FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)
IMPROVED PROCESS FOR PREPARATION OF FROVATRIPTAN SUCCINATE MONOHYDRATE AND INTERMEDIATES THEREOF
UNICHEM LABORATORIES LIMITED,
A COMPANY REGISTERED UNDER THE COMPANIES ACT, 1956, HAVING ITS REGISTERED OFFICE LOCATED AT UNICHEM BHAVAN, PRABHAT ESTATE, OFF S. V. ROAD, JOGESHWARI (WEST), MUMBAI
-400 102, MAHARASTRA, INDIA
The following specification particularly describes the invention and the manner in which it is to be performed.

IMPROVED PROCESS FOR PREPARATION OF FROVATRIPTAN SUCCINATE MONOHYDRATE AND INTERMEDIATES THEREOF
TECHNICAL FIELD OF THE INVENTION:
The present invention relates to an improved and efficient process for the preparation of Frovatriptan succinate monohydrate, chemically known as R (+)-6-carboxamido-3-N-methylamino-1, 2. 3, 4-tetrahydrocarbazole succinate monohydrate. In particular, it relates to the isolation of novel intermediate. (+)-3-N-benzylamino-6-carboxamido-l, 2,3,4-tetrahydrocarbazole monohydrate, used in the synthesis of Frovatriptan succinate monohydrate.
BACKGROUND OF THE INVENTION:
(+)-6-carboxamido-3-N-methylamino-l,2,3,4-tetrahydrocarbazole known as
Frovatriptan, having activity as 5HT1 receptor agonists, is useful for treatment of migraine. Frovatriptan is marketed under the brand name FROVA as its succinate monohydrate salt and chemically known as R (+)-6-carboxamido-3-N-methylamino-l, 2, 3, 4-
tetrahydrocarbazole succinate monohydrate (I).

WO 93/00086 (King, Francis, David et al, 1991) discloses the tetrahydrocarbazole derivatives and specifically racemic 3-amino-6-carboxamido-l,2,3,4-tetrahydrocarbazole hydrochloride prepared by Fischer indole reaction. 4-cyanophenyl hydrazine hydrochloride

was reacted with 4-phthalimidocyclohexanone to yield 3-phthalimido-6-cyano-l,2,3,4,-tetrahydrocarbazole. The phthalimido group of the above indole derivative was deprotected with hydrazine hydrate, followed by N-Boc protection and purification by column chromatography. Thus, the obtained cyano derivative was converted to its amide derivative, purified by column chromatography and its hydrochloride salt formed.
The '086 patent also describes another method for preparation of racemic frovatriptan hydrochloride by reacting 4-cyanophenyl hydrazine hydrochloride with 4-benzoyloxycyclohexanone in acetic acid and the crude intermediate (3-benzoyloxy-6-cyno-1,2,3,4-tetrahydrocarbazole) was obtained by column chromatography. The isolated pure product was converted to 3-hydroxy-6-cyano-l,2.3,4-tetrahydrocarbazole, which was further transformed to its tosyl derivative followed by reaction with 33% methyl amine in alcohol and purification by column chromatography to give 3-methylamino-6-cyano-1,2,3,4-tetrahydrocarbazole. The N-methyl amine derivative was treated with di-tert-butyl carbonate to give N-boc protected methyl amine derivative. The protected derivative was converted to racemic Frovatriptan by treating with 20% aqueous sodium hydroxide and 30% hydrogen peroxide. The crude product obtained was purified using column chromatography.
Both the processes of '086 had major drawbacks such as purification by column chromatography, use of protection and deprotection chemistry, as well as the overall yields obtained were very low.
WO94/14772 (Borrett, Gary, Thomas et al, 1992) describes (+) and (-) enantiomers of 6-carboxamido-3-N-methylamino-l,2,3,4-tetrahydrocarbazole. The enantiomers were obtained by resolving racemic 3-amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole by (i) chiral HPLC using a derivative such as 3-N-t-butyloxycarbonyl-N-methylamino-6-carboxamido-l,2,3.4-tetrahydrocarbazole or (ii) by formation of a chiral salt of the 3-amino compound, using for example, 2,3:4.6-di-0-isopropylidene-2-keto-L-guIonic acid (DIKGA), followed by-selective crystallisation. '772 describes resolution of 3-N-benzoyloxycarbonyl-6-carboxamido-3-N-methylamino-l,2,3,4-tetrahydrocarbazole (i) by chiral HPLC or (ii) by making its chiral salt with (IS)-(+)-10-camphorsulphonic acid. The obtained residue was

recrystallised ten times followed by formation of free base and its 2,3,4,6-tetra-Oacetyl-beta-D-glucopyranosulthiourea derivative. '772 also describes resolution of 6-caboxamido-3-N-methylamino-l,2,3,4-tetrahydrocarbazole by making its diastereomeric salt with R-2-pyrrolidone-5-carboxylic acid followed by making its free base on extraction with l-butanol. Butanol was evaporated from the reaction mixture and the corresponding succinate salt was synthesized. On considering commercial aspects, resolution of amine or its benzoyloxy-N-methyl derivative by HPLC was not possible, whereas the last process mentioned above, had a major draw back involving removal of l-butanol which was quite tedious and time consuming,
In addition, '772 describes the preparation of Frovatriptan comprising the reaction of 4-carboxamidophenylhydrazine hydrochloride with 4-phthalimido cyclohexanone in acetic acid media to give 6-carboxamido-3-phthalimido-l,2,3,4-tetrahydrocarbazole. The product obtained was purified by column chromatography followed by deprotection of phthalimido group using hydrazine hydrate in ethanol as reaction media to yield (±)-3-amino-6-caboxamido-l,2,3,4-tetrahydrocarbazole. The racemic amine was resolved by using DIKGA to give diastereomeric salt. This salt was crystallized twice from methanol to obtain optical purity more than 98%. The diastereomeric salt was treated with aqueous potassium carbonate to yield (+)-3-amino-6-carboxamido-l,2,3,4-tetrahydrocarbazole (Desmethyl frovatriptan). Desmethyl frovatriptan was treated with benzaldehyde, followed by reduction with sodium cyanoborohydride and subsequent addition of formalin and in-situ reduction to give N-benzyl Frovatriptan. The crude product obtained was purified using column chromatography. Further, debenzylation using Pearlman's catalyst and succinic acid in ethanol under hydrogen atmosphere gave Frovatriptan succinate salt. This process had a draw back, wherein column chromatography for purification of N-benzyl Frovatriptan was used and also the use of Pearlman's catalyst was quite expensive as compared to commonly used catalyst such as Palladium on carbon and the use of hydrazine hydrate involved major process safety hazards.
'772 further disclosed an alternate process for preparation of Frovatriptan, involving reaction of (+)-3-amino-6-carboxamido-l,2,3,4-tetrahydrocarbazole in pyridine, dicyclohexylcarbodiimide and carbon disulfide to give 6-carboxamido-3-isolhiocyanato-

1,2,3,4-tetrahydrocarbazole, which was treated with sodium borohydride in ethanolic media to yield Frovatriptan, that was purified by column chromatography.
Yet another process for preparation of (+)-6-carboxamido-3-N-methylamino-l,2,3,4-tetrahydrocarbazole is described in WO99/54302 (Brackenridge, Ian et al, 1998). The process involved preparation of 6-cyano-3-N-methylamino-1,2,3,4-tetrahydrocarbazole by reacting 4-cyanophenyl hydrazine hydrochloride with 4-methylaminocyclohexanone (2,2'-dimethyl trimelhylene) ketal hydrochloride. The obtained product was resolved with L-pyroglutamic acid to give its pyroglutamate salt. The diastereomeric salt was recrystallized followed by resolution to its free base and hydrolysis of the cyano group to amide group. The obtained (+)-6-carboxamido-3-N-methylamino-1,2,3.4-tetrahydrocarbazole was converted to succinate salt. This process had a number of limitations such as hydrolysis of the cyano group was done by using boron trifluoride and acetic acid complex to obtain the amide derivative. In this reaction, the indole carboxylic acid derivative is formed as an impurity. In addition to this, the work up involved basification of the reaction mass with sodium hydroxide, that may lead to the hydrolysis of amide group. Also, the extraction of the obtained frovatriptan free base with 1-butanol and removal of 1-butanol was a time and energy consuming operation.
WO2010/073253 (Amala, Kompella et al, 2008) discloses resolution of (±)-6-cyano-3-N-methylamino-1,2,3,4-tetrahydrocarbazoIe by making its diastereomeric salt with D pyroglutamic acid to give desired product in mother liquor. The obtained product -was converted to its hydrochloride salt with isopropanolic HC1 followed by hydrolysis with phosphoric acid. For the resolution of the cyano derivative, D-pyroglutamic acid was used, which is an unnatural amino acid and hence much costlier. The reaction mass was quenched with aqueous sodium hydroxide, extracted with 1-butanol and distilled using 1-butanol, which had drawbacks as mentioned earlier.
WO2010/122343 (Gore, Vinayak Govind et al, 2009) describes process for the preparation of 6-carboxamido-3-phthalimido-l,2,3,4-tetrahydrocarhazole comprising reaction of 4-aminobenzamide with a nitrite ion in the presence of a mineral acid and a sulphonic acid and

reduction of the diazonium salt formed followed by reaction with 4-phthalimido-
cyclohexanone. The phthalimido group was deprotected with hydrazine in the presence of
another organic base, trialkyl amine to give 3-amino-6-carboxamido-1,2,3,4-
tetrahydrocarbazole. The racemic amine, 3-amino-6-carboxamido-l,2,3,4-
tetrahydrocarbazole was resolved by making diastereomeric salt with DIKGA, followed by generation of desired resolved amine, (+)-3-ammo-6-carboxamido-1,2,3,4-tetrahydrocarbazole. The resolved amine was further converted into 3-N-benzyl-6-carboxamido-3-methylamino-1,2,3,4-tetrahydrocarbazole by reductive amination of 3-amino-6-carboxamido-I.2,3,4-tetrahydrocarbazole with benzaldehyde and formaldehyde. The N-benzyl frovatriptan was converted to frovatriptan free base by catalytic hydrogenolysis of 3-N-benzyl-6-carboxamido-3-methylamino-1,2,3,4-tetrahydrocarbazole. Frovatriptan was further converted to its succinate salt. The main draw back of this process was the use of hydrazine hydrate for deprotection of phthalimido group to obtain racemic amine which has major safety hazards.
OBJECT OF THE INVENTION
An object of the present invention is to provide an improved process for the preparation of Frovatriptan succinate monohydrate.
Another object of the present invention is to provide an simple and environmentally friendly process for the preparation of Frovatriptan succinate monohydrate, which avoids use of hazardous agents.
Further, object of the present invention is to provide good quality Frovatriptan succinate
monohydrate with high yields and purity
Yet another object of the present invention is to provide an industrially scalable process for the preparation of Frovatriptan succinate monohydrate

SUMMARY OF INVENTION
The present invention relates to an improved, scalable process for preparation of high quality Frovatriptan succinate monohydrate of formula (I).
According to one aspect of the present invention provides the process for preparation of Frovatriptan succinate monohydrate of formula (I) comprising

Formula (I)
a. deprotection of racemic-6-carboxamido-3-phthalimido-l ,2,3,4-tetrahydrocarbazole of formula (II)

Formula-II
by using alkyl amine, in a solvent to obtain (±)-3-Ammo-6-carboxamido-1,2,3.4-tetrahydrocarbazole of formula (III)


Formula-Ill
• b. resolution of (±)-3-Amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole of formula (III) by chiral auxiliary in an alcoholic solvent to obtain diastereomer salt of formula-IV

Formula-IV
c. basification of diastereomeric salt of Formula (IV) by using base to obtain optically pure (+)-3-Aminor6-carboxamido-1,2,3,4-tetrahydrocarbazole of Formula (V) in an aqueous medium.

Formula-V
d. reductive alkylation of (+)-3-Amino-6-carboxamido-l,2 3,4-tetrahydrocarbazole of formula (V) in a solvent with benzaldehyde and alkali metal borohydride provides novel

intermediate, (+)-3-N-benzylamino-6-carboxamido-l,2,3,44etrahydrocarbazole monohydrate of Formula (VJ)

Formula-VI
e. reductive methylation of (+)-3-N-benzylamino-6-carboxamido-l,2,3,4-tetrahydrocarbazole monohydrate of formula (VI) with formaldehyde in a solvent to obtain (+)-3-N-benzyl-6-Carboxamido-3-methylamino-1,2,3,4-tetrahydrocarbazole of formula
(VII)

f. salt formation of (+)-3-N-benzyl-6-Carboxamido-3-methylamino-l,2,3,4-tetrahydrocarbazole of formula (VII) with succinic acid in a solvent to obtain (+)-3-N-benzyl-6-Carboxamido-3-methylamino-l,2,3,4-tetrahydrocarbazole succinate of Formula (IX)


Formula-IX
g. debenzylation of (+)-3-N-benzyl-6-Carboxamido-3-methylamino-1,2,3,4-tetrahydro-carbazole succinate of formula (IX) in presence of noble metal catalyst or their derivatives in hydrogen atmosphere in a solvent to obtain Frovatriptan succinate monohydrate of Formula
(I)

Formula (I)
h. purification of Frovatripan succinate monohydrate in a solvent.
According -to another aspect of the present invention provides an improved process for the preparation of (±)-3-Amino-6-carboxamido-l,2,3,4-tetrahydrocarbazole of formula (III),
which comprises


deprotection of racemic-6-carboxamido-3-phthalimido-1,2,3,4-tetrahydrocarbazole of formula (II) •

Formula-II
by using alkyl amine, preferably monomethylamine in a solvent, preferably in water.
According to another aspect of the present invention provides a novel intermediate, (+)-3-N-benzylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole monohydrate of Formula (VI)

Formula- VI
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved process for the preparation of Frovatriptan succinate monohydrate. The improved process is free from use of any hazardous reagents and is relatively simple and can be used for large scale production. In addition to this, the process involves the use of high purity novel intermediate for the synthesis of Frovatriptan succinate monohydrate. Frovatriptan succinate monohydrate prepared by the improved process meets the criteria of quality required as per ICM guidelines. The preferred approach for the preparation of Frovatriptan succinate monohydrate is outlined in Scheme 1.

According to present invention, (±)-6-Carbaxamido-3-phthalimido-1,2,3,4-tetrahydrocarbazole (Formula II) is used as starting raw material for the synthesis of Frovatriptan succinate monohydrate. The (±)-6-Carbaxamido-3-phthalimido-1,2,3,4-tetrahydrocarbazole can be prepared by known methods involving the diazotization of 4-aminobenzamide, followed by reduction of diazonium salt to obtain 4-carboxamidophenyl hydrazine hydrochloride. The hydrazine hydrochloride thus obtained is indolized with ,4-phtahlimidocyclohexanone in acetic acid to obtain (±)-6-Carbaxamido-3-phthalimido-1,2,3,4-tetrahvdrocarbazole.
(±)-6-Carbaxamido-3-phthalimido-1,2,3,4-tetrahydrocarbazole thus obtained' is deprotected with alkyl amine such as monomethylamine, dimethylamine in aqueous medium, preferably the alkyl amine used is mono methylamine in water.
The resolution of (±)-3-amino-6-carboxamido1,2,3,4-tetrahydrocarabazole (Formula III) is carried out by converting it into a diastereomer by using chiral auxiliary such as (-)-2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid monohydrate (DIKGA). The diastereomer salt formation is done in an alcoholic solvent such as methanol, ethanol, isopropanol, by using 1.0 to 1.25 mole of (-)-2,3:4,6-di-0-isopropylidene-2-keto-L-gulonic acid monohydrate (DIKGA), and the preferred alcoholic solvent used is methanol. The reaction is carried out at room temperature to reflux temperature, preferably at reflux temperature. The salt thus formed, is gradually cooled to 5-10°C and collected by filtration. To increase the enantiomeric excess of the DIKGA salt, it can be crystallized from methanol to obtain pure diastereomeric salt.
The optically pure (+)-3-amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole (Formula V) is obtained by treating the (+)-3-amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole-2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid salt with base. The base used for the reaction is alkali or alkaline metal carbonate and hydroxide such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, preferably the base used is potassium carbonate. (+)-3-amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole is collected by filtration from water at basic pH.

(+)-3-amino-6-carboxamido-l,2,3,4-tetrahydrocarbazole thus obtained is subjected to reductive alkylalion to obtain (+)-3-N-benzylamino-6-carbomxamido-1,2,3,4-tetrahydrocarbazole monohydrate. (+)-3-amino-6-carboxamido-l,2,3,4-tetrahydrocarbazole is first reacted with benzaldehyde followed by reduction with metal borohydride. The metal borohydrides used are sodium borohydride, potassium borohydride, preferably sodium borohydride. The solvents which can be used for the reaction are protic, aprotic solvents or mixture thereof such as methanol, ethanol, isopropanol, DMF, DMSO, preferably alcohol such as methanol, ethanol, isopropanol and more preferably methanol. The temperature at which reaction is carried out is -10° to 0°C, more preferably -8 to -5°C. After the reaction is over, water is added to the reaction mass followed by ethyl acetate to quench the reaction. Further, the pH of the reaction mass is adjusted to acidic by using dilute hydrochloric acid. The solid obtained is collected by filtration and the ethyl acetate layer from the mother liquor is separated. The filtered solid is added to mother liquor and the pH is again adjusted to basic by using a base. The solid obtained is filtered, washed with water and dried to obtain (+)-3-N-benzylamino-6-carbomxamido-l,2,3,4-tetrahydrocarbazole monohydrate. Further it can be purified to obtain desired purity.
The (+)-3-N-benzylamino-6-carbomxamido-1,2,3,4-tetrahydrocarbazole monohydrate (Formula VI), thus obtained is subjected to reductive methylation to obtain (+)-3-N-benzyl-6-carboxamido-3-methylamino-1,2,3,4-tetrahydrocarbazole (Formula VII), The reductive methylation involves reaction of (+)-3-N-benzvlamino-6-carbomxamido-1,2,3,4-tetrahydrocarbazole monohydrate with formalin and metal borohydride. The metal borohydrides which can be used are sodium borohydride, sodium cyanoborohydride or mixtures thereof, preferably sodium cyanoborohydride. The temperature of the reaction is -10° to 0 °C, preferably-8° to -5°C. The reaction media used is alcohol, ether, water or mixture thereof such as methanol, ethanol, isopropanol, preferably alcohol such as methanol, ethanol, isopropanol and more preferably methanol. After the reaction is over, the reaction mixture is quenched by adding water and ethyl acetate. The ethyl acetate layer containing product is separated and the aqueous layer is extracted with ethyl acetate. Both the ethyl acetate layers are combined and water is added to it; the pFI is adjusted to acidic by using dilute hydrochloric acid. The organic layer is separated and discarded. To the aqueous layer, ethyl

acetate is again added and the pH is adjusted to basic by using base. The bases which can be used are alkali and alkaline metal hydroxide or carbonate, particularly carbonates are preferred, such as sodium carbonate, potassium carbonate, more particularly alkali carbonate like potassium carbonate. The organic layer containing the product is separated and the aqueous layer is re-extracted with ethyl acetate. Both the ethyl acetate layers are combined and washed with water. Further, the solvent is distilled of completely to get the solid (+)-3-N-benzyl-6-carboxamido-3-methylamino-1,2,3,4-tetrahydrocarbazole.
The (+)-3-N-benzyl-6-carboxamido-3-met"hylamino-1,2,3,4-tetrahydrocarbazole, thus obtained is converted into its succinate salt by treating it with succinic acid. The solvents which can be used for the salt formation are alcohol, ketone, esters and nitriles and mixture thereof, such as ethanol, methanol, isopropanol, methyl ethyl ketone, methyl isobutyl ketone, acetone, ethyl acetate, propyl acetate, acetonitrile, preferably alcohols such as ethanol, methanol, isopropanol and more preferably methanol. Methanol used for the salt formation is distilled out and another solvent is added for the precipitation of the salt, preferably ethyl acetate is added to the residue after methanol distillation and the solution is stirred for some time and filtered to obtain (+)-3-N-benzyl-6-carboxamido-3-methylamino-l,2,3,4-tetrahydrocarbazole succinate (Formula-IX).
Further the debenzylation of (+)-3-N-benzyl-6-carboxamido-3-methylamino-l,2,3,4-tetrahydrocarbazole succinate is performed using a noble metal catalyst in a solvent under hydrogen gas atmosphere. The noble metal catalyst can be palladium, platinum hodium or ruthenium or their derivative. Suitable derivatives of noble metal catalyst include, but are not limited to oxides, chlorides or sulfates. The noble metal catalyst or derivative thereof can be supported on carriers like carbon, alumina, preferably the palladium metal supported on carbon is used for debenzylation reaction. The solvents used for the catalytic debenzylation are methanol, ethanol, isopropanol, water, ethyl acetate, toluene or mixture thereof, preferably mixture of water and methanol is used for debenzylation. The reaction is carried out at 0 to 60 °C preferably 15 to 40°C and more preferably 25 to 30°C. The hydrogen gas can be purged into the reaction or trapped inside by closing vents for generating nominal pressure. After debenzylation is over the carbon is filtered off and washed with methanol. The solvent is distilled of from the filtrate. Traces of the solvent are removed by ethyl acetate

stripping. The suspension thus obtained is stirred and filtered to obtain Frovatriptan succinate monohydrate
The purification of Frovatriptan succinate monohydrate is done by recrystallisation or slurry wash with organic solvents such as ketone, ether, ester, alcohol, nitrile and mixture thereof. The ketones which can be used for the purification are acetone, methyl ethyl ketone, methyl isobutyl ketone. The ethers which can be used are tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether. The esters which can be used are ethyl acetate, methyl acetate. The nitrile which can be used is acetonitrile and the alcohols which can be used are methanol, ethanol and isopropanol. The preferred solvents used for purification are alcohols and more preferably ethanol. Water can be added to enhance the solubility. To dissolve Frovatriptan succinate monohydrate in solvent it can be heated to reflux temperature of the solvent and the resulting clear solution cooled, crystallized and filtered to give pure frovatriptan succinate monohydrate. For precipitation, antisolvent can also be added to the clear solution and the resulting precipitate is filtered.
Further, the present invention involves an improved process for the preparation of an improved process for the preparation of (±)-3-Amino-6-carboxamido-l,2,3,4-tetrahydrocarbazole of formula (III), which comprises

deprotection of racemic-6-carboxamido-3-phthalimido-l,2,3,4-tetrahydrocarbazole of formula (II)

Formula-II
by using alkyl amine, preferably monomethylamine in a solvent, preferably water.
Further, the present invention also involves the synthesis of novel intermediate (+)-3-N-benzylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole monohydrate of Formula (VI)

Formula-VI
Although the invention has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the said invention, will become apparent to persons skilled in the art upon reference to the description of the invention. It is therefore contemplated that such modifications can be made without departing from the true spirit or scope of the present invention as defined herein above and as exemplified and claimed herein below.

EXAMPLES
The following examples are presented for illustration only, and are not intended to limit the scope of the invention or appended claims.
Examplc-I: Preparation of 4-carboxamidophenyl hydrazine hydrochloride
Charged 4-Aminobenzamide (250 g, 1.84 moles) and water (750 ml) in a four neck five liter round bottom flask fitted with overhead stirrer, thermometer pocket and pressure equalizing funnel in plastic bath. The stirred contents in the .flask were cooled at 15-20 °C. Concentrated hydrochloric acid (750 ml) was added to the reaction mixture and cooled further at -5 to -10 °C. Aqueous sodium nitrite solution (164.9 g, 2.39 moles dissolved in 365 ml water) was added at -5 to -10°C and the obtained diazonium salt solution was stirred at -5 to -10 °C for an hour. Aqueous sodium sulfite solution (463.8 g, 3.68 moles dissolved in 1500 ml water) was added to the reaction mass at -5 to -10 °C. The reaction mass was warmed to 10-15 °C and stirred for 3.5 hours at the same temperature. The solid obtained was filtered and washed with water (500 ml, 2 vol.). The slurry was again washed with acetone (1250 ml, 5 vol.) and dried at 55-60 °C to obtain 330 g of 4-carboxamidophenyl hydrazine hydrochloride. Molar Yield: 95.93%.
Example-II: Preparation of (±)-6-Carbaxamido-3-phthalimido-1,2,3,4-
tetrahydrocarbazole
Charged 4-Carboxamisophenylhydrazine hydrochloride (300 g, 1.6mole), 4-phthalimido cyclohexanone (300 g, 1.23 moles) and acetic acid (900 ml) in four neck five liter round bottom flask fitted with overhead stirrer, thermometer pocket in an oil bath. The contents of flask were heated at 108-110 °C for 90 minutes. The reaction mass was cooled to 80-85 °C and charged water (450 ml). It was cooled further to 15-20°C. The reaction mass was diluted with water (450 ml.), the pH of the reaction mass was adjusted to 8.5-9 by using 40% sodium hydroxide solution. The product obtained was filtered off and the slurry was washed with

water (3 lit.) followed by drying at 55-60°C to obtain (±)-6-Carbaxamido-3-phthaIimido-1,2,3,4-tetrahydrocarbazole (400 g), Molar Yield: 69.6%.
Example-III: Preparation of (±)-3-Amino-6-carboxamido-l,2,3,4-tctrahydrocarbazoIe
Charged (±)-6-Carbaxamido-3-phlhalimido-l,2,3,4-tetrahydrocarbazole (225 g, 0.626 mole) and 40% aqueous monomethyl amine solution (675ml) in two liter four neck round bottom flask fitted with over head stirrer in a water bath. The reaction mass was stirred at 25-30 °C for an hour. The temperature was further increased to 50-55°C and maintained for 4 hours. After completion of the reaction, it was cooled to 10-15°C and stirred for an hour at 10-15°C. The product was filtered, followed by washing with water (450ml) and dried at 55-60°C to obtain (J=)-3-Amino-6-carboxamido-l,2,3,4-tetrahydrocarbazole (135 g). Molar Yield: 93.75%.
Example-IV: (+)-3-Amino-6-carboxamido-l,2,3,4-tetrahydrocarbazole-2,3:4,6-di-0-isopropylidcnc-2-keto-L-gulonic acid salt
Charged (±)-3-Amino-6-carboxamido-l,2,3,4-tetrahydrocarbazole (63 g, 0.275 mole) and methanol (220.5ml, 3 vol.) in one liter four neck round bottom flask fitted with over head stirrer, thermometer pocket, pressure equalizinsfunnel and water condenser in a water bath.. A solution of 2,3:4,6-di-0-isopropylidene-2-keto-L-gulonic acid (DIKGA) (82.7 g, 0.28 mole dissolved in methanol (94.5ml) was added to the resulting mixture at 40-45 °C. The reaction mass was further heated to 60-65 °C for an hour. The contents in the flask were cooled to 5-10 °C and stirred for an hour. The salt obtained was filtered, washed with chilled methanol (189ml) and dried at 55-60 °C to obtain (+)-3-Amino-6-carboxamido-l,2,3,4-tetrahydrocarbazole-2,3:4,6-di-0-isopropylidene-2-keto-L-gulonic acid salt. (60 g). The salt thus obtained, was re-crystallized twice with 10 vol. of methanol followed by washing with 2 vol. of methanol. The obtained product was dried at 55-60 oC to yield white colored diastereomeric salt (42 g). Molar yield: 30.45%.

Example-V: (+)-3-Amino-6-carhoxamido-l,2,3,4-tetrahydrocarbazolc
Charged (+)-3-Amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole-2,3:4,6-di-0-isopropylidene-2-keto-L-gulonic acid salt (41 g, 0.082 mole) and water (820 ml, 20vol.) in three liter four neck flask fitted with over head stirrer, thermometer pocket and pressure equalizing funnel in a plastic bath. Charged aqueous potassium carbonate solution (22 g, 0.158 mole) dissolved in water (82 ml) to the solution at 0-5 °C. The solution was stirred at the same temperature for an hour. The product was filtered, washed the wet cake with chilled water (82 ml) and dried at 55-60 °C to obtain white colored optically pure (+)-3-Amino-6-carboxamido-l,2,3,4-tetrahydrocarbazole (18.3 g). Molar Yield: 98.07%
Example-VI: Preparation of (+)-6-carboxamido-3-benzylarnino-l,2,3,4-tetrahydro carbazole (N-bcnzyl desmcthyl frovatriptan)
Charged (+)-3-Amino-6-carboxamido-l,2,3,4-tetrahydrocarbazole (17 g, 0.074 mole) and methanol (136 ml) in 500 ml four neck round bottom flask fitted with over head stirrer, thermometer pocket in a plastic bath. Charged benzaldehyde (10.22 g, 0.097 mole) to the solution at 25-30 °C. stirred for two hours at 25-30 °C. Cooled the contents in the flask to -10°C and sodium borohydride (3.5 g, 0.093 mole) was added in small lots to the reaction mass at -8 to -5 °C, stirred for 30 minutes and charged water (408 ml) followed by addition of ethyl acetate (170 ml, 10vol.)- The pH of the reaction mass was adjusted to 2 with 5N hydrochloric acid, stirred for 30 minutes, followed by filtration and the aqueous layer was separated. To the aqueous layer, filtered product was added and the pH was adjusted to 10 using 30% aqueous potassium carbonate solution. It was stirred for an hour, followed by filtration, washed with water (170 ml, 10vol.) and dried at 55-60°C to obtain off white to white colored N-benzyl desmethyl frovatriptan (20g). Molar yield: 86.46%
Example-VII: Preparation of (+)-3-N-benzyl-6-carboxamido-3-methylamino -1,2,3,4-tetrahydrocarbazole (N-Benzyl Frovatriptan)

Charged (+)-6-carboxamido-3-benzylamino-l,2,3,4-tetrahydrocarbazole (20 g, 0.063 mole) and methanol(140 ml, 7 vol.) in 500 ml four neck round bottom flask, fitted with over head stirrer, thermometer pocket in a plastic tub. Charged formalin and cooled the contents in the flask to -8 to -5 °C. Charged sodium cyanoborohydride (4 g, 0.063 mole) in small lots within 10-15 minutes and stirred for 30 minutes. The reaction mass was quenched with water (420 ml) and ethyl acetate (200 ml). The organic layer was separated and the aqueous layer was extracted with 2 x 200 ml ethyl acetate. The total organic layer was taken in 200 ml of water. The pH of the biphasic layer was adjusted to 2 using 2.5N hydrochloric acid and stirred for 60 minutes. The organic layer was discarded. 200 ml of ethyl acetate was added to the aqueous layer, the pH was adjusted to 7.0 with.30% aqueous potassium carbonate solution and stirred for 15 minutes. The organic layer was separated and the aqueous layer was extracted with 2 x 200ml of ethyl acetate. The organic layer was concentrated to obtain N-Benzyl Frovatriptan (17 g). Molar yield: 81.48%.
Example-VIII: Preparation of Succinate salt of (+)-3-N-benzyl-6-Carboxamido-N-merhyl- 3-amino-l,2,3,4-tetrahydrocarbazole (N-Benzyl Frovatriptan succinate)
Charged (+)-3-N-benzyl-6-carboxamido-3-methylamino-l,2,3,4-tetrahydrocarbazole (14.5 g. 0.044 mole) and methanol (145 ml, 10vol.) in a 500ml four neck round bottom flask fitted with over head stirrer, thermometer pocket and pressure equalizing funnel. Succinic acid solution (5.2 g, 0.045 mole dissolved in methanol (72.5 ml) was added to the resulting mixture and stirred for three hours at 25-30 °C. It was concentrated under reduced pressure followed by stripping with 2x100 ml of ethyl acetate and finally stirred in 100 ml of ethyl acetate. The resulting mixture was filtered and dried to obtain N-Benzyl Frovatriptan succinate (19.50 g). Molar Yield: 98.56%.
Example-VIII: Preparation of Frovatriptan succinate monohydratc
Charged (+)-3-N-benzyl-6-carboxamido-N-methyl-3-amino-l,2,3,4-tetrahydrocarbazole
succinate (20 g, 0.044 mole), methanol (300 ml, 15 vol.) and water (50 ml, 2.5vol.) in 500 ml

four neck round bottom flask fitted with overhead stirrer and thermometer pocket. Charged 10% Pd/C (4 g) to the clear reaction mass. Hydrogen gas was purged under stirring. After completion of the reaction, the reaction mass was filtered off through hyflo bed. The filtrate was concentrated followed by stripping with 2 x 200 ml of methanol to obtain off white color Frovatriptan succinate monohydrate (22 g). Molar Yield: 89.71%.
Example-IX: Purification of Frovatriptan succinate monohydrate
Charged crude frovatriptan succinate (22 g) and methanol (88 ml, 4 vol.) in 250 ml four neck round bottom flask fitted with overhead stirrer in a plastic tub. The contents in the flask were stirred for 60 minutes. The filtered product was washed with methanol (44 ml), dried at 45-50°C to obtain pure Frovatriptan succinate monohydrate as white powder (10.5 g). Molar Yield: 65.25%, HPLC Purity > 99.50%, Chiral HPLC purity > 99.9%.
Example-X: Crystallization of Frovatriptan succinate
Charged Frovatriptan succinate (0.5 g) and ethanol (50 ml, 100vol.) in 250ml four neck flask fitted with over head stirrer, thermometer pocket and water condenser in an water bath. The contents in the flask were refluxcd to get a clear solution. It was cooled slowly to 25-30°C and filtered off to give off white to white color Frovatriptan succinate.(0.3g). Molar Yield: 60.00%, HPLC purity >99.70%., Chiral HPLC purity > 99.9%


Scheme-1

We Claim:
1. An improved process for the preparation of R(+)-6-carboxamido-3-N-methylamino-1,2,3,4-tetrahydrocarbazole succinate monohydrate i.e. Frovatriptan succinate monohydrate
of formula-I, comprising

Formula (I)
a. deprolection of racemic-6-carboxamido-3-phthalimido-l,2,3,4-tetrahydrocarbazole of formula (II)

Formula-II
in presence of alkyl amine, in a solvent to obtain (±)-3-Ammo-6-carboxamido-l,2,3,4-tetrahydrocarbazole of formula (III)


Formula-Ill
b. resolution of (±)-3-Amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole of formula (III) by chiral auxiliary in an alcoholic solvent to obtain diastereomer salt of formula-IV

Formula-IV
c. basification of diastereomeric salt of Formula (IV) by using base to obtain optically pure (+)-3-Amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole of Formula (V) in an aqueous medium.

Formula-V
d. reductive alkylation of (+)-3-Amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole of formula (V) in a solvent with benzaldehyde and alkali metal borohydride provides novel

intermediate, (+)-3-N-benzylamino-6-carboxamido-l,2,3,4-tetrahydrocarbazole monohydrate of Formula (VI)

Formula-VI
e. reductive methylation of (+)-3-N-benzylamino-6-carboxamido-l,2,3,4-tetrahydrocarbazole monohydrate of formula (VI) with formaldehyde in a solvent to obtain (+)-3-N-benzyl-6-Carboxamido-3-methylamino-1,2,3,4-tetrahydrocarbazole of formula
(VII)

f. salt formation of (+)-3-N-benzyl-6-Carboxamido-3-methylamino-l,2,3.4-tetrahydrocarbazole of formula (VII) with succinic acid in a solvent to obtain (+)-3-N-bcnzyl-6-Carboxamido-3-methylamino-l,2,3,4-tetrahydrocarbazole succinate of Formula (IX)


g. debcnzylation of (+)-3-N-benzyl-6-Carboxamido-3-methylamino-l,2,3,4-tetrahydro-carbazole succinate of formula (IX) in presence of noble metal catalyst or their derivatives in hydrogen atmosphere in a solvent to obtain Frovatriptan succinate monohydrate of Formula
(I)

h. purification of Frovatripan succinate monohydrate in a solvent.
2. A process according to claim la), wherein the alkylamine comprises of monomethylamine or dimethylamine, preferably, monomethylamine and the solvent comprises of water, methanol or ethanol, preferably water.
3. A process according to claim 1b), wherein the chiral auxiliary comprises of 2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid (DIKGA), and alcoholic solvent comprises of methanol, ethanol, isopropanol, preferably methanol.
4. A process according to claim 1c), wherein the base comprises of alkali or alkaline metal carbonates and hydroxides like sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, preferably potassium carbonate.

5. A process according to claim 1d), wherein the alkali metal borohydride used for reductive alkylalion comprises of sodium borohydride, potassium borohydride, preferably sodium borohydride.
6. A process according to claim 1d), wherein the solvent comprises of protic, aprotic solvents or mixture thereof such as methanol, ethanol, isopropanol, DMF, DMSO, preferably alcohol, such as methanol, ethanol, isopropanol, more preferably methanol, and reaction temperature comprises of -10 to 0 °C, preferably -8 to -5 °C.
7. A process according to claim 1e), wherein metal borohydrides used for reduction
comprises of sodium borohydride, sodium cyanoborohydride or mixtures thereof, preferably
sodium cyanoborohydride
8. A process according to claim le), wherein the solvent comprises of alcohol, ether, water or mixture thereof, preferably alcohol such as ethanol, methanol, isopropanol, more preferably methanol, and reaction temperature comprises of -10 to 0 °C and more preferably -8 to -5°C
9. A process according to claim 1f), wherein solvents comprise of alcohol, ketone, esters and nitriles and mixture thereof, such as ethanol, methanol, isopropanol, methyl ethyl ketone, methyl isobutyl ketone, acetone, ethyl acetate, propyl acetate, acetonitrile, preferably alcohols such as ethanol, methanol, isopropanol, more preferably methanol.

10. A process according to claim lg), wherein noble metal catalyst comprises of palladium, platinum, rhodium or ruthenium and their derivatives which are not limited to oxides, chlorides or sulfates.
11. A process according to claim lg), wherein the noble metal catalyst or derivative thereof can be supported on carriers like carbon, alumina, preferably palladium metal supported on carbon.
12. A process according to claim lg), wherein the solvents comprises of methanol, ethanol, isopropanol, water, ethyl acetate, toluene or mixture thereof, preferably mixture of water and methanol, and reaction temperature ranges from 0 to 60 °C, preferably 15 to 40°C and more preferably 25 to 30 °C.
13. A process according to claim 1h), wherein the solvent for purification comprises of organic solvent like alcohol, ether, ester, ketone or mixture thereof, preferably ethanol

14. An improved process for the preparation of (±)-3-Amino-6-carboxamido-l,2,3,4-tetrahydrocarbazole of formula (III), which comprises

Formula-Ill
deprolection of racemic-6-carboxamido-3-phthalimido-l,2,3,4-tetrahydrocarbazole of
formula (II)

by using alkyl amine, preferably monomelhylamine in a solvent, preferably water. 15. (+)-3-N-benzylamino-6-carboxamido-l,2,3,4-tetrahydrocarbazole monohydrate of


16. A process for the preparation of Frovatriptan succinate monohydrate substantially as herein described with reference to the examples.