FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE 2003
(SECTION 10 and rule 13)
PROVISIONAL SPECIFICATION
"A NOVEL PROCESS FOR THE PREPARATION OF RIZATRIPTAN AND
INTERMEDIATES THEREOF


Glenmark Generics Limited an Indian Company, registered under the Indian company's Act 1957 and having its
registered office at
Glenmark House,
HDO - Corporate Bldg, Wing-A,
B.D. Sawant Marg, Chakala, Andheri (East), Mumbai - 400 099

THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION


FIELD OF THE INVENTION
The present invention generally relates to a process for the preparation of Rizatriptan and its intermediates.
BACKGROUND OF THE INVENTION
Rizatriptan has the chemical name N,N-dimethyl-5-(lH-l,2,4-triazol-l-ylmethyl)-lH-indole-3-ethanamine and is represented structurally by Formula I.

Formula I
Rizatriptan is a selective 5-hydroxytryptamine IB/ID (5-HTIB/ID) receptor agonist and is of particular use in the treatment of migraine and associated conditions. Products containing rizatriptan monobenzoate as the active ingredient are commercially available under the trademarks MAXALT and MAXALT-MLT.
U.S. Patent Nos. 5,298,520 and 5,602,162 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 an aldehyde. Rizatriptan and its benzoate salt are described in the prior art as depicted in Schemes 1 and 2 below. In brief, rizatriptan base can be obtained starting from l-(4-hydrazinophenyl)methyl-l,2,4-triazole dihydrochloride of Formula 111 by reacting it with 4-N,N-dimethylaminobutanal dimethylacetal in the presence of sulphuric acid as given in Scheme 1, or by reacting with 4-chlorobutanal dimethylacetal in
2

Scheme 1

the 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 2.

Scheme 2
The prior art process involved fisher indole cyclization at higher temperature which results in formation of dimeric impurity of formula II and requirement of tedious column chromatography to isolate desired product. Also use of hazardous reagents like sodium hydride & NaCNBH3 makes process commercially unviable.
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Formula II
U.S.Pat.No. 5,567,819 discloses preparation of l-(4-hydrazinophenyIphenyl)methyI-1,2,4-triazole hydrochloride which comprises reacting 4-amino-l,2,4-triazole with nitrobenzene derivative containing a readily displaceable group. This process can reduce the unwanted regioisomer of l,2,4-triazole-4-yl, however the end product has been required to be isolated by column chromatography.
U. S. Pat. No. 5,567,824 discloses different route by employing palladium catalyzed coupling ring closure of 3-iodine-4-aminobenzyltriazole with a protected butynol derivative to corresponding tryptophol followed by conversion of hydroxyethyl moiety to dimethylaminomethyl moiety, with overall yield of 30%. However, benzoate salt gave only 95% quality product, which is not acceptable for pharmaceutical formulations. Therefore the quality of product and use of costly palladium catalyst, toxic reagents such as iodine chloride and flammable reagents such as n-butyl lithium makes process commercially unviable.
WO 200414877 describes the synthesis of rizatriptan by preparation of diazonium salt followed by reduction of aniline hydrochloride. The hydrazine hydrochloride is reacted with a-keto-8-valerolactone to get hydrazone. Hydrazone derivative on fisher indole cyclization to give pyranoindolone which on hydrolysis and esterification gives hydroxyl ester tryptan. Conversion of hydroxyl group into dimethylamino gives indolecarboxylate. Indolecarboxylate on saponification followed by decarboxylation give rizatriptan. However, lengthy process with overall low yield makes process tedious.
In all the above discussed prior art processes there are significant draw backs with yield, quality and cost effectiveness
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1. Formation of polymeric impurities
. 2. Column chromatography or other conventional techniques to remove
polymeric impurities and undesired regioisomers
3. Use of toxic, hazardous and costly reagents like Palladium, Butyl lithium,
sodium hydride and iodine chloride
The present invention, which has not been reported previously, presents a solution for the preparation of rizatriptan, by providing an advantageous route that avoids the use of costly and hazardous chemicals.
SUMMARY OF THE INVENTION
In accordance with a first embodiment of the present invention a process for the preparation of N,N-dimethyl-5-( 1H-1,2,4-triazol-1 -ylmethyl)-1 H-indole-3-ethanamine of the formula (I) or a salt thereof, comprises:


-CH3

0)

reacting an indole derivative of formula II or a salt thereof

wherein X represents halogen, with 1,2,4-triazole.
In accordance with a second embodiment of the present invention A compound of formula (II)
(II)

5


-CH,

wherein X represents halogen.

In accordance with a third embodiment of the present invention a process for the preparation of an indole derivative of formula II,or a salt thereof:
-CH,
. H . (II)
wherein X represents halogen; the process comprising reacting N,N-dimethyl-2-(5-methyl-1 H-indole-3-yl) ethanamine of formula III or a salt thereof

-CH,
H,C
H (in)
with a halogenating agent in a halogenated hydrocarbon solvent.
In accordance with a fourth embodiment of the present invention a process for the preparation of N,N-dimethyl-5-( 1H-1,2,4-triazol-1 -ylmethyl)-1 H-indole-3 -ethanamine of the formula (I) or a salt thereof:

the process comprising;
i) reacting N,N-dimethyl-2-(5-methyl-lH-indole-3-yl) ethanamine of formula III or a salt thereof
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(III)
with a brominating agent in a halogenated hydrocarbon solvent;
ii) reacting the resulting 2-[5-(bromomethyl)-lH-indole-3-yl)]-N,N-dimethyl ethanamine with 1,2,4-triazole in presence of a base and an organic solvent.
In accordance with a fifth embodiment of the present invention a process for the preparation of rizatriptan benzoate having relatively high purity, e.g. greater than about 99.5%, with dimerie impurity less than 0.1% no use of chromatographic separation. Said process comprising;
(i) Fisher indole cyclization of (4-methylphenyl)hydrazine with 4,4-diethoxy-N,N-dimethylbutan-l-amine in presence of 4% aqueous sulfuric acid to get N,N-dimethyl-2-(5-methyl-lH-indole-3-yl)ethanamine (ii) Benzylic bromination of N,N-dimethyl-2-(5 -methyl- lH-indole-3-yl)ethanamine
to get2-[5-(bromomethyl)-lH-indole-3-yl)]-N.N-dimethylethanamine
(iii) Condensation of 2-[5-(bromomethyl)-lH-indole-3-yl)]-N.N-
dimethylethanamine with 1,2,4-triazole in presence of potassium carbonate to get rizatriptan base (iv) Purification of rizatriptan with a mixture of solvents to get Rizatriptan with
purity 99.0 % and dimerie impurity less than 0.15% (v) Salt formation of pure rizatriptan with benzoic acid to get Rizatriptan benzoate with purity 99.0% and dimerie impurity less than 0.15%
In accordance with a sixth embodiment of the present invention rizatriptan or a salt thereof substantially free of phenyl hydrazine derivative of formula (IV).

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DETAILED DESCRIPTION OF THE INVENTION
In one embodiment of the present invention provides a process for the preparation of N,N-dimethyl-5-(lH-l,2,4-triazol-l-ylmethyl)-lH-indole-3-ethanamine (Rizatriptan) of the formula [I] or a salt thereof,

the process comprising, reacting a compound of the formula [II]

wherein X is a halogen,
with a 1,2,4-triazole, in the presence of a suitable base.



Rizatriptan
The reaction can be conveniently carried out by mixing the reactants, optionally in a reaction inert solvent such as, for example, water; an aromatic solvent, e.g. benzene, methylbenzene, dimethyl benzene, chlordbenzene, methoxybenzene, and the like; a CI-6 alkanol, e.g. methanol, ethanol, 1-butanol, and the like; a ketone, e.g. 2-propanone, 4-methyl-2-pentanone, and the like; an e.g. ethyl acetate, y-butyrolactone and the like; an ether,


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e.g. l,l'-oxybisethane, tetrahydrofuran, l,4-dioaxane,and the like; a dipolar aprotic solvent, e.g. N,N-dimethylformafnide, N,N-dimethylacetamide, dimethylsulfoxide, pyridine, 1,3-dimethyl-3,4,5,6-tetrahydro-2(l H)-pyrimidihone, 1,3-dimethyl-2-imidazoldinone, nitrobenzene, acetonitrile and the like;, or a mixture of such solvents.
The suitable base such as, for example, an alkali metal or an earth alkaline metal carbonate, hydrogen carbonate, hydroxide, oxide, carboxylate, alkoxide, hydride or amide, e.g. sodium carbonate, potassium carbonate, sodium hydroxide, calcium oxide, sodium acetate, sodium methoxide, sodium hydride, sodium amide and the like, or an organic base such as, for example, a. tertiary amine, e.g. N,N-diethylethanamine, N-(l-methylethyl)-2-propanamine, 4-ethylmorpholine, 1,4-diazabicyclo[2,2,2]octane, pyridine and the like.
The compound of Formula II is novel, and can be synthesized by Benzylic halogenation of the compound of Formula III.

In one embodiment the compound of Formula III is treated with N-bromosuccinamide to get compound of Formula Ila, wherein X is Br.


The halogenation reaction can be carried out, optionally, in a suitable reaction inert solvent such as, for example, an aromatic solvent, e.g. benzene, methylbenzene, dimethylbenzene, chlorobenzene, methoxybenzene, and the like; a CI-6 alkanol, e.g. methanol, ethanol, 1-butanol, and the like; a ketone, e.g. 2-propanone, 4-methyl-2-pentanone, and the like; an ester, e.g. ethyl acetate, y-butyrolactone and the like; an ether, e.g. l,l'-oxybisethane, tetrahydrofuran, 1,4-dioaxane, and the like; a dipolar aprotic solvent, e.g. N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, pyridine, 1,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone, l,3-dimethyl-2-imidazoldinone, nitrobenzene, acetonitrile and the like; or a mixture of such solvents.
The compound of Formula III can be prepared by the process which is disclosed in Cheng-yi chenl, J. Org. Chem. 1994, 59, 3738., incorporated herein by reference.
In another embodiment the present invention provides an intermediate of Formula [II], and process for preparation thereof
H3C


Formula [II]
wherein X is a halogen, comprising:
a) Fisher indole cyclization of (4-methylphenyl)hydrazine with 4,4-diethoxy-N,N-
dimethylbutan-1-amine in presence of acid to get N,N-dimethyl-2-(5-methyl-lH-
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indole-3-yl)ethanamine


(b) Benzylic Haiogenation of N,N-dimethyl-2-(5-methyl-lH-indole-3-yl)ethanamine, using suitable halogenating reagent to get 2-[5-(halomethyl)-lH-indole-3-yl)]-N.N-dimethylethanamine

Advantageously, the acid used in above step (a) is dilute hydrochloric acid or dilute sulphuric acid, e.g. 4% aqueous sulphuric acid.
The halogenating reagent used in step (b) above may be selected from 1,3-dibromo-5,5-dimethylhydantoin, halogen, n-halo phthalimide, HX/H2O2 mixture and N-bromo succinamide The haiogenation reaction can be carried out, optionally, in a suitable reaction inert solvent such as, for example, an aromatic solvent, e.g. benzene, methylbenzene, dimethylbenzene, chlorobenzene, methoxybenzene, and the like; a CI-6 alkanol, e.g. methanol, ethanol, 1-butanol, and the like; a ketone, e.g. 2-propanbne, 4-methyl-2-pentanone, and the like; an ester, e.g. ethyl acetate, y-butyrolactone and the like; an ether, e.g. l,l'-oxybisethane, tetrahydrofuran, 1,4-dioaxane, and the like; a dipolar aprotic solvent, e.g. N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, pyridine, 1,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone, 1,3-dimethyl-2-imidazoldinone, nitrobenzene, acetonitrile and the like; or a mixture of such solvents.
In another embodiment the present invention provides a novel process for the preparation of N,N-dimethyl-5-(lH-l,2,4-triazol-l-ylmethyl)-lH-indole-3-ethanamine, comprising:
a) Fisher indole cyclization of (4-methylphenyl)hydrazine with 4,4-diethoxy-N,N-dimethylbutan-1-amine in presence of 4% aqueous sulfuric acid to get N,N-dimethyl-2-(5-methyl-1 H-indole-3-yl)ethanamine
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(b) Benzylic Halogenation of N,N-dimethyl-2-(5-methyl-lH-indole-3-yl)ethanamine, using suitable halogenating reagent . to get 2-[5-(halomethyl)-lH-indole-3-yl)]-N.N-dimethylethanamine

(c) Condensation of 2-[5-(halomethyl)-lH-indole-3-yl)]-N.N-dimethylethanamine with 1,2,4-triazole in presence of a suitable base to get rizatriptan base

