Form 2THE PATENTS ACT, 1970(39 of 1970)&THE PATENTS RULE 2003PROVISIONAL SPECIFICATION [See section 10 and rule 13]
1. TITLE OF THE INVENTION “A process for preparation of Zolmitriptan”
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 nature of this invention and the manner in which it is to be performed.
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A process for preparation of Zolmitriptan
TECHNICAL FIELD:
The present invention relates to an improved process for the preparation of (S)-4-[3-(2-dimethylaminoethyl)-lH-indol-5-ylmethyl]-l,3-oxazolidin-2-one, (Zolmitriptan) of formula (I).

BACKGROUND OF INVENTION:
US 54466699 discloses Zolmitriptan which is used in the treatment of migraine, cluster headache and headache associated with vascular disorders. The aforesaid patent also describes a process for preparation of Zolmitriptan (Scheme I). The process comprises esterification of (S)-4-nitro phenylalanine (II) in presence of thionyl chloride in methanol to yield (S)-methyl-4-nitrophenylalanate (III). The compound (III) was reduced with sodiumborohydride to give (S)-methyl-4-nitrophenylalanilol (IV) which was then cyclised using phosgene in toluene to obtain (S)-4-(4-nitrobenzyl)-l,3-oxazolidine (V). The compound (V) was then hydrogenated with 10% Pd-C in a mixture of ethanol, water, ethyl acetate and 2N HCl to provide (S)-4-(4-aminobenzyl)-l,3-oxazolidin-2-one hydrochloride (VI), which was further diazotized and treated with stannous chloride to give (S)-4-(4-hydrazinobenzyl)-l,3-oxazolidin-2-one hydrochloride (VII). The compound (VII) was treated with 4-dimethyaminobutanal diethylacetal in a mixture of acetic acid
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and water to obtain crude zolmitriptan. The crude product was purified by column chromatography using a eluent mixture comprising dichloromethane : ethanol : ammonia and then recrystallized in isopropanol to obtain pure Zolmitriptan.
SCHEME I:

The disadvantages of the prior art processes is the purification using column chromatography, which requires high quantity of solvent, expensive, inconsistent and time consuming.
Another disadvantage is the use of ammonia. By virtue of being a gas it is difficult to maintain the uniform composition, leading to wide variations in retention time, thus affecting the purity of the product.
WO2004014901 discloses preparation of Zolmitriptan by preparing diazonium salt of (S)-4-(4-aminobenzyl)l,3-oxazolidin-2-one followed by reduction and acidification to give hydrazine derivative, reacting with α-keto-δ-valerolactone to provide hydrazone derivative. Fisher indole synthesis of hydroazone derivative yields pyroindolone which when transesterfied, the hydroxyl group is converted into dimethylamino group. Saponification of 2-carboxyalkoxy group is followed by decorboxylation to provide Zolmitriptan.
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The above process is lengthy and time consuming. The process includes the formation of pyranindolone derivative, transesterification of pyranindolone provided carboxlic acid methyl ester. Hydroylsis of the methyl ester followed by decarboxylation provided Zolmitriptan. The said reactions provides undesirable side products, hence require purification.
US200641160 describes several novel polymorphs of Zolmitriptan as solvates.
US2006148868 discloses novel polymorphs of Zolmitriptan viz. Form II, form III and amorphous forms.
WO200575467 discloses novel crystalline polymorphs as Zolmitriptan solvates.
WO2004063175 discloses preparation of the (S)-4- (4-aminobenzyl)-2-oxazolidinone of formula (I) by preparation of 4-nitro-(S)-phenylalaninol of formula (IV) by conventional methods and further reducing the nitro compound of formula (IV) and then reacting the novel compound of the formula (II) with dialkyl carbonate at a temperature in the range of 80-200 °C. (S)-4- (4-aminobenzyl)-2-oxazolidinone is an intermediate used in the preparation of Zolmitriptan.
WO2005105792 describes a process for preparation of Zolmitriptan by forming diazo salt from (4S)-4-(4-aminobenzyl)-l,3-oxazolan-2-one and enol derivative from alkyl-2-acetyl-5-(l,3-dioxo-2,3-dihydro-lH-2-isoindolyl) pentanoate followed by coupling these two, cyclizing the resultant hydroazone derivative, deprotecting pthalimido derivative, N,N-dimethylation of primary amine group to form a tertiary amine and decarboxylation. Zolmitriptan is purified, by dissolving
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it in isopropyl alcohol at an elevated temperature, cooled and further adding n-heptane and isolating Zolmitriptan.
The above process is a lengthy route involving protection and deprotection reactions.
The cyclisation step leading to formation of pthalimido derivative providing undesirable side products. Hence this step requires purification and thus results in reduced yields.
WO20031010931 discloses a process for preparation of N,N-disubstituted amino butyraldehyde acetals, intermediates used in the preparation of Zolmitriptan.
US6084103 describes a process for preparation of S-Zolmitriptan by forming a
carbamate from methyl-4-nitro-(L)-phenylalaninate hydrochloride by adding sodium carbonate or NaHC03 and n-butylchloroformate, reducing the N02 group, reducing methyl ester group to yield (S)-N-butoxycarbonyl-4-aminophenylalanilol followed by ring closure with sodium methoxide in methanol, preparation of diazonium chloride using sodium sulfite, fischer reaction.
OBJECTS OF THE INVENTION:
An object of the present invention is to isolate Zolmitriptan avoiding column chromatography
Another object of the present invention is to avoid the use of large volumes of stannous chloride in the reduction stage.
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A further object of the present invention is to provide a cost effective, simple, scalable and robust process.
Another object of the present invention is to provide a process for the preparation of (S)-4-[3-(2-dimethylaminoethyl)-lH-indol-5-ylmethyl]-l,3-oxazolidin-2-one (Zolmitriptan) of formula (I), in good yield and high purity.
SUMMARY OF THE INVENTION:
The present invention provides a process for preparation of highly pure (S)-4-[3-(2-dimethylaminoethyl)-1 H-indol-5-ylmethyl]-1,3-oxazolidin-2-one(Zolmitriptan) (I) in high yield(Scheme II) comprising:
(S)-4-(4-Aminobenzyl)-l,3-oxazolidin-2-one hydrochloride (VI) is diazotized and treated with stannous chloride (1:2 mole ratio) to provide (S)-4-(4-hydrazinobenzyl)-l,3-oxazolidin-2-one hydrochloride (VII). The cyclisation of the hydrochloride salt (VII) with 4-dimethylaminobutanal diethylacetal in acetic acid and water mixture affords Zolmitriptan. After the completion of the reaction, the mass is basified by aqueous sodium hydroxide/ammonia solution and extracted from ethyl acetate. On evaporation of ethyl acetate, residue obtained is then adsorbed over silica gel and treated with ethyl acetate. On evaporation of ethyl acetate residue obtained is readsorbed over silica gel and treated with isopropanol (IPA)-toluene mixture, followed by isopropanol and water to afford Zolmitriptan. Purification is achieved using isopropanol.
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SCHEME II:
DETAILED DESCRIPTION OF THE INVENTION:
According to an embodiment of the present invention there is provided a process for preparation of Zolmitriptan or (S)-4-[3-(2-dimethylaminoethyl)-lH-indol-5-ylmethyl]-l,3-oxazolidin-2-one having formula (I) comprising:

a. Diazotizing (S)-4-(4-Aminobenzyl)-l,3-oxazolidin-2-one (VI)
and treating with stannous chloride (2 moles) to give (S)-4-(4-
hydrazinobenzyl)-l,3-oxazolidin-2-one hydrochloride (VII);
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b. Reacting the compound of formula (VII)


with 4-dimethylamino-butanal diethylacetal in a mixture of acetic acid and water. The reaction mixture is basified with sodium hydroxide or ammonia solution, extracting with ethyl acetate, adsorbing over silica gel.
c. Ethyl acetate treatment to silica gel mass. Concentrating the
ethyl acetate to provide residue.
d. The residue readsorbing over Silica gel, treated with
isopropanol-toluene mixture.
e. Treatment of isopropanol followed by water to provide crude
Zolmitriptan.
f. Recrystallization in isopropanol to obtain pure Zolmitriptan.
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According to another embodiment of the present invention there is provided a process for preparation of Zolmitriptan or (S)-4-[3-(2-dimethylaminoethyl)-lH-
indol-5-ylmethyl]-l,3-oxazolidin-2-one having formula (I) comprising:

c. Diazotizing (S)-4-(4-Aminobenzyl)-l,3-oxazolidin-2-one (VI)
and treating with stannous chloride (2 moles) to give (S)-4-(4-hydrazinobenzyl)-l,3-oxazolidin-2-one hydrochloride (VII);

d. Treating the compound of formula (VII) with 4-
dimethylamino-butanal diethylacetal in a mixture of acetic acid and water to obtain zolmitriptan;

e. Purifying the crude Zolmitriptan by column chromatography
using a stationary phase (Silica gel 60-120 mesh) and a mobile
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phase (10% Ethanol in ethyl acetate) followed by treatment of isopropanol and water to pure Zolmitriptan.
f. crystallization in isopropanol to obtain pure Zolmitriptan.
EXAMPLES:
Example 1
Preparation of (S)-4-[3-(2-dimethylaminoethyl)-1 H-indol-5-ylmethyl]-1,3-oxazolidin-2-one (Zolmitriptan)
(S)-4-(4-Aminobenzyl l,3-oxazolidin-2-one (5.0 g, 0.26 M) dissolved in 50 ml water-HCl mixture (1:1). Add aqueous Sodium nitrite solution (1.95 g in 5 ml) at 0 to 5° C. Add the above solution to Stannous chloride 10 g dissolved in cone HCl (20 ml) at 0 to 5° C. Stir the reaction mix for 3 hrs at 25-35° C. Concentrate the reaction mixture under vacuum, the residue obtained is dissolved in water-acetic acid (37.5 ml-12.5 ml) mixture. Add 4-dimethyl amino butraldehyde diacetal (5 g) and stir for 15 min at 110-115° C. Concentrate the reaction mixture under vacuum. Treat the residue with 200 ml liq ammonia. Extract the aqueous layer with ethyl acetate (3 x 150 ml). Add Silica gel 15 g and 100 ml of Toluene to the ethyl acetate extract. Remove Ethyl acetate at 75-85° C and filter the slurry. Pass pre-absorbed compound over silica gel through column using 10% ethanol in ethyl acetate as eluent. Concentrated the effluent and dissolve the oil in 50 ml MDC, stir for 5 hrs. Pass through hyflow and concentrate MDC under vacuum. Dissolve the oil obtain in 40 ml IP A at 60-70° C. Charcoalise the reaction mixture and concentrate under vacuum. Stir the residue with water 20 ml at 25-35° C for 4 hrs. Filter the solid, wash with 10 ml water and dry at 60-70° C.
Yield: 2.5 g; 33.45% Purity: 99.5 ++
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Example 2
Preparation of (S)-4-[3-(2-dimethylaminoethyl)-1 H-indol-5-ylmethyl]-1,3-oxazolidin-2-one (Zolmitriptan)
(S)-4-(4-Aminobenzyl l,3-oxazolidin-2-one (5.0 g, 0.26 M) dissolved in 50 ml water-HCl mixture (1:1). Add aqueous Sodium nitrite solution (1.95 g in 5 ml) at 0 to 5° C. Add the above solution to Stannous chloride 10 g dissolved in cone HCL (20 ml) at 0 to 5° C. Stir the reaction mix for 3 hrs at 25-35° C. Concentrate the reaction mixture under vacuum, the residue obtained is dissolved in water-acetic acid (37.5ml-12.5 ml) mixture. Add 4-dimethyl amino butraldehyde diacetal (5 g) and stir for 15 min at 110-115° C. Concentrate the reaction mixture under vacuum. Concentrate the reaction mixture under vacuum. Treat the residue with 200 ml liq ammonia. Extract the aqueous ml with ethyl acetate (3 x 150 ml). Add Silica gel 15 g and 100 ml of Toluene to the ethyl acetate extract. Remove Ethyl acetate at 75-85° C and filter the slurry. Treat the Silica gel mass with 200 ml Ethyl acetate and filter, wash with 2 x 100 ml Ethyl acetate. Combine the ethyl acetate filtrates and concentrate under vacuum. Dissolve the oil in 50 ml MDC, stir for 5 hrs. Pass through hyflow and concentrate MDC under vacuum. Dissolve the oil in 40 ml IPA at 60-70° C. Charcoalise the reaction mixture and concentrate under vacuum. Stir the residue with water 20 ml at 25-35° C for 4 hrs. Filter the solid, wash with 10 ml water and dried at 60-70° C.
Yield:2.2 g; 29.43% Purity: 99.5 ++
Example 3
Preparation of (S)-4-[3-(2-dimethylaminoethyl)-lH-indol-5-ylmethyl]-l,3-oxazolidin-2-one (Zolmitriptan)
(S)-4-(4-Aminobenzyl l,3-oxazolidin-2-one (5.0 g, 0.26 M) dissolved in 50 ml water-HCl mixture (1:1). Add aqueous sodium nitrite solution (2 g in 7.5 ml) at 0 to 5° C. Add the above solution to stannous chloride 10 g (1.56 mole) dissolved in cone HCl (20 ml) at 0 to 5° C. Stir the reaction mix for 3 hrs at 25-35° C. Concentrate the reaction mixture under vacuum, the residue obtained is dissolved
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in water-acetic acid (37.5 ml-12.5 ml) mixture. Add 4-dimethyl amino butraldehyde diacetal (6 g) and stir for 5 hr. at 90-95° C. Concentrate reaction mixture under vacuum. Treat the residue with 50 ml 20% sodium hydroxide solution. Extract the aqueous ml with ethyl acetate (3 x 80 ml). Add silica gel 15 g
and 50 ml of Toluene to the ethyl acetate extract. Remove ethyl acetate at 75-85°
C and filter the slurry. Treat the silica gel mass with 200 ml ethyl acetate and filter, wash with 2 x 100 ml ethyl acetate. Combine the ethyl acetate filtrates and concentrate under vacuum. Dissolve the residue in 25 ml isopropanol, add silica gel 5 g and 25 ml of toluene. Stir the mass for 1 hr. at 75-85° C. Cool to 25-35° C and filter the slurry. Treat the silica gel mass with 20 ml isopropanol and filter, wash with 10 ml isopropanol. Charcoalise the isopropanol filtrate and concentrate completely under vacuum. Stir the residue with water 20 ml at 25-35° C for 4 hrs. Filter the solid, wash with 10 ml water and dry at 60-70° C.
Yield: 2.8 g; Purity: 37.45%
Purity 99.5++
Example 4
Crystallisation of Zolmitriptan
2 g of Zolmiriptan from Example 1, was dissolved in 10 ml isopropanol at 70-
75°C. The mixture was gradually cooled to 10-15°C. The solid obtained was
filtered, washed with 5 ml cold isopropanol and dried at 60-70°C.
Yield: 1.7 g.; Percentage: 85%
Purity 99.8++
Dated 19th day of January, 2007

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Abstract:
The present invention provides an improved process for preparation of highly pure Zolmitriptan or (S)-4-[3-(2-dimethylaminoethyl)-lH-indol-5-ylmethyl]-l,3-oxazolidin-2-one wherein (S)-4-(4-Aminobenzyl)-l,3-oxazolidine was diazotized and treated with stannous chloride to give (S)-4-(4-hydrazinobenzyl)-l,3-oxazolidine hydrochloride, and further condensed with 4-dimethylaminobutanal diethylacetal in a mixture of acetic acid and water to provide Zolmitriptan. The mass is basified with NaOH/NH3 and further extracted with ethyl acetate. On evaporation of ethyl acetate, residue obtained was then adsorbed over silica gel and treated with ethyl acetate and the residue obtained on evaporation of ethyl acetate is readsorbed over silica gel and treated with isopropanol (IPA)-toluene mixture, followed by isopropanol and water to afford Zolmitriptan. Purification is achieved using isopropanol.
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