The following specification particularly describes the nature of this application and the manner in which it is to be performed.

PROCESS FOR PREPARATION OF TADALAFIL

INTRODUCTION TO THE INVENTION
The present application relates to facile and selective approaches for the synthesis of tadalafil and its isomers along with its derivatives.

Tadalafil is chemically known as (6R  12aR)-2 3 6 7 12 12a-hexahydro-2-methyl-6-(3  4-methylene dioxyphenyl)-pyrazino [2’ 1’:6  1] pyrido [3  4-b] indole-  1 4-dione (hereinafter referred to by the adopted name “tadalafil”)  and is structurally represented by Formula I.

Formula I
Tadalafil is a potent and selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). Tadalafil is used in the treatment of erectile dysfunction. It is available in the market under the brand name CIALIS™ as tablets for oral administration  each tablet containing 5  10  or 20 mg of tadalafil.
U.S. Patent No. 5 859 006 describes tadalafil  its related compounds  and methods for their synthesis. The patent describes the preparation of tadalafil as depicted by Scheme 1. Briefly  the process involves condensation of D-tryptophan methyl ester of Formula 1 with piperonal of Formula 2 to yield a mixture of isomers of the beta carboline ester of Formula 3 which are separated using column chromatography. Reacting the required isomer of Beta-carboline ester of Formula 4 with a haloacetyl halide like chloroacetyl chloride in a suitable solvent in the presence of a base or an alkaline metal carbonate to give (1R 3R)-methyl 1 2 3 4-tetrahydro-2-chloroacetyl-(3 4-methylenedioxyphenyl)-9H-pyrido[3  4-b] indole 3-carboxylate of Formula 5  which on treatment with a primary amine in a suitable solvent such as alcohol gives tadalafil of Formula I.

Scheme 1
The method described in the above patent employs toxic reagents like chloroacetyl chloride and involves the purification of intermediates by column chromatography at various stages  the process is time consuming  taking 4-5 days for completion of the reaction  and the overall yield obtained is also very low. All these factors make the process uneconomical and difficult for scaling up.
International Application Publication No. WO 2005/068464 describes a process  which follows the same scheme  but involves the usage of molecular sieves in stage a  which makes the process less time consuming  and avoids fractional crystallization of the product. The process described in this application  although showing considerable advantages over the previous process  does not reduce the number of stages  and also does not avoid the use of hazardous reagents like chloroacetyl chloride.
A subsequent application WO2004/011463 covers a process starting from easily available D tryptophan by Pictet Spengler type cyclization followed by acid mediated transformation of trans isomer to desired cis isomer predominently.
Processes for the preparation of tadalafil have also been described in International Application Publication Nos. WO 2005/068464  WO 2006/091980  WO2006/091975  and many other subsequent applications.
The processes described in the above mentioned documents do not reduce the number of stages  and also do not avoid use of the reagents like chloroacetyl chloride.
Thus there is a need to develop a process  which involves the use of safer reagents  avoids column chromatography of the intermediates and final product  and gives higher yields. A process  which involves a fewer number of stages  thereby reducing the process time cycle also would be helpful.
The present invention provides a process for the preparation of tadalafil and its isomers having a reduced number of stages and has a shorter time cycle.

SUMMARY
The present application relates to facile and selective approaches for the synthesis of Tadalafil and its isomers via new amide intermediates.

DETAILED DESCRIPTION
The present application relates to alternative synthesis of tadalafil and its isomers via new intermediates.
In one embodiment  the present application relates to a process for the preparation of Tadalafil comprising:
a) Reaction of the intermediate of Formula II with ethyl chloroformate followed by reaction with hydrochloride salt of sarcosine acid or its ester of Formula III to give the intermediate of Formula IV.

Formula II Formula III Formula IV

b) Reaction of the intermediate of Formula IV with piperonal in the presence of trifluoroacetic acid at low temperatures to provide Tadalafil of Formula I.
In another embodiment  the present invention relates to a process for the preparation of S R isomer of tadalafil comprising:
a) Reaction of the intermediate of Formula II with ethyl chloroformate followed by reaction with hydrochloride salt of sarcosine acid or its ester of Formula III to give the intermediate of Formula IV;

Formula II Formula III Formula IV
b) Reaction of the intermediate of Formula IV with piperonal at high temperature reaction conditions to provide S R isomer of Tadalafil of Formula V.