The suitable base for step C , for example, an alkali metal or an earth alkaline metal carbonate, hydrogen carbonate, hydroxide, oxide, carboxylate, alkoxide, hydride or amide, e.g. sodium carbonate, potassium carbonate, sodium hydroxide, calcium oxide, sodium acetate, sodium methoxide, sodium hydride, sodium amide and the like, or an organic base such as, for example, a tertiary amine, e.g. N,N-diethylathanamine, N-(l-methylethyl)-2-propanamine, 4-ethylmorpholine, l,4-diazabicyclo[2,2,2]octane, pyridine and the like may be used.
In another embodiment of the present invention provides Rizatriptan or a salt thereof substantially free of phenyl hydrazine derivative of formula (IV).
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Rizatriptan prepared by the present invention can be converted into its pharmaceutically acceptable salts such as benzoate, oxalate with purity greater than 99%.
In one embodiment the present invention provides a process for the preparation of rizatriptan benzoate having high purity, e.g. greater than about 99.5%, with dimeric impurity less than 0.1%, without use of chromatographic separation technique, comprising:
(a) Fisher indole cyclization of (4-methylphenyl)hydrazine with 4,4-diethoxy-N,N-dimethylbutan-1-amine in presence of 4% aqueous sulfuric acid to get N,N-dimethyl-2-(5 -methyl-1 H-indole-3 -yl)ethanamine
(b) Benzylic bromination of N,N-dimethyl-2-(5-methyl-lH-indole-3-yl)ethanamine to get 2-[5-(bromomethyl)-lH-indole-3-yl)]-N.N-dimethylethanamine
(c) Condensation of 2-[5-(bromomethyl)-lH-indole-3-yl)]-N.N-dimethylethanamine with 1,2,4-triazole in presence of potassium carbonate to get rizatriptan base
(d) Optional purification of rizatriptan base with a mixture of solvents to get Rizatriptan with purity 99.0 % and dimeric impurity less than 0.15%
(e) Salt formation of pure rizatriptan with benzoic acid to get Rizatriptan benzoate with purity 99.0% and above, and with dimeric impurity less than 0.15%.
The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features.
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EXAMPLE 1
Preparation of N,N-dimethyl-2-(5-methyl-lH-indoIe-3-yl)ethanamine:
Into a clean round bottom flask 100 gm (4-methylphenyl)hydrazine and 186 gm 4,4-diethoxyl-N,N-dimethylbutan-l-amine in 5.0 liter of 4% sulphuric acid was charged. The reaction mass was heated to 58-62°C and stirred for 2 hours to complete the cyclization. The reaction mass was cooled to 0-5°C and added 25gm hyflo powder. The pH of reaction mass was adjusted to 9.5-10.0 using liquor ammonia (1.0 lit) maintaining the temperature at 0-5°C. The reaction mass was filtered over hyflo bed and the filtrate was extracted with ethyl acetate (3x500ml). The organic layer was washed with water (750ml), and distilled out under vacuum at 40°C to obtain N,N-dimethyl-2-(5-methyl-lH-indole-3-yl)ethanamine (85gm) as solid.
EXAMPLE 2 Bromination of N,N-dimethyI-2-(5-imethyl-lH-indole-3-yl)ethanamine :
Into a clean round bottom flask, charge a solution of 80.0 gm N,N-dimethyl-2-(5-tmethyl-lH-indole-3-yl)ethanamine in 400ml of carbon tetrachloride, heat the reaction mass to 78-80°C and add 70.39 gm of recrystallized N-bromosuccinamide & 0.8 gm benzoyl peroxide. Reflux the reaction mass for about four hours, cool and filter, concentrate the filtrate to get oily mass of 2-[5-(bromomethyl)-lH-indole-3-yl)]-N,N-dimethylethanamine
EXAMPLE 3 Condensation of 2-[5-(bromomethyl)-lH-indole-3-yl)]-N,N-dimethylethanamine with 1,2,4-Triazole:
Into a clean round bottom flask, charge 75 gm of 2-[5-(bromomethyl)-lH-indole-3-yl)]-N,N-dimethylethanamine & 23.9 gm of 1,2,4-Triazole in 450 ml of acetone. Cool the reaction mass to 0-5°C under stirring, add 73.6 gm of potassium carbonate to the reaction mass in six equal lots. Stir the reaction mass for about 2-hours. Add 450 ml of ethyl acetate & water to reaction mass & separate the layers. Wash the organic layer with water, dry over sodium sulfate and concentrate. Add 75 ml of ethyl acetate: hexane mixture (1:1) and stirr at room
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temperature for about one hour, filter the solid, and wash it with 37.5 ml of ethyl acetate: hexane mixture (1:1).
EXAMPLE 4 Purification of rizatriptan:
Into a clean 100ml round bottom flask, 150ml mixture of ethyl acetate+acetone (7:3) was charged and 50.0gm of rizatriptan base was added. The reaction mass was heated to 60-65°C under stirring to get clear solution and cooled to room temperature under stirring. The solid was filtered and washed with 50ml of ethyl acetate. Yield = 45.0gm HPLC purity: NLT 98.5%
EXAMPLE 5
Preparation of rizatriptan benzdate:
In a clean four neck 250ml R.B flask, 50.0gm rizatriptan and 150 ml of acetone was charged under nitrogen atmosphere and the reaction mass was stirred at 25°C-30°C for 15 minutes. A solution of benzoic acid (25gm) in 100ml acetone was added to the reaction mass and stirred at 25-30°C for one hour. The solid obtained was filtered and washed with 100ml of acetone and dried at 40-45°C in vacuum oven. Yield= 70.0gm.
HPLC purity: >99 %
EXAMPLE 6
Recrystallization of rizatriptan benzoate:
In a clean four neck R.B flask, 560ml of ethanol was charged and heated to 70-75°C, added 70.Og of crude Rizatriptan benzoate. The reaction mass was heated to reflux (75-80°C) to get a clear solution and 3.5 g of activated charcoal was added to the reaction mass and stirred for 30 minutes. The reaction mass was filtered over hyflo bed and the bed was washed with 70.0ml hot ethanol (70-75°C). The filtrate was transferred to clean flask and cooled to room temperature under stirring (solid comes out). The reaction mass was stirred at room temperature for one hour. The solid obtained was filtered and washed with 140ml chilled
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ethanol (0-5°C) and dried at 40-45°C in vacuum oven to get pure rizatriptan benzoate. Yield=56gm.
HPLC purity: >99%
IR(KBr):3120.9,3024.1,2917.0,2341.9,1608.3,1569.8,1505.5,1458.2,1432.5,1376.2,1338.4,1 294.7,1270.9,1204.4,1139.8,1064.1,1016.3,973.9,959.9,944.3,888.6,853.1,836.2,772.5,754.7, 746.6,681.9,673.9,651.6,632.6,606.2,575.3,527.1 and470.2 cm"1
DSC: Integral:-346.80 Mj Onsets : 180.9°C
Peak : 181.3 °C Endset : 184.5°C
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Features and advantages of the Invention:
A. A process for the preparation of N,N-dimethyl-5-(lH-l,2,4-triazol-l-ylmethyl)-lH-indole-3-ethanamine (Rizatriptan) of the formula (I) or a salt thereof:

(I) -CH,

the process comprising; reacting an indole derivative of formula II or a salt thereof

(ID -CH-,
wherein X represents halogen, with 1,2,4-triazole.
B. The process as defined in 'A' above, wherein the X is bromine.

C. The process as defined in 'A' above, wherein the reaction is carried out in presence of
base.
D. The process as defined in 'A' above, wherein the reaction is carried out in presence of
an organic solvent or in neat condition.
E. The process as defined in 'A' above, wherein the reaction is carried out in presence of
base and an organic solvent.
F. A process for the preparation of an indole derivative of formula II or a salt thereof:

N-—CH3
H , ' (II)
wherein X represents halogen; the process comprising reacting N,N-dimethyl-2-(5-methyl-1 H-indole-3-yl) ethanamine of formula III or a salt thereof

17


with a halogenating agent.

G. The process as defined in 'F' above, wherein the X is bromine; H. A compound of formula (II)

-CH-,
wherein X represents halogen.
I. The compound as defined in 'H' above, wherein the X is bromine.
J. A process for the preparation of N,N-dimethyl-5-(lH-l,2,4-triazol-l-ylmethyl)-lH-
indole-3-ethanamine (Rizatriptan) of the formula (I) or a salt thereof:

(I)
-cm
the process comprising;

i) reacting N,N-dimethyl-2-(5-methyl-lH-indole-3-yl) ethanamine of formula III or a salt thereof
N—-CH3
H (III)
with a brominating agent in a halogenated hydrocarbon solvent;

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ii) reacting the resulting 2[5-(bromorhethyl)-lH-indole-3-yl)]-N.N-dimethyl ethanamine with 1,2,4-triazole in presence of a base and an organic solvent.
K. Rizatriptan or a salt thereof substantially free of phenyl hydrazine derivative of formula (IV).

Dated this Thirteenth (13th) day of June, 2008

(Signed).
DR. MADHAVI KARNIK
DY GENERAL MANAGER - IPM
Glenmark Generics Limited
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