WO2006054311A2 - Improved process for the preparation of high purity sumatriptan - Google Patents

Improved process for the preparation of high purity sumatriptan Download PDF

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Publication number
WO2006054311A2
WO2006054311A2 PCT/IN2004/000353 IN2004000353W WO2006054311A2 WO 2006054311 A2 WO2006054311 A2 WO 2006054311A2 IN 2004000353 W IN2004000353 W IN 2004000353W WO 2006054311 A2 WO2006054311 A2 WO 2006054311A2
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sumatriptan
improved process
range
base
reaction mass
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PCT/IN2004/000353
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French (fr)
Inventor
Muddasani Pulla Reddy
Durgaprasad Konakanchi
Nannapaneni Venkaiah Chowdary
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Natco Pharma Limited
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Publication of WO2006054311A2 publication Critical patent/WO2006054311A2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical

Definitions

  • the present invention relates to an improved process for the preparation of sumatriptan.
  • Sumatriptan which is 3-(2-dimethylamino)ethyl-N-methyl-lH-indole-5-methane- sulfonamide has the formula-I given below.
  • Sumatriptan and its pharmaceutically acceptable salts are widely used as antimigraine agents and also for cluster headaches.
  • Sumatriptan is reported for the first time by Glaxo in GB patent no 2162522 (corresponding to the US patent no 5037845 (1989)). It is found to be serotonin 5HT 1 - receptor agonist. Its clinical evaluation in migraine is described in Lancet, 1, 1309 (1988) and its studies on cluster headache are revealed in Engl. J. Med. 325, 322 (1991). Sumatriptan succinate is available in the market as Imigran or Imitrex.
  • the indolyzation reaction was done by mixing 4 g of the hydrazone of formula-IV with 20 g polyphosphate ester in 80 ml chloroform medium at room temperature for 4 h.
  • the crude sumatriptan (2.5 g) thus obtained after water work up was subjected to column chromatography to yield an oil (1.13 g) which on salt formation with succinic acid gave the corresponding hemi-succinate salt (0.83 g, overall yield is 14.8%).
  • yield of sumatriptan was less than 5%.
  • the main impurities formed during the process are dimeric compounds of the formulae-V and VI and also some polymeric material.
  • mixing of reactants is very exothermic and the yield of sumatriptan during indolization is also temperature dependant, rate of addition of reactant dependant, and reaction maintenance time dependant. With increasing temperature and maintenance time formation of impurities increased drastically.
  • Sumatriptan has become a well-known anti-migraine drug that has now been on the market and has shown great promise . as a valuable anti-migraine drug with few side effects.
  • the main objective of the present invention is to provide an improved process for the preparation of sumatriptan of the formula-I which is commercially applicable.
  • Yet another objective of the present invention is to provide an improved process for the preparation of sumatriptan of the formula-I, which is simple avoiding column chromatography techniques thereby making the process economical.
  • Still another objective of the present invention is to provide an improved process for the preparation of solid crystalline sumatriptan of the formula-I which is directly obtained from the reaction mass by simple crystallization techniques.
  • the present invention has been developed based on our finding that the above Fischer indolization process is very sensitive to (i) temperature, (ii) the amount of polyphosphate ester used, (iii) rate of addition of polyphosphate ester and (iv) maintenance time of reaction. We also found that the optimization of these process parameters will result in the better yield and quality of sumatriptan formed. Also, the crude sumatriptan prepared under the above mentioned modified conditions can be easily crystallized from a number of solvents without requiring any column chromatography techniques.
  • the rate of addition of polyphosphate ester to the compound of the formula-IV should be preferably within the period of 5-30 min, more preferably during the period of 10-15min.
  • the maintenance temperature of the reaction mass should be preferably in the range of 15-3O 0 C, more preferably in the range of 20-25 °C.
  • the maintenance time of reaction mass is preferably in the range of 2-4 h, more preferably in the range of 2.5-3.0 h.
  • the amount of ethyl polyphosphate ester used in the reaction is preferably in the range of 4-8 times the weight of the compound of the formula-IV, more preferably in the range of 5-6 times.
  • the reaction can be monitored by HPLC and the optimum percentage of sumatriptan produced was found to be in the range of 60-75%.
  • the present invention provides an improved process for the preparation of high purity (at least 99 %) sumatripan of the formula-I,
  • step ( ⁇ ) Adding polyphosphate ester to the cooled solution of the compound of the formula-IV obtained in step (i) at a temperature in the range of 0-15 0 C (i ⁇ ) Maintaining the resulting reaction mass obtained in step (ii) at a temperature in the range of 20-25 0 C (iv) Quenching the reaction mass of the step (iii) into water and separating the organic layer
  • the solvent used in step (i) may be selected from methylene chloride, chloroform, THF 5 acetonitirile, etc, preferably methylene chloride or chloroform.
  • the cooling temperature used in step (i) may be preferably in the range of 5-10 0 C.
  • the addition time of polyphosphate ester in step (ii) may be in the range of 5-25 min, preferably 10-15 min.
  • the amount of polyphosphate ester used in step (ii) may be in the range of 4-8 times the weight of the compound of the formuIa-IV, preferably in the range of 5-6 times.
  • the reaction maintenance time in step (iii) may be in the range of 3-5 h, preferably 2.5-3.0 h.
  • the base used in the neutralization step (v) may be selected from sodium carbonate, sodium hydroxide, potassium hydroxide, potassium carbonate, preferably sodium carbonate or potassium carbonate.
  • the polar solvent used in step (vi) for the extraction of crude sumatriptan base may be selected from methyl isobutyl ketone, methyl ethyl ketone, isopropyl acetate, ethyl acetate, diethyl ether, preferably diethyl ether or ethyl acetate.
  • the solvent used for crystallization of crude sumatriptan may be selected from ethyl acetate, isopropyl acetate, methanol, ethanol, isopropanol, methyl ethyl ketone, methyl isobutyl ketone, diethyl ether, diisopropyl ether, acetonitrile, preferably ethyl acetate or acetonitrile.
  • the sumatriptan base obtained by this crystallization technique is of at least 98% purity.
  • the alcoholic solvent used in step (ix) for recrystallization of sumatriptan base is selected from methanol, ethanol, isopropanol, or a mixture thereof, preferably methanol or ethanol. Purity of sumatriptan base thus obtained is of >99%.
  • Example 1 (i) Preparation of sumatriptan base Into a 1-L three-necked RB flask was charged 125 ml of water, 20 g of cone. HCl, and 50 g of 4-hydrazino-N-methylbenzenemethanesulfonamide hydrochloride. The reaction mass was stirred at 25-30 0 C for 15min and added 45 g of 4-dimeth.ylar ⁇ inobutyraldehyde diethyl acetal. The reaction mass was maintained at 25-30 °C for 2 hr. Reaction was found to be over by TLC. Reaction mass was diluted with water (200ml) and the pH adjusted to 2.5 using sodium carbonate.
  • reaction mass is treated with carbon and adjusted the pH to 9.0 with sodium carbonate.
  • Product was extracted into chloroform (2 x 400 ml). Chloroform layer was washed with water and dried over sodium > sulfate. Chloroform (50-75 ml) was distilled out from the solution.
  • the concentrated chloroform solution was transferred into a 2-L, three-necked RB flask. Chloroform (100 ml) was added to the reaction mass and cooled to below 5 °C under nitrogen atmosphere. Ethyl polyphosphate (200 g) was taken into addition funnel and added to the reaction mass over a period of lOmin keeping the temperature below 15 0 C. After maintaining at same temperature for 30min, reaction mass was allowed to reach 25 °C and maintained for 2 hr at 20-25 0 G. HPLC of the reaction showed 68% of sumatriptan present in reaction mass. The reaction mass was diluted with 800 ml of water and stirred for 20 min. Layers were separated and the aqueous layer extracted with 100 ml of chloroform.
  • Example 2 (i) Preparation of sumatriptan base Into a 100-L glass flask was charged 12.5 L of water, 2 kg of cone. HCl 5 and 5 kg of 4- hydrazino-N-rnethylbenzenemethanesulfonamide hydrochloride. The reaction mass was stirred at 25-30 0 C for 15min and added 4.5 kg of 4-dimethylaminobutyraldehyde diethyl acetal. The reaction mass was maintained at 25-30 0 C for 2 hr. Reaction was found to be over by TLC. Reaction mass was diluted with water (20 L) and the pH adjusted to 2.5 using sodium carbonate.
  • reaction mass is treated with carbon (0.5 kg), filtered and filtrate pH adjusted to 9.0-9.5 with sodium carbonate.
  • Reaction mass was extracted with chloroform (2 x 30 L). Chloroform layer was washed with water (20 L) and dried over sodium sulfate.
  • Chloroform (5-7 L) was distilled out from the reaction mass below 40 0 C and the residue diluted with fresh chloroform (10 L). The reaction mass was cooled to below 5 0 C under nitrogen atmosphere. Ethyl polyphosphate (18 kg) was added to the reaction mass over a period of 10-15 min keeping the temperature below 15 0 C. After maintaining at same temperature for 30min, reaction mass was allowed to reach 25 0 C and maintained for 2.0 hr at 20-25 0 C. HPLC of the reaction mass showed 64 % of sumatriptan. The reaction mass was transferred into 200-L glass flask containing water (80L) keeping the temperature below 25 °C. The reaction mass was stirred for 20 min. Layers were separated and the aqueous layer extracted with 10 L of chloroform.
  • Acetonitrile (4 L) was added to the residue obtained in step (i) and heated to 40 0 C to get a clear solution.
  • the solution was stirred at 20-25 0 C for lhr and cooled to 5-10 0 C. After maintaining for 4-5 hr at 5-10 0 C crystalline sumatriptan base was isolated by filtration. Drying at 40-50 °C afforded 1.5 kg of light yellow-colored sumatriptan base. Purity by HPLC was 97.5%.
  • Example 3 Recrystallization of sumatriptan base Into a 1-L, three-necked RB flask was charged 100 g of sumatriptan base (obtained from the process described in example 2) and 900 ml of methanol. The reaction mass was heated to reflux temperature and maintained for 30 min to get a clear solution. Carbon (20 g) was added to the reaction mass and maintained at reflux for 30 min. The reaction mass was filtered and the carbon bed washed with 100 ml of hot methanol. The filtrate was cooled to 0-5 0 C and maintained for 2 hr. Crystalline sumatriptan base was isolated by filtration under vaccum and the wet cake washed with 50 ml of chilled methanol.
  • the process produces sumatriptan directly from the reaction mass by simple crystallization techniques. Thereby making the process simple and economical.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses an improved process for the preparation of sumatriptan of formula-I by Fischer indolization which comprises adding ethyl polyphosphate to hydrazone in an amount in the range of 4-8 times the weight of hydrazone, during a period in the range of 5-30 min and at a temperature below 15 °C, maintaining the reaction mass at 20-25 °C for a period of 2.5-3.0 hr by monitoring the HPLC and isolating the sumatriptan after water work-up and crystallization. On recrystallization from an alcoholic solvent provides high purity sumatriptan base. Present process avoids the usage of column chromatography and gives sumatriptan base in higher yield and better purity. Also, the process is optimized on a commercial scale to solve the problems associated with scale up operations of the Fischer indolization.

Description

IMPROVED PROCESS FOR THE PREPARATION OF HIGH
PURITY SUMATRIPTAN
FIELD OF INVENTION The present invention relates to an improved process for the preparation of sumatriptan. Sumatriptan which is 3-(2-dimethylamino)ethyl-N-methyl-lH-indole-5-methane- sulfonamide has the formula-I given below.
Figure imgf000002_0001
Sumatriptan and its pharmaceutically acceptable salts are widely used as antimigraine agents and also for cluster headaches.
BACKGROUND OF INVENTION
Sumatriptan is reported for the first time by Glaxo in GB patent no 2162522 (corresponding to the US patent no 5037845 (1989)). It is found to be serotonin 5HT1- receptor agonist. Its clinical evaluation in migraine is described in Lancet, 1, 1309 (1988) and its studies on cluster headache are revealed in Engl. J. Med. 325, 322 (1991). Sumatriptan succinate is available in the market as Imigran or Imitrex.
Process for the preparation of sumatriptan described in the GB patent no 2162522 is based on a Fischer indole synthesis. Accordingly, the compound of the formula-II is reacted with compound of the formula-Ill to get the corresponding hydrazone of the formula-IV which on cyclization using ethyl polyphosphate ester gave sumatriptan of the formula-I. This reaction sequence is shown in Scheme-I.
Figure imgf000003_0001
IV
Scheme-I
The indolyzation reaction was done by mixing 4 g of the hydrazone of formula-IV with 20 g polyphosphate ester in 80 ml chloroform medium at room temperature for 4 h. The crude sumatriptan (2.5 g) thus obtained after water work up was subjected to column chromatography to yield an oil (1.13 g) which on salt formation with succinic acid gave the corresponding hemi-succinate salt (0.83 g, overall yield is 14.8%).
The process does not mention about the mode of addition of reactants (hydrazone intermediate of formula-IV and polyphosphate ester) and the temperature during the mixing of reactants. During the process development for sumatriptan on a commercial scale we found that the Fischer indolization process shown in Scheme-I is highly scale dependent and yield dropped considerably with increasing the batch size.
Under the conditions employed in the above reported process on a typically 1 kg scale, yield of sumatriptan was less than 5%. The main impurities formed during the process are dimeric compounds of the formulae-V and VI and also some polymeric material. We also observed that mixing of reactants is very exothermic and the yield of sumatriptan during indolization is also temperature dependant, rate of addition of reactant dependant, and reaction maintenance time dependant. With increasing temperature and maintenance time formation of impurities increased drastically.
Figure imgf000004_0001
Sumatriptan has become a well-known anti-migraine drug that has now been on the market and has shown great promise . as a valuable anti-migraine drug with few side effects. Keeping in view of the difficulties in commercialization of the above-mentioned process for the preparation of sumatriptan, we aimed to develop a simple and economical process for commercial production of sumatriptan based on the process given in GB 2162522.
We observed that a promising approach for increasing/maintaining the yield and quality of sumatriptan (purity of at least 99%) during the scale up operations would be to (a) optimize the reaction temperature during the mixing of reactants, (b) optimize the amount of polyphosphate ester to suit the scale up operations, (c) fix the mode of addition of reactants (whether to add polyphosphate ester to the hydrazone intermediate or the intermediate to the polyphosphate ester, (d) optimize the rate of addition of polyphosphate ester to the hydrazone derivative, (e) optimize the maintenance time of reaction, and (f) avoid the usage of column chromatography.
Accordingly, the main objective of the present invention is to provide an improved process for the preparation of sumatriptan of the formula-I which is commercially applicable.
Another objective of the present invention is to provide an improved process for the preparation of sumatriptan of the formula-I of purity of at least 99% avoiding the formation of impurities. Still another objective of the present invention is to provide an improved process for the preparation of sumatriptan with high yield (>30%) and high purity (>99%).
Yet another objective of the present invention is to provide an improved process for the preparation of sumatriptan of the formula-I, which is simple avoiding column chromatography techniques thereby making the process economical.
Still another objective of the present invention is to provide an improved process for the preparation of solid crystalline sumatriptan of the formula-I which is directly obtained from the reaction mass by simple crystallization techniques.
The present invention has been developed based on our finding that the above Fischer indolization process is very sensitive to (i) temperature, (ii) the amount of polyphosphate ester used, (iii) rate of addition of polyphosphate ester and (iv) maintenance time of reaction. We also found that the optimization of these process parameters will result in the better yield and quality of sumatriptan formed. Also, the crude sumatriptan prepared under the above mentioned modified conditions can be easily crystallized from a number of solvents without requiring any column chromatography techniques.
During the studies on above Fischer indolization process for making sumatriptan on a commercial scale we observed that the mode of addition of reactants is very important. Addition of polyphosphate ester to the hydrazone intermediate of formula-IV gives' better yield and quality of product than the vice versa. During the Fischer indolization process addition of polyphosphate ester to the compound of the formula-IV is exothermic and controlling the temperature below 15 0C is very essential. To overcome the exothermic problem during scale up operations, cooling the reaction mass to below 5°C is also found to be very critical before the addition of polyphosphate ester. The rate of addition of polyphosphate ester to the compound of the formula-IV should be preferably within the period of 5-30 min, more preferably during the period of 10-15min. The maintenance temperature of the reaction mass should be preferably in the range of 15-3O0C, more preferably in the range of 20-25 °C. The maintenance time of reaction mass is preferably in the range of 2-4 h, more preferably in the range of 2.5-3.0 h. The amount of ethyl polyphosphate ester used in the reaction is preferably in the range of 4-8 times the weight of the compound of the formula-IV, more preferably in the range of 5-6 times. The reaction can be monitored by HPLC and the optimum percentage of sumatriptan produced was found to be in the range of 60-75%.
Modification of the process in the above suggested manner avoided the usage of costly column chromatography techniques and also resulting in the increase in yield of sumatriptan and tolerability of the process in scale up operations for industrial applications. These features of the improved process constitute the novelty of the present invention.
Accordingly, the present invention provides an improved process for the preparation of high purity (at least 99 %) sumatripan of the formula-I,
Figure imgf000006_0001
I which comprises:
(i) Cooling a solution of the phenylhydrazone of the formula-IV
Figure imgf000006_0002
IV to a temperature in the range of 0-10 0C
(ϋ) Adding polyphosphate ester to the cooled solution of the compound of the formula-IV obtained in step (i) at a temperature in the range of 0-15 0C (iϋ) Maintaining the resulting reaction mass obtained in step (ii) at a temperature in the range of 20-25 0C (iv) Quenching the reaction mass of the step (iii) into water and separating the organic layer
(v) Neutralizing the water layer obtained to above 10 pH using a base (vi) Extracting the sumatriptan formed with a polar solvent (vϋ) Concentrating the solvent extract obtained in step (vi) and crystallizing the crude mass containing sumatriptan from a polar solvent (viϋ) Isolating crystalline sumatriptan base by filtration (ix) Dissolving the solid sumatriptan base in an alcoholic solvent medium (x) Treating the alcoholic solution obtained in step (ix) with activated carbon (xi) Isolating the high purity (at least 99 %) crystalline sumatriptan base by filtration technique
The solvent used in step (i) may be selected from methylene chloride, chloroform, THF5 acetonitirile, etc, preferably methylene chloride or chloroform. The cooling temperature used in step (i) may be preferably in the range of 5-10 0C. The addition time of polyphosphate ester in step (ii) may be in the range of 5-25 min, preferably 10-15 min. The amount of polyphosphate ester used in step (ii) may be in the range of 4-8 times the weight of the compound of the formuIa-IV, preferably in the range of 5-6 times. The reaction maintenance time in step (iii) may be in the range of 3-5 h, preferably 2.5-3.0 h.
The base used in the neutralization step (v) may be selected from sodium carbonate, sodium hydroxide, potassium hydroxide, potassium carbonate, preferably sodium carbonate or potassium carbonate.
