Description:FIELD OF INVENTION
The present invention relates to a process for the preparation of a tetracyclic compound.

The present invention relates to an improved process for the preparation of tetracyclic compound of formula I.

Formula-I

BACKGROUND OF THE INVENTION
Tadalafil, is a potent and selective cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5) inhibitor, is chemically known as (6R,12aR)-6-(1,3-benzodioxol-5-yl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6] pyrido[3,4-b]indole-1,4-dione.

Tadalafil is marketed under the brand name CialisTM 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 (clinical code), a phosphodiesterase type 5 (PDE5) enzyme inhibitor. The product is available in a film coated tablet for oral administration. Tadalafil is a white solid particulate material that is practically insoluble in water. It is sparingly soluble in tetrahydrofuran and chloroform but is soluble in dioxane. Tadalafil has an apparent partition co-efficient (log P)ppp = 1,7in n-octanol / buffer pH 7.4

Problem associated with low solubility of Tadalafil in ethanol and most of other organic solvents resulted in the use of large volume of solvents required to perform synthesis and followed by crystallization to get pure Tadalafil at industrial scale, is causing an unwanted technical, environmental and economical impact.

The compound Tadalafil is first disclosed in the WO 95/19978 in a wider group of potentially active molecules. And the process for the preparation of Tadalafil as per above patent application is depicted in Scheme-1

Scheme-I

Reacting D-tryptophan methyl ester with a piperonal in the presence of dichloromethane and trifluoroacetic acid which provides a mixture of desired cis and undesired trans-isomer with poor selectivity. The isomers are further separated by column chromatography. The cis-isomer is further reacted with chloroacetyl chloride in chloroform, and the obtained product was reacted with methylamine to give Tadalafil of formula (1) in methanol slurry requiring an additional purification step by flash chromatography. The process suffers from the disadvantages such as use of corrosive trifluoroacetic acid, separation of isomers by column chromatography and use of flash column for purification of Tadalafil.

Later the patent application WO 04/011463, tries to surpass the drawbacks of above mentioned prior art process by avoiding the use of trifluoroacetic acid and replacing with anhydrous isopropyl alcohol for the condensation of D-tryptophan methyl ester hydrochloride and piperonal. Further avoids the separation of isomers by column chromatography and replaced with a suitable solvent/s to get precipitate of cis isomer during the Pictet-Spengler reaction. Further reacted with chloroacetyl chloride and then with methylamine in THF to give Tadalafil. The disadvantage of using anhydrous isopropyl alcohol being thus of scarce industrial applicability

In WO2005/068464, described a preparation process where D-tryptophan methyl ester and piperonal are condensed in the presence of trifluoroacetic acid, in a suitable solvent and in the presence of molecular sleeves to absorb water released during the reaction. Both cis and trans diastereoisomers are obtained which, by treatment with aqueous hydrochloric acid, give the hydrochloride salt of the cis isomer, that precipitates in the reaction media and subsequently is isolated and reacted with the suitable reactants to give Tadalafil. The above described process has the disadvantage of using molecular sieves, difficult to be exploited in an industrial scale, and the fact that the reaction is carried out in two steps requiring intermediates isolation.

In WO2006/110893, described a process to obtain Tadalafil by reaction of D-tryptophan methyl ester (or) its suitable salt with piperonal in a solvent chosen among alkyl esters of lower carboxylic acids such as for example, ethyl acetate in the presence of trifluoroacetic acid, at room temperature pr at 50°C for long reaction times (7 days). The cis diastereoisomers is then obtained by filtration with a yield variable between 32% and 76%. The described process presents the disadvantage of using the highly corrosive trifluoroacetic acid and long reaction times

In WO2007/052283, described a process to obtain Tadalafil by reaction of D-tryptophan methyl ester (or) its suitable salt with piperonal in a high boiling solvent and dehydrating agent and subsequently treated with aqueous HCl for 10 h at 60° C., to produce 3-cis isomer as a major product with a yield of 65%.

In WO2009/047613, discloses a process for the preparation of Tadalafil comprising a reaction of an acid addition salt of D-Tryptophan methyl ester with piperonal in a mixture of aromatic hydrocarbon solvents and a glycol. Most preferably the solvent is mixture of toluene & polyethylene glycols.

