FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
PROVISIONAL SPECIFICATION
(See section 10]
1. Title of the invention: "An improved process for Rizatriptan and its pharmaceutically accepted salts"
2. Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road, Andheri (East), Mumbai - 400 059, Maharashta, India.

INTRODUCTION TO THE INVENTION:
The present invention relates to an improved process for the preparation of rizatriptan and its pharmaceutically acceptable salts. More particularly, the invention relates to an improved process that provides rizatriptan with a high degree of consistency in purity and yield.
Rizatriptan base has the chemical name N, N-dimethyl - 2-[5 -(1,2, 4-triazol-l- yl -methyl)-lH - indoI-3-yl) ethanamine and is represented structurally by Formula-l

Formula-1 Rizatriptan is a selective serotonin 5-hydroxy tryptamine (5-HT IB/ID) receptor agonist and is currently marketed, as the benzoate salt, for the acute treatment of migraine and associated conditions. Products containing rizatriptan benzoate, as the active ingredient are commercially available under the trademark MAXALT and MAXALT-MLT.
Various patents describe processes for the preparation of rizatriptan base. U.S.Patent Nos 5298520 and 5602162 describe derivatives of imidazole, triazole and tetrazole,

including rizatriptan and the synthesis and purification of such compounds and their salts, pharmaceutical compositions containing them and their use. These patents describe the preparation of rizatriptan by Fischer indole synthesis, using the corresponding phenylhydrazine and a protected aldehyde. Rizatriptan and rizatriptan benzoate are prepared as depicted in Scheme-1 and Scheme-2 below. Accordingly, 4-(lH-l, 2, 4-triazole-l-yl methyl) phenylhydrazine dihydrochloride of Formula-Ill was reacted with 4-dimetylamino butyraldehyde diethyl acetal in the presence of sulphuric acid as given in Scheme-I, or is reacted with 4-chlorobutanol dimethyl acetal in presence of hydrochloric acid, followed by reaction of the ethylamine derivative of Formula-IV with sodium cyanoborohydride in the presence of formaldehyde and acetic acid, as depicted in Scheme-I I



SCHEME-II
However, both these methods demonstrate poor yields and the purity of the product is also low.
PCT Publication No. WO 94/02476 aiso describes the preparation of the intermediate l-(4-hydrazinophenyI) methyl-1 yl-1, 2, 4-trizole of Formula-V

Conversion of this intermediate into rizatriptan is carried out by Fisher indole synthesis in the same way as in the above discussed patents.

The processes indicated in Scheme-I and Scheme-]] involve the Fisher indole reaction wherein an acid catalyst is involved. The indole derivative is susceptible to degradation in the presence of acidic species which results in the formation of many impurities one of them being dimer impurity 3-[2-(N, N - dimethylamino) ethyl -[[3-[2-(N, N - dimethylamino) ethyl] - 1H- indol-5-yl] methyl] - 1H- indol-5-yl] methyl - 1H - 1, 2, 4-triazole, having structural Formula-II. It demands repeated purifications to bring the levels of this dimer impurity and other unknown impurities to the desired level, stipulated by regulatory authorities. Thus, process will be commercially non-viable.

Formula-II There remains a need for a simple, efficient and consistent process for the manufacture of rizatriptan substantially free from dimer as well as any unknown impurities. The present invention removes impurities by adsorbing the impurities on adsorbent such as alumina and provides the cost effective process to prepare rizatriptan.

SUMMARY OF THE INVENTION
In an aspect, the invention provides a process for preparing rizatriptan comprising.
Reacting 4-QH-l, 2, 4-triazole-l-yl methyl) phenyl hydrazine
dihydrochloride with 4-dimethylamino butyraldehyde diethyl acetal in the
presence of sulphuric acid and hydrochloric acid to from crude rizatriptan
base.
Adsorbing crude rizatriptan base on to neutral alumina and eluting rizatriptan
base from the alumina with solvents.
Reacting purified rizatriptan base with benzoic acid to form rizatriptan
benzoate and recrystallizing rizatriptan benzoate from solvent.
In an embodiment of the invention rizatriptan is eluted from alumina using a
solvent comprising of polar and non polar solvents such as aliphatic
hydrocarbon, polar solvents includes alcohols, esters, ketone such as
methanol, ethyl acetate, acetone, and non polar solvents includes hexane,
toluene, cyclohexane.
DETAILED DESCRIPTION
The present invention relates to rizatriptan substantially free from dimer as well as
any unknown impurities. The invention provides a process which allows the
preparation of rizatriptan of high purity free from dimer and other related impurities.
In an embodiment, the invention provides a method of synthesizing rizatriptan of
high purity comprises of the following steps:

Reacting 4-(IH-l, 2, 4-triazole-l-yl methyl) phenyl hydrazine
dihydrochloride with 4-dimethylamino butyraldehyde diethyl acetal in the
presence of sulphuric acid and hydrochloric acid to from crude rizatriptan
base.
Adsorbing crude rizatriptan base on to neutral alumina and eluting purified
rizatriptan base from the alumina with solvents.
Reacting purified rizatriptan base with benzoic acid to form rizatriptan
benzoate and recrystallizing rizatriptan benzoate from solvent.
In an embodiment of the invention rizatriptan is eluted from alumina using a
solvent comprising of polar and non polar solvents such as aliphatic
hydrocarbon, polar solvents includes alcohols, esters, ketones such as
methanol, ethyl acetate, acetone, and non polar solvents includes hexane,
toluene, cyclohexane.
An embodiment of a process for the preparation of rizatriptan benzoate is described
in Scheme-111

SCHEME:

Scheme - III
Step a) involves reacting 4-(lH-l, 2, 4-triazole-l-yl methyl) phenyl hydrazine
dihydrochloride with 4-dimethyIamino butyraldehyde diethyl acetal in the presence
of sulphuric acid and hydrochloric acid to from crude rizatriptan base.
The reaction is carried out at 85 - 90°C, neutralized using liquor ammonia and then
made basic using aqueous sodium hydroxide to pH 9.5 - 10.
Extraction is done using methylene chloride.

The compound is then adsorbed on neutral alumina, quantity is in the range of 3-4
volumes based on starting material 4-(lH-l, 2, 4-triazole-l-yl methyl) phenyl
hydrazine dihydrochloride. This is charged to 4 volumes of neutral alumina and
eluted with organic solvents. The elution solvent is a mixture of ethyl acetate and
hexanes or methanol and cyclohexane or ethyl acetate and toluene, most preferably
ethyl acetate and hexane in the ratio of 1:0.1 to 1:1 and most preferably 1:1.
The elution volume is 2 volumes, first elution volume contains impurities, second
and third elution volumes contains product.
The elutes are combined and then concentrated under vacuum at 55 - 60°C.
The residue is dissolved in ethanol and benzoic acid is added to make Rizatriptan
benzoate.
Example-I
Preparation of 2-f5-f(lH-l. 2, 4-triazol-l-vn methvn-lH-indol-3-vl)-N. N-
dimethyl ethanamtne benzoate:
A solution of 250 gm of 4-(lH-l, 2,4-triazole-l-yl methy])phenyl hydrazine
dihydrochloride in 10 volume of water was added to a mixture of 1.5 volume of
cone, hydrochloric acid, catalytic amount of cone, sulfuric acid and 1.0 vol of 4-
dimethylamino butyraldehyde diethyl acetal and the reaction mixture was heated to
85 - 90°C and maintained for 30 min. The solution was cooled using ice bath and the
pH adjusted to neutral with aqueous ammonia solution. pH was further adjusted to
9.5 to 10 with 20% sodium hydroxide solution at 10 - 15°C and product was

extracted with methylene chloride and then adsorbed on neutral alumina. Mixture of ethyl acetate and hexane (1:1) was used as eluent and solvents was distilled under vacuum and degassed for 30min at 55 - 60°C. Above residue was dissolved in 6 vol. of ethanol and 52.5 gm of benzoic acid was added at 40°C and reaction mass stirred for 6 hrs. The precipitated product was filtered through buckner funnel, washed with chilled ethanol and suck dried for 30min. Product was dried in a try drier at 65 to 70°Cfor3hr. Yield-100 gm.

We claim:
I. A process for preparing Rizatriptan base free from impurity comprising of:
a. Reacting 4-(1 H- J, 2, 4-Triazole-1 -y] methyl) phenyl hydrazine
dihydrochloride with 4-dimetylamino butyraldehyde diethyl acetal in presence
mixture of hydrochloric acid and sulphuric acid to form rizatriptan base.
b. Adsorbing the Rizatriptan base on neutral alumina.
c. Eluting the compound using mixture of solvents such as polar and non polar
solvents.
2. The process as claimed in claim 1, where in polar solvents are methanol, ethyl acetate, acetone and non polar solvents are hexane, cyclohexane, toluene.
3. The process as claimed in claim 1 and 2. solvents are ethyl acetate and hexane