METHOD FOR PREPARING AN OPTICALLY ACTIVE FROVATRTPTAN
Frovatriptan succinate, also known as (R)-(+)-6-carboxamido-3-N-methylamino-1,2,3,4-tetrahydrocarbazole, has the following formula (IV)

Frovatriptan succinate is a 5HT1 receptor agonist. It is marketed under the name FROVA® for the treatment of migraine.
WO 93/00086(PCT/GB02/01082) discloses a group of tetrahydrocarbazole derivatives, which have activity as 5HT1 receptor agonists, and are therefore useful in the treatment of migraines, A specific compound disclosed therein is 3-methylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole hydrochloride prepared by a six stage process, and 3-methylamino-6-cyano-l,2,3,4-tetrahydrocarbazole, via 3-methylamino-6-cyano-l,2,3,4-tetrahydrocarbazole, involving a number of protection and deportation steps.
WO 94/14772 discloses enantiomers of certain carbazole derivatives, including the aforementioned compound (R)-(+)-6-carboxamido-3-N-methylamino-1,2,3,4-tetrahydrocarbazole, salts and solvates thereof
WO 94/14772 further discloses various methods by which single enantiomers can be prepared; one of which involves:
(a) separation of an elastomeric mixture of the compound or a derivative thereof by chromatography, e.g. on a choral HPLC column;
(b) alkylation’s of (+) or (-) enantiomer of 3-amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole or a salt thereof; and

(c) separation of diastereoisomers of a chiral derivative e.g. a chiral salt of the compound by crystallization or chromatography
Although the above mentioned methods of the prior art provide processes to prepare desked enantiomerthe processes available are highly unsatisfactory and unviable for industrial application
WO 99/54302 discloses novel process for the preparation of (R)-(+)-6-carboxamido-3-N-methylamino-l,2,3,4-tetrahydrocarbazole which involves :
i. Resolving a mixture of enantiomers of an indole nitrile of the formula(I) using L-pyroglutamic acid.

ii. Separation of desired (+)-6-cyano-3-N-methylamino-l,2,3,4.-tetrahydrocarbazole of the formula (II) as diastereomeric salt (V) with L-Pyroglutamic acid.

iii. Regeneration of (+)-6-cyano-3-N-methylamino-l,2,3,4-tetrahydrocarbazole of
the formula (III) using base, iv. Hydrolyzing compound of formula (III) with boron trifluoride/acetic acid
complex to get R-(+)-6-carboxamido-3-N-methylamino-l,2,3,4-
tetrahydrocarbazole (frovatriptan) of the formula (IV)


When we earned out the above process in our laboratory as per the details provided in the above said patent we observed the following important points :
The said application disclosed that for resolution of indole enantiomers D-pyroglutamic acid gave the 'wrong' enantiomer. It has now been surprisingly found by our studies, that D-pyroglutamic acid can indeed be employed to selectively separate undesired s(-) isomer of the racemic indole derivative(I). Thus, when the racemic cyano indole (I) is treated with D-pyroglutamic acid in a select solvent, exclusive formation of the salt(II) of the undesired s(-) isomer is observed which is filtered off. The filtrate is found to contain selectively the desired enantiomer R(+)6-Cyano-3N-Methylamino-l,2,3,4-tetrahydro carbazole
Further the hydrolysis of nitrile to carboxamide in above process suffers from the following drawbacks:
1. For hydrolysis It involves use of corrosive reagents like boron trifluoride/acetic acid complex which is extremely hazardous and beset vdth handling problems
2. Further it is used in huge volumes. As this reagent is highly expensive it affects economy of the process.
3. The realized reaction time for hydrolysis is very lengthy that is 20 hours, which
could be problematic for commercial scale operations .
Summary of invention:
Keeping in view of the difficulties in commercialization and applicability for manufacturing scale of the process for the preparation of optically active frovatriptan disclosed in the above mentioned prior art patents and considering the importance of this

