friendly. Considering the drawbacks of prior art and very complex methodologies applied, for the preparation of the Tadalafil, there is a urgent and pressing need for simple, energy economical, financially cheaper plant friendly process, environment friendly process for the preparation of (I), particularly an improved process which will selectively give us the required isomer of the compound.
Present invention discloses an improved process to prepare Tadalafil by in-situ conversion of the undesired trans-isomer into a cis-isomer with improved yield and quality, without the use of corrosive chemicals and without the use of costly techniques.
OBJECT OF INVENTION
The object of the present invention is to provide an improved process for the synthesis of Tadalafil (I).
Another object of present invention is to provide an improved process to selectively produce higher yields of required cis-isomer of Pictet-Spengler product.
Another object of present invention is to provide an improved process to eliminate the use of hazardous chemicals such as TFA and to eliminate the use of high boiling solvent like DME, DMF etc.
Still another object of the present invention is to avoid column chromatography for preparation of different stages of Tadalafil.

Another object of the present invention is to provide a simple process which will avoid stringent requirements like maintaining anhydrous conditions during reaction and can be scaled up easily.
SUMMARY OF INVENTION
The present invention relates to an improved process for the preparation of Tadalafil (I) which comprises of:
a) reaction between D-Tryptophan methyl ester hydrochloride (III) and piperonal (II) in the presence of a mixture of Cyclohexane and Methanol using a dean stark apparatus to obtain cis-isomer of methyl-l,2,3,4-tetrahydro-l-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate as a major product, (IV). This was followed by the reaction of optionally isolated cis-isomer of formula (IV) with chloroacetyl chloride in presence of a base to obtain intermediate (V),


(b). Further a reaction of (V) with aqueous methyl amine to get crude Tadalafil (I) and finally the purification of Tadalafil by recrystallization.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved, efficient process for producing pharmaceutically acceptable Tadalafil (I) comprising an efficient synthesis of a tetrahydro-β-carboline compound in a Cyclohexane and methanol, followed by a series of reactions with Chloroacetyl chloride and methylamine to obtain crude Tadalafil (I). Crude Tadalafil was converted to pharmaceutically acceptable Tadalafil (I) by recrystallization.
The process is efficient because it produces remarkably higher yield of desired isomer in a modified Pictet-Spengler cyclization.
An inventive aspect to the present invention is the reaction between D-Tryptophan alkyl or aryl ester hydrochloride (VI) and piperonal (II) in the presence of a solvent such as mixture of cyclohexane and methanol at ambient temperature (Scheme-I) to obtain cis-isomer of alkyl or aryl-1,2,3,4-tetrahydro-1 -β,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate as a major product.

The alkyl and aryl groups in D-Tryptophan alkyl or aryl ester hydrochlorides can be selected from methyl, ethyl, propyl, allyl, substituted ally!, phenyl, substituted phenyl etc. More preferably D-Tryptophan methyl ester hydrochloride is used. The reaction can be carried out at temperature range of 50°C to 80°C more preferably 60°C to 65°C. The percentage of Cyclohexane in the mixture of Cyclohexane and Methanol can vary from 95% to 5% more preferably in the range of 80% to 20% and most preferably 50%.
Dean stark apparatus was used to remove the water generated during the reaction. After completion of the reaction as monitored by the disappearance of the D-Tryptophan alkyl or aryl ester hydrochloride (VI), the solvent was distilled out and then 5 volume water was added to the reaction mixture.
The required product (1R,3R)-alkyl or aryl-1,2,3,4-tetrahydro-1 β,4-methylenedioxyphenyl)-9H-pyrido [3,4-b] indo!e-3-carboxylate (VII) was then extracted with dichloromethane after basification with sodium carbonate solution.
After that the dichloromethane layer of formula (VII) was reacted with
Chloroacetyl chloride in presence of a base at 5-10°C to get a crude (6R, 12aR)-alkyl
or aryll-l,2,3,4-tetrahydro-2-chloroacetyl-l-(3,4-methylenedioxyphenyl)-9H-
pyrido[3,4-b] indole-3-carboxylate (VIII) which was purified by using slurry wash with methanol to get solid compound (VIII). Examples of bases used are sodium carbonate, sodium bicarbonate triethyl amine, sodium hydroxide, potassium hydroxide more preferably sodium bicarbonate. The reaction can be carried out at a temperature between 0°C to 35°C, more preferably 5-10°C.
The compound (VIII) was then reacted with aqueous methylamine (40% in water or as may be commercially available) in a solvent at 50 - 55°C for 5h (monitored by HPLC) to get crude Tadalafil (I). The reaction may take 3 to 7 hours. The solvent is selected from water, methanol, ethanol, n-propanol, isopropyl alcohol, more generally C1-C5 alcohol or mixture thereof, more preferably isopropyl alcohol.

The crude product (I) was then recrystallized from suitable solvent to get white crystalline solid of (6R, 12aR)-2,3,6,7,12,12a-Hexahydro-2-methyl - 6-(3,4-methylenedioxyphenyl)-pyrazino[2,1,:6,l]pyrido [3,4-b] indole-1,4-dione having formula (I) (Mp: 302-303°C), [a]D20° = +71° (c = 1.00;CHC13).
The suitable solvent for recrystallization may be selected from acetic acid, n-propanol, isopropyl alcohol, N5N-Dimethyl formamide, THF, Water, or mixture thereof, more preferably acetic acid.
The process according to present invention is represented as in Scheme 1.
Scheme-1

Thus according to the present invention the pharmaceutically acceptable Tadalafil (I) is prepared by the process comprising a reaction between D-Tryptophan methyl ester

hydrochloride (III) and piperonal (II) in the presence of a mixture of Cyclohexane and methanol using dean stark apparatus to obtain cis-isomer of methyl-1,2,3,4-tetrahydro-l-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate (IV) as a major product. The reaction of optionally isolated cis-isomer (IV) with chloroacetyl chloride in presence of sodium bicarbonate furnishes intermediate (V), which on further reaction with aqueous methyl amine gives crude Tadalafil (I). The final pure Tadalafil is obtained by recrystallization of the crude product using acetic acid (Scheme II).
Scheme II


In the present invention the starting material D-Tryptophan methyl ester hydrochloride (III) and piperonal (II) was obtained from commercially available source and used.
Yet another aspect of the present invention is a Pictet-Spengler cyclization
between a D-Tryptophan methyl ester hydrochloride (III) and piperonal (II) in the
presence of a mixture of methanol and cyclohexane at 50-80°C as described herein to
produces (lR,3R)-Methyl-l,2,3,4-tetrahydro-l(3,4-methylenedioxyphenyl)-9H-
pyrido [3,4-b] indole-3-carboxylate, formula (IV) as a major product.
Inventive step of the present invention resides in selection of or identification of unique combination of solvents in the Pictet-Spengler cyclization between a D-Tryptophan methyl ester hydrochloride (III) and piperonal (II), especially when the solvents used in combination produce discouraging results when used alone. Cyclohexane and Methanol individually, produce very discouraging results. The reaction does not go well with cyclohexane alone and in methanol it is further interesting to note that reaction produces mixture of cis- and trans-isomers making separation an additional problem. In short use of cyclohexane and Methanol individually or alone is discouraging.
Improved process is to be interpreted as a process which is more economic than those reported in prior art, which selectively produces required isomer in significant proportion. Improved process is free from the defects or drawbacks observed when a singular solvent such as Methanol or Cyclohexane is used. It is interesting to note that aliphatic hydrocarbon and or an alcoholic solvent is described in WO 2004/011463 for the Pictet-Spengler cyclization, the patent does not give any hint to select a particular combination of solvent for best performance. The patent does not provide any motivation for selection of combination of Cyclohexane and Methanol in a proportion as disclosed in the present invention.

In the light of absence of any hint or motivation for selection of combination of solvents in WO 2004/011463 and the discouraging results obtained by use of individual solvent, present invention is non obvious over prior art.
In the present invention we have not used any acid for the cyclization reaction which is commonly known and used in Pictet-Spengler cyclization. An unique combination of solvent such as mixture of cyclohexane and methanol is used for the Pictet-Spengler cyclization between a D-Tryptophan methyl ester hydrochloride (III) and piperonal (II).
Pictet-Spengler cyclization between a D-Tryptophan methyl ester hydrochloride (III) and piperonal (II) in the presence of a solvent such as cyclohexane (8-10 vol) at 80°C require long time for completion. After 40 h of reaction time 20% of D-Tryptophan methyl ester hydrochloride (III) was present in the reaction mixture along with close to 10% unwanted trans-isomsr and 37% of required (1R,3R)-Methyl-1,2,3,4-tetrahydro-1 (3,4-methylenedioxyphenyl)-9H-pyrido [3,4-b] indole-3-carboxylate (IV). Dean stark apparatus was used to remove the water generated in the reaction.
Pictet-Spengler cyclization between a D-Tryptophan methyl ester hydrochloride (III) and piperonal (II) in the presence of a solvent such as methanol (8-10 vol) at 60-65°C require long time for completion of reaction. After 60 h of reaction less than 5% of D-Tryptophan methyl ester hydrochloride (III) was present in the reaction mixture along with close to 35% unwanted trans-isomer and 45% of required (lR,3R)-Methyl-l,2,3,4-tetrahydro-l(3,4-methylenedioxyphenyl)-9H-pyrido [3,4-b] indole-3-carboxylate (IV).
Interestingly in presence of mixture of methanol and cyclohexane (3:3 v/v), Pictet-Spengler cyclization between a D-Tryptophan methyl ester hydrochloride (III)