In WO2009/103787, discloses a process for the preparation of Tadalafil comprising a reaction of tryptophan with piperonal in presence of alcoholic solvent and molar excess of inorganic protic acid.

In WO2009/144734, discloses a Tadalafil process, in which chloroacetyl intermediate is treated with 3-12 moles of methylamine, in 15-20 times by a volume of alcohol solvents.

In WO2009/148341, discloses a “one-pot” process of Tadalafil in which cis- isomer is treated with acetyl chloride and followed by cyclization with methylamine in presence of cyclic ethers or aliphatic ketone or mixture thereof.

In WO2010/049500, in which (1R,3R)-methyl-1,2,3,4-tetrahydro-2-(2-(benzyl-(methyl) amino) acetyl)-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylte is used as a novel intermediate for the preparation of Tadalafil.

Apart from the above process Tadalafil process is well disclosed in some of the following patent publications WO 2012/107549, WO 2012/143801, WO 2014/183730, WO 2020/218941, WO 2007/100387, WO 2009/004557, , WO 2009/121791, WO 2010/037190, WO 2010/099323, WO 2010/115886, , WO 2012/085927, WO 2014/183730, WO 2014/006604, CN102180876, CN102367253, CN103524502, CN103554108, CN103772384, CN103980275, CN104086546, CN104140424, CN104262340, CN104844600, CN104876930, CN105061428, CN105106132, CN105106216, IN326814, WO 2016/012539, CN111721874, CN113582992, CN113880837, CN113999228, CN114213414, CN116063303, CN116496276, CN116574102, CN116715667, CN109970736, CN109970739, CN109988167, CN110343106, CN110437228, CN110606847, CN110615789, CN110684025, CN110734443, CN110790764, CN111072662, CN111253399, IN 2003CH00307, IN2005DE02969, IN2005DE02968, IN201621022369, IN2011CH03522, IN2012DE01800, IN201641037387, IN2012DE01800 and IN326814

Even though there are so many Tadalafil process reported in a prior art, still there exists a need for an improved process for a synthesis and purification of Tadalafil, which would overcome the disadvantages of the prior art processes.

OBJECT OF THE INVENTION:
The main objective of the present invention is to provide a economical and commercial feasible process for the preparation of Tadalafil compound of formula-I

In an objective of the present invention is to provide an improved process for the preparation of Tadalafil by avoiding toxic and corrosive reagents.

SUMMARY OF THE INVENTION
The present invention is to provide a process for preparation of Tadalafil a compound of formula I, comprises steps of,

Formula-I
a) esterifying the D-tryptophan of formula-II,

Formula-II
in a lower alcoholic solvents, thionly chloride optionally in presence of catalyst to provide D- typtophan alkyl ester (or) salt (or) its derivatives; lower alcohols are selected from (C1-4)

Formula-III (or) salts
b) treating the D- typtophan alkyl ester (or) salt (or) its derivatives, with piperonal in suitable solvents or its mixture to provide cis-isomer of formula-IV

Formula-IV (or) salt
c) treating the product of step (b) with chloroacetyl chloride in presence of base and suitable solvent to give formula-V

Formula-V (or) salt
d) treating the product of step (c) with methylamine to get crude Tadalafil of compound-I.
e) the product of step (d), is subjected to purification to give pure Tadalafil compound of formula-I.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure-1 is a characteristic NMR spectra of step-a
Figure-2 is a characteristic mass spectrum of step-a
Figure-3 is a characteristic IR spectrum of step-a
Figure-4 is a characteristic NMR spectra of step-b
Figure-5 is a characteristic mass spectrum of step-b
Figure-6 is a characteristic IR spectrum of step- b
Figure-7 is a characteristic NMR spectra of step-c
Figure-8 is a characteristic mass spectrum of step-c
Figure-9 is a characteristic IR spectrum of step- c
Figure-10 is a characteristic NMR spectra of step-d
Figure-11 is a characteristic mass spectrum of step-d
Figure-12 is a characteristic IR spectrum of step- d
Figure-13 is a characteristic NMR spectra of Tadalafil
Figure-14 is a characteristic mass spectrum of Tadalafil
Figure-15 is a characteristic IR spectrum of Tadalafil
Figure-16 is a characteristic DSC of Tadalafil
Figure-17 is a characteristic XRPD of Tadalafil

DETAILED DESCRIPTION OF THE INVENTION
The first aspect of the invention is to provide a process for preparation of Tadalafil a compound of formula I, comprises steps of,
a) esterifying the D-tryptophan of formula-II,

Formula-II
in a methanol solvents and thionly chloride to provide D- typtophan methyl ester hydrochloride salt

Formula-III
b) treating the D- typtophan metyl ester hydrochloride with piperonal in suitable solvents to provide cis-isomer of formula-IV

Formula-IV
c) treating the product of step (b) with chloroacetyl chloride in presence of base and suitable solvent to give formula-V

Formula-V
d) treating the product of step (c) with methylamine to get crude Tadalafil of compound-I.
e) product of step (d), is subjected to purification to give pure Tadalafil compound of formula-I.

The second aspect of the invention is to provide a process for preparation of Tadalafil a compound of formula I, comprises steps of,
b) treating the D- typtophan metyl ester hydrochloride with piperonal in suitable mixture of solvents optionally in presence of catalyst to provide cis-isomer of formula-IV
c) treating the product of step (b) with chloroacetyl chloride in presence of base optionally in presence of catalyst and suitable solvent to give formula-V
d) treating the product of step (c) with methylamine to get Tadalafil of compound-I.

The third aspect of the invention is to provide a pure Tadalafil of formula I, by isolating in suitable solvent (or) mixture of solvent.

The fourth aspect of the invention is to use with or without isolation of one or more intermediates to prepare the compound of formula-I.

The fifth aspect of the invention has following advantage
(a) Avoids the use of corrosive and toxic reagents.
(b) Avoids the use of column chromatography (or) flash chromatography.
(c) Time cycle for overall process is relatively less.
(d) The yield of cis-isomer is high
(e) Limiting the high volumes of solvents during the process.

The process of the present invention can be represented schematically as follows

Scheme-2

Step-a, esterification is performed in presence of suitable solvent and acid optionally in presence of catalyst. The most suitable solvent are alcoholic solvent and acid is selected from aliphatic acids (or) inorganic acids. More preferably inorganic acids
Step-b, coupling reaction (or) Pictet- Spengler reaction is preformed in presence of suitable (or) solvent mixture at a preferable temperature and optionally in presence of catalyst.

Step-c, N-acylation performed using chloroacetyl chloride in presence of suitable base and solvent optionally in presence of catalyst

Step-d, cyclization (or) ring-closure performed using aq methylamine (or) alcoholic methyl amine at a preferable temperature

Step-e, purification using solvent (or) solvent mixture to get desired pure product

The solvent is selected from water, hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, formic acid, acetic acid and the like or mixture of any of the afore mentioned solvents (or) its mixture thereof.

The ‘‘base’’ used in the present invention can be selected from but not limited to "inorganic bases" selected from "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide and the like; "alkali metal hydrides" such as sodium hydride, potassium hydride, lithium hydride and the like; "alkali metal amides" such as sodium amide, potassium amide, lithium amide and the like; ammonia; organic bases’’ like "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium methoxide, lithium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; alkali metal and alkali earth metal salts of acetic acid such as sodium acetate, potassium acetate, magnesium acetate, calcium acetate and the like; dimethylamine, diethylamine, diisopropyl mine, diisopropylethylamine (DIPEA), diisobutylamine, trimethylamine, triethylamine, triisopropylamine, tributylamine, tert.butyl amine, pyridine, piperidine, 4-dimethylamino pyridine (DMAP), quinoline, imidazole, N-methylimidazole, l,8-diazabicyclo[5.4.0]undec-7- ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), dimethylaniline, N-methylmorpholine (NMM), l,4-diazabicyclo[2.2.2]octane (DABCO), 2,6-lutidine and the like;

The catalyst used in the reaction is selected from but not limited to phase transfer catalyst.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

Example-1: D-tryptophan methyl ester hydrochloride
To a stirred solution of D-Tryptophan (100 gm, 0.5 mol) in methanol (5 vol) at 25-30°C, catalytic amount of dimethylformamide was added. To this stirred solution thionly chloride (82 gm, 0.7mol) was added slowly for 1 to 1.5 h. The resultant reaction mass was stirred at 60-65 °C. After completion of the reaction the reaction mass was distill out under vacuum at 60-65 °C. The obtained residue was isolated with isopropyl alcohol by heating and cooling method to get desired compound as a solid (120 gm).