The polar solvent used in step (vi) for the extraction of crude sumatriptan base may be selected from methyl isobutyl ketone, methyl ethyl ketone, isopropyl acetate, ethyl acetate, diethyl ether, preferably diethyl ether or ethyl acetate.
The solvent used for crystallization of crude sumatriptan may be selected from ethyl acetate, isopropyl acetate, methanol, ethanol, isopropanol, methyl ethyl ketone, methyl isobutyl ketone, diethyl ether, diisopropyl ether, acetonitrile, preferably ethyl acetate or acetonitrile. The sumatriptan base obtained by this crystallization technique is of at least 98% purity. The alcoholic solvent used in step (ix) for recrystallization of sumatriptan base is selected from methanol, ethanol, isopropanol, or a mixture thereof, preferably methanol or ethanol. Purity of sumatriptan base thus obtained is of >99%.
According to the process of present invention 20-50 kg of the phenylhydrazone of formula-IV can be converted into sumatriptan base in >30% yield with >99% quality.
The details of the invention are described in Examples given below which are provided to illustrate the invention only and therefore should not be construed to limit the scope of the present invention.
Example 1 (i) Preparation of sumatriptan base Into a 1-L three-necked RB flask was charged 125 ml of water, 20 g of cone. HCl, and 50 g of 4-hydrazino-N-methylbenzenemethanesulfonamide hydrochloride. The reaction mass was stirred at 25-30 0C for 15min and added 45 g of 4-dimeth.ylarαinobutyraldehyde diethyl acetal. The reaction mass was maintained at 25-30 °C for 2 hr. Reaction was found to be over by TLC. Reaction mass was diluted with water (200ml) and the pH adjusted to 2.5 using sodium carbonate. The reaction mass is treated with carbon and adjusted the pH to 9.0 with sodium carbonate. Product was extracted into chloroform (2 x 400 ml). Chloroform layer was washed with water and dried over sodium > sulfate. Chloroform (50-75 ml) was distilled out from the solution.
The concentrated chloroform solution was transferred into a 2-L, three-necked RB flask. Chloroform (100 ml) was added to the reaction mass and cooled to below 5 °C under nitrogen atmosphere. Ethyl polyphosphate (200 g) was taken into addition funnel and added to the reaction mass over a period of lOmin keeping the temperature below 15 0C. After maintaining at same temperature for 30min, reaction mass was allowed to reach 25 °C and maintained for 2 hr at 20-25 0G. HPLC of the reaction showed 68% of sumatriptan present in reaction mass. The reaction mass was diluted with 800 ml of water and stirred for 20 min. Layers were separated and the aqueous layer extracted with 100 ml of chloroform. Water layer was treated with carbon and the pH adjusted to 9.0-9.5 with solid potassium carbonate. Crude sumatrptan was extracted into ethyl acetate (2 x 400 ml). Combined ethyl acetate layer was washed with water, dried and treated with carbon. Distillation of solvent under vaccum afforded 35 g of crude sumatriptan as syrup.
(ii) Crystallization of sumatriptan base
Acetonitrile (50 ml) was added to the residue and heated to 40 0C to get a clear solution. The solution was stirred at 20-25 °C for lhr and cooled to 5-10 0C. After maintaining for 4-5 hr solid sumatriptan base was isolated by filtration. Drying at 40-50 0C afforded 15 g of light yellow-colored sumatriptan base. Purity by HPLC was 97.8%.
Example 2 (i) Preparation of sumatriptan base Into a 100-L glass flask was charged 12.5 L of water, 2 kg of cone. HCl5 and 5 kg of 4- hydrazino-N-rnethylbenzenemethanesulfonamide hydrochloride. The reaction mass was stirred at 25-30 0C for 15min and added 4.5 kg of 4-dimethylaminobutyraldehyde diethyl acetal. The reaction mass was maintained at 25-30 0C for 2 hr. Reaction was found to be over by TLC. Reaction mass was diluted with water (20 L) and the pH adjusted to 2.5 using sodium carbonate. The reaction mass is treated with carbon (0.5 kg), filtered and filtrate pH adjusted to 9.0-9.5 with sodium carbonate. Reaction mass was extracted with chloroform (2 x 30 L). Chloroform layer was washed with water (20 L) and dried over sodium sulfate.