Formula V
In still another embodiment  the present application relates to a process for the preparation of S R isomer of tadalafil comprising:
a) N-deprotection of the compound of Formula II to provide an intermediate of Formula VI  which cyclizes to give the intermediate of Formula VII;

Formula VI Formula VII
b) reaction of the intermediate of Formula VII with piperonal.
In still another embodiment  the present application relates to a process for the preparation of S R diastereomers of derivatives of Tadalafil represented by the Formula VIII by reacting the compound of Formula VII with a piperonal derivative of Formula IX.

Formula VIII Formula IX
R1=Br or H and R2  R3  R4 =H or OCH3.
Suitable solvents which can be used for conducting the above reactions include  but are not limited to halogenated hydrocarbon solvents such as dichloromethane; hydrocarbon solvents such as toluene  xylene  ortho-xylene  n-heptane  n-hexane  cyclohexane  methylcyclohexane  or the like; ester solvents such as ethyl acetate  n-propyl acetate  n-butyl acetate  t-butyl acetate  or the like; aprotic polar solvents such as dimethylsulfoxide (DMSO)  N N-dimethylformamide (DMF)  N N-dimethylacetamide  tetrahydrofuran (THF)  acetone  acetonitrile  or the like; alcohol solvents like methanol  ethanol  ethylene glycol  isopropyl alcohol  2-methoxy ethanol or the like; or mixtures thereof. Suitable temperatures for the reactions of a) to e) range from about -50°C to about the reflux temperature of the solvent  or in the range of about -50°C to about 150°C.
The products obtained in each of the stages may be isolated by techniques well known in the art  or they may be used for the subsequent reaction steps without isolation. The products may be isolated by adding water and separating the organic layer and aqueous layer  wherein the product is further isolated by evaporating the organic layer under vacuum  or the product may be isolated by direct filtration if the product is precipitated in the reaction mass. The isolated intermediates may be further purified by precipitation from a solvent or a mixture of solvents.
Suitable solvents which can be used for extraction of the product or precipitation include but are not limited to alcohols such as methanol  ethanol  2-propanol  1-butanol  tertiary-butanol  or the like; ethers such as diethyl ether  dimethyl ether  diisopropyl ether  tetrahydrofuran  1 4 dioxane  or the like; aromatic hydrocarbons such as toluene  xylene  or the like; halogenated hydrocarbons such as dichloromethane  chloroform  carbon tetrachloride  chlorobenzene  or the like; ketones such as acetone  methyl isobutyl ketone  or the like; and any mixtures of such solvents and combinations with water  in various proportions.
Suitably  the products at each stage when isolated as solid can be dried. Drying can be suitably carried out in a tray dryer  vacuum oven  air oven  fluidized bed dryer  spin flash dryer  flash dryer  spray dryer  thin film dryer  or the like. The drying can be carried out at temperatures about 35°C to about 90°C  or other temperatures suitable for removing the solvent without affecting purity of the product. The drying can be carried out for any desired time periods such as about 1 to 20 hours  or longer.
Tadalafil and its isomers when prepared according to a process of the present application may have a chemical purity greater than about 95% by weight  as determined using high performance liquid chromatography (“HPLC”)  and a chiral purity of more than about 99% by HPLC..
Still another embodiment of the present invention provides a pharmaceutical composition comprising pure tadalafil or its pharmaceutically acceptable salts along with one or more pharmaceutically acceptable carriers  diluents and/or other excipients.
The pharmaceutical composition may be formulated as: solid oral dosage forms such as  but not limited to  powders  granules  pellets  tablets  and capsules; liquid oral dosage forms such as but not limited to syrups  suspensions  dispersions  and emulsions; and injectable preparations such as but not limited to solutions  dispersions  and freeze dried compositions. Formulations may be in the form of immediate release  delayed release or modified release. Further  immediate release compositions may be conventional  dispersible  chewable  mouth dissolving  or flash melt preparations  and modified release compositions that may comprise hydrophilic or hydrophobic  or combinations of hydrophilic and hydrophobic  release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared by direct blending  dry granulation or wet granulation or by extrusion and spheronization. Compositions may be presented as uncoated  film coated  sugar coated  powder coated  enteric coated or modified release coated. Compositions of the present invention may further comprise one or more pharmaceutically acceptable excipients.
Pharmaceutically acceptable excipients that find use in the present invention include  but are not limited to: diluents such as starch  pregelatinized starch  lactose  powdered cellulose  microcrystalline cellulose  dicalcium phosphate  tricalcium phosphate  mannitol  sorbitol  sugar and the like; binders such as acacia  guar gum  tragacanth  gelatin  polyvinylpyrrolidone  hydroxypropyl cellulose  hydroxypropyl methylcellulose  pregelatinized starch and the like; disintegrants such as starch  sodium starch glycolate  pregelatinized starch  crospovidone  croscarmellose sodium  colloidal silicon dioxide and the like; lubricants such as stearic acid  magnesium stearate  zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins  resins; release rate controlling agents such as hydroxypropyl cellulose  hydroxymethyl cellulose  hydroxypropyl methylcellulose  ethyl cellulose  methyl cellulose  various grades of methyl methacrylates  waxes and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers  plasticizers  colorants  flavoring agents  sweeteners  viscosity enhancers  preservatives  antioxidants and the like.
In the compositions of present invention tadalafil or its pharmaceutically acceptable salts is a useful active ingredient in the range of 0.5 mg to 50 mg  or 1 mg to 25 mg  per dosage form unit.
Certain specific aspects and embodiments of this invention are described in further detail by the examples below  which examples are only illustrative and not intended to limit the scope of the appended claims in any manner.