Example-2: Methyl (1R,3R)-1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indole-3-carboxylate hydrochloride
To a stirred solution of D-tryptohan methyl ester hydrochloride (100 gm, 0.4 moles) in a mixture of dimethylformamide and toluene (2:8) at 25-30 °C, piperonal (62 gm) was slowly added. And the resultant reaction mass was stirred at reflux temperature. After completion of the reaction, the reaction mass was cooled to 25-30°C for 2 h. Then the reaction mass was filtered and the obtained wet solid was washed with toluene. The product obtained was dried to get desired compound (140 gm).

Example-3: Methyl (1R,3R)-2-(2-chloroacetyl)-1-(3-hydroxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate
To the stirred solution of Example-2 (100 gm, 0.25 mol) in water (200 mL) and dichloromethane (800 mL) was stirred for 10-15 min. To this sodium carbonate solution (20 gm in 100 mL of water) was slowly added at 25-35°C and the resultant reaction mass was stirred for 30 min. To the separated organic layer cat amount of DMAP (1.0 gm) and sodium carbonate solution (38 g in 127 mL water) was added and the reaction mass was cooled to 0-10°C. To this Chloroacetyl chloride (40.6 gm, 0.35mol) was added and the resultant reaction mass was stirred for 5 hr at 0-10 °C. After completion of the reaction the reaction mass was distilled out under reduced pressure, and co-distilled with methanol at 50°C.
Further methanol was added to the residue and cools the mass to 10-15 °C. Filter the reaction mass after 2-3 hr and the obtained solid was washed with methanol and dried for 1 h at 30-35 °C to get the titled compound as a solid (105 gm)

Example-4: Methyl (1R,3R)-2-(2-chloroacetyl)-1-(3-hydroxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate
To a stirred solution of D-tryptohan methyl ester hydrochloride (100 gm, 0.4 moles) in a mixture of dimethylformamide and toluene (1:1) 60 mL at 25-30 °C, piperonal (62 gm) was slowly added. And the resultant reaction mass was stirred at reflux temperature for 24-27 hrs. After completion of the reaction the solvents was distilled out under reduced pressure and to the residue, water was added. The pH of the reaction mass was adjusted to 8-9 by using sodium carbonate solution. The crude product was extracted by using dichloromethane three times. The resultant organic layer was washed with water and dried over sodium sulphate. This combined organic layer can be used for further reaction conversion.
Sodium bicarbonate (34 gm, 0.40 mol) was added at room temperature. The reaction mass was cooled to 0°C and chloroacetyl chloride (114 gm, 1.00 mol) diluted with 100 mL dichloromethane was added drop wise. The reaction mass was stirred for 2-3 hr at same temperature. After completion of the reaction the reaction mass was diluted with water and stirred for 30 min at 0°C and the pH of the reaction mass was adjusted to 8-9 by liquid ammonia. The dichloromethane was then distilled out under reduced pressure and filtered the solid under vaccum. The obtained solid was washed with water and crystallized from methanol to obtain title compound as a solid (87 gm).

Example-5: (6R,12aR)-6-(benzo[d][1,3]dioxol-5-yl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione
To the stirred solution of Methyl (1R,3R)-2-(2-chloroacetyl)-1-(3-hydroxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido [3,4-b]indole-3-carboxylate (100 gm, 0.25 mol) in methanol (1 L), methanolic methylamine (200 ml) was added and slowly raised the reaction mass temperature to 45-50°C for 5-6 hr. After completion of the reaction the reaction mass was cooled to 10-15oC and stirred for 2-3 hr. Filter the reaction mass and the obtained solid wet cake was washed with methanol. The wet cake was dried to get titled compound as a desired product (85 gm)

Example-6: (6R,12aR)-6-(benzo[d][1,3]dioxol-5-yl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione
To the stirred solution of Methyl (1R,3R)-2-(2-chloroacetyl)-1-(3-hydroxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido [3,4-b]indole-3-carboxylate (100 gm, 0.25 mol) in n-propanol (1 L), 40% aqueous methylamine (300 ml) was added and slowly raised the reaction mass temperature to 45-50°C for 5-6 hr. After completion of the reaction the mass was cooled to 10-15oC and stir for 2-3 hrs. Filter the reaction mass and the obtained solid wet cake was washed with methanol. The wet cake was dried to get titled compound as a desired product (78 gm).

