Form 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULE 2003
PROVISIONAL SPECIFICATION
[See section 10 and rule 13]

1. TITLE OF THE INVENTION
"Process for preparation of Rizatriptan benzoate"
2. APPLICANT
(a) NAME: USV LIMITED
(b) NATIONALITY: Indian Company incorporated under the Companies ACT 1956
(c) ADDRESS: B.S.D. Marg, Govandi, Mumbai 400 088, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.

Technical field:
The present invention relates to an improved process for the preparation of N,N-
dimethyl-5-(l H-1,2,4-triazol-1 -ylmethyl)-1 H-Indole-3-Cthanamine monobenzoate
(Rizatriptan benzoate). The present invention further relates to an isolated impurity of Rizatriptan, Rizatriptan methyl chloride, its preparation and its use as a reference standard.
Background of invention:
Rizatriptan benzoate is described chemically as N,N-dimethyl-5-(lH-l,2,4-triazol-l-ylmethyl)-lH-Indole-3-ethanamine monobenzoate and its structural formula is ;

(I) Rizatriptan and its physiologically acceptable salts are useful as 5-HT1B/1D receptor
agonist and is marketed as an oral formulation for acute treatment of migraine.
US 5298520 discloses process for preparation of Rizatriptan benzoate which comprises condensation of 4-nitrobenzyl bromide with 1,2,4-triazole sodium salt to yield l-(4-rutrophenyl)methyl-1,2,4-triazole. The triazole derivative is further hydrogenated using 10% Pd-C to provide l-(4-aminophenyl)methyl-1,2,4-triazole. The obtained amino derivative is further diazotized and treated with stannous chloride to give l-(4-hydrazinophenyl)methyl-1,2,4-triazole hydrochloride. The hydrazine derivative is treated with 4-dimethylaminobutanal dimethylacetal in a mixture of sulphuric acid and water. The Rizatriptan base product is isolated by column chromatography using an eluent mixture comprising dichloromethane : ethanol : amrnonia and then converted to its benzoate salt.
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Isolation of the desired product in this process is very cumbersome and expensive. The product obtained with poor yield (about 11%) and purity of the product is not mentioned.
Another disadvantage of the process is that the product degrades in presence of highly acidic conditions which results in the formation of a closely related dimer derivative of formula (II), about 11%, thus affecting the purity of the product.

(ID
WO2006/053116 discloses preparation of Rizatriptan benzoate by reacting l-(4-hydrazinophenyl) methyl-1,2,4-triazole hydrochloride with 4-dimethyl amino butanal
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dimethylacetal in presence of hydrochloric acid to form Rizatriptan base. The Rizatriptan base is isolated using column chromatography and converted to Rizatriptan benzoate salt. The above prior art processes are involving column chromatography for the isolation of the product. The above process also results in low purity and yields of Rizatriptan benzoate.
WO/2007/054979 discloses preparation of Rizatriptan benzoate by reacting l-(4-hydrazinophenyl) methyl-1,2,4-triazole hydrochloride with 4-dimethylaminobutanal dimethylacetal in presence of hydrochloric acid to form Rizatriptan base. The Rizatriptan base is isolated and converted to Rizatriptan benzoate.
WO2006137083 discloses preparation of Rizatriptan benzoate by reacting l-(4-hydrazino phenyl)methyl-l,2,4-triazole hydrochloride with 4-dimethylaminobutanal dimethylacetal in presence of aqueous sulphuric acid to form Rizatriptan base. The Rizatriptan base is isolated and converted to Rizatriptan benzoate.
There is a need to develop a simple, ecofriendly, robust and commercially viable process for the preparation of Rizatriptan benzoate with minimized impurities and obtaining high yield and purity of Rizatriptan.
Object of the invention:
The main object of the present invention is to provide cost effective, simple, readily scalable to industrial requirements and robust process for preparation of Rizatriptan benzoate in good yield and high purity.
Another object of the present invention provides an isolated Rizatriptan benzoate (I) impurity, Rizatriptan methyl chloride of the formula (VII), method of preparation thereof.
Yet another object of the invention is to provide method of using the isolated methyl chloride Rizatriptan (VII) as a reference standard to analyze the purity of Rizatriptan and analytical method for determining the impurity profile of Rizatriptan.
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Summary of the invention:
The present invention discloses process for preparation of pure N,N-dimethyl-5-(1H-1,2,4-triazol-1 -ylmethyl)-1 H-Indole-3 -ethanamine monobenzoate (Rizatriptan benzoate) of formula (I) in high yield. (Scheme II):

