FORM 2
THE PATENT ACT, 1970
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"PROCESS FOR THE PURIFICATION OF FROVATRIPTAN AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF"
Enaltec Labs Pvt. Ltd. an Indian Company, having its Registered Office at 17th Floor, Kesar Solitaire, Plot No.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India. Pin Code: 400705
1. The following specification particularly describes the invention and the manner in which it is to be performed.

PROCESS FOR THE PURIFICATION OF FROVATRIPTAN AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
FIELD OF THE INVENTION:
The present invention relates to a process for the purification of frovatriptan and its pharmaceutically acceptable salts thereof by using simulated moving bed technology (SMB).
BACKGROUND OF THE INVENTION:
Chemically frovatriptan succinate is R - (+) - 3-methylamino -6-carboxamido-1,2,3,4-tetrahydrocarbazole monosuccinate monohydrate and it is known from U.S. patent no. 5,616,603 and U.S. patent no. 5,962,501 and is represented by compound of structural formula 1.

Formula 1
The proprietary name of frovatriptan succinate is "FROVA". Frova is an antimigraine drug and is indicated for the acute treatment of migraine attack with or aura in adults.
U.S. patent no. 5,616,603 described the preparation of frovatriptan by separating (+) and (-) enantiomers of racemic 3-N-benzyloxycarbonyl-6-carboxamido-3-N-methylamino-i, 2, 3, 4-tetrahydrocarbazole by chiral HPLC followed by the deprotection of protecting group of isolated enantiomer of 3-N-benzyloxycarbonyl-6-carboxamido-3-N-methylamino-], 2, 3, 4-tetrahydrocarbazole. U.S patent no. 5.616.603 and 5,618,947 also described the purification of frovatriptan succinate by the formation of salt with R-2-pyrrolidone-5-carboxylic acid in an ethanol solvent.

U.S. patent no. 5, 616, 603 also describes the preparation of frovatriptan by resolution of racemic mixture of 2, 3, 4, 9-tetrahydro-3-(methylamino)-lH-carbazole-6-carboxamide with (lS)-(+)-10-camphor sulphonic acid.
U.S. patent no. 6,359,146 describes the purification of frovatriptan succinate by recrystallization of frovatriptan succinate in a mixture of ethanol and water.
P.C.T publication no. 2010/122343 describe the purification of frovatriptan by recrystallization of crude frovatriptan in isopropanol solvent.
The isolation of (+) enantiomer of (±)-3-N-benzyloxycarbonyl-6-carboxamido- 3-N-methylamino-1, 2, 3, 4-tetrahydrocarbazole by chiral HPLC is not commercially viable at industrial scale manufacturing due to expensive chiral column , long timing for isolation, use of plenty of organic solvents and capacity constraints.
Moreover, the indole carboxylic acid is always being formed as a by-product in the processes of forming frovatriptan and its pharmaceutically acceptable salts thereof, and therefore the purification processes comprising forming of salts of frovatriptan with R-2-pyrrolidone-5-carboxylic acid and crystallization / recrystallization of frovatriptan and its pharmaceutically acceptable salts thereof are reported in the literature.
The method reported in art for purifying frovatriptan and its pharmaceutically acceptable salts thereof are not commercially viable due to the loss of yield due to crystallization, which add-on the cost of final product.
Simulated moving bed is chromatographic technique used for the purification of sugar molecules and pharmaceutical substance. The used of simulated moving bed technology in the pharmaceutical industry provide high purity and high recovery of product in a very short time and hence it is commercially viable.