EXAMPLES
EXAMPLE 1: Preparation of (R)-ethyl 2-(2-((tert-butoxycarbonyl)amino)-3-(1H-indol-3-yl)-N-methylpropanamido)acetate (Formula IV).
A mixture of N-Boc-D-tryptophan (5 g  16.4 mmol) and THF (25 mL) was cooled to -20 °C under nitrogen atmosphere. To the mixture  charged N-methylmorpholine (1.83 g  18 mmol) and stirred for 20 min. Then  a solution of ethylchloroformate (1.95 g  18 mmol) in THF (2 mL) was slowly added and stirred the reaction mass for 30 min. Prepared a solution of sarcosine ethylester in THF (5 mL) by treating sarcosine ethylester hydrochloride (2.76 g  18 mmol) with N-methylmorpholine (2 g). This solution was added to the solution of mixed anhydride dropwise at -20 °C. Then  reaction mass temperature was raised to ambient temperature and maintained for 1 h. After completion of the reaction  solvent was removed by distillation and to the obtained residue water and DCM were charged. After stirring  organic layer was separated and 2N HCl washings were given followed by bicarbonate washings. The organic layer was evaporated to give the title compound.
EXAMPLE 2: Preparation of (6R 12aR)-6-(benzo[d][1 3]dioxol-5-yl)-2-methyl-2 3 12 12a-tetrahydropyrazino [1"" 2"":1 6]pyrido[3 4-b]indole-1 4(6H 7H)-dione (Formula I).
A mixture of toluene (10 mL)  compound of Formula IV (1 g  12.4 mmol) and piepronal (0.36 g  12.65 mmol) were stirred for 10 min. Trifluoroacetic acid was added slowly and the reaction mass was heated to 45-50 °C and maintained at the same temperature for 15 h. Then  concentrate the reaction mass under vacuum. To the obtained residue  charged water (5 mL) and dichloromethane (5 mL) and the mixture was neutralized with saturated sodium bicarbonate solution. Organic layer was separated and concentrated below 35 °C under vacuum. Charged toluene (5 mL) to the obtained residue and the mixture was heated to reflux. After 8 h of aging  reaction mass was cooled to ambient temperature and the product separated was filtered to give tadalafil (0.39 g  50%). The obtained product can be optionally purified by column chromatography.
EXAMPLE 3: Preparation of (R)-3-((1H-indol-3-yl) methyl)-1-methylpiperazine-2 5-dione (Formula VII).
Method a:
A mixture of the compound of Formula IV (2 g  12.4 mmol) is taken along with hydrochloric acid in dioxane (20 mL  4N) and stirred at ambient temperature for 5 h. Then  reaction mass was concentrated under reduced pressure. Charged DCM and washed with saturated sodium bicarbonate solution (15 mL). Then  solvent was evaporated under reduced pressure to get the title compound (0.9 g  70%).
Method b:
D tryptophan methyl ester (1 g  3.926 mmol) was taken along with chloroform (10 mL)  to that added aqueous ammonia solution (2 mL) and water (10 mL) and stirred at ambient temperature for 10 min. Organic layer was separated and solvent was evaporated under reduced pressure. The obtained residue was diluted with chloroform (10 mL)  then added triethyl amine (0.394 g  3.894 mmol) and cooled to 0 °C. Chloroacetyl chloride (066 g  5.84 mmol) was added and the reaction mass was aged for 1 h. Later  water (10 mL) was added to the mass below 10 °C  and organic layer was separated and washed with saturated sodium bicarbonate solution followed by water. Finally  organic layer was distilled under vacuum. To the obtained compound  methylamine (0.42 g  13.548 mmol) in methanol (10 mL) was added and stirred for 6 h at 55 °C for completion of the reaction. Then  reaction mass was cooled to ambient temperature and separated solids were filtered off. The filtrate was evaporated to get the title compound (0.95 g  80%); 1H NMR(400 MHz 
Example 4: Preparation of (6S 12aR)-6-(benzo[d][1 3]dioxol-5-yl)-2-methyl-2 3 12 12a-tetrahydropyrazino [1"" 2"":1 6]pyrido[3 4-b]indole-1 4(6H 7H)-dione (Formula V).
Method a:
A mixture of toluene (10 mL)  compound of Formula IV (1 g  12.4 mmol) and compound piperonal (0.36 g  12.65 mmol) were stirred for 10 min. Trifluoroacetic acid was added slowly and the reaction mass was heated to reflux and maintained at the same temperature for 8 h. Then  cool the reaction mass to ambient temperature  neutralize it with saturated sodium bicarbonate solution. Charge dichloromethane (15 mL) to the mass and stir for 10 min. Organic layer was separated and concentrated below 35 °C under vacuum and the product was purified by column chromatography to give pure S  R isomer of tadalafil ( 0.7 g  65%).
Method b:
A mixture of compound of Formula VII (2 g  7.78 mmol) and piperonal (1.17 g  7.78 mmol) is taken along with aqueous HCl (10 mL  6N) and dioxane (10 mL) and stirred at reflux temperature for 1 h. Then  reaction mass was concentrated under reduced pressure. Charged DCM and washed with saturated sodium bicarbonate solution (30 mL). Then  solvent was evaporated under reduced pressure followed by purification through column chromatography using petroleum ethers: ethyl acetate (7:3) to give the title compound.