Rizatriptan base 'Rizatriptan benzoate
(I)
According to the present invention, process for the preparation of Rizatriptan benzoate of formula (I) comprises the following steps :
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a) reacting 4-nitrobenzyl bromide (III) with 1,2,4-triazole to yield l-(4-nitrophenyl)methyl- 1,2,4-triazole (IV);.
b) hydrogenating the triazole derivative to provide l-(4-aminophenyl)rnethyl- 1,2,4-triazole (V);
c) diazotizing the amino derivative followed by reduction using reducing agent to give l-(4-hydrazinophenyl)methyl- 1,2,4-triazole hydrochloride (VI);
d) combining the compound l-(4-hydrazinophenyl)methyl-l,2,4-triazole hydrochloride (VI) with 4-dimethylamino-butanal dialkylacetal in methanesulphonic acid.
e) basifying the reaction mixture;
f) decanting the reaction mixture;
g) filtering of the reaction mixture through hyflo bed;
h) extracting the filtrate with organic solvent;
i) concentrating the organic layer to provide the residue;
j) treating the obtained residue with benzoic acid in mixture of aliphatic alcohol and
ethereal solvent to provide Rizatriptan benzoate and k) optionally purifying the compound of the formula (I) by column chromatography
or by recrystallization to obtain compound (I) with purity more than 99.8%.

(I)
According to another aspect, the present invention provides an isolated Rizatriptan methyl chloride of the following structure;
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as well as the preparation thereof.
The present invention also encompasses method for detecting Rizatriptan methyl chloride (VII) in a sample of Rizatriptan benzoate.
The invention also encompasses the use of Rizatriptan methyl chloride (VII) as a reference standard to quantify the amount of impurity in a sample of Rizatriptan benzoate.
The invention also encompasses a quantification method of Rizatriptan methyl chloride (VII) in a Rizatriptan sample.
In a further embodiment, the invention encompasses an analytical method for testing the impurity profile of Rizatriptan or pharmaceutically acceptable salts.
Detail description of the invention:
The present invention describes process for the preparation of Rizatriptan benzoate having purity of more than 95% more preferably more than 99.8%. The present invention further provides process for preparation of Rizatriptan methyl chloride (VII) impurity and its used as a reference standard/ reference marker to analyze the purity of Rizatriptan or its salts.
The process for the preparation of Rizatriptan benzoate of formula (I) according to the present invention comprises following steps :
a) reacting 4-nitrobenzyl bromide (III) with 1,2,4-triazole to yield 1 -(4-nitrophenyl)methyl-1,2,4-triazole (IV);
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b) hydrogenating the triazole derivative (IV) to provide l-(4-
aminophenyl)methyl-l,2,4-triazole hydrochloride (V);

Formula (V) c) diazotizing the amino derivative (V) followed by reduction using reducing agent to give I -(4-hydrazinophenyf)methyf-l ,2,4-triazole hydrochloride (VI);
N.

Formula VI
d) combining the compound 1 -(4-hydrazinophenyl)methyl-1,2,4-triazole hydrochloride of formula (VI) with 4-dimethylamino-butanal dialkylacetal.
e) basifying the reaction mixture;
f) decanting the reaction mixture;
g) filtering of the reaction mixture through hyflo bed;
h) extracting filtrate with organic solvent;
i) concentrating the organic layer to provide the residue;
j) treating the obtained residue with benzoic acid in mixture of aliphatic alcohol and ethereal solvent to provide Rizatriptan benzoate and

k) optionally purifying the compound of the formula (I) by column chromatography or by recrystallization to obtain the compound (I) with purity more than 99.8%.

Formula (I)
According to the invention, Rizatriptan benzoate (I) obtained after purification of step (k) having less than 1% of dimer derivative (II), which can be easily reduced below 0.15% by further purification. According to the present invention all the known impurities are controlled below 0.15% and all unknown impurities are controlled below 0.1% by using process for preparation of Rizatriptan as disclosed herein.
According to preferred embodiment of the present invention, condensation of 4-nitrobenzyl bromide (HI) with 1,2,4-triazole is carried out in presence of base in organic solvent to get 1-(4-nitrophenyl) methyl-1,2,4-triazole (IV) or by condensing 4-nitrobenzyl bromide (III) with alkali metal salts of 1,2,4-triazole in organic solvent. The alkali metal salt of 1,2,4-triazole used in the condensation stage is selected from sodium or potassium salts and the like.
The base used in condensation stage is selected from sodium hydride, lithium hydride or calcium hydride. The organic solvent used is selected from N,N-dimethylformamide or N,N-dimethylacetam ide.
The triazole derivative (TV) is hydrogenated using catalyst selected from noble metals such as Pd, Pt or Raney nickel. This reduction reaction is carried out in a mixture of ethanol, water, ethyl acetate and HC1 to provide l-(4-aminophenyl)methyl-1,2,4-triazole hydrochloride(V). The amino derivative (V) thus obtained is further diazotized by known methods to get the diazonium salt followed by reduction to get l-(4-
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hydrazinophenyl)methyl-l,2,4-triazole hydrochloride (VI). The reduction reagent used for reduction of diazonium salt is selected from stannous chloride or sodium sulphite.
l-(4-hydrazmophenyl)methyl-l32,4-triazole hydrochloride (VI) is then condensed with 4-dimethylamino-butanal dialkyl acetal in a mixture of acid and water at temperature between 50° C to 100° C for about 1 to 6 hr, preferably between 80° C to 90° C for about 4 hr. The reaction mixture is cooled to 15-25° C followed by addition of base at below 25°C. The reaction mixture is filtered and the aqueous layer is extracted with organic solvent. The separated organic layer is concentrated and the obtained reaction mass dissolved in organic solvent followed by addition of benzoic acid dissolved in a mixture of aliphatic alcohol and ethereal solvent (15:85) and stirred for 1 hr at 0-10° C. The obtained solid is further filtered and washed with organic solvent at temperature 60-70°C to get crude Rizatritan benzoate..
The ratio of acid to water is selected from the range of 2 to 10%, preferably 6%. 4-dimethylamino-butanal dialkyl acetal is selected from 4-dimethylamino-butanal dimethyl acetal or 4-dimethylamino-butanal diethyl acetal. The acid is selected from sulphuric acid, methanesulphonic acid, acetic acid or formic acid preferably methanesulphonic acid The base used is selected from the group consists of liquor ammonia, sodium hydroxide, potassium hydroxide, sodium bicarbonate or sodium carbonate, preferably sodium hydroxide. The reaction mixture is basified to pH range of 8 to 11, preferably to pH 10. The organic solvent is selected from ethyl acetate, toluene or methylene dichloride (MDC). The aliphatic alcohol is selected from methanol, ethanol, isopropanol and ethereal solvent is selected from diisopropyl ether, methyltertiarybutylether (MTBE) or diethyl ether preferably diethyl ether.
Rizatriptan benzoate thus obtained is purified by crystallisation method which comprises dissolving crude Rizatriptan benzoate in alcohol at 70-80°C and the mixture is gradually cooled to 10-15° C. The solid obtained is filtered, washed with cold alcohol and dried at 60-70°C to get pure Rizatriptan benzoate having purity of greater than 99%.
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The prior art methods for preparation of Rizatriptan benzoate in presence of highly acidic conditions results in the formation of about 11% of dimer derivative (II). According to the process of the present invention use of methansulphonic acid for condensation of compound (IV) with 4-dimethylamino butanal diethyl acetal, the obtained crude Rizatriptan benzoate which has less than 1% of dimer derivative (II), which can be easily reduced below 0.15% by further purification using solvent crystallization with aliphatic alcohol selected from methanol, ethanol or isopropanol to have a purity of greater than 99%.
According to another embodiment of the present invention, Rizatriptan benzoate is purified by column chromatography method. The stationary phase of the column chromatography is selected from silica gel or alumina preferably silica gel having particle size between 60-120 mesh. The mobile phase of the column chromatography is the mixture of halogenated aliphatic organic solvent-aliphatic alcohol-base. The halogenated aliphatic organic solvent is dichloromethane. The aliphatic alcohol is selected from methanol, ethanol or isopropanol. The base is selected from liquor ammonia or triethyl amine.
The present invention also provides an isolated Rizatriptan methyl chloride of the formula (VII) of the following structure