and piperonal (II) at 60-65°C require less time for completion of the reaction. After 22 h of reaction less than 4% of D-Tryptophan methyl ester hydrochloride (III) was present in the reaction mixture along with close to less than 5% unwanted trans-isomer and 85% of required (lR,3R)-Methyl-l,2,3,4-tetrahydro-l(3,4-methylenedioxyphenyl)-9H-pyrido [3,4-b] indole-3-carboxylate (IV). Dean stark apparatus was used to remove the water generated in the reaction.
Therefore inventive step of the present invention resides in identifying and using a proper combination of solvents in certain ratio or in identifying and using a unique mixture of solvents for a Pictet-Spengler cyclization between a D-Tryptophan methyl ester hydrochloride (III) and piperonal (II) that is a mixture of methanol and cyclohexane (3:3 v/v) at 60-65°C to get required (lR,3R)-Methyl-l,2,3,4-tetrahydro-l(3,4-methylenedioxyphenyl)-9H-pyrido [3,4-b] indole-3-carboxylate as major product within 22-30 h. The overall yield of Tadalafil using this process is around more than 50%. In this reaction condition the formation of required (1R,3R)-Methyl-1,2,3,4-tetrahydro-1 (3,4-methylenedioxyphenyl)-9H-pyrido [3,4-b] indole-3-carboxylate was more than 80% and unwanted trans-isomer was less than 10% in the reaction mixture.
Term major product is to be interpreted as product where the unwanted isomer is not more than 10 %.
Examples:
The following examples are presented for illustration only, and are not intended to limit the scope of the invention or appended claims.
Example 1

Preparation of (6R, 12aR) - methyl -l,2,3,4-tetrahydro-2-chloroacetyl-l -(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b] indole-3-carboxylate
To a stirred suspension of D-Tryptophan methyl ester hydrochloride (III) 100 gm (0.40 mole) a mixture of methanol and cyclohexane (3:3 v/v) 600 mL, piperonal (II) 62 gm (0.41 mole) was added and the reaction mixture was heated to reflux at around 60-65°C for 24-30 h. The progress of the reaction was monitored by TLC (HPLC monitoring). After completion of the reaction the solvent was distilled out followed by addition of 5 volume water to get heterogeneous mixture. The pH of the reaction mass was adjusted to 8-9 by using 20% sodium carbonate. The crude product (lR,3R)-Methyl-l,2,3,4-tetrahydro-l(3,4-methylenedioxyphenyl)-9H-pyrido [3,4-b] indole-3-carboxylate was then extracted by using dichloromethane (700 mL). The dichloromethane layer was then dried over sodium sulphate. After that, to the dichloromethane (700 mL) layer, Sodium bicarbonate 33.3 gm (0.40 mole) was added at room temperature. The reaction mixture was cooled to 0°C and chloroacetyl chloride 113 gm (1.00 mole) diluted with 100 mL dichloromethane was added drop wise. The reaction mixture was stirred for 2 - 3 h at same temperature, as the progress of reaction was monitored by TLC (HPLC monitor). After completion of the reaction, 300 mL water was added slowly at 0-5°C and stirred for 30 minutes and the pH of the reaction mixture was adjusted around 8-9 by liquid ammonia. The dichloromethane was then distilled out atmospherically from the reaction mixture and then filtered the solid under vacuum. The wet cake was then washed with water to get crude product of (6R, 12aR )- Methyl -l,2,3,4-tetrahydro-2-chloroacetyl-l -(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b] indole-3-carboxylate which was crystallized from methanol (300 ml) to obtain solid of title compound (V) (85.0 g) Mp: 233°C. HPLC purity >99 %.
Example 2

Preparation of (6R, 12aR )-2,3,6,7,12,12a-Hexahydro-2-methyl _ 6-(3,4. methylenedioxyphenyI)-pyrazino[2',1,:6,l]pyrido [3,4-b] indole-l,4-dione
To a stirred suspension of (6R, 12aR )- Methyl -l,2,3,4-tetrahydro-2-chloroacetyl-l -(3,4-methylenedioxyphenyl)-9H-pyrido[3s4-b] indole-3-carboxylate (250.0g), 2-propanol (1250 mL) was added at room temperature. A solution of 40% aqueous methylamine 375 mL was added to the reaction mixture and the mixture was heated to 50 - 55°C for 2-5 h. The progress of the reaction was monitored by TLC or HPLC. After completion of reaction the mixture was cooled gradually to 40- 45°C. The reaction mass was then filtered under reduced pressure and washed with 2-propanol (lx250 mL) to get wet solid of title compound. The crude product was dissolved in acetic acid (3250 mL, 13 vol) at 80-85°C and stirred for 1 h. The reaction mass was then cooled to room temperature gradually and stirred for 4-5 h. The reaction mass was then filtered off under vacuum and dried at 75-80 C in air oven to get white crystalline solid of Tadalafil (I) (6R, 12aR )-2,3,6,7,12,12a-Hexahydro-2-methyl - 6-(3,4-methylenedioxyphenyl)-pyrazino[2',1,:6,l]pyrido [3,4-b] indole-1,4-dione title compound (175.0g). (Mp: 302-303°C) ,[a]D200 = +710 (c= 1.00;CHC13).
Although the invention has been described with reference to specific embodiments, it is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments and alternate embodiments of the said invention, will become apparent to persons skilled in the art upon reference to the description of the invention. It is therefore contemplated that such modifications can be made without departing from the true spirit or scope of the present invention as exemplified and claimed herein below.

