The present invention relates to a process for the preparation of cis-intermediates of Formula II,
(Formula Removed)
wherein RT represents hydrogen, (un)substituted alkyl, alkenyl, aryl and X represents a leaving group, which are useful for the preparation of tetracyclic compounds of Formula I,
(Formula Removed)
Formula I wherein RT is as defined above and R2 represents (un)substituted alkyl.
(6R, 12aR) 6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl
pyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione (compound of Formula I wherein R1 = 1,3-benzodioxol-5-yl and R2 = methyl) also known as Tadalafil, is a potent, selective and reversible inhibitor of cyclic guanosine 3',5'-monophosphate specific phosphodiesterase type 5 enzyme (cGMP specific PDE5).
The biochemical, physiological, and clinical effects of cyclic guanosine 3',5'-monophosphate specific phosphodiesterase (cGMP-specific PDE) inhibitors suggest their utility in a variety of disease states in which modulation of smooth muscle, renal, hemostatic, inflammatory, and/or endocrine function is desired. Type 5 cGMP-specific phosphodiesterase (PDE5) is the major cGMP hydrolyzing enzyme in vascular smooth muscle and its expression in penile corpus cavernosum has been reported (Taher et al., J. Urol., 149:285A (1993). PDE5 is an attractive target in the treatment of sexual dysfunction (Murray, Drug News and Perspectives 6(3): 150-156 (1993)).
U.S. Pat. No. 5,859,006 (herein after the '006 patent) discloses a class of p-carboline compounds, which are useful in the treatment of conditions wherein inhibition of PDE5 is desired. The '006 patent discloses two synthetic pathways for preparation of tadalafil. Path (I) involves Pictet-Spengler reaction of D-tryptophan methyl ester with piperonal leading to formation of a mixture of cis- and trans-tetrahydro p-carboline intermediates of Formula A and B (herein after the cis-intermediate of Formula A and trans-intermediate of Formula B respectively) in a 3:2 ratio.
(Formula Removed)
The cis-intermediate of Formula A is then converted to tadalafil in two steps. However the reaction times are longer and the yield of the cis-intermediate of Formula A which is the desired isomer, is poor and additionally it has to be separated from the trans-intermediate of Formula B. The Pictet-Spengler reaction in path (I) is carried out in the presence of trifluoroacetic acid which is a highly corrosive and hazardous reagent. Path (II) starts with the reaction of D-tryptophan methyl ester with piperonoyl chloride and involves four steps to prepare the cis-intermediate of Formula A. Though this a better yielding process but it is cumbersome as it involves many synthetic steps.
PCT Application No. WO 2004/11463 discloses a process for the preparation of cis-intermediate of Formula A wherein D-tryptophan methyl ester hydrochloride is reacted with piperonal in isopropanol. However alternative solvents are desirable as isopropanol requires control of reaction temperature on account of its low boiling point and low flash point. Isopropanol may also be contaminated with peroxides which can cause undesired side reactions.
PCT Application No. WO 2005/068464 discloses a process for the preparation of cis-intermediate of Formula A wherein the reaction of D-tryptophan methyl ester hydrochloride with piperonal is carried out in the presence of molecular sieves.
US Patent Application No. 2006/0276652 discloses a process for the preparation of cis-intermediate of Formula A wherein D-tryptophan methyl ester hydrochloride is reacted with piperonal in ethyl acetate in the presence of trifluoroacetic acid. However trifluoroacetic acid is a hazardous and corrosive chemical and poses safety problems during handling.
US Patent Applciation No. 2006/0258865 discloses a process for the preparation of cis-intermediate of Formula A wherein D-tryptophan methyl ester hydrochloride is reacted with piperonal in dimethyl acetamide with or without the use of a dehydrating agent. However the reaction times are longer and the work up is tedious and involves acid-base treatment which can be done away with.
The present inventors have developed an industrially useful process for the preparation of cis-intermediate of Formula II,
(Formula Removed)
wherein R1 represents hydrogen, (un)substituted alkyl, alkenyl, aryl, and X represents a leaving group. The present process is highly diastereoselective and provides cis-intermediate of Formula II in good yield. The present process is amenable to scale-up conditions and does not require the use of a dehydrating agent or hazardous chemical like trifluoroacetic acid.