We Claim:
1. A process for the preparation of Tadalafil comprising:
a) Reaction of the intermediate of Formula II with ethyl chloroformate followed by reaction with sarcosine ethyl ester hydrochloride of Formula III to give the intermediate of Formula IV.

Formula II Formula III Formula IV
b) Reaction of the intermediate of Formula IV with piperonal in the presence of trifluoroacetic acid at low temperatures to provide Tadalafil of Formula I.
2. A process for the preparation of S R isomer of tadalafil comprising:
a) Reaction of the intermediate of Formula II with ethyl chloroformate followed by reaction with sarcosine ethyl ester hydrochloride of Formula III to give the intermediate of Formula IV.

Formula II Formula III Formula IV
c) Reaction of the intermediate of Formula IV with piperonal at high temperature reaction conditions to provide S R isomer of Tadalafil of Formula V.

Formula V
3. A process for the preparation of S R isomer of tadalafil comprising:
a) N-deprotection of the compound of Formula II to provide an intermediate of Formula VI  which cyclizes to give the intermediate of Formula VII

Formula VI Formula VII
b) Reaction of the intermediate of Formula VII with piperonal.
4. A process for the preparation of S R diastereomers of derivatives of Tadalafil represented by the Formula VIII by reacting the compound of Formula VII with a piperonal derivative of Formula IX.

Formula VIII Formula IX
R1=Br or H and R2  R3  R4 =H or OCH3