WO2009047613A2

WO2009047613A2 - An improved process for the preparation of tadalafil intermediate

Info

Publication number: WO2009047613A2
Application number: PCT/IB2008/002642
Authority: WO
Inventors: Vijayabaskar Veerappan; Susi Swaminathan; Rao Siripragada Mahender
Original assignee: Orchid Chemicals & Pharmaceuticals Limited
Priority date: 2007-10-08
Filing date: 2008-10-07
Publication date: 2009-04-16
Also published as: WO2009047613A3

Abstract

The present invention relates to an improved process for the preparation of Tadalafil intermediate (1R,3R)Methyl-1,2,3,4-tetrahydro-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate of formula III comprising a modified Pictet-Spengler reaction between the compound of formula II and piperonal in a mixture of aromatic hydrocarbon solvent and a glycol.

Description

ANIMPROVED PROCESS FORTHE PREPARATION OF TADALAFIL

INTERMEDIATE

Field of the invention

The present invention relates to an improved process for the preparation of compound of formula III, which is an important intermediate in the preparation of Tadalafil.

Background of the invention

The chemical name of Tadalafil is pyrazino(6R, 12aR)-2,3,6,7, 12, 12a- hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',r:6,l]pyrido[3,4- b]indole-l,4-dione. It is marketed in the brand name of CIALIS for oral treatment for erectile dysfunction. Tadalafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). It is represented by the following formula I. 0

(lR,3R)Methyl-l,2,3,4-tetrahydro-l-(3,4-methylenedioxyphenyl)-9H- pyrido[3,4-b]indole-3-carboxylate of formula III is a key intermediate in the preparation of Tadalafil. Tadalafil was first reported in US patent No. 5,859,006; this patent describes the preparation of this key intermediate by reacting Tryptophan methyl ester of formula II or its acid addition salt with piperonal by using dichloromethane/toluene as a solvent and in the presence of trifluoroacetic acid. This patent also describes the process for preparation of Tadalafil as shown in the below scheme:

US patent 7,223,863 discloses a process for the preparation of Tadalafil comprising a step of reacting an acid addition salt of D-Tryptophan methyl ester with piperonal in the presence of high boiling solvent wherein high boiling solvent is selected from N, N-Dimethyl acetamide, Dimethyl sulfoxide, N,N-dimethyl formamide, N-methyl pyrrolidine or mixture thereof and in the presence of dehydrating agent.

US2006/0276652 discloses a process for preparing compound of the formula III comprising combining D-Tryptophan methyl ester or a salt thereof and piperonal with at least one organic reaction solvent selected from the group consisting of alky! esters of lower carboxylic acids and aromatic hydrocarbons.

US2006/0004203 discloses a process to obtain ( 1R,3 R)M ethyl- 1, 2,3,4- tetrahydro-l-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate by reacting the D-tryptophan methyl ester hydrochloride with piperonal in refluxing isopropyl alcohol.

US patent 6,911,542 discloses that a D-Tryptophan methyl ester hydrochloride is suspended in acetic acid, water then piperonal to form tadalafil intermediate of formula III.

Most of the prior art processes discussed above have the disadvantages of a long cycle time, a low yield of the desired cis-diastereomer and use of corrosive trifluoroacetic acid. Therefore, there was a long felt need to develop such a process, which can obviate the problems associated with the prior art processes.

Object of the invention

The main objective of the present invention is to provide a facile diastereoselective process for the preparation of tadalafil intermediate of formula III.

Another objective of the present invention is to provide a process for the preparation of Tadalafil, which would be easy to implement on commercial scale and will be economically viable.

Summary of the invention

The present invention provides a process for the preparation of (I R^F^Methyl- l^S^-tetrahydro-l-β^-inethylenedioxyphenyO^H-pyridoIl^-bjindole-θ- carboxylate of formula III, which comprises reacting the compound of formula II with piperonal in a mixture of aromatic hydrocarbon solvent and a glycol.

III Detailed description of the invention

Accordingly, the process of the present invention overcomes the above discussed problems associated with prior art and provides the following advantages:

1. Exclusive formation of cis-isomer

2. Reaction time was reduced more than 10 fold

3. Avoiding the use of corrosive trifluoroacetic acid

In an embodiment of the present invention D-tryptophancmethyl ester - hydrochloride is reacted with piperonal in a mixture of aromatic solvent and glycol to obtain (lR,3R)Methyl-l,2,3,4-tetrahydro-l-(3,4-methylenedioxyphenyl)~9H- pyrido[3,4-b]indole-3-carboxylate.

In another embodiment of the present invention, the glycol is preferably polyethylene glycol, which is selected from PEG 200, PEG 300, PEG 400, PEG 600. PEG 100, etc. more preferably PEG 400.

In another embodiment of the present invention, the aromatic hydrocarbon solvent is selected from group consisting of toluene, benzene, xylene or mixtures thereof, preferably toluene.

The obtained (lR,3R)Methyl-l,2,3,4-tetrahydro-l -(3,4-methylenedioxyphenyl)-

9H-pyrido[3,4-b]indole-3-carboxylate is reacted with a chlorinating agent in a suitable solvent to get (lR,3R)-Methyll,2,3,4-tetrahydro-2-chloroacetyl-(3,4-

•^" rriethylenedioxyphenyl)-9H-pyrido[3,4 -b]indole-3-carboxylate, which is further treated with primary amine to obtain Tadalafil.

Alternatively, a person skilled in the art can use further (lR,3R.)Methyl~ 1,2,3,4- tetrahydro-l-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate to obtain Tadalafil as per the process available in prior art.

The starting materials used in the invention are either commercially available or can be made by the person skilled in the art according to the process available in prior art. The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.

Example(l)

Preparation of (lR,3R)Methyl-l,2,3,4-tetrahydro-l-(3,4-methylenedioxyphenyl)- 9H-pyrido[3,4-b]indoIe-3-carboxylate (III)

D-Tryptophan methyl ester hydrochloride (100 g), 750 mL of toluene, 250 ml PEG 400 and 64.41 g piperonal were taken in 3 L RBF and stirred the contents at room temperature. The mixture was heated to reflux azeotropically at 100-110⁰C. After completion of the reaction, the reaction mixture was cooled to 30-35⁰C. To the above reaction mixture 2 L of water followed by 1000ml of ethyl acetate was added with stirring and basified to pH 7.5 - 8.5 by using sodium bicarbonate solution. To this mixture ethyl acetate was added with stirring and the organic layer was separated out and concentrated under vacuum at 60⁰C. To residue To residue isopropyl ether was added. The obtained solid was filtered and washed with isopropyl ether. The solid material was dried under vacuum at 50-55⁰C.

Yield: 80 - 9O g.

Example (2)

(lR,3R)-MethyIl,2,3,4-tetrahydro-2-chloroacetyI-(3,4-methyIenedioxyphenyl)-9H- pyrido[3,4 -b]indole~3-carboxylate (IV)

To compound of formula (III) (100 g) in 2.5 L dichloromethane, triethylamine (79.65 mL) and chloroacetyl chloride (31.2 ^'mL) were added at 0-5⁰C. After completion of the reaction the reaction mixture was quenched with water. The organic layer was separated out and washed with saturated sodium bicarbonate solution twice followed by water. The organic layer was concentrated up to the residual volume of 2 equivalents with respect to the starting material. Isopropyl alcohol was added to this reaction mass and stirred for 30 minutes. The obtained yellow solid was washed with isopropyl alcohol, filtered and dried at 50 - 60⁰C. Yield: 80.0 g. Example (3) Preparation of Tadalafil (I)

To compound of formula (IV) (100 g) in 1 L of isopropyl alcohol, a solution of methylamine in methanol (25 - 29%; 200 ml) was added at 30 - 35°C. The reaction mass was heated to 50— 55°C till the completion of reaction. The reaction mass was cooled the to 30 — 35°C. The obtained white precipitate was filtered and washed with IPA. The wet cake was dried under vacuum at 60 - 65°C. Yield: 8O g.

Claims

We claim:

1. An improved process for the preparation of (lR,3R)Methyl-l,2,3,4-tetrahydro- l-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate of formula III, which comprises reacting the compound of formula II with piperonal in a mixture of aromatic hydrocarbon solvent and a glycol.

2. A process according to claim 1, wherein the aromatic hydrocarbon solvent is selected from group consists of toluene, benzene, xylene or mixtures thereof.

3. A process according to claim 1, wherein the aromatic hydrocarbon solvent is toluene.

4. A process according to claim 1, wherein the glycol is selected from polyethylene glycols.

5. A process according to claim 1, wherein the polyethylene glycol is selected from PEG 200, PEG 300, PEG 400, PEG 600 and PEG 100.

6. A process according to claim 1, wherein the glycol is PEG 400.

7. A process according to claim 1, which is used further for the preparation of tadalafil.