We Claim
1. An improved process to produce pharmaceutically acceptable Tadalafil (I), (6R, 12aR )-2,3,6,7,12,12a-Hexahydro-2-methyl - 6-(3,4-methylenedioxyphenyl)-pyrazino[2',l',:6,l]pyrido [3,4-b] indole- 1,4-dione comprising the steps of:
a) a cyclization reaction between a D-Tryptophan alkyl or aryl ester hydrochloride (VI) and piperonal (II) in the presence of a mixture of Cyclohexane and Methanol to obtain m-isomer of alkyl or aryl-l,2,3,4-tetrahydro-l-(3,4-methylenedioxyphenyl)-9H-pyrido [3,4-b] indoIe-3-carboxylate as a major product at an ambient temperature;
b) optionally isolated cis-isomer of alky or aryl-l,2,3,4-tetrahydro-l-(3,4-methylenedioxyphenyl)-9H-pyrido [3,4-b] indole-3-carboxylate, formula (IV) obtained in step a) is converted to (6R, 12aR )-alkyl or aryl-l;2,3,4-tetrahydro-2-chloroacetyl-l -(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b] indole-3-carboxylate by reaction with chloroacetyl chloride in presence of a base at an ambient temperature;
c) reacting (6R, 12aR )-alkyl or aryl-l,2,3,4-tetrahydro-2-chloroacetyl-1 -(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b] indole-3-carboxylate obtained in step b) with aqueous methyl amine or methanolic methyl amine in presence of a solvent selected from water, methanol, ethanol, n-propanol, isopropyl alcohol, more generally C1-C5 alcohol or mixture thereof, more preferably isopropyl alcohol, to get crude Tadalafil (I);
d) recrystallizing. crude Tadalafil obtained in step c) using a solvent selected from acetic acid, n-propanol, isopropyl alcohol, N,N-Dimethyl formamide, THF, Water, or mixture thereof more

preferably acetic acid, to obtain pharmaceutically acceptable Tadalafil.
2. An improved process according to claim la), wherein the said temperature is 50°C to 80°C, more preferably 60°C to 65°C.
3. An improved process according to claim la), wherein the said alkyl or aryl group in D-Tryptophan alkyl or aryl ester hydrochloride (VI) is selected from methyl, ethyl, propyl, allyl, substituted allyl, phenyl, substituted phenyl etc. more preferably methyl.
4. An improved process according to claim la), wherein the percentage of Cyclohexane in the mixture of Cyclohexane and Methanol is from 95% to 5% more preferably in the range of 80% to 20% and is most preferably 50%.
5. An improved process according to claim lb), wherein the said base is selected from sodium carbonate, sodium bicarbonate, triethyl amine, sodium hydroxide, potassium hydroxide more preferably sodium bicarbonate.
6. An improved process according to claim lb), wherein the said temperature is in the range of 0°C to 35°C more preferably 5-10°C.
7. A cyclization reaction between a D-Tryptophan alkyl or aryl ester hydrochloride (VI) and piperonal (II) in the presence of a mixture of methanol and cyclohexane at 50-80°C to obtain cis-isomer of alkyl or aryl-l,2,3,4-tetrahydro-l(3,4-methylenedioxyphenyl)-9H-pyrido [3,4-b] indole-3-carboxylate as a major product.
8. A cyclization reaction according to claim 7, wherein the said temperature is 50°C to 80°C more preferably 60°C to 65°C.
9. A cyclization reaction according to claim 7, wherein the said alkyl or aryl groups in D-Tryptophan alkyl or ary l ester hydrochloride (VI) is selected

from methyl, ethyl, propyl, allyl. substituted allyl, phenyl, substituted phenyl etc. more preferably methyl. 10. An improved process according to claim 7, wherein the percentage of Cyclohexane in the mixture of Cyclohexane and Methanol is 95% to 5% more preferably in the range of 80% to 20% and is most preferably 50%.