A first aspect of the present invention provides a process for the preparation of the cis-intermediate of Formula II,

(Formula Removed)
wherein R1 represents hydrogen, (un)substituted alkyl, alkenyl, aryl, and X represents a leaving group and wherein the said process comprises of, a) reacting D-tryptophan derivative of Formula III or salt thereof,
(Formula Removed)
wherein X represents a leaving group, with a compound of Formula IV,
(Formula Removed)
wherein RI as defined above, in the presence of sulfolane b) isolating the cis-intermediate of Formula II from the reaction mass thereof.
D-tryptophan derivative of Formula III and the compound of Formula IV are suspended in sulfolane at about 20-40°C. The reaction mixture is stirred at about 60-90°C for 10-15 hours and cooled to about 20-40°C. From the resultant mixture the cis-intermediate of Formula II can be isolated by optional addition of an anti-solvent and suitable work up.
The D-tryptophan derivative of Formula III above can be prepared from D-tryptophan by methods known in the art or as exemplified in the present invention. Suitable leaving group can be selected from halogens, alkoxy, acyloxy, sulphonyloxy and the
like.
A second aspect of the present invention provides a process for the preparation of a tetracyclic compound of Formula I,
(Formula Removed)
wherein R1 represents hydrogen, (un)substituted alkyl, alkenyl, aryl and R2 represents (un)substituted alkyl and wherein the said process comprises of, a) reacting D-tryptophan derivative of Formula III or salt thereof,
(Formula Removed)
wherein X represents a leaving group, with a compound of Formula IV,
(Formula Removed)
wherein R1 is as defined above, in the presence of sulfolane, to obtain the cis-intermediate of Formula II,
(Formula Removed)
wherein R1 and X are as defined above,
b) reacting the cis-intermediate of Formula II with a compound of Formula V,
(Formula Removed)
wherein X1 and X2 may be the same or different and each represents a leaving group, in the presence of a base, to obtain a compound of Formula VI,
(Formula Removed)
wherein R1 X and X2 are as defined above,
c) reacting the compound of Formula VI with a compound of Formula VII,
(Formula Removed)
wherein R2 represents (un)substituted alkyl,
d) isolating the tetracyclic compound of Formula I from the reaction mass thereof.
The cis-intermediate of Formula II can be prepared by the method disclosed in the first aspect of the present invention. The cis-intermediate of Formula II prepared by the process of the present invention can be converted to the tetracyclic compound of Formula I by methods known in the art. For example, the cis-intermediate of Formula II is reacted with a compound of Formula V in the presence of a base to obtain a compound of Formula VI. The compound of Formula VI is reacted with a compound of Formula VII to obtain the tetracyclic compound of Formula I.
Suitable leaving groups have already been defined in the first aspect of the present invention. Suitable bases can be selected from the group comprising of alkali and alkaline earth metal hydroxides, carbonates, bicarbonates and the like or mixtures thereof. For example the base can be selected from the group comprising of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like or mixtures thereof.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE Step 1: Preparation of D-Tryptophan methyl ester hydrochloride
D-Tryptophan (100.0 g) was suspended in methanol (500 ml) and the suspension added to a solution of SOCI2 (82.14 g) in methanol (500 ml) at 25-30°C under nitrogen atmosphere. The resultant solution was stirred at reflux for 3 to 4 hours and the reaction mixture was concentrated to a residual volume of 150 ml. To the concentrated mixture dichloromethane (700 ml) was added and the resultant solution was cooled to 0-5°C with continuous stirring for 0.5 hour. The solid so obtained was filtered, washed with dichloromethane (200 ml) and dried in air at 40-45°C to afford the title compound. Yield: 100g
Step 2: Preparation of cis 1-Benzo[1,3]dioxol-5-yl-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid methyl ester hydrochloride
D-Tryptophan methyl ester hydrochloride (100 g) and piperonal (65 g) were suspended in sulfolane (500 ml) at 25-30°C. The reaction mixture was stirred at 80-85°C for 14 hours and then cooled to 25-30°C. To the cooled mixture dichloromethane (500 ml) was added and the resultant mixture continuously stirred for 1 hour. The solid so obtained was filtered, washed with dichloromethane (500 ml) and dried in air at 40-45°C to afford the title compound. Yield: 135g(89%)
Step 3: Preparation of cis 1-Benzo[1,3]dioxol-5-yl-2-(2-chloro-acetyl)-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid methyl ester
cis 1 -Benzo[1,3]dioxol-5-yl-2,3,4,9-tetrahydro-1 H-beta-carboline-3-carboxylic acid methyl ester hydrochloride (50 g) was dissolved in dichloromethane and 5% aqueous sodium bicarbonate (500 ml). The organic layer was separated and washed with deionized water (500 ml). The organic layer was added into deionized water (50 ml) and treated with sodium bicarbonate (15 g) at 25-30°C. To the resultant mixture chloroacetyl chloride (25 g) in dichloromethane (50 ml) was added at a rate sufficient to maintain the temperature of the reaction mixture between 0 and 5°C. The reaction mixture was stirred for three hours and monitored by Thin Layer Chromatography. After the completion of reaction, dichloromethane (500 ml) and Dl water (1 L) were added. The organic layer was separated and washed sequentially with water
followed by aqueous sodium bicarbonate solution till pH was 6.5-7.0, and finally with water. The organic layer was concentrated under reduced pressure to obtain a solid. The solid was dissolved in acetone (750 ml) and the resultant solution was concentrated to a residual volume of about 75 ml. To the concentrated solution, deionized water was slowly added at 20-25°C and the resultant mixture cooled to 0-5°C with continuous stirring for 0.5 hour. The solid so obtained was filtered and dried to afford the title compound. Yield: 48.5 g
Step 4: Preparation of Tadalafil
cis 1 -Benzo[1,3]dioxol-5-yl-2-(2-chloro-acetyl)-2,3,4,9-tetrahydro-1 H-beta-carboline-3-carboxylic acid methyl ester (30 g) was taken in methanol (450 ml). The resultant mixture was heated to 35-40°C and aqueous methyl amine (27 ml; 40%) was added. The reaction mixture was stirred at 50-55°C for 5 hours and then cooled to 10-15°C with continuous stirring for 0.5 hour. The solid so obtained was filtered and dried to afford the title compound. Yield: 24.6 g (90%)

WE CLAIM:
1. A process for the preparation of the cis-intermediate of Formula II,

(Formula Removed)
wherein R1 represents hydrogen, (un)substituted alkyl, alkenyl, aryl, and X represents a leaving group and wherein the said process comprises of, a) reacting D-tryptophan derivative of Formula III or salt thereof,
(Formula Removed)
wherein X represents a leaving group, with a compound of Formula IV,
(Formula Removed)
wherein R1 as defined above, in the presence of sulfolane b) isolating the cis-intermediate of Formula II from the reaction mass thereof.
2 The process according to claim 1 wherein X is selected from the group comprising of halogens, alkoxy, acyloxy, sulphonyloxy.
3 A process for the preparation of a tetracyclic compound of Formula I,
(Formula Removed)
wherein R1 represents hydrogen, (un)substituted alkyl, alkenyl, aryl and R2 represents (un)substituted alkyl and wherein the said process comprises of,
a) reacting D-tryptophan derivative of Formula III or salt thereof,
(Formula Removed)
wherein X represents a leaving group, with a compound of Formula IV,
(Formula Removed)
wherein R1 as defined above, in the presence of sulfolane, to obtain the cis-intermediate of Formula II,
(Formula Removed)
wherein RI and X are as defined above, b) reacting the cis-interrnediate of Formula II with a compound of Formula V,
(Formula Removed)
wherein X1 and X2 may be the same or different and each represents a leaving group, in the presence of a base, to obtain a compound of Formula VI,
(Formula Removed)

wherein RI X and X2 are as defined above, c) reacting the compound of Formula VI with a compound of Formula VII,
(Formula Removed)
wherein R2 represents (un)substituted alkyl, d) isolating the tetracyclic compound of Formula I from the reaction mass thereof.
4. The process according to claim 3 wherein X, X1 and X2 are selected from the
group comprising of halogens, alkoxy, acyloxy, sulphonyloxy.
5. The process according to claim 2 and 4 wherein X is alkoxy.
6. The process according to claim 4 wherein X1 and X2 each represents a halogen.
7. The process according to claim 3 wherein X is methoxy, R1 is 1,3-benzodioxol-5-yl
and R2 is methyl.
8. The process according to claim 3 wherein the base is selected from the group
comprising of alkali and alkaline earth metal hydroxides, carbonates, bicarbonates or
mixtures thereof.
9 The process according to claim 8 wherein the base is selected from the group comprising of sodium carbonate, potassium carbonate, sodium bicarbonate potassium bicarbonate or mixtures thereof.
10. A process for the preparation of the cis-intermediate of Formula II as described herein and disclosed in the Example.