OBJECT OF THE INVENTION:
A first object of the present invention is to provide a process of purifying frovatriptan and its pharmaceutically acceptable salts thereof by using simulated moving bed technology (SMB).
A second object of the present invention is to provide a process for the isolation of substantially pure frovatriptan and its pharmaceutically acceptable salts thereof by feeding crude reaction mixture comprising frovatriptan and its pharmaceutically acceptable salts thereof and the by-products of the reaction into a simulated moving bed (SMB) unit.
A third object of the present invention is to provide substantially pure frovatriptan and its pharmaceutically acceptable salts thereof obtained by the application of simulated moving bed technology.
A further aspect of the present invention is to provide a process of preparing frovatriptan and its pharmaceutically acceptable salts thereof comprising the steps of:
a. providing a solution of crude frovatriptan,
b. isolating substantially pure frovatriptan by the application of simulated moving bed
technology and
c. optionally converting substantially pure frovatriptan into pharmaceutically acceptable
salts of frovatriptan.
A further aspect of the present invention is to provide a process of preparing frovatriptan and its pharmaceutically acceptable salts thereof comprising the step of:
a. isolating R-(+)-3-methylamino-6-carboxamido-l,2,3,4-tetrahydrocarbazole from a
racemic mixture of 2,3,4,9-tetrahydro-3(methylamino)-lH-carbazole-6-carboxamide by
the application of simulated moving bed technology and
b. converting R-(+)-3-methylamino-6-carboxamido-l, 2, 3, 4-tetrahydrocarbazole into its
pharmaceutically acceptable salts.

A further aspect of the present invention is to provide a process of preparing substantially pure 2, 3, 4, 9-tetrahydro-3-(methylamino)-l H-carbazole-6-carboxamide comprising the steps of:
a. providing the solution of crude 2, 3, 4, 9-tetrahydro -3- (methylamino) -1H -carbazole-6-
carboxamide and
b. isolating substantially pure 2, 3, 4, 9-tetrahydro-3-(methylamino)-lH-carbazole-6-
carboxamide by the application of simulated moving bed technology.
STATEMENT OF THE INVENTION:
The solution of crude frovatriptan may consist of by-product of reaction such as indole-5-carboxylic acid compound of formula II and frovatriptan compound of formula III.

The solution of crude frovatriptan may be obtained by resolving racemic 2, 3, 4. 9 - tetrahydro -3- (methylamino) -1H - carbazole - 6 - carboxamide with (1S) - (+) - 10-camphorsulphonic acid in an organic solvent, water or a mixture of water and organic solvents.
The example of organic solvent may include alcohols, halogenated hydrocarbons, ethers, ketones or alkyl acetates.
The example of alcohols may include methanol, ethanol, n-propanol. isopropanol, n-butanol or isobutanol.
The example of halogenated hydrocarbons may include methylene dichloride. ethylene dichloride. chloroform, carbon tetrachloride or mixture (s) thereof.

The example of ether solvents may include diethyl ether, diisopropyl ether, dipropyl ether, methyl tertiary butyl ether, dibutyl ether, methyl isobutyl ether, tetrahydrofuran, 2-methyl-tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane or mixture (s) thereof.
The example of ketone solvents may include acetone, methyl isobutyl ketone, 2-butanone or mixture(s) thereof.
The example of alkyl acetate solvents may include methyl acetate, ethyl acetate, propyl acetate, n-butyl acetate or isobutyl acetate.
A solution of crude racemic 2, 3, 4, 9 - tetrahydro -3-(methyl amino) -1H- carbazole- 6-carboxamide may consist of following compounds of formula IV and V.

Wherein P1 is the nitrogen protecting group.
A solution of crude racemic 2. 3, 4, 9-tetrahydro- 3 - (methylamino) -1H- carbazole- 6-carboxamide may be obtained by following the prior-art methods such as those described in U.S. Patent nos. 5,616,603; 6,359,146 and PCT Publication No. 2010/122343.

EXAMPLE:
In the following example, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.
A feed solution containing a racemic mixture of frovatriptan was prepared by dissolving the racemic frovatriptan (106gm) in a mobile phase mixture consisting of 85% methylene dichloride (technical grade) and 15% t-butyl alcohol (HPLC grade) and 0.1% acetic acid (all by volume) to achieve a frovatriptan concentration of 34.2 g/L for a total feed mixture volume of 3.1 L. The feed solution was fed into a simulated moving bed (SMB) unit equipped with eight columns in four groups of two columns each, each column having an interna! diameter of 4.6mm and a length of 10cm and packed with CH1RALP AK™ AD (20 urn). The mobile phase mixture identified above was used as the eluent in the SMB unit, the flow rates 3.39 mL/min of eluent, 0.15 mL/min of feed, and the withdrawal rates were 0.46 mL/min of extract (R-frovatriptan) and 1.25 mL/min of raffinate (S-frovatriptan). The zone I flow rate, i.e., the flow rate in the zone between the removal of the extract and the introduction of the eluent, was 5.2 mL/min. The unit was operated with a column switching period of 0.8 min, and at a temperature of 25°C. Both the extract and the raffinate were concentrated by evaporation on rotary evaporators at a pressure of 100 mbar and a temperature of 40° C. After allowing the extract and raffinate to stand for at least 24 hours, the extract and raffinate were then separately analyzed for purity by HPLC. The analysis determined that the enantiomeric purity of the R-enantiomer in the extract was 99%. and the enantiomeric purity of the S- enantiomer in the raffinate was 98%. Yield:
R-Frovatriptan: 40 gm (Chemical Purity: 99.96%) w/w) S-Frovatriptan: 42gm (Chemical Purity: 99.98% w/vv)

