EP2004644A1

EP2004644A1 - Process for the preparation of tadalafil

Info

Publication number: EP2004644A1
Application number: EP07734067A
Authority: EP
Inventors: Anthony Melvin Crasto; Narendra Shriram Joshi; Nitin Sharad Chandra Pradhan
Original assignee: Glenmark Pharmaceuticals Ltd
Current assignee: Glenmark Pharmaceuticals Ltd
Priority date: 2006-03-24
Filing date: 2007-03-23
Publication date: 2008-12-24
Also published as: WO2007110734A1

Abstract

The present invention provides novel intermediates of tadalafil and processes for their preparation. The present invention also provides for the preparation of tadalafil or a pharmaceutically acceptable salt or solvate thereof using the intermediates.

Description

PROCESS FOR THE PREPARATION OF TADALAFIL

PRIORITY

[0001] This application claims the benefit of U.S. Provisional Application No.

60/872,648, filed on December 4, 2006, and entitled "A PROCESS FOR THE PREPARATION OF TADALAFIL", to Indian Provisional Application No. 1918/MUM/2006, filed on November 20, 2006, and entitled "A PROCESS FOR THE PREPARATION OF TADALAFIL", to Indian Provisional Application No. 1135/MUM/2006, filed on July 17, 2006, and entitled "IMPROVED PROCESS FOR THE PREPARATION OF TADALAFIL", and to Indian Provisional Application No. 438/MUM/2006, filed on March 24, 2006, and entitled "IMPROVED PROCESS FOR THE PREPARATION OF TADALAFIL AND ITS INTERMEDIATE THEREOF", the contents of each of which are incorporated by reference herein.

BACKGROUND OF THE INVENTION

1. Technical Field

[0002] The present invention relates generally to a process for preparing tadalafil or a pharmaceutically acceptable salt or derivative thereof.

2. Description of the Related Art

[0003] Tadalafil, also known as (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-l ,4-dione, can be represented by the structure of Formula I:

Tadalafil is an orally administered phosphodiesterase type 5 (PDE5) inhibitor and has been developed as a treatment for male erectile dysfunction and the treatment of female sexual dysfunction. [0004] Tadalafil can be prepared via a series of intermediates. One synthesis for preparing tadalafil is illustrated below in Scheme I:

SCHEME I

[0005] U.S. Patent No. 5,859,006 discloses the synthesis of a tadalafil intermediate

(Compound III) from D-tryptophan methyl ester (Compound II) and piperonal (Compound

I) using trifluoroacetic acid and dichloromethane, a halogenated solvent. Compound III is then reacted with chloroacetyl chloride (Compound IV) and chloroform to provide another intermediate of tadalafil (Compound V).

[0006] WO 2004/011463 discloses a process of preparing tadalafil intermediates from D-tryptophan methyl ester HCl salt and piperonal by refluxing the reagents in isopropyl alcohol, reacting the intermediate thus obtained with chloroacetyl chloride and tetrahydrofuran (THF) to provide another intermediate of tadalafil.

[0007] WO 2006/110893 discloses a process for the preparation of methyl ester intermediate (Compound III), and tadalafil using the methyl ester intermediate (Compound

II).

[0008] U.S. Patent Application Publication No. 2006/0258865 Al discloses a synthesis of the tadalafil intermediate (Compound III) from D-tryptophan methyl ester

(Compound II) and piperonal (Compound I) using a dehydrating agent selected from Na₂SO₄, K₂SO₄, MgSO₄, CaSO₄, CaCl_2, molecular sieve or mixtures thereof and a high boiling solvent such as N,N-Dimethyl acetamide. Compound III is then reacted with chloroacetyl chloride (Compound IV) in the presence of a base such as NaHCO₃ and an organic solvent such as dichloromethane, providing another intermediate of tadalafil (Compound V), which is further reacted with aqueous methyl amine solution to provide tadalafil.

[0009] Cost effective methods of synthesizing tadalafil utilizing safe reagents are highly desirable.

SUMMARY OF THE INVENTION

[0010] In accordance with one embodiment of the present invention, a compound of Formula II is provided:

wherein X is a leaving group.

[0011] In accordance with a second embodiment of the present invention, a process for the preparation of a compound of Formula II is provided comprising reacting a compound of Formula III:

with a compound of Formula IV: O

Il

Y- -C — CH₂X (IV) wherein Y is a halogen and X is a leaving group.

[0012] In accordance with a third embodiment of the present invention, a process for preparing tadalafil or a pharmaceutically acceptable salt or derivative thereof is provided comprising cyclizing a cis-isomer of a compound of Formula II in the presence of a base:

wherein X is leaving group.

[0013] In accordance with a fourth embodiment of the present invention, a pharmaceutical composition is provided comprising tadalafil or a pharmaceutically acceptable salt or derivative thereof prepared by the processes of the present invention. [0014] In accordance with a fifth embodiment of the present invention, a pharmaceutical composition is provided comprising a therapeutically effective amount of substantially pure tadalafil or a pharmaceutically acceptable salt or derivative thereof.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] One embodiment of the present invention provides an intermediate of tadalafil of Formula II and a process for its preparation

(H) wherein X is a leaving group such as a halogen, e.g., chlorine, bromine and the like and preferably chlorine. Preferably, the compound of Formula II is represented as follows.

[0016] As used herein, X may be any suitable leaving group known in the art, which facilitates cyclization of compound of Formula II to provide the compound of formula I. Representative examples of a leaving group include halogen, preferably chlorine; mesylate, tosylate and the like.

[0017] The process for preparing intermediate compound of Formula II includes the step of reacting a compound of Formula III or a salt thereof (e.g., a hydrochloride salt):

with a compound of Formula IV:

O

Y C-CH₂X (_IV) wherein Y is a halogen, e.g., chlorine, bromine, iodide, etc., and X has the aforestated meaning in the presence of an organic reaction solvent and a base.

[0018] Suitable organic reaction solvents include halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, carbon tetrachloride and the like and mixtures thereof; aromatic hydrocarbons such as benzene, toluene, xylene and the like and mixtures thereof; non-cyclic ethers such as 1,2-dimethoxy ethane, di- or Methylene glycol dimethyl ether and the like and mixtures thereof. Generally, the solvent is used in an amount of about 2 volumes to about 25 volumes.

[0019] Suitable bases include, but are not limited to, Ci-C₆ mono-, di- or tri-alkyl amines wherein the alkyl groups may be the same or different, e.g., triethylamine (TEA), C₃-C₂₅ cyclic amines, e.g., pyridine; alkali metal carbonate and bicarbonates, e.g., sodium, potassium or lithium carbonates or bicarbonates, and the like and mixtures thereof. Generally, the base is present in an amount of about 1 equivalent to about 5 equivalents per equivalent of the compound of Formula III.

[0020] The reaction of the compound of Formula III with the compound of

Formula IV is carried out at a temperature ranging from about -10⁰C to about 25⁰C and maintaining the reaction mixture at a temperature less than about 10⁰C for a time period of about 1 to about 5 hours, where the temperature and time may be suitably based on the base and solvent selected, to obtain a compound of Formula II. Generally, the compound of Formula III can be reacted with the compound of Formula IV in an amount sufficient to form the compound of Formula II, e.g., an amount of compound of Formula III ranging from about 1 equivalent to about 3 equivalents and preferably from about 1 equivalent to about 1.8 equivalents per equivalent of the compound of Formula IV. [0021] The compound of Formula II may be present in any form, for example, a mixture of cis and trans isomers. In one embodiment, the compound of Formula II is advantageously a mixture of cis:trans isomers in the ratio of from about 90:10 to about 10:90 and preferably from about 60:40 to about 40:60. The desired cis-isomer of the compound of Formula II may be isolated by any known techniques in the art, for example, by crystallizing the cis isomer out from an organic solvent such as a halogenating solvent, for example, methylene chloride, ethylene chloride, chloroform and the like. [0022] Another embodiment of the present invention provides a process for the preparation of intermediate compound of Formula III:

Generally, the process involves reacting D-tryptophan methyl amide of Formula VI or a salt thereof (e.g., the hydrochloride salt)

with piperonal of Formula VII

in the presence of trifluoroacetic acid in an organic reaction solvent selected from the group consisting of halogenated solvents, alkyl esters of lower carboxylic acids, aromatic hydrocarbons and mixtures thereof.

[0023] Suitable halogenated solvents include dichloromethane, ethylene dichloride, chloroform, carbon tetrachloride and the like and mixtures thereof. [0024] Suitable alkyl esters of lower carboxylic acids include those having the general formula R'-COOR² wherein R¹ and R² are each independently is a linear or branched alkyl group having 1 to 6 carbon atoms. Representative examples of alkyl esters of lower carboxylic acids for use herein include ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, isobutyl acetate and the like and mixtures thereof. [0025] Suitable aromatic hydrocarbons include, but are not limited to, benzene, toluene, xylene and the like and mixtures thereof. [0026] The organic reaction solvent is ordinarily present in the reaction in an amount ranging from about 5 volumes to about 40 volumes.

[0027] The reaction of the compound of Formula VI with the compound of

Formula VII can be carried out at a temperature ranging from about 0⁰C to about 50⁰C for a time period of about 1 to about 20 hours where the temperature and time may be suitably based on the base and solvent employed, to obtain compound of Formula III. Generally, the compound of Formula VI can be reacted with the compound of Formula VII in an amount sufficient to form the compound of Formula III, e.g., an amount of compound of Formula VI ranging from about 1 equivalent to about 2 equivalents and preferably from about 1 equivalents to about 1.5 equivalents per equivalent of the compound of Formula VII. Advantageously, the compound of Formula III is a mixture of cis:trans isomers in the ratio of from about 90:10 to about 10:90 and preferably from about 60:40 to about 40:60. [0028] In a further embodiment the invention provides a process for the preparation of intermediate compound of Formula III involves reacting mono methyl amine (MMA) with a compound of Formula V:

wherein R is selected from the group consisting of -OH, -halogen and -OCi-C₈ alkyl; in the presence of an organic reaction solvent selected from the group consisting of alcoholic solvents such as Ci-C₈ cyclic or aromatic alcohols; halogenated solvents such as dichloromethane, ethylene dichloride, chloroform and carbon tetrachloride; aromatic hydrocarbon; non-cyclic ethers and mixtures thereof with preferred solvents being the alcoholic solvents such as methanol and ethanol. The reaction can be carried out at temperature ranging from about 0⁰C to about 9O⁰C for a period of about 1 to about 20 hours where the temperature and time may be suitably based on the base and solvent employed, to obtain compound of Formula III. [0029] In another embodiment of the present invention a process for preparing tadalafϊl is provided involving cyclization of a cis-isomer of a compound of Formula II:

wherein X is a leaving group in the presence of a base. Any suitable leaving group can be used such as a halogen leaving group, e.g., chlorine, bromine and the like with chlorine being most preferred.

[0030] The cyclization of a cis-isomer of the compound of Formula II can be carried out in the presence of a base and a suitable solvent. A suitable base includes, but is not limited to, inorganic bases such as alkali or alkaline earth metal hydroxides, alkali or alkaline earth metal carbonates; organic bases such as amine derivatives, alkyl lithium and the like and mixtures thereof. Representative examples of suitable inorganic bases include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and the like. Suitable organic bases includes such as isopropyl amine, diisopropyl amine, n-butyl lithium, lithium diisopropyl amide and the like and mixtures thereof. Generally, the base will be present in an amount of about 1 equivalent to about 5 equivalents per equivalent of the compound of Formula II.

[0031] Suitable solvents include, but are not limited to, alcoholic solvents having from about Ci to about Ci₂ carbon atom such as methanol, ethanol, isopropanol and the like, aromatic hydrocarbon solvents such as benzene, toluene, xylene and the like, non- aromatic hydrocarbon solvents such as hexane and the like and mixtures thereof. The solvent can be present in an amount of about 5 to about 50 volumes. The cyclization can be carried out at a temperature ranging from about -90⁰C to about 20⁰C, for a time period ranging from about 1 to about 8 hours. As one skilled in the art will readily appreciate the temperature and time for the reaction may be suitably based on the base and solvent employed in the reaction. [0032] In one embodiment, the base used is lithium diisopropyl amide, preferably generated in situ by the reaction of n-butyl lithium and diisopropyl amine. [0033] Preferred embodiments of the process of the present invention can be generally set forth below in Scheme II and III.

Formula I

SCHEME III

[0034] The tadalafil or a pharmaceutically acceptable salt or derivative thereof thus obtained can then be purified using a suitable solvent. Suitable solvents include, but are not limited to, alcoholic solvents having from 1 to about 6 carbon atoms, aromatic hydrocarbon solvents, non-aromatic hydrocarbon solvents and the like and mixtures thereof. The process of the present invention advantageously provides tadalafil in relatively high purity, e.g., greater than or equal to about 98%, preferably greater than or equal to about 99% and more preferably greater than or equal to about 99.5%. [0035] The tadalafil or pharmaceutically acceptable salt or derivative thereof of the present invention may then be formulated into a pharmaceutical composition or dosage form. Such pharmaceutical compositions may be administered to a mammalian patient in any dosage form, e.g., liquid, powder, elixir, injectable solution, etc. Dosage forms may be adapted for administration to the patient by oral, buccal, parenteral, ophthalmic, rectal and transdermal routes. Oral dosage forms include, but are not limited to, tablets, pills, capsules, troches, sachets, suspensions, powders, lozenges, elixirs and the like. The tadalafil or pharmaceutically acceptable salt or derivative thereof of the present invention also may be administered as suppositories, ophthalmic ointments and suspensions, and parenteral suspensions, which are administered by other routes. The dosage forms may contain the tadalafil or pharmaceutically acceptable salt or derivative thereof of the present invention as is or, alternatively, as part of a composition.

[0036] The following examples illustrate the invention further. It should be understood, however that the invention is not confined to the specific limitations set forth in the individual examples but rather to the scope of the appended claims.

Experimental

[0037] The purity was measured by high performance liquid chromatography

(HPLC) under the following conditions:

[0038] Column: Xterra RP 18, 250 X 4.6mm, 5μ (manufactured by Waters

Xterra.)

[0039] Moving phase: A = 0.05M disodium hydrogen phosphate in water with the pH being adjusted to 6.6 with o-phosphoric acid. B = Acetonitrile

Time % A % B

0 62 38

15 62 38

25 38 62

35 38 62

40 62 38

45 62 38

[0040] Detector: UV, 225 nm

[0041] Flow rate: l.O ml/min.

[0042] Retention time: about 11 min

EXAMPLE l

[0043] The reaction scheme of this example is generally shown below in Scheme

IV.

SCHEME IV

Compound - 1 Compound - II

[0044] Into a clean dry glass flask charged with ethanol (250 ml) under a nitrogen atmosphere was added Compound 1 (25 g) under stirring. The reaction mass was cooled to 0 to 5⁰C and monomethylamine gas was purged into the reaction mixture for about 2 hours while maintaining the temperature between 0 to 5⁰C. The temperature was raised to 75 to 8O⁰C and the reaction mixture was stirred under reflux for 2 hours. The reaction mixture was then cooled to 0 to 5°C and monomethylamine gas was again purged into the reaction mixture at 0 to 5°C. The temperature was again raised to 75 to 80⁰C and stirred for about 1 hour. The reaction mixture was concentrated under vacuum to about 1/3 its original volume, cooled to 5 to 1O⁰C and stirred for 1 hour at this temperature. The solids were filtered and washed with chilled ethanol (50 ml). The wet solids were dried under vacuum for 6 hours.

[0045] Yield: 25g; Mp: 202-206.7⁰C

[0046] Specific rotation (25°C) :+44.0 ( C=l% in DMSO)

[0047] ¹³C NMR, DMSO-D6 : 25.78, 25.92, 57.89, 57.98, 101.17, 108.09, 108.32,

109.08, 111.48, 117.82, 118.62, 122.23, 122.97, 126.97, 135.97, 136.22, 136.55, 146.99,

147.48, 173.13

[0048] ¹H NMR, DMSO-D6, 300 MHz, Delta values: 2.6(m,lH), 2.7(m,3H),

2.8(d,lH), 3.0(d,lH), 3.6(bs,lH), 5.1(m,lH), 6.0(s,3H), 6.9-7.1(m, 5H), 7.2(d,lH),

7.4(d,lH), 7.8(bs, IH), 10.3(s, IH)

EXAMPLE 2

[0049] The reaction scheme of this example is generally shown below in Scheme

V.

SCHEME V

Formula III Formula II

[0050] Into a clean dry flask charged with dichloromethane (200 ml) was added

Compound II (25 g) obtained in Example 1 under stirring at 25 to 30⁰C. Next, triethylamine (16.11 g) was added to the reaction mixture and stirred for 30 minutes at 20 to 30⁰C. The reaction mixture was cooled to 0 to 5°C and a solution of chloroacetyl chloride (12.93 g) in chloroform (50 ml) was added to the reaction mixture while maintaining temperature between -5 to 5⁰C. The reaction mixture was stirred at -5 to 5°C for about 2 hours. Saturated aqueous sodium bicarbonate solution (50 ml) was added to the reaction mass slowly and the temperature of the reaction mixture was raised to 25 to 30⁰C. The lower organic layer was separated and washed twice with water (75 ml). The chloroform extract was dried over anhydrous sodium sulfate. The organic layer was concentrated under vacuum until a thick yellow slurry was obtained. The slurry was cooled to 0 to5°C. The solids obtained were filtered and washed with 50 ml chilled chloroform. The wet product was dried at 75⁰C under vacuum for 6 hours.

[0051] Yield: 22.5 g; HPLC Purity: 97%; Mp: 180-182⁰C

[0052] Specific rotation(25°C): -154.3(C=1% in DMSO)

[0053] ¹³C. NMR(DMSO-Do, 300 MHZ)= 21.11, 25.88, 44.207, 51.60, 53.95,

101.16,107.66 109.56, 111.38, 118.36, 118.75, 121.58,122.74, 126.30, 130.31, 134.13,

136.57, 146.66, 147.03,167.43, 168.45

[0054] ¹H. NMR (CDC13, 300 MHZ):2.4(bs,3H), 3.1(m,lH), 3.8(m,lH),

4.3(bs,2H), 4.9(m,lH), 5.4(m,lH), 5.9(s,2H), 6.6-6.8(m,3H), 6.9(bs,lH), 7.1-7.3(m,3H),

7.6(d, IH), 7.7(bs,lH)

[0055] ¹H. NMR (DMSO-D6, 300 MHZ): 2.0 (bs,3H), 2.9(m,lH), 3.4(m,lH),

4.5(m,lH), 4.8(m,lH), 4.9(m,lH), 6.0(m,2H), 6.4-6.8(m,4H), 6.9-7.2(m,2H), 7.3(d, IH),

7.4(bs,lH), 7.5(d,lH), 10.8(s,lH)

EXAMPLE 3

[0056] The reaction scheme of this example is generally shown below in Scheme

VI.

SCHEME VI

Formula II Formula I

[0057] Into a clean dry round bottom (RB) flask was charged tetrahydrofuran

(THF) (175 ml) under a nitrogen blanket and then cooled to -35 to -40⁰C. Next 92 ml n- butyllithium (1.6 m solution in hexane) was added while maintaining the temperature between -35 to -40⁰C. After the addition was complete, the reaction mixture was stirred at -35 to -40⁰C for 15 minutes. A solution of compound of formula II (22.5 g) obtained in Example 2 in THF (75 ml) was prepared and slowly added to the reaction mixture while maintaining the temperature between -35 to -40⁰C. After the addition was complete, the reaction mixture was stirred at -35 to -40⁰C for 2.5 hours. Saturated aqueous ammonium chloride solution (25 ml) and 50 ml ethyl acetate was added to the reaction mixture at -35 to -40⁰C. The temperature was raised to 25 to 30⁰C and the two layers formed were separated. The upper organic layer was collected. The lower aqueous layer was thrice extracted with ethyl acetate (25 ml). The organic layers were combined together and washed with water (50 ml). The organic extract was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain crude tadalafil as a dark brown solid. [0058] Yield: 22 g; HPLC Purity: 50%.

EXAMPLE 4

[0059] Purification of crude tadalafil

[0060] The crude tadalafil (22 g) obtained in Example 3 was suspended in 110 ml methanol and stirred for 1 hour at 25 to 30⁰C. The solids obtained were filtered and washed with 25 ml chilled methanol. The wet product was dried at 60⁰C under vacuum for 6 hours. This was further purified by using isopropyl alcohol. Yield: 9 g; HPLC Purity: >99.5%.

EXAMPLE 5

[0061] The reaction scheme of this example is generally shown below in Scheme

VII.

Scheme VII

Formula VI where R = -OCH3 Formula VIA [0062] Into a clean dry RB flask charged with methanol (1900 ml) was added D- tryptophan methyl ester (190 g) under stirring at 25 to 30⁰C. The reaction mixture was cooled to 0 to 5⁰C. Monomethylamine gas was purged into the reaction mixture at 0 to 5°C for about 5-7 hours under stirring. The temperature of the reaction mixture was slowly raised to about 25 to 3O⁰C and stirred at this temperature for 5-7 hours. The reaction mixture was concentrated under vacuum to distill out the solvent. Diisopropyl ether (950 ml) was added and cooled to 25 to 3O⁰C under stirring for 1-2 hrs. The solids obtained were filtered, washed with Diisopropyl ether and dried under vacuum. [0063] MP: 122.4-124⁰C; Yield: 150 g (78.9 % w/w).

[0064] Specific rotation(25°C): +12.5 (C=I % in DMSO)

[0065] 13 C NMR (300 MHZ,DMSO-D6): 25.71, 31.40, 55.67, 110.93, 111.55,

118.42, 118.73, 121.09, 123.95, 127.66,136.44, 175.39.

[0066] ¹H NMR (300 MHZ,DMSO-D6): 1.6(bs,2H), 2.5(m,3H), 2.8(m,lH),

3.1(m,lH), 3.4(m, IH), 6.9-7.2(m,3H), 7.3(d,lH), 7.5(d,lH), 7.8(bs,lH), 10.8(bs,lH)

EXAMPLE 6

[0067] The reaction scheme of this example is generally shown below in Scheme VIII.

SCHEME VIII

Formula VIA Formula VII

[0068] Into a clean, dry flask charged with methylene dichloride (MDC) (1000 ml) was added D-tryptophan methyl amide, the compound of Formula VIA (50 g), and piperonal, the compound of Formula VII (31.09 g), under stirring at 25 to 30⁰C. The reaction mixture was cooled to 0 to 5°Cunder nitrogen atmosphere. Trifluoroacetic acid (85.3 g) was dissolved in MDC (250 ml) and the solution was slowly added to the reaction mixture at 0 to 5°C. The temperature of the reaction mixture was raised to 20 to 30⁰C and stirred at this temperature for 14-16 hours. The reaction was monitored by TLC, workup was done as follows, the pH of the reaction mixture was adjusted to 8-9 using sodium carbonate solution under stirring, the two layers were settled, separated and the lower MDC layer was washed with water. The MDC layer was then dried over anhydrous sodium sulfate. The reaction mass was concentrated under vacuum at 40 to 5O⁰C to remove the solvent. The compound was precipitated using ethyl acetate, the solids were filtered, washed with ethyl acetate and dried.

[0069] Yield: 52.5 g; Yield: 105% w/w, HPLC Purity: 71% cis and 27% trans isomer (HPLC).

EXAMPLE 7

[0070] The reaction scheme of this example is generally shown below in Scheme IX.

SCHEME IX

1]CICOCH2C1 2]crystn

Formula m Formula H

[0071] Into a clean dry flask charge with dichloromethane (400 ml) under a nitrogen atmosphere was added the compound of Formula III obtained in Example 6 and triethylamine (28.96 g) under stirring at 20 to 3O⁰C. The reaction mixture was then cooled to 0 to 5⁰C. A mixture of chloroacetyl chloride (25.85 g) in dichloromethane (100 ml) was prepared and slowly added to the reaction mixture while maintaining the temperature between -5 to 5⁰C in 1-2 hrs. The reaction mixture was stirred at 0 to 5⁰C for 30 min and then saturated sodium bicarbonate solution (100 ml) was added at 5 to 10⁰C under stirring. The temperature of the reaction mixture was raised to 25 to 30⁰C and stirred at this temperature for 15 minutes. The layers were then separated. The lower MDC layer was collected, washed twice with 100 ml water and dried over anhydrous sodium sulfate. The

MDC layer was concentrated to distill out MDC until a stirrable mass was left behind. The mass was cooled to 25-3O⁰C and filtered, washed, to yield off-white to light yellow colored solids. The resulted product was the cis isomer, the trans isomer left behind in the mother liquor.

[0072] Yield = 25.5 g (50%w/w); HPLC Purity: > 97%.

[0073] The physical and spectral data was similar to that obtained in Example 2.

EXAMPLE 8

[0074] The reaction scheme of this example is generally shown below in Scheme

X.

SCHEME X

Formula II

[0075] Into a clean dry round bottom (RB) flask was charged THF (1625 ml) under a nitrogen blanket and then cooled to -35 to -40⁰C. Next, 505 ml n-butyllithium (1.6 m solution in hexane) was added while maintaining the temperature between -35 to -4O⁰C. After the addition was complete, the reaction mixture was stirred at -35 to -4O⁰C for 15 minutes. 72 ml diisopropyl amine was then added at -35 to -40⁰C and then stirred at 0-5⁰C for 1 hr. A solution of Compound of formula II (125 g) obtained in Example 7 in THF (625 ml) was prepared and slowly added to the reaction mixture while maintaining the temperature between -40 to -5O⁰C. After the addition was complete, the reaction mixture was stirred at -35 to -40⁰C for 2-6 hours. Saturated aqueous ammonium chloride solution (250 ml) and ethyl acetate (125 ml) was added to the reaction mixture at -35 to -40⁰C. The temperature was raised to 25 to 30⁰C and the two layers formed were separated. The upper organic layer was collected. The lower aqueous layer was extracted with ethyl acetate (65 ml). The organic layers were combined together and distilled. Isopropyl alcohol (1250 ml) was added and the distillation was continued. A mixture of methanol (250 ml) and isopropanol (375 ml) were added and crude tadalafϊl was obtained upon cooling. The crude product was filtered, washed with water and dried. [0076] Yield: 60 g; (48% w/w); HPLC Purity: >99%.

EXAMPLE 9

[0077] Purification of crude Tadalafil

[0078] The crude tadalafil obtained in Example 8 was suspended in methanol (600 ml) and stirred for 1 hour at reflux. The mixture was cooled and the solids obtained were filtered and washed with chilled methanol (60 ml). The wet product was dried at under vacuum.

[0079] Yield: 56 g; HPLC Purity: 99.8%.

[0080] It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the features and advantages appended hereto.

Claims

WHAT IS CLAIMED IS:

1. A process for the preparation of (6R, 12aR)-2,3 ,6,7, 12,12a-hexahydro-2-methyl- 6-(3,4-methylenedioxyphenyl)pyrazino[r,2':l,6]pyrido[3,4-b]indole-l,4-dione of Formula I:

the process comprising cyclizing a cis-isomer of a compound of Formula II:

wherein X is a leaving group, in presence of a base.

2. The process of Claim 1, wherein X is a halogen.

3. The process of Claims 1 and 2, wherein X is chlorine.

4. The process of Claims 1-3, wherein the base is selected from the group consisting of an alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, alkaline earth metal carbonate, amine base, alkyl lithium and mixtures thereof.

5. The process of Claims 1-4, wherein the base is lithium diisopropylamide.

6. The process of Claims 1-5, wherein the base is present in an amount of about 1 equivalents to about 5 equivalents per equivalent of the compound of Formula II.

7. The process of Claims 1-6, wherein the step of cyclizing is carried out in a solvent.

8. The process of Claim 7, wherein the solvent is present in an amount of about 5 volumes to about 50 volumes.

9. The process of Claims 1-8, wherein the step of cyclizing is carried out at a temperature of about -90⁰C to about 20°C for a time period of about 1 to about 8 hours.

10. The process of Claims 1-9, wherein the compound of Formula I is substantially pure.

11. The process of Claims 1-9, wherein the compound of Formula I has a purity of greater than or equal to about 99%.

12. A compound of Formula II:

wherein X is a leaving group.

13. The compound of Formula II, wherein X is Cl.

14. A cis-isomer (lR,3R)-l-(benzo[d][l,3]dioxol-5-yl)-2-(2-chloroacetyl)-N- methyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indole-3-carboxamide.

15. A process for the preparation of compound of Formula II:

wherein X is a leaving group, the process comprising reacting a compound of Formula III:

with a compound of Formula IV:

O

Y C-CH₂X _(IV) wherein Y is a halogen and X has the aforestated meaning in the presence of an organic reaction solvent and a base.

16. The process of Claim 15, wherein the organic solvent is selected from the group consisting of a halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, non-cyclic ether solvent and mixtures thereof.

17. The process of Claims 15 and 16, wherein the organic solvent is selected from the group consisting of dichloromethane, ethylene dichloride, chloroform, carbon tetrachloride and mixtures thereof.

18. The process of Claims 15-17, wherein the organic solvent is selected from the group consisting of benzene, toluene, xylene and mixtures thereof.

19. The process of Claims 15-18, wherein, the organic solvent is used in an amount of about 2 volumes to about 25 volumes.

20. The process of Claims 15-19, wherein the base is selected from the group consisting of a C₁-Ce mono-, di- or tri-alkyl amine wherein the alkyl groups may be the same or different, C₃-C_2S cyclic amine, alkali metal carbonate, alkali metal bicarbonate and mixtures thereof.

21. The process of Claims 15-20, wherein the base is triethylamine.

22. The process of Claims 15-21, wherein the base is present in an amount of about 1 equivalent to about 5 equivalents per equivalent of the compound of Formula III.

23. The process of Claims 15-22, wherein the reaction is carried out at a temperature of about -10⁰C to about 25°C.

24. The process of Claims 15-23, wherein the compound of Formula III is present in an amount of about 1 equivalent to about 3 equivalents per equivalent of the compound of Formula IV.

25. The process of Claims 15-24, wherein the compound of Formula II is a mixture of cis and trans isomers.

26. The process of Claim 25, further comprising isolating the cis isomer from the mixture.

27. The process of Claims 15-26, wherein the compound of Formula II is thereafter converted to tadalafil.

28. A process for the preparation of intermediate compound of Formula III:

the process comprising reacting D-tryptophan methyl amide of Formula VI or a salt thereof

with piperonal of Formula VII

in the presence of trifluoroacetic acid and in an organic reaction solvent.

29. The process of Claim 28, wherein the organic reaction solvent is selected from the group consisting of a halogenated solvent, alkyl ester of a lower carboxylic acid, aromatic hydrocarbon and mixtures thereof.

30. The process of Claims 28 and 29, wherein the organic reaction solvent is selected from the group consisting of dichloromethane, ethylene dichloride, chloroform, carbon tetrachloride ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, isobutyl acetate, benzene, toluene, xylene and mixtures thereof.

31. The process of Claims 28-30, wherein the organic reaction solvent is present in an amount of about 5 volumes to about 40 volumes.

32. The process of Claims 28-31, wherein the reaction is carried out at a temperature of about O⁰C to about 50⁰C.

33. The process of Claims 28-32, wherein the reaction is carried out for a time period of about 1 to about 20 hours.

34. The process of Claims 28-33, wherein the compound of Formula VI is reacted with the compound of Formula VII in an amount of about 1 equivalent to about 2 equivalents per equivalent of the compound of Formula VII.

35. The process of Claims 28-34, wherein the compound of Formula III is a mixture of cis:trans isomers in a ratio of from about 90:10 to about 10:90.

36. The process of Claims 28-34, wherein the compound of Formula III is a mixture of cis:trans isomers in a ratio of from about 60:40 to about 40:60.

37. The process of Claims 28-36, wherein the compound of Formula III is thereafter converted to tadalafil.

38. A process for the preparation of intermediate compound of Formula III, the process comprising reacting mono methyl amine with a compound of Formula V:

wherein R is-OH, -halogen or -OCi-Cg alkyl, in the presence of an organic reaction solvent.

39. The process of Claim 38, wherein R is -OCH₃.

40. The process of Claims 38 and 39, wherein the solvent is selected from the group consisting of an alcoholic solvent, halogenated solvent, aromatic hydrocarbon, non- cyclic ether and mixtures thereof.

41. The process of Claims 38-40, wherein the solvent is methanol or ethanol.

42. The process of Claims 38-41, wherein the compound of Formula III is thereafter converted to tadalafil.

43. Substantially pure tadalafil.

44. Tadalafil having a purity of equal to or greater than about 99%.

45. A pharmaceutical composition comprising a therapeutically effective amount of tadalafil as claimed in Claims 43 and 44.