WO2006137083A1

WO2006137083A1 - Improved process for the preparation of rizatriptan benzoate

Info

Publication number: WO2006137083A1
Application number: PCT/IN2006/000199
Authority: WO
Inventors: Muddasani Pulla Reddy; Hanumara Satyasrinivas; Kagitha Radharani; Nannapaneni Venkaiah Chowdary
Original assignee: Natco Pharma Limited
Priority date: 2005-06-20
Filing date: 2006-06-13
Publication date: 2006-12-28

Abstract

Present invention discloses an improved and commercially viable process for the preparation of rizatriptan benzoate of formula (I). According to the present process the hydrazone intermediate derived from the phenylhydrazine of formula- (III) and 4- dimethylaminobutyraldehyde diethyl acetal is gradually heated to 60-70 °C in aqueous sulfuric acid medium and maintained for 3-4hr to get rizatriptan with less dimeric impurity of formula (X). The resultant rizatriptan is isolated and converted into the pharmaceutically acceptable benzoate salt. Present process produces less percentage of dimeric (less than 3 %) or polymeric impurities compared to the prior art process and more yield of rizatriptan. Rizatriptan benzoate produced according to the present process has more than 99.5 % purity with less than 0.1% dimeric impurity of formula (X) by HPLC. Rizatriptan benzoate is useful for the treatment of migraine.

Description

IMPROVED PROCESS FOR THE PREPARATION OF RIZATRIPTAN BENZOATE

FIELD OF INVENTION

The present invention relates to an improved process for the preparation of rizatriptan benzoate. Rizatriptan benzoate which is 3-(2-(dimethylamino)ethyl)-5-(l,2,4-triazol-l- yl)methyl-lH-indole benzoic acid salt has the formula-I given below.

Rizatriptan (I(a))and its pharmaceutical salts such as benzoate are widely used as antimigraine agents and also for cluster headaches. Rizatriptan benzoate (maxalt) is widely used as anti-migraine drug in the market.

BACKGROUND OF INVENTION

Rizatriptan (I(a)) is reported for the first time by Merck Shark & Dohme in EP 497512

(1992). Rizatriptan is a selective serotonin 5-HT_1D receptor agonist.

The aforesaid European patent describes a process for the preparation of rizatriptan of formula-I(a) based on Fischer indole synthesis, using the corresponding phenylhydrazine and an aldehyde. Accordingly, phneylhydrazine derivative of formula-Ill is reacted with 4-chlorobutyraldehyde dimethyl acetal to get the tryptamine derivative of formula-IV which on N-methylation gave rizatriptan (Scheme-I). Over all yield of rizatriptan as its

IV l(a)

Scheme-I oxalate salt from the aniline derivative of formula-II is 11%.

Another process for the preparation of rizatriptan is also described in the above said European patent based on the same Fischer indole synthesis. Phenyl hydrazine derivative of formula-Ill is reacted with 4-(N,N-dimethylamino)-l,l_>-dimethoxybutane to get the rizatriptan. Overall yield of rizatriptan from the aniline compound of formula-II is 16.8%.

The main draw back in both the processes is low yield and requirement of column chromatography to isolate rizatriptan. Therefore, the processes are not amenable for commercial scale.

A slightly improved process for the preparation of rizatriptan is disclosed in EP 573221 based on above mentioned Fischer indole synthesis. The aniline compound of formula-II is reacted with sodium nitrite/HCl and reduced with sodium sulfite to get the phenylhydrazine derivative of formula-Ill. The reaction mass containing the phenylhydrazine derivative of formula-Ill is directly reacted with 4-(N₅N- dimethylamino)-l,l,-dimethoxybutane at 90-93 °C for 15 min to get rizatriptan in 45% yield after doing column chromatography. The main drawback in the process is requirement of column chromatography to remove polymeric side products. Therefore the process is not viable for commercial scale up. An improved process for the preparation of rizatriptan based on palladium catalyzed coupling between the iodoaniline and acetylene compound is disclosed in US pat 5567824 (Scheme-II). Aniline derivative of formula-II was reacted with iodine monochloride to get the iodo derivative of formula-V. 3-Butyn-l-ol was reacted with n- butyl lithium and triethylsilyl chloride to get the corresponding bis-silylated derivative of formula- VI. Coupling of the iodo-aniline derivative of formula-V and the bis-silylated derivative of formula- VI in the presence of palladium acetate gave the tryptopol derivative of formula- VII. Desