DESC:CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of the earlier filing date of Indian provisional patent application No. 6565/CHE/2015 filed on December 08, 2015.

BACKGROUND OF THE INVENTION

FIELD OF THE DISCLOUSRE

The present disclosure relates to an improved process for the preparation of tadalafil.
DESCRIPTION OF THE RELATED ART

Tadalafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). CIALIS® tablets containing tadalafil is being sold by Icos-Lilly.

Tadalafil is disclosed in US Patent No. 5,859,006. Tadalafil is chemically known as (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino [2',1':6,1]pyrido[3,4-b]indole-1,4-dione and having the below structure:

Formula-I
U.S Patent No. 5,859,006 discloses a process for the preparation of tadalafil, which involves the condensation of D-tryptophan methyl ester of formula IV with a piperonal of formula V in the presence of dichloromethane and trifluoroacetic acid which provides cis and trans isomers of compound of formula III. The isomers are separated by chromatography. The cis isomer is then reacted with chloroacetyl chloride and methylamine to give tadalafil of formula I.

PCT Publication No. 2004/011463A1 discloses a process for the preparation of tadalafil intermediate of formula III from D-tryptophan methyl ester HCl salt and piperonal of formula V by refluxing the reagents in isopropyl alcohol; the obtained intermediate of formula III is reacted with chloroacetyl chloride and THF, resulting in another intermediate of tadalafil.

U.S. Patent Publication No. 2006/0258865 Al discloses a synthesis of the tadalafil intermediate from D-tryptophan methyl ester of formula IV and piperonal of formula V using a dehydrating agent selected from Na2SO4, K2SO4, MgSO4, CaSO4, CaCl2, molecular sieve or mixtures thereof and a high boiling solvent such as N,N-Dimethyl acetamide. The obtained intermediate of formula III is then reacted with chloroacetyl chloride in the presence of a base such as NaHCO3 and an organic solvent such as dichloromethane, providing another intermediate of formula II, which is further reacted with aqueous methyl amine solution to provide tadalafil. The work up process involves additional acid-base treatment which can be done away with.

According to the processes described above, the reaction of D-tryptophan ester and piperonal is key of the entire process and requires improvement in order to achieve a cheaper and more effective industrial process. The invention of the present application provides a simple, cost effective and rapid work up process for the preparation of compound of formula III with high chiral purity and good yield on commercial scale.

SUMMARY OF THE DISCLOSURE

A first aspect of the present disclosure is to provide a process for the preparation of tadalafil.

Another aspect of the present invention provides a process for the preparation of tadalafil, which comprises, reacting D-tryptophan methyl ester of formula IV or its salt

with piperonal of formula V

in presence of methyl isobutyl ketone to obtain a compound of formula III

In another aspect the present invention provides a process for the preparation of tadalafil, which comprises:
a) reacting D-tryptophan methyl ester of formula IV or salt with piperonal of formula V in presence of methyl isobutyl ketone to obtain a compound of formula III;
b) the compound obtained in step (a) is reacted in-situ with chloroacetyl chloride to yield a compound of formula II;
c) treating the compound of formula III with methylamine to obtain tadalafil; and
d) optionally, recrystallizing the tadalafil obtained in step (c) with dimethyl formamide and methanol.

DETAILED DESCRIPTION OF THE DISCLOSURE

It is to be understood that the description of the present invention has been simplified to illustrate elements that are relevant for a clear understanding of the invention, while eliminating, for purposes of clarity, other elements that may be well known.
In one embodiment, the present invention provides a process for the preparation of tadalafil, which comprises:
a) reacting D-tryptophan methyl ester of formula IV or salt with piperonal of formula V in presence of methyl isobutyl ketone to obtain a compound of formula III;
b) the compound obtained in step (a) is reacted in-situ with chloroacetyl chloride to yield a compound of formula II;
c) treating the compound of formula II with methylamine to obtain tadalafil; and
d) optionally, recrystallizing the tadalafil obtained in step (c) with dimethyl formamide and methanol.

According to the present invention, D-tryptophan methyl ester is reacted with piperonal in presence of methyl isobutyl ketone at a temperature of about 85-95 °C to give a compound of formula III, which was in-situ reacted with chloroacetyl chloride in presence of base at a temperature of about 8-12 °C to obtain a compound of formula II. The compound of formula II is treated with methyl amine solution at a temperature of about 50-60 °C to get tadalafil.

Within the context of the present disclosure, the base used in step (b) may include, as examples inorganic base like alkali metal hydroxides, alkali metal carbonates or an organic base like amine bases, alcoholic amine bases and mixtures thereof. One of skill in the art will recognize numerous well-known inorganic and organic bases that may be useful within the context of the present invention. In certain embodiments, it has been found that triethyl amine is a particularly useful base.

According to the present invention, D-tryptophan methyl ester hydrochloride salt is prepared by reacting D-Tryptophan with methanolic hydrochloride and methanol at a temperature of 45-55 °C.

In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules, compositions and Formulations according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.

Example 1: Preparation of Tadalafil
Tryptophan methyl ester (100 g), methyl isobutyl ketone (200 mL) and piperonal (88 g) were charged into RBF. The reaction temperature was raised to 90-95 °C and maintained for 10 hours. After completion of the reaction the solvent was distilled off followed by stripping with acetone and this crude was diluted with acetone (1500 mL), charged triethylamine (114 g). The reaction mass was cooled to 8-12 °C followed by addition of chloroacetylchloride (63.5 g) and maintain for 5 hours. After acetylation the solvent was distilled off under vacuum and then isolated the material from isopropyl alcohol (550mL) and water (150mL) at 8-12 °C. Dried the material at 50-55°C gives (1R,3R)-methyl-1,2,3,4tetrahydro-2-chloroacetyl-1-(3,4-methylene dioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate.

Methylamine solution (25% in methanol, 2285 mL) was added to a suspension of (1R,3R)-methyl-1,2,3,4tetrahydro-2-chloroacetyl-1-(3,4-methylene dioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate(chloroacetyl intermediate) (138 g) in methanol (1380 mL).Temperature of the reaction mass was raised and maintain at 50-55 °C for 6 hours. The reaction mass was then cooled and maintained at 25-30 °C for 1 hour, filtered, washed with methanol(90 mL) and dried at 45-50 °C to get the crude Tadalafil (116 g).

,CLAIMS:What is claimed is:
1. A process for the preparation of compound of formula III,

which comprises, reacting D-tryptophan methyl ester of formula IV or its salt

with piperonal of formula V


in presence of methyl isobutyl ketone.

2. The process according to claim 1, where in the compound of formula III further converted into tadalafil.