CI
Formula (VII) The Rizatriptan methyl chloride (VII) is isolated in about 98% purity by weight with respect to other compounds, including Rizatriptan. Thus, the isolated Rizatriptan methyl chloride (VII) contains less than about 2% and even more preferably less than about 1% by weight of Rizatriptan.
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The isolated Rizatriptan methyl chloride (VII) according to the present invention is characterized by 'H NMR spectrum (in DMSO-d6, 200 MHz) 5 (ppm): 3.13-3.22 (m, 2H), 3.31 & 3.38 (s, 6H), 3.67-3.76 (m, 2H), 5.46 (s, 2H), 5.61 (s, 2H), 7.07-8.69 (m, 6Ar-H), 11.24 (s, 1H); 13C NMR spectrum (in DMSO-d6, 50MHz) 18.10,48.66,52.91, 61.75, 67.96, 107.86, 114.28, 118.21, 121.57, 124.39, 126.26, 126.40, 135.72, 143.79 & 151.29. This isolated impurity (VII) is detected by HPLC and used as a reference marker/standard to analyse the purity of Rizatriptan or its pharmaceutical acceptable acid addition salts. The isolated Rizatriptan methyl chloride (VII) is detected at an RRT (relative retention time)^of about 1.4 relative to Rizatriptan (an HPLC retention time unusually long with respect to Rizatriptan).
According to the present invention Rizatriptan benzoate as obtained in example 7 has about 4% of Rizatriptan methyl chloride (VII) which is further reduced to less than 2%, preferably less than about 1% and even more preferably less than about 0.15% by weight of Rizatriptan base by purification.
As used herein, the term "isolated" refers to a compound that is at least 80%, preferably at least 90%, even more preferably at least 95%, and most preferably at least 99% pure, as judged by GC or HPLC.
As used herein, the term "reference standard" refers to a compound that may be used both for quantitative and qualitative analysis of an active pharmaceutical ingredient. For example, the retention time of the compound in HPLC allows for setting a relative retention time, thus making qualitative analysis possible. The concentration of the compound in solution before injection into an HPLC column allows for comparison of the areas under the peaks in an HPLC chromatogram, thus making quantitative analysis possible. A "reference marker" is used in qualitative analysis to identify components of a mixture based upon their position, e.g. in a chromatogram or on a Thin Layer Chromatography (TLC) plate (Strobel pp. 921, 922, 953). For this purpose, the compound does not necessarily have to be added to the mixture if it is present in the mixture. A "reference marker" is used only for qualitative analysis, while a reference standard may be used for quantitative or qualitative analysis, or both. Hence, a reference marker is a
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subset of a reference standard, and is included within the definition of a reference standard.
In further embodiment, the present invention provides process for the preparation and isolation of Rizatriptan methyl chloride (VII) which comprises the steps of:
a) dissolving Rizatriptan benzoate in water;
b) basifying the reaction mixture with base;
c) extracting the reaction mixture with organic solvent;
d) stirring the organic extract for at least 12 hours and
e) isolating Rizatriptan methyl chloride (VII).
The base used in step (b) is selected from liquor ammonia, sodium hydroxide solution, sodium bicarbonate solution or sodium carbonate solution and organic solvent used in step (c) is dichloromethane.
Quantitative analysis of Rizatriptan methyl chloride (VII) may be performed with HPLC
method, conditions of HPLC method for isolating the impurity of Rizatriptan methyl
chloride (VII) are
Column : intersil ODS 3, 4.6 x 250 mm, 5 pm
Detection limit: 0.01%
Eluents: buffer (0.01 M K2HP04, pH 3.4) :acetonitrile:methanoI in the ratio 85:7.5:7.5
Runtime : 120 min.
Flowchart: 1.0 ml/min
In another embodiment, the present invention provides an analytical method for detecting Rizatriptan methyl chloride (VII) in a sample of Rizatriptan benzoate which comprises the steps of;
a) providing a sample of Rizatriptan benzoate (I) containing or suspected of containing Rizatriptan methyl chloride (VII);
b) subjecting the sample of step a) to HPLC and
c) determining the peak having RRT of about 1.4 with respect to Rizatriptan ;
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According to the present invention an isolated Rizatriptan methyl chloride (VII) has HPLC retention time detected at an RRT (relative retention time) of about 1.4 relative to Rizatriptan .The presence of a peak with an RRT of about 1.4 with respect to Rizatriptan indicates presence of Rizatriptan methyl chloride (VII).
According to another embodiment of the present invention the isolated Rizatriptan methyl chloride (VII) impurity is used as a reference standard for Rizatriptan or its pharmaceutically aceptable salts, in order to quantify impurities present in Rizatriptan sample which comprises the following steps;
a) subjecting a reference standard solution of Rizatriptan methyl chloride (VII) comprising a known amount of Rizatriptan methyl chloride (VII) to HPLC for at least 120 min and measuring by HPLC the area under a peak corresponding to Rizatriptan methyl chloride (VII);
b) subjecting a sample solution comprising Rizatriptan benzoate (I) and Rizatriptan methyl chloride (VII) to HPLC for at least 120 min and measuring by HPLC the area under a peak corresponding to Rizatriptan methyl chloride (VII) and
c) determining the amount of Rizatriptan methyl chloride (VII) in the sample by comparing the area of step (a) to the area of step (b).
The present invention provides a method of determining the amount of Rizatriptan methyl chloride impurity in a sample of Rizatriptan benzoate (1) comprising;
a) measuring the area under a peak corresponding to Rizatriptan methyl chloride (VII) in a sample comprising a known amount of Rizatriptan methyl chloride (VII) by HPLC;
b) measuring the area under a peak corresponding to Rizatriptan methyl chloride (VII) in Rizatriptan benzoate (I) sample containing Rizatriptan methyl chloride (VII) by HPLC and
c) determining the amount of Rizatriptan methyl chloride (VII) in Rizatriptan benzoate sample by comparing the area of step (a) to the area of step (b).
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The present invention also provides a quantification method of Rizatriptan methyl chloride (VII) for testing the impurity profile of Rizatriptan or pharmaceutically acceptable salts which comprising:
a) combining Rizatriptan benzoate (I) sample in a mixture of buffer (0.01 M K2HPO4, pH 3.4):acetonitrile:methanol diluent having a ratio of about 85:7.5:7.5 to obtain a solution;
b) injecting the solution of step (a) into a intersil ODS 3, 4.6 x 250 mm, 5 pm column of HPLC;
c) eluting the sample from the column at about 12 times the elution time of Rizatriptan using a mixture of buffer:acetonitrile:methanol diluent of ratio about 85:7.5:7.5 and
d) measuring the Rizatriptan methyl chloride (VII) content in the relevant sample with a UV detector.
The Rizatriptan methyl chloride (VII) in step (d) is measured at a wavelength of 230 nm and the eluting time is about 120 min.
The present invention is further illustrated by the following examples and should not be construed to limit the scope of the present invention in any manner.;
EXAMPLES:
Example 1
Preparation of l-(4-nitrophenyl) methyl-l,2,4-triazoIe:
4-nitrobenzyl bromide (432 g) was added to 1,2,4-triazole sodium salt (182 g, 2 M) suspended in 500 L dimethylformamide (DMF) under stirring. The reaction mass was stirred for 10 hr at 35-45°C. 1500 ml water and 1500 ml ethyl acetate were added to the reaction mixture and stirred for 30 min. The separated ethyl acetate layer was washed with 500 ml water and evaporated under reduced pressure at 60-65° C to get l-(4-nitrophenyl)methyl-l,2,4-triazoIe. Yield 335 g; (82%)
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Example 2
Preparation of l-(4-aminophenyl)methyI-l,2,4-triazolehydrochloride:
l-(4-nitrophenyl) methyl- 1,2,4-triazole (330 g, 1.62 M) and 10% Pd/C (16.5 g, 50% moist) were suspended in a mixture of ethyl acetate (1.25 L), ethanol (1.25 L), cone. HC1 (100 ml) and watef (300ml). The reaction mixture was then hydrogenated in presence of hydrogen gas at 50 psi at 25-35° C for \ hr. Aftar the completing of reaction, the catalyst was filtered off, solvent was removed under reduced pressure at 60-65°C. The obtained residue was stirred in ethanol (500 ml). The slurry was filtered and washed with ethanol (100 ml) to get the desired compound. Yield 323 g; ( 95%).
Example 3
Preparation of l-(4-hydrazinophenyl)methyl-l,2,,4-triazolehydrochloride:
300 g of l-(4-aminophenyl)methyl-1,2,4-triazole hydrochloride (1.43 moles) was added to 1.5 L cone, hydrochloric acid-water (1:1) mixture. The reaction mixture was cooled at temperature between 0-5° C and aqueous sodium nitrite solution (98.4 g, 1.43 moles) in 600 ml water) was added maintaining temperature below 5°C. The reaction mixture was stirred for about 30 min and the obtained diazonium salt solution was added to a chilled aqueous solution of stannous chloride (600 g SnCl2 dissolved in cone. HC1 1200 ml) at 0 to 5°C. The reaction mixture was stirred for 3 hrs at 25-35°C and basified with 20% sodium hydroxide solution. The reaction mixture was extracted with ethyl acetate (3x7.5 L) and the separated organic layer was evaporated to dryness to get the desired compound.Yield 185 g ( 69.06%)
Example 4
Preparation of lH-Indole-3-ethamine, N,N-dimethyl-5-(lH-l,2,4-triazol-l-ylmethyI)
benzoate (Rizatriptan benzoate)
l-(4-hydrazinophenyl)methyl-l,2,4-triazole hydrochloride (200 g, 0.763 M) was suspended in 5.64 L water. 533 g of methanesulphonic acid and 4-dimethylamino butanal diethyl acetal (170 g, 0.899 M) were added to it under stirring. The reaction mixture was stirred for 2 hr at temperature 80-90°C and then cooled to 15-25°C. 1.34 L of 20% sodium hydroxide solution was added to cooled solution maintaining the
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temperature below 25°C. The aqueous layer was filtered over hyflo bed and the filtrate was extracted with ethyl acetate (3 x 2.4 L). The ethyl acetate layer was concentrated to obtain oil which was dissolved in 68 ml ethanol and 272 ml diethyl ether, 37 g benzoic acid dissolved in 150 ml ethanol-diethyl ether mixture (15:85) was added to it and stirred for 1 hr at temperature 0-10°C. The solid separated was filtered, washed with 2 x 100 ml diethyl ether and dried at 60-70°C. Yield: 142 g; (34.4%) Purity: 98.5 ++
Example 5
1st purification of Rizatriptan benzoate (crystallization)
142 g of Rizatriptan benzoate was dissolved in 994 ml ethanol at 70-80°C and the mixture
was gradually cooled to 10-15° C. The solid obtained was filtered, washed with 100 ml
cold ethanol and dried at 60-70°C.
Yield: 108.63 g.; (76.5%)
Purity 99.2++
2nd purification of Rizatriptan benzoate (crystallization)
108 g of Rizatriptan benzoate was dissolved in 756 ml ethanol at temperature 70-75°C
and reaction mixture was gradually cooled to 10-15° C. The solid obtained was filtered,
washed with 100 ml cold ethanol and dried at 60-70°C.
Yield: 84.34 g.; (78.1%)Purity 99.8++
Example 6
Purification of Rizatriptan benzoate ( column chromatography):
142 g Rizatriptan benzoate was dissolved in water (710 ml) and 20% sodium hydroxide solution (100 ml) was added at temperature below 25°C. The obtained solution was extracted with dichloromethane (3 x 600 ml). The dichloromethane layer was evaporated to get brown oil (95 g) which was chromatographed on silica gel (dichloromethane : ethanol: ammonia 98 : 1 : 1 v:v to 94 : 5 : 1 v:v.. The obtained oil (86 g) was dissolved in 258 ml ethanol and 33 g benzoic acid dissolved in 200 ml ethanol was added to it at temperature 50-60°C. The reaction mixture was cooled to 0-10°C and stirred for 1 hr. The separated solid was filtered, wash with 2 x 100 ml ethanol and dried at 60-70° C. Yield: 122.6 g.; (86.4%); Purity 95++
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Example 8
122 g of Rizatriptan benzoate obtained from Example 7 was dissolved in ethanol (854 ml ) at 70-75°C and reaction mixture was gradually cooled to 10-15° C. The solid obtained was filtered, washed with 100 ml cold ethanol and dried at 60-70°C. Yield: 112.48 g ; (92.2%), Purity 99.8++
Example 9
Isolation of Rizatriptan methyl chloride (VII) impurity.
5 gm of the crude Rizatriptan benzoate obtained from column chromatography was
dissolved in 50 ml water and 5 ml of 20% sodium hydroxide solution was added to the
obtained reaction mixture at temperature below 25°C. The reaction mixture was extracted
with dichloromethane (3 x 30 ml) and the dichloromethane extract was stirred for 12 hr at
25-35° C. The solid obtained was filtered , washed with ethanol (2 x 10 ml) and dried at
60-70° C.
Yield: 2.4 g; (48%) , Purity 98++
Dated this 3rd day of July 2008.

Dr. KAG. Hajendran
usv LMITED
Applicant
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