Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF HIGH PURITY SUMATRIPTAN

Abstract

A process for inhibiting the fouling of a substrate in a marine fouling environment, which comprises forming on the substrate, before exposure to the said environment, a coating comprising a curable fluorinated resin of the general formula: W - L - YFC - O - R?f¿ - CFY - L - W wherein : W is a group of the general formula -Si(R?1¿)¿$g(a)?(OR?2¿)¿3-$g(a)?, wherein $g(a) = 0, 1, or 2, preferably $g(a) = 0, R?1¿ and R?2¿ independently have the meaning of linear of branched C¿1?-C¿6? alkyl groups, optionally containing one or more ether groups, or C¿7?-C¿12? aryl or alkyl groups, and preferably R?1¿ and R?2¿ are C1-C4 alkyl groups; L is an organic linking group; Y is F or CF¿3?; and R?f¿ is a group having an average molecular weight by number between 350 and 8000, preferably between 500 and 3000, and comprising repeating units having at least one of the following structures randomly distributed along the chain: -CFXO-, CF¿2?CF¿2?O-, CF¿2?CF¿2?CF¿2?O-, CF¿2?CF¿2?CF¿2?CF¿2?O-, CR?4¿R?5¿CF¿2?CF¿2?O-, -(CF(CF¿3?)CF¿2?O)-, -CF¿2?CF(CF¿3?)O-, wherein X is F or CF¿3?, R?4¿ and R?5¿ independently have the meaning of H, Cl, or C1-C4 perfluoroalkyl.

Full Text

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-1 H-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. 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 5HTi-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. 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. 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 °C 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 15-30°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%. 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, to a temperature in the range of 0-10 °C (ii) 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 ""C (iii) Maintaining the resulting reaction mass obtained in step (ii) at a temperature in the range of 20-25 *^C (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) 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, THF, acetonitirile, etc, preferably methylene chloride or chloroform. The cooling temperature used in step (i) may be preferably in the range of 5-10 °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 formula-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 fi'om 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 °C for 15min and added 45 g of 4-dimethylaminobutyraldehyde 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 °C. After maintaining at same temperature for 30min, reaction mass was allowed to reach 25 °C and maintained for 2 hr at 20-25 °C. 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 °C to get a clear solution. The solution was stirred at 20-25 °C for Ihr and cooled to 5-10 °C. After maintaining for 4-5 hr solid sumatriptan base was isolated by filtration. Drying at 40-50 °C 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. HCl, and 5 kg of 4-hydrazino-N-methylbenzenemethanesuIfonamide hydrochloride. The reaction mass was stirred at 25-30 °C for 15min and added 4.5 kg of 4-dimethylaminobutyraldehyde 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 (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 fi'om the reaction mass below 40 °C and the residue diluted with fresh chloroform (10 L). The reaction mass was cooled to below 5 °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 °C. After maintaining at same temperature for 30min, reaction mass was allowed to reach 25 °C and maintained for 2.0 hr at 20-25 °C. HPLC of the reaction mass showed 64 % of sumatriptan. The reaction mass was transferred into 200-L glass flask containing water (SOL) 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 °C. Crude sumatriptan was extracted into ethyl acetate (2 x 15 L). Combined ethyl acetate layer was washed with water (2 L), 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 °C to get a clear solution. The solution was stirred at 20-25 °C for Ihr and cooled to 5-10 °C. After maintaining for 4-5 hr at 5-10 °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 °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. Drying of sumatriptan base crystals at 40-50 °C afforded 83 g of pure sumatriptan base as off-white crystalline solid. M.P is 164 °C. 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. We Claim: 1. An improved process for the preparation of high purity (more than 99%) sumatripan base of the formula-I, which comprises: (i) Cooling a solution of the phenylhydrazone of the formula-IV to a temperature in the range of 0-10 °C (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 °C (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 °C. 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 10) 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 °C, more preferably 0-5 °C. 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.

Documents:

1195-che-2004-abstract.pdf

1195-che-2004-claims filed.pdf

1195-che-2004-claims granted.pdf

1195-che-2004-correspondnece-others.pdf

1195-che-2004-correspondnece-po.pdf

1195-che-2004-description(complete)filed.pdf

1195-che-2004-description(complete)granted.pdf

1195-che-2004-form 1.pdf

1195-che-2004-form 19.pdf

1195-che-2004-form 5.pdf

1195-che-2004-pct.pdf