drug for the society and health-care industry, we aimed our research work towards developing an industrially feasible and cost effective novel process for the preparation of optically active frovatriptan of the formula (IV),
Therefore the main objective of the present invention is to provide an improved process for the preparation of optically active Frovatriptan overcoming the difficulties of hitherto known processes
According to present invention the resolution of cyano indole enantiomers(I) with the optically active acid D-pyroglutamic acid can be carried out as follows :
1. Combining the racemic 6-cyano-3-N-methylamino-l ,2,3,4-tetrahydrocarbazole of formula (I) with D-Pyroglutamic acid as the resolving agent in a solvent for example mixture of polar solvents to crystallize selectively the imdesired D-pyroglutamate diastereomeric salt of compound of formula (I) in the said mixture
2. Separation of undesired D-pyroglutamate diastereomeric salt(II) by filtration
3. Distillation of filtrate containing exclusively (+)-6-cyano-3-N-methylamino-1,2,3,4-tetrahydrocarbazole(III) under vacuum
4. dissolving the residue in suitable solvent .Water washing Solvent layer and distilling offcompletely under vacuum to get(+)-6-cyano-3-N-methylamino-l,2,3,4-tetrahydrocarbazole of the formula (III)
5. Dissolving (+)-6-cyano-3-N-methylamino-1,2,3,4-tetrahydrocarbazole in alcohol.
6. Forming (+)-6-Cyano-3-N-methylamino-l,2,3,4-tetrahydrocarbazole hydrochloride salt with Isopropanolic -HCl to improve purity.
7. Treating hydrochloride salt of (+)-6-cyano-3-N-methylamino-l,2,3,4-tetrahydrocarbazole with phosphoric acid.
8. Heating till reaction completion and quenching in crushed ice.
9. Basification and extraction with solvent and distillation. 3
10. precipitation of (+)-6-carboxamido-3-N-methylamino-l,2,3,4-tetrahydrocarbazole(IV) with suitable solvent.
Preferred reaction conditions for the various steps are as follows:

Step 1: mixture of solvents are preferably alcohol and acetone more preferably
methanol and acetone.
Step 4: The solvents preferred for dissolution are isopropyl acetate or ethyl acetate
more preferably Ethyl acetate.
Step 5 : The alcohol preferred for dissolution are ethanol or methanol more
preferably methanol
Step 8: Heating temperature is 100-130°C more preferably 110-120°C
Step 9: The solvent preferred for extraction is n-Butanol
Step 10; The solvents preferred for precipitation are isopropyl acetate or ethyl acetate
more preferably Ethyl acetate.
Optionally the resulting compound (IV) from step 10 can easily be converted to a pharmaceutically acceptable salt for example succinate salt by reaction of succinic acid in methanol medium.
In a preferred embodiment the present invention provides a process for the preparation of
(+)-6-carboxamido-3-N-methylamino-l,2,3,4-tetrahydrocarbazole of the formula(IV) or a salt thereof, which comprises reaction steps from 1 to 10 above and optionally involving salt formation step.
In a further embodiment present invention provides the use of D-pyroglutamic acid in resolving the racemic mixture of 6-cyano-3-N-methylamino-l,2,3,4-tetrahydrocarbazole of the formula(I).
The present invention will now be described with reference to the following examples which should not be construed as in any way limiting the invention.
Examples

Example-l: Preparation of (+)-6-cyano-3-N-methylamino-l,2,3,4-tetrahydrocarbazole(II)
A) Racemic 6-cyano-3-N-methylammo-l,2,3,4-tetrahydrocarbazole(I) (1.33mol, 300g) obtained directly from the synthesis was suspended in a mixture of methanol(3L) and Acetone(3L) and stirred at room temperature for 15-30 minutes to get a clear solution. D-pyroglutamic acid(0.69mol, 90g) was charged to the reaction mass and heated to reflux temperature. Reaction mass was maintained at reflux temperature for 2hours and slowly brought to room temperature during 1 hour. The slurry was kept over night at room temperature under stirring. The resulting solid was filtered and washed with acetone. The filtrate was completely distilled under vacuimi and residue was brought to room temperature. The residue was dissolved by adding 6L ethyl acetate and washed with 3x3L demineralized water. Ethyl acetate layer was distilled under vacuum and residue was dissolved in 2L methanol. The methanol solution is treated with Isopropanolic-HCl gave hydrochloride salt of the title compound(120g), [a]D (C, 0.5% methanol^= +23°C
Example-2 : Preparation of (+)-6-carbaxamido-3-N-methylamino-l,2,3,4-tetrahydrocarbazole(IV):
(+)6-cyano-3-N-methylamino-l,2,3,4-tetrahydrocarbazole HCl (0.46mol, 120g) obtained from Example-1 was suspended in phosphoric acid(l Imol, 1.08kg). The reaction mass was heated to 110-115°C and maintained at the same temperature for 3hours. The reaction mass was brought to room temperature and quenched into crushed ice(4kgs). It was basified with50% sodium hydroxide solution(2L) and extracted with n-butanol (2x2L).Organic layer was separated and distilled under vacuum .The residue was suspended in 300ml Ethyl acetate at room temperature and maintained at the same temperature for 1-2 hours. The resulted titled compound of formula(IV) was filtered and washed with Ethyl acetate


The following are the Advantages of the invention
1. The use of D-pyroglutamic acid in the resolution of 6-cyano-3-N-methylamino-1,2,3,4- tetrahydrocarbazole(I) is novel
2. Corrosive, difficult to handle reagents are avoided making the process environmentally safe for commercial application.
3. The process can be used for commercial preparation of frovatriptan salts of pharmaceutical grade.
4. The process is suitable for operation on industrial scale runs.
5. The desired R(+) isomer is obtained in the free form.

WE CLAIM:
1. Process for the preparation of R-(+)-6-carboxainido-3-N-methylainitvo 1,2,3,4-
tetrahydrocarbazole(III) comprises of the step of resolving racemic mixture of 6-
cyano-3 -N-methylamino 1,2,3,4-tetrahydrocarbazole(I).

2. A process as claimed in claim 1 wherein resolution of the enantiomers is achieved by treating the compound of formula (I) vnih D-pyroglutamic acid.
3. A process for the preparation of R(+)-6-carboxamido-3-N-methylamino 1,2,3,4-tetrahydrocarbazole of the formula (III) or a salt thereof comprises
I. Combining the racemic 6-cyano-3-N-methylamino-1,2,3,4-tetrahydrocarbazole of formula (I) with D-Pyroglutamic acid as the resolving agent in a resolution solvent for example mixture ofmethanol and acetone to crystallize selectively the undesired D-pyroglutamate diastereomeric salt of compound of formula (I) in the said mixture
II. Separation of undesired D-pyroglutamate diastereomeric salt by filtration
III. Distillation of filtrate containing exclusively (+)-6-cyano-3-N-methylamino-l,2,3,4-tetrahydrocarbazole of the formula (II) under vacuum.


IV. dissolving the residue in Ethyl acetate .Water washing Solvent layer and distilling off completely under vacuum to get(+)-6-cyano-3-N-methylamino-l,2,3,4-tetrahydrocarba2X)le of the formula (II)
V. Dissolving (+)-6-cyano-3 -N-methylamino-1,2,3,4-tetrahydrocarbazole in methyl alcohol.
VI. Forming (+)-6-Cyano-3-N-methylamino-l,2,3,4-tetrahydrocarbazole hydrochloride salt with Isopropanolic -HCl to improve purity.
VII. Treating hydrochloride salt of (+)-6-cyano-3-N-methylamino-l,2,3,4-
tetrahydrocarbazole of the formula(II) with phosphoric acid for hydrolysis
VIII. Heating till reaction completion and quenching in crushed ice
IX. Basification and extraction with n-butanol and distillation.
X. precipitation of (+)-6-carboxamido-3-N-methylamino-1,2,3,4-tetrahydrocarbazole(in) with suitable solvent.