Example-7: (6R,12aR)-6-(benzo[d][1,3]dioxol-5-yl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione
To the stirred solution of crude Tadalafil (100 g, 0.24mol) in DMF (400 ml) was stirred for 30-45 min at 25-30°C. After getting clear solution the reaction mass was filtered through micron filter. To the obtained filtrate, methanol (2 Lt) was added and stirred for 25-30°C for 60-90 min. Cool the reaction mass to 0-5°C and stir the mass for 2-3 h. Filter the reaction mass and wash with methanol and the obtained solid was dried for 8 h at 45-50°C to get the pure Tadalafil as a product (90 gm).
, Claims:We claim:
1. A process for preparation of Tadalafil a compound of formula I, comprises steps of,
a) esterifying the D-tryptophan of formula-II,

Formula-II
in a methanol solvents and thionly chloride to provide D- typtophan methyl ester hydrochloride salt

Formula-III
b) treating the D- typtophan methyl ester hydrochloride with piperonal in suitable mixture of solvents to provide cis-isomer of formula-IV

Formula-IV
c) treating the product of step (b) with chloroacetyl chloride in presence of base and suitable solvent optionally in presence of catalyst to give formula-V

Formula-V
d) treating the product of step (c) with methylamine to get crude Tadalafil of compound-I.
e) product of step (d), is subjected to purification to give pure Tadalafil compound of formula-I.

2. The process according to claim-1 (step-a), wherein mixture of solvent is polar solvent and hydrocarbon solvent.

3. The process according to claim-2, wherein polar solvent is selected from but not limited to water, acetone, N- methylpyrrolidone, acetonitrile, dimethylformamide (DMF), dimelthylsulfoxide (DMSO), dimethylaetamide (DMA) and hydrocarbon solvent selected from but not limited to toluene, xylene, benzene, ethylbenzene.

4. The process according to claim-3, wherein mixture of solvent is dimethylformamide (DMF) and toluene (or) dimethylsulfoxide (DMSO) and toluene; most preferably dimethylformamide (DMF) and toluene.

5. The process according to claim-4, the ratio of dimethyl formamide and toluene is in ratio of 2:8 to 5:5, more preferably 2:8

6. The process for the preparation of Tadalafil a compound of formula I, comprises steps of,

Formula-III
b) treating the D- typtophan metyl ester hydrochloride with piperonal in presence of mixture of dimethylformamide and toluene to provide cis-isomer of formula-IV

Formula-IV
c) treating the product of step (b) with chloroacetyl chloride in presence of organic base and suitable chlorinated solvent in presence of catalyst to give formula-V

Formula-V
d) treating the product of step (c) with methylamine in presence of suitable alcohol solvent to get crude Tadalafil of compound-I.
e) product of step (d), is subjected to crystallization in presence of solvent (or) its mixture to give pure Tadalafil compound of formula-I.

7. The process according to claim-1, the suitable solvent system in
step-a is alcoholic solvent
step-b, is mixture polar solvent and hydrocarbon solvent.
step-c, is chlorinated solvent
step-d, is alcoholic solvent

8. The process according to claim-7, the suitable solvent system in
step-a & d, is methanol, ethanol; more preferably methanol
step-b, is mixture DMSO and toluene, dimethylformamide and toluene, THF and toluene; more preferably dimethylformamide and toluene;
step-c, is dichloromethane and chloroform; more preferably dichloromethane

9. The process according to claim-1, step-e, solvent system used for purification is selected from dimethylformamide, methanol or its mixture thereof

10. The process according to claim-1, one or more stages are performed in presence of catalyst