NOVEL PROCESS FOR THE PREPARATION OF TADALAFIL INTERMEDIATE
INTRODUCTION TO THE INVENTION The present application relates to modified Pictet-Spengler reaction that provides desired cis isomer of tetrahydro-p-carboline compound in the preparation of. Tadalafil.
Tadalafil is chemically known as (6R, 12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3, 4-methylene dioxyphenyl)-pyrazino [2',V:6, 1] pyrido [3, 4-b] indole-, 1,4-dione (hereinafter referred to by the adopted name "Tadalafil"), and is structurally represented by Formula I.
Formula I
Tadalafil is a potent and selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). Tadalafil is used in the treatment of erectile dysfunction. It is available in the market under the brand name CIALIS™ as tablets for oral administration, each tablet containing 5, 10, or 20 mg of Tadalafil.
U.S. Patent No. 5,859,006 describes Tadalafil, its related compounds, and methods' for their synthesis. The patent describes the preparation of Tadalafil as depicted by Scheme 1. Briefly, the process involves condensation of D-tryptophan methyl ester of Formula 1 with piperonal of Formula 2 to yield a mixture of isomers of the beta carboline ester of Formula 3 which are separated using column chromatography. Reacting the required isomer of Beta-carboline ester of Formula 4 with a haloacetyl halide like chloroacetyl chloride in a suitable solvent in the presence of a base or an alkaline metal carbonate to give (1R,3R)-methyl 1,2,3,4-

tetrahydro-2-chloroacetyl-(3,4-methylenedioxyphenyl)-9H-pyrido[3, 4-b] indole 3-carboxylate of Formula 5, which on treatment with a primary amine in a suitable solvent such as alcohol gives Tadalafil of Formula I.
The method described in the above patent employs toxic reagents and involves the purification of intermediates by column chromatography at various stages, the process is time consuming, 4-5 days for completion of the reaction, and the overall yield obtained is also very low. All these factors make the process uneconomical and difficult for scaling up.
International Application Publication No. WO 2005/068464 describes a' process, which follows the same scheme, but involves the usage of molecular sieves in stage a, which makes the process less time consuming, and avoids fractional crystallization of the product. The process described in this application, although showing considerable advantages over the previous process, does not reduce .the number of stages, and also does not avoid the use of hazardous reagents.

-t-
A subsequent application WO2004/011463 covers a process starting from easily available D tryptophan by Pictet Spengler type cyclization followed by acid mediated transformation of trans isomer to desired cis isomer predominantly.
Processes for the preparation of Tadalafil have also been described in International Application Publication Nos. WO 2005/068464, WO 2006/091980, WO2006/091975, and many other subsequent applications.
Prior investigators attempted to prepare a desired isomer of a polycyclic ring system containing two asymmetric ring carbon atoms by performing a Pictet-Spengler cyclization reaction. These attempts generally were limited in success because the reaction was performed in a corrosive medium, led to mixtures of isomers that adversely affected reaction yield, and required several days to perform. The present method provides the desired isomer in good yield and short reaction times.
Thus there is a need to develop a process, which involves the solvent system which totally avoids column chromatography for the separation of isomers, hence avoiding purification step in isolation of intermediates and further gives higher yields.
The present invention provides a process for the preparation of Tadalafil in which process yielded in producing desired isomer, i.e., cis, of a polycyclic compound with negligible production of trans isomers, hence avoiding the number of steps of purification and isolation of intermediates leads to shorter time cycle.
SUMMARY
The present invention is directed to a method of preparing a desired isomer, i.e., cis, of a polycyclic compound having two asymmetric ring carbon atoms. More particularly, the present invention is directed to a method of preparing a desired isomer of a tetrahydro-p-carboline compound having two asymmetric carbon atoms utilizing a modified Pictet-Spengler reaction.

In one aspect, the present invention is directed to a method of preparing a desired isomer of a tetrahydro-p-carboline compound having two asymmetric carbons utilizing a modified Pictet-Spengler cyclization reaction.
In another embodiment, the present invention is directed to a method of preparing a desired isomer of a tetrahydro-p-carboline compound having two asymmetric carbons utilizing a modified Pictet-Spengler cyclization reaction wherein the reaction is performed using a combination of solvent i.e dimethylformamide and toluene in which only one of the desired isomers resulted in high yield.
This novel features of the present invention will become apparent from the following detailed description of the preferred embodiments.
DETAILED DESCRIPTION
The present invention is directed to a method of preparing a desired isomer of a polycyclic compound having two asymmetric carbon atoms as members of a ring system. The method utilizes an improved Pictet-Spengler reaction that provides a desired tetrahydro-p-carboline isomer in high yield, high purity, and in a short process time. The improved Pictet-Spengler reaction also avoids the use of TFA in the reaction.
The selection of a proper solvent for use in the present modified Pictet-Spengler reaction is well within the skill of persons in the art. For example, in the preparation of Compound of formula (II) by the Pictet-Spengler cyclization reaction, combination of DMF and toluene produces higher yield of desired cis-isomer precipitated from the heterogeneous reaction mixture.
In addition, the solubilized trans-isomer is in dynamic equilibrium with the desired cis-isomer. Accordingly, as the cis-isomer compound (II) is formed in solution and immediately precipitates, its concentration is lowered relative to the remaining trans-isomer, thereby providing a concentration differential that forces the equilibrium to provide additional cis-isomer. This continuous driving of the reaction increases both the yield and purity of the desired cis-isomer (II)..

In particular, the present invention utilizes a modified Pictet-Spengier cyclization reaction to form a tetrahydro-p-carboline ring system having two stereogenic centers. The reaction is performed in a solvent wherein the desired isomer results in higher yield. Furthermore, the dynamic cis-trans equilibrium in solution allows a more complete conversion of the starting materials to the desired isomer, and a more complete separation of the desired isomer from the undesired. isomer. Accordingly, another advantage of the present invention is a decrease in costs attributed to a zero separation techniques.
An inventive aspect with the present invention is the reaction between D-tryptophan methyl ester. HCI (I) with piperonal in the presence of solvent mixture of at ambient temperature to produce desired isomer.
In general, the process for the preparation of desired cis isomer of compound of formula (II) i.e cis-l-tl.S-benzodioxol-S-yO^.a^.Q-tetrahydro-IH-pyridoIS.A-b]indole-3-carboxylic acid methyl ester, where D-tryptophan methyl ester hydrochloride compound of formula (III) is admixed with piperonal in the presence of solvent mixtures toluene and dimethylformamide (DMF) at ambient temperature ' under nitrogen atmosphere.
The process for the preparation of desired cis isomer of compound of formula (II) i.e cis-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b3indole-3-carboxylic acid methyl ester, where reaction of D-tryptophan methyl ester hydrochloride compound of formula (III) with piperonal in the presence of solvent mixtures toluene and dimethylformamide (DMF) at ambient temperature under nitrogen atmosphere. The reaction can be carried out at a temperature range of 70 °C to 90 °C more preferably from 70 °C to 90 °C more preferably from 80 °C to 90 °C most preferably from 82 °C to 87 °C for a time period from 15 to 30 hours more preferably from 20 to 24 hours. The percentage of toluene and DMF in the mixture of toluene and DMF can vary from 90 % to 30 % more preferably from 85 % to 25% most preferably 80 % to 20%.

The process according to the present invention is represented in below Scheme I.
In the present invention the stating materials D-tryptophan methyl ester of formula III is obtained as known in the prior-art.
Thus according to the present invention, the pharmaceutically acceptable Tadalafil is prepared by the process comprising esterification of D-tryptophan in methanol using thionyl chloride under reflux. The product is crystallized and isolated by filtration. Further steps involves the present novel and simplified variation of Pictet-Spengler reaction, wherein D-tryptophan methyl ester hydrochloride is admixed with piperonal in solvent mixture toluene and DMF and heated under reflux to form a desired cis-isomer (Compound (II)), is substantially insoluble in solvent mixture toluene and DMF at reflux temperature and below, the cis-isomer crystallizes from solution leaving a dynamic cis-trans equilibrium in solution. As the cis-isomer precipitates from solvent mixture toluene and DMF, the equilibrium is driven towards the cis-isomer until the concentration of the cis-isomer is sufficiently low to remain in solution. The desired isomer is greater than 85% yield by crystallization and filtration. Further reaction involves an acylation of the amino (NH2) moiety of Compound (II) using DCM in tri-ethyl amine and treating the reaction with chloroacetyl chloride under reflux. Ring closure with methylamine (MeNH2) completes the ring-forming sequence. After solvent exchange, the product is crystallized using acetone and water solvent or any other suitable solvent form, and filtration provides Compound (I) in an overall yield of about 52%.
The process according to the method described for the preparation of Tadalafil of compound I is represented in below Scheme II

Certain specific aspects and embodiments of this invention are described in further detail by the examples below, which examples are only illustrative and not intended to limit the scope of the appended claims in any manner.
EXAMPLE 1: Preparation of cis-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester (Formula II).
D-Tryptophan methyl ester hydrochloride (100.0 g, 39.26 mol) was suspended in a mixture of toluene (800 mL) and dimethylformamide (200 mL) treated with Piperonal (61.88 g, 41.21 mol) at ambient temperature under an N2 atmosphere. The mixture' was stirred between 85 °C to 90 °C for 20 to 24 hours. At this time, the reaction mixture contained less than 2% of D-Tryptophan methyl ester hydrochloride and less than 6% of trans isomer of carboline hydrochloride by HPLC. The reaction mixture then was cooled to ambient temperature, filtered, and washed with toluene (150 mL). The product was dried under vacuum at less than 60° C. to yield 130 g (85.5%) and of cis-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester.

EXAMPLE 2 : Preparation of cis-1-(1>benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester (Formula II).
D-Tryptophan methyl ester hydrochloride (100.0 g, 39.26 mol) was suspended in a mixture of toluene (1200 ml_) and dimethylformamide (200 ml_) treated with Piperonal (61.88 g, 41.21 mol) at ambient temperature under an N2 atmosphere. The mixture was stirred between 85 °C to 90 °C for 20 to 24 hours. At this time, the reaction mixture contained less than 2% of D-Tryptophan methyl ester hydrochloride and less than 6% of trans isomer of carboline hydrochloride by HPLC. The reaction mixture then was cooled to ambient temperature, filtered, and washed with toluene (150 ml_). The product was dried under vacuum at less than 60° C. to yield 135 g (88.93%) and of cis-l-CI^-benzodioxol-S-yO^.a^.Q-tetrahydro-IH-pyridoia^-b]indole-3-carboxylic acid methyl ester.

We Claim:
1. An improved process to produce pharmaceutical^ acceptable cis-isomer of
Tadalafil intermediate alky! or aryl-l,2,3,4-tetrahydro-l-(3,4-
methylenedioxyphenyl)-9H-pyrido [3,4-b] indole-3-carboxylate comprising the
steps of:
a) A cyclization reaction between a D-Tryptophan alkyl or aryl ester hydrochloride (III) and piperonal in the presence of solvent mixture of dimethyl formamide (DMF) and Toluene to obtain desired cis-isomer of alkyl or aryl-l,2,3,4-tetrahydro-l-(3,4-methylenedioxyphenyl)-9H-pyrido [3,4-b] indole-3-carboxylate as a major product at an ambient temperature;
b) Isolation of cis-isomer of alky or aryl-l,2,3,4-tetrahydro-l-(3,4-methylenedioxyphenyl)-9H-pyrido [3,4-b] indole-3-carboxylate, formula (II) obtained in step a)

2. An improved process according to claim la), wherein the said temperature is about 80 °C to 90 °C more preferably from 82 °C to 87 °C.
3. An improved process according to claim la), wherein the said alkyl or aryl group in D-Tryptophan alkyl or aryl ester hydrochloride (III) is selected from methyl, ethyl, propyl, allyl, substituted allyl, phenyl, substituted phenyl etc. more preferably methyl.
4. An improved process according to claim la), wherein the percentage of mixture of dimethyl-formamide (DMF) and toluene is from 90% to 30% more preferably in the range of 85% to 25% and is most preferably 80% to 20%.
5. A cyclization reaction between a D-Tryptophan alkyl or aryl ester hydrochloride (III) and piperonal in the presence of a mixture of Dimethyl formamide (DMF) and toluene at 85-90°C to obtain cis-isomer

of methyl-l^^^-tetrahydro-KS^-methylenedioxyphenyO-SH-pyrido
[3,4-b] indole-3-carboxylate (II) as a major product.