WE CLAIM:
1. A process of purifying frovatriptan and its pharmaceutically acceptable salts thereof by using simulated moving bed technology (SMB).
2. A process for the isolation of substantially pure frovatriptan and its pharmaceutically acceptable salts thereof by feeding crude reaction mixture comprising frovatriptan and its pharmaceutically acceptable salts thereof and the by-products of the reaction into a simulated moving bed (SMB) unit.
3. A process of preparing frovatriptan and its pharmaceutically acceptable salts thereof comprising the steps of:
a. providing a solution of crude frovatriptan,
b. isolating substantially pure frovatriptan by the application of simulated moving bed
technology and
c. optionally converting substantially pure frovatriptan into pharmaceutically acceptable
salts of frovatriptan.
4. A process of preparing frovatriptan and its pharmaceutically acceptable salts thereof
comprising the step of:
a. isolating R-(+)-3-methylamino-6-carboxamido-l,2,3,4-tetrahydrocarbazole from a
racemic mixture of 2,3,4,9-tetrahydro-3(methylamino)-1H-carbazole'6-carboxamide by
the application of simulated moving bed technology and
b. converting R-(+)-3-methylarnino-6-carboxarnido-l, 2, 3, 4-tetrahydrocarbazole into its
pharmaceutically acceptable salts.
5. A process of preparing substantially pure 2, 3. 4, 9-tetrahydro-3-(methylamino)-lH-
carbazoie-6-carboxamide comprising the steps of:
a. providing the solution of crude 2, 3, 4, 9-tetrahydro -3- (methylamino) -1H -carbazole-6-carboxamide and

c. isolating substantially pure 2, 3. 4, 9-tetrahydro-3-(methylamino)-lH-carbazole-6-carboxamide by the application of simulated moving bed technology.
6. The process according to claim no, 2, wherein the by-products of the reaction is selected from the group comprising of indoie-5-carboxyiic acid compound of formula II.

7. The process according to claim no. 3 wherein the solution of crude frovatriptan is obtained by resolving racemic 2, 3, 4, 9 - tetrahydro - 3- (methylamino) -1H - carbazole - 6 - carboxamide with (1S) - (+) - 10-camphorsulphonic acid in an organic solvent, water or a mixture of water and organic solvents.
8. The process according to claim no. 7 wherein organic solvent is selected from the group comprising of alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or isobutanol; halogenated hydrocarbons such as methylene dichloride, ethylene dichloride, chloroform, carbon tetrachloride or mixture (s) thereof; ethers such as diethyl ether, diisopropyl ether, dipropyl ether, methyl tertiary butyl ether, dibutyl ether, methyl isobutyl ether, tetrahydrofuran, 2-methyl-tetrahydrofuran. 1, 4-dioxane. 1, 2-dimethoxyethane or mixture (s) thereof; ketones such as acetone, methyl isobutyl ketone, 2-butanone or mixture(s) thereof or alkyl acetates such as methyl acetate, ethyl acetate, propyl acetate, n-butyl acetate or isobutyl acetate.
9. The process according to claim no 2 and 3 wherein substantially pure frovatriptan and its pharmaceutically acceptable salts thereof contain less than 0.15 % w/w of indole-5-carboxylic acid compound of formula II.


10. The process according to claim no 1, 2, 3, 4 and 9 wherein pharmaceutically acceptable salt of frovatriptan is Frovatriptan succinate.