Chloroform (5-7 L) was distilled out from the reaction mass below 40 0C and the residue diluted with fresh chloroform (10 L). The reaction mass was cooled to below 5 0C under nitrogen atmosphere. Ethyl polyphosphate (18 kg) was added to the reaction mass over a period of 10-15 min keeping the temperature below 15 0C. After maintaining at same temperature for 30min, reaction mass was allowed to reach 25 0C and maintained for 2.0 hr at 20-25 0C. HPLC of the reaction mass showed 64 % of sumatriptan. The reaction mass was transferred into 200-L glass flask containing water (80L) keeping the temperature below 25 °C. The reaction mass was stirred for 20 min. Layers were separated and the aqueous layer extracted with 10 L of chloroform. Water layer was. taken into the reactor and treated with carbon (0.5 kg) and filtered under vaccum. Filtrate pH was adjusted to 9.0-9.5 with solid potassium carbonate keeping the temperature below 20 0C. Crude sumatriptan was extracted into ethyl acetate (2 x 15 L). Combined ethyl acetate layer was washed with water (2 L)5 dried with sodium sulfate and treated with carbon (1 kg). Distillation of solvent under vaccum afforded 3.5 kg of crude sumatriptan base as syrup.
(ii) Crystallization of sumatriptan base
Acetonitrile (4 L) was added to the residue obtained in step (i) and heated to 40 0C to get a clear solution. The solution was stirred at 20-25 0C for lhr and cooled to 5-10 0C. After maintaining for 4-5 hr at 5-10 0C crystalline sumatriptan base was isolated by filtration. Drying at 40-50 °C afforded 1.5 kg of light yellow-colored sumatriptan base. Purity by HPLC was 97.5%.
Example 3 Recrystallization of sumatriptan base Into a 1-L, three-necked RB flask was charged 100 g of sumatriptan base (obtained from the process described in example 2) and 900 ml of methanol. The reaction mass was heated to reflux temperature and maintained for 30 min to get a clear solution. Carbon (20 g) was added to the reaction mass and maintained at reflux for 30 min. The reaction mass was filtered and the carbon bed washed with 100 ml of hot methanol. The filtrate was cooled to 0-5 0C and maintained for 2 hr. Crystalline sumatriptan base was isolated by filtration under vaccum and the wet cake washed with 50 ml of chilled methanol. Drying of sumatriptan base crystals at 40-50 °C afforded 83 g of pure sumatriptan base as off-white crystalline solid. MP is 164 0C. Purity by HPLC is 99.2%. Advantages of Present Invention:
1. The process is suitable for a commercial preparation of sumatriptan
2. The process avoids costly column chromatographic purification of crude sumatriptan base thereby making the process not only simple but also economical.
3. The process produces sumatriptan base of purity of more than 99%.
4. The process gives improved yield (>30%) of sumatriptan base.
5. The process produces sumatriptan directly from the reaction mass by simple crystallization techniques. Thereby making the process simple and economical.

Claims

We Claim:
1. An improved process for the preparation of high purity (more than 99%) sumatripan base of the formula-I,
Figure imgf000012_0001
I which comprises:
(i) Cooling a solution of the phenylhydrazone of the formula-IV
Figure imgf000012_0002
IV to a temperature in the range of 0-10 0C
(ii) Adding ethyl polyphosphate to the cooled solution of the compound of the formula-IV obtained in step (i) at a temperature in the range of 0-30 °C (iii) Maintaining the resulting reaction mass obtained in step (ii) at a temperature in the range of 20-25 0C (iv) Quenching the reaction mass of the step (iii) into water and separating the organic layer
(v) Neutralizing the water layer obtained to above 10 pH using a base (vi) Extracting the sumatriptan formed with a polar solvent (vii) Concentrating the solvent extract obtained in step (vi) and crystallizing the crude mass containing sumatriptan from a polar solvent
(viii) Isolating crystalline sumatriptan base by filtration (ix) Recrystallizing the solid sumatriptan base obtained in step (viii) from an alcoholic solvent medium and (x) Isolating the pure crystals of sumatriptan base by filtration at low temperature 2) An improved process as claimed in claim 1 wherein the solvent used in step (i) is selected from, methylene chloride, chloroform, ethyl acetate, acetonitrile, preferably chloroform or methylene chloride.
3) An improved process as claimed in claims 1 & 2 wherein the amount of ethyl polyphosphate used in step (ii) is in the range of 5-8 times the weight of compound of the formula-IV, preferably in the range of 5-6 times.
4) An improved process as claimed in claims 1-3 wherein the preferred temperature during the addition of ethyl polyphosphate in step (ii) is between 0-15 0C.
5) An improved process as claimed in claim 1-4 wherein the maintenance time of reaction mass in step (iii) is in the range of 2-5 hr, preferably in the range of 2.5-3.0 hr.
6) An improved process as claimed in claims 1-5 wherein the base used in the neutralization step (v) is selected from sodium carbonate, sodium hydroxide, potassium hydroxide, potassium carbonate, preferably sodium carbonate or potassium carbonate.
7) An improved process as claimed in claims 1-6 wherein the polar solvent used for extraction of crude sumatriptan base in step (vi) is selected from methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, diethyl ether, preferably diethyl ether or isopropyl acetate.
8) An improved process as claimed in claims 1-7 wherein the solvent used for crystallization of crude sumatriptan base in step (vii) is selected from ethyl acetate, isopropyl acetate, methanol, ethanol, isopropanol, methyl ethyl ketone, methyl isobutyl ketone, diethyl ether, diisopropyl ether, acetonitrile, preferably ethyl acetate or acetonitrile. 9) An improved process as claimed in claim 1-8 wherein the alcoholic solvent used for recrystallizing the sumatriptan base in step (ix) is selected from methanol, ethanol, isopropanol, sec-butanaol, t-butanol, preferably methanol, or ethanol or a mixture thereof.
1O) An improved process as claimed in claims 1-9 wherein the low temperature used for the isolation of recrystallized sumatriptan base in step (xi) is in the range of 0-25°C, preferably in the range of 0-15 0C, more preferably 0-5 0C.
11) An improved process for the preparation of high purity (at least of 99%) sumatriptan base substantially as herein described with reference to the Examples.
PCT/IN2004/000353 2004-11-16 2004-11-16 Improved process for the preparation of high purity sumatriptan WO2006054311A2 (en)

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PCT/IN2004/000353 WO2006054311A2 (en) 2004-11-16 2004-11-16 Improved process for the preparation of high purity sumatriptan

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006137083A1 (en) * 2005-06-20 2006-12-28 Natco Pharma Limited Improved process for the preparation of rizatriptan benzoate
WO2009016414A1 (en) * 2007-08-02 2009-02-05 Generics [Uk] Limited Novel process
CN102212027A (en) * 2011-05-04 2011-10-12 苏州莱克施德药业有限公司 Preparation method for sumatriptan

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006137083A1 (en) * 2005-06-20 2006-12-28 Natco Pharma Limited Improved process for the preparation of rizatriptan benzoate
WO2009016414A1 (en) * 2007-08-02 2009-02-05 Generics [Uk] Limited Novel process
JP2010535187A (en) * 2007-08-02 2010-11-18 ジェネリクス・（ユーケー）・リミテッド New method
CN102212027A (en) * 2011-05-04 2011-10-12 苏州莱克施德药业有限公司 Preparation method for sumatriptan

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