FROVATRIPTAN

Field of the Invention:

The present invention relates to an improved process for the preparation of Frovatriptan of formula (I) and its enantiomers, particularly R-enantiomer.

(I)

Background of the Invention:

Frovatriptan (I), chemically named as R-(+)-6-carboxamido-3-methylamino- 1,2,3,4 tetrahydrocarbazole, is currently marketed as the monosuccinate salt monohydrate (II) under the brand name Frova® for the treatment of migraine.

(II) Various processes reported for the preparation of Frovatriptan succinate of formula (II). Some of which are relevant to the present invention are summarized below. US patent 5,616,603 discloses the process for the preparation of Frovatriptan free base and pharmaceutically acceptable salts thereof. The said process comprises the reaction of 4-cyanophenylhydrazine hydrochloride and 4-benzyloxy- cyclohexanone in acetic acid to afford 3-benzyloxy-6-cyano-l,2,3,4- tetrahydrocarbazole, which was isolated after column chromatography. This product was hydrolyzed with sodium hydroxide to give 3-hydroxy-6-cyano-l, 2,3,4- tetrahydrocarbazole, which was further treated with tosyl chloride in the presence of pyridine to yield corresponding tosylated tetrahydrocarbazole. The tosyloxy group was removed by treatment with methylamine in a sealed tube at 100°C to yield 3- methylamino-6-cyano-l,2,3,4-tetrahydrocarbazole, which was isolated after column chromatography. The 3-methylamino-6-cyano-l,2,3,4-tetrahydrocarbazole was N- protected to afford 3-tert-butyloxycarbonylmethylamino-o-cyano-l,2,3,4- tetrahydrocarbazole which in turn oxidized with hydrogen peroxide to afford racemic Frovatriptan, which was isolated by column chromatographic method. The reaction is shown below:

Frovatriptan

The above reported process suffers in view of the industrial point of view since it involves several steps including protection, deprotection in addition it has chromatographic methods for the isolation of intermediates and final product.

WO 94/014772 discloses the process for preparation of (±)-6-Carboxamido- 3-N-methylamino-l,2,3,4-tetrahydrocarbazole which involves the basification of the solution of (±)-6-carboxamido-3-N-methylamino-l,2,3,4-tetrahydrocarbazo le hydrochloride salt in water with 5M aqueous sodium hydroxide to pH 10.5 followed by the extraction with of the resultant mixture with butan-l-ol. These extractions were combined and evaporated to give the racemic Frovatriptan free base as dark oil. This oil containing about 40% butanol was taken as such for resolution using chiral acid. As the base was not isolated from the reaction mass and used in the form of oil, the purity of base is less; since the oily mass contains large amount of butanol, assaying the exact quantity of Frovatriptan in the oil is required in order to calculate the exact quantity of chiral acid needed for the next stage. In view of this, said process is not suitable for industrial scale and does not yield Frovatriptan succinate in good chiral purity.

WO 94/14772 discloses enantiomers of Frovatriptan, further it discloses various methods for the preparation of optically pure enantiomer of Frovatriptan;

(i) separation of an enantiomeric mixture of the compound of formula (A) or a derivative thereof by chromato raphy, e.g. on a chiral HPLC column.

(ii) separation of diastereoisomers of a chiral derivative (e.g. a chiral salt) of the compound o formula (A) e.g. by crystallization or chromatography.

(iii) alkylation of (+) or (-) enantiomer of 3-amino-6-carboxamido-l, 2,3,4- tetrahydrocarbazole or a salt thereof. This process is not suitable as it involves chiral chromatography for resolution.

US 6,359,146 discloses the resolution process in which, the racemic 3- methylamino-6-cyano-l,2,3,4-tetrahydrocarbazole was resolved by formation of a diastereomeric salt using L-pyroglutamic acid and the optically pure diastereomeric salt was further treated with boron-trifmoride-acetic acid complex to afford Frovatriptan. The reaction mixture was basified with sodium hydroxide solution and extracted with n-butanol to give Frovatriptan free base, which was further treated with succinic acid to afford the monosuccinate salt monohydrate. In this process during the Frovatriptan formation, indole carboxylic acid formed as a side product. In view of the above reported processes, there is a need for an improved process for the synthesis of Frovatriptan or its pharmaceutically acceptable salts thereof. In our continued research, we have identified a novel process for the isolation of racemic Frovatriptan free base as a solid and also provided an improved process for the resolution of Frovatriptan. None of the prior art suggests or even motivates the present invention.

Objectives of the Invention: The primary objective of the invention is to provide an improved process for the preparation of Frovatriptan formula (I) with good purity which is easy to implement on commercial scale and avoids chromatographic methods.

Another objective of the present invention is to provide an improved process for the preparation of Frovatriptan formula (I) i.e racemic Frovatriptan as a solid form.

One more objective of the present invention is to provide a novel chiral resolution process for the preparation of optically pure Frovatriptan particularly R- isomer of Frovatriptan (R-(+)-6-carboxamido-3-methylamino-l,2,3,4 tetrahydrocarbazole) using optically active acids.

Still more objective of the present invention is to provide a novel Frovatriptan Di-p-toluoyl-D-(+)-tartaric acid (DPTTA) salt. Summary of the Invention:

Accordingly the present invention provides an improved process for the preparation of R-isomer of Frovatriptan or its salt, the said process comprising the steps of:

a. obtaining racemic Frovatriptan;

b. optionally treating the racemic Frovatriptan with an organic solvent; c. optionally isolating racemic Frovatriptan as a solid by filtration;

d. treating racemic Frovatriptan of step (a or c) with di-p-toluoyl-(D)- (+)-tartaric acid, in the presence of solvent(s);

e. isolating optically pure Frovatriptan DPTTA salt; and

f. converting Frovatriptan DPTTA salt into R-isomer of Frovatriptan or its salt.:

In another aspect, the present invention also provides an improved process for the preparation of Frovatriptan of formula (I);

the said process comprises treating racemic Frovatriptan free base residue with an organic solvent followed by isolating the free base by filtration. Drawings of the Invention:

Figure- 1 : Powder XRD pattern of crystalline form of racemic Frovatriptan free base obtained by the present invention.

Figure-2: Powder XRD pattern of Frovatriptan DPTTA salt obtained by the present invention.

The PXRD analyzed using following condition:

Detailed Description of the Invention:

In an embodiment of the present invention, the present invention provides a simple crystallization method for the isolation of racemic Frovatriptan as a solid form. The said process involves treating the residue of racemic Frovatriptan with an organic solvent.

In another embodiment of the present invention the organic solvent employed for the crystallization of racemic Frovatriptan (i.e. step b) is selected from acetone, methyl isobutyl ketone, methylethyl ketone, tetrahydrofuran, methyl acetate, ethyl acetate, n-butyl acetate, t-butyl acetate, isobutyl acetate , methyl t- butyl ether, isopropyl ether, n-hexane, n-heptane, cyclohexane, and the like or mixtures thereof, however, other organic solvents which do not adversely affect the crystallization can also be present or used; preferably ethyl acetate, acetone and cyclohexane. The residue of racemic Frovatriptan may be in the form of oil or gummy paste that may optionally contain small amount of solvent are obtained from the reaction mass directly.

Applicant surprisingly found that use of said organic solvent(s) for crystallization of racemic Frovatriptan yields Frovatriptan free base as a solid with improved yield. None of the prior art discloses or motivates the simple crystallization method to isolate the racemic Frovatriptan free base as a solid. The isolation of Frovatriptan as a solid form either in amorphous form or crystal form provides many advantages like i) storage ii) ease handling iii) storage stability iv) enhanced purity.

In yet another embodiment of the present invention, applicant found simple resolution process for separating the desired optically active Frovatriptan preferably R-(+)-isomer using Di-p-toluoyl-D-(+)-tartaric acid. The use of said chiral acid has several advantages like high chiral purity, good stability and high yield. Di-p- toluoyl-(D)-(+)-tartaric acid can be added directly in to the reaction mass or in the form of solution. The unwanted isomer from filtrate can be racemized and can be recycled by using conventional technique for example treating with base or an acid. Applicant observed that the usage of pyroglutamic acid as reported in prior art process is costly and difficult to scale up because of the inconsistency during the diastereomeric salt formation. In one more embodiment of the present invention, the solvent used for resolution in step (d) is selected from methanol, ethanol, 1-propanol, isopropanol, butanol, methylt-butyl ether (MTBE), acetone, water and the like or mixtures thereof.

The obtained Frovatriptan DPTTA salt, if required, can be purified using a solvent system including but not limited to methanol, ethanol, isopropanol, acetone, water and the like or mixtures thereof by crystallization method or by using dissolution and anti-solvent precipitation method etc.

Another aspect of the present invention, the present invention provides purification process of racemic frovatriptan which involves treating the racemic frovatriptan with Copper sulfate (CuSO ₄ ) or its hydrate to reduce the undesired hydrazine impurity. Applicant of the present invention observed that the presence of hydrazine impurity affects the resolution process. Applicant surprisingly found that, use of CuSO ₄ or its hydrate in the purification of racemic frovatriptan reduces the hydrazine impurity namely 4-carboxamido-phenylhydrazine, which ultimately enhances the efficiency of resolution of racemic Frovatriptan. The present invention removes hydrazine impurity from 5% to 0.75% preferably less than 0.2%.

Apart from said chiral agent other chiral agent like R(+)-2-(4- Hydroxyphenoxy)-propionic acid, S(+)-2-(4-Hydroxyphenoxy)-propionic acid, N- Acetyl-L-glutamic acid, N-Acetyl-D-glutamic acid, N-CBZ-L-Glutamic acid, N- BOC-L-Glutamic acid, Dibenzoyl-L(+)-tartaric acid, Dibenzoyl-D-(+)-tartaric acid, L-lysine can also be used for chiral resolution. In still another embodiment of the present invention, the obtained novel optically active Frovatriptan salts can be converted to (R)-(+)-Frovatriptan or its pharmaceutically acceptable solvate by the conventional method. Racemic Frovatriptan used in the present invention can be obtained by following the procedure disclosed in prior art or by following the reference example provided in the specification or by following the scheme provided below ;

HCI

4-Aminobenzamide

Racemic Frovatriptan HCI Frovatriptan racemate free base

(oil form)

In yet another embodiment of the present invention, the chiral salt of the present invention can be converted to Frovatriptan succinate by any suitable conventional method or by the methods reported in the prior art.

Many other beneficial results can be obtained by applying disclosed invention in a different manner or by modifying the invention with the scope of disclosure.

The present invention is provided by the examples below, which are provided by way of illustration only and should not be considered to limit the scope of the invention. Preparation of (±)-6-Carboxamide-3-methylamino-l,2,3,4-tetrahydrocarbazole (Racemic Frovatriptan free base )

Example-1:

Frovatriptan racemate hydrochloride (30g) was dissolved in water (300 mL) and heated to 65-70° C under stirring. To this, water was added at 65-70°C and heated to 65-70°C and the pH was adjusted to 10.5 with 20% sodium hydroxide (or aq ammonia solution) solution. To the reaction mixture, n-butanol was added and stirred. The organic layer was separated and the aqueous layer was extracted with n- butanol 2-3 times. Organic layers were combined. The organic layer was distilled under vacuum at 50-55°C. To the obtained gummy mass, acetone was added and heated to 40-45°C, it was cooled to 30-35°C. The solid obtained was filtered, washed with acetone, and dried under vacuum at 55-60°C to afford the title compound.

Yield: 10 g

HPLC purity: > 97.8 - 99.9 %

Example-2:

Frovatriptan racemate hydrochloride (75 g) was dissolved in water (1125 mL) followed by the addition of CuSO ₄ hydrate (3.8g), and heated to 65-70° C under stirring. The hazy material obtained was filtered and washed with water. To this, water was added at 65-70° C and cooled followed by addition of n-butanol. The reaction mass pH was adjusted to 10.5 with aq.ammonia. The racemic frovatriptan was extracted in organic layer which was distilled under vacuum at less than 65° C until to get 1- 1.5 v. To the pasty mass ethyl acetate was added and refluxed at 75 °C then cooled. To this optionally hydrocarbon solvent was added and refluxed at 75° C then cooled. The product obtained was filtered, washed with ethyl acetate and suck dried under vacuum at 55-60°C to yield the solid Racemic

Frovatriptan.

Yield- 48g Example 2(a):

Frovatriptan racemate hydrochloride (75 g) was dissolved in water (1125 mL) followed by the addition of CuSO ₄ hydrate (3.8g) and heated to 65-70° C under stirring. The hazy material obtained was filtered and washed with water. To this, water was added at 65-70° C and cooled followed by addition of n-butanol. The racemic frovatriptan was extracted in organic layer by adjusting the pH of the mass with sodium hydroxide.

Below is the comparative table which shows the percentage of impurity (i.e. 4- carboxamido-phenylhydrazine) present in the racemic Frovatriptan obtained in the above example 2(a).

Table-1:

Example-3:

Frovatriptan racemate hydrochloride (30 g) was dissolved in water (450 mL) to which small amount of CuSO4 are its hydrate was added and heated to 70°C under stirring. The reaction mass cooled and THF was added. Then pH was adjusted to 10.5 with sodium hydroxide. The racemic frovatriptan was extracted in organic layer (THF) which was distilled under vacuum at 55°C until to get 2v. To this IPA was added and distilled until to 2v followed by the addition of Ethyl acetate. The reaction mass was distilled until to reach 2V. To this, Ethyl acetate was added and heated to 60-70°C which was maintained for lhr then cooled to 10-15°C. The product obtained was filtered, washed with ethyl acetate and suck dried under vacuum to yield the Racemic Frovatriptan.

Yield: lOg

Melting point of Frovatriptan free base = 208-211°C Resolution of Racemic Frovatriptan free base:

Preparation of DPTTA salt of Frovatriptan:

Example-4:

To a solution of (±}-6-carboxamido-3-N-methylamino-l, 2,3,4- tetrahydrocarbazole (3 g) in a mixture of methanol and isopropanol /?-toluoyl-D- (+)-tartaric acid monohydrate was added at 65-70°C and stirred. To the obtained mass was added methanol and maintained at 65 -70° C for several hours. The solid obtained was filtered and suck dried to obtain the (+) -Frovatriptan DPTTA salt. (Chiral purity: > 98%) Example-5:

To a solution of (±}-6-carboxamido-3-N-methylamino-l, 2,3,4- tetrahydrocarbazole (10 g) in a mixture of methanol and isopropanol /?-toluoyl-D- (+)-tartaric acid (16.6 g) in acetone was added at 65-70°C and stirred. The reaction mass cooled and the solid filtered, washed with IPA. The wet solid was taken in methanol and water at 45-55°C. To which IPA was added and the mass cooled to room temperature. . Then the reaction mass stirred and the solid obtained was filtered and suck dried under nitrogen to obtain the (+) -Frovatriptan DPTTA salt. (Chiral purity: > 98%) R-(+)-Frovatriptan-(+)-Di-p-toluoyl-d-tartarate = 224-226°C

Preparation of Frovatriptan Succinate;

Example-6:

To the mixture of DM water (165ml) and n-Butanol (77ml) FTN-DPTTA (12g) was added and the pH was adjusted to 12-12.5 using sodium hydroxide solution at 25-35°C. Product was extracted in the butanol layer and it was distilled under vacuum at less than 60°C until to reach 5V. To the mass, methanol was added and the solution was given carbon treatment and filtered. The filtrate was distilled to 5v under vacuum at temperature less than 55°C. To this, succinic acid dissolved in methanol and water was added. The reaction mass was cooled to 0-5°C then filtered and washed with chilled methanol. The wet product was dried under vacuum at less than 50°C to yield Frovatriptan Succinate.

Yield: 6.5-7.5g

Starting materials of the present invention can be prepared according to the methods reported in literature or by the methods provided in the reference examples.

Reference example- 1:

Preparation of 4-Methylaminocyclohexanone (2',2'-dimethyltrimethylene) ketal hydrochloride:

1,4 cyclohexane dione (200 grams) was dissolved in MDC. To this con sulfuric acid was added followed by the addition of neopentyl glycol in dichloromethane. After completion of the reaction, sodium bicarbonate was added and stirred. Organic layer was filtered and the filtrate was distilled under vacuum then work up carried out using petroleum ether to filter the by-products. To the reaction mass methanol was added and un-dissolved material was filtered. To the filtrate, methanol was added followed by the addition of methanolic methylamine. This solution was charged with Pd/C and was hydrogenated. The reaction mass filtered and to the filtrate IPA was added, it was distilled to reach 2V. To this IPA was added followed by the addition of IPA.HC1. The product obtained was filtered and washed with IPA then dried. The dried product was slurried with THF at 25-35° for 30-45 min. The solid obtained was filtered and washed with THF then suck dried to yield the title compound.

Reference Example 2

Preparation of ((±)-6-Carboxamide-3-methylamino-l,2,3,4- tetrahydrocarbazole hydrochloride:

4-Aminobenzamide (30 g) was dissolved in 5N HC1 (210 mL) at -5° to 0°. This mixture was further cooled to around -15° C. To this sodium nitrite (20 g) solution was added at -15 to -20°C and stirred for an hour. Chilled water was then added followed by solid sodium dithionite (76.6g). To the resulting mass, was added cone. HC1 (210mL) followed by 4-methylaminocyclohexanone (2'2'- dimethyltrimethylene) ketal hydrochloride (54.9 g) and the mixture heated to 65- 70° C. The reaction was monitored by HPLC. After completion of reaction the reaction mass was neutralized with sodium hydroxide solution, (aq. 40%) to pH 10 and stirred at 15°C. The product obtained was filtered and washed with water which was dried to afford the title compound. Advantages of the present invention: Isolation of Racemic Frovatriptan free base as a solid by simple precipitation (crystallization) method.

It avoids the chromatographic method which is time consuming.

> The process is suitable for large scale production.

Use of novel chiral resolution agents which are more efficient towards Frovatriptan resolution with high chiral purity.

Cost of resolution of process is less when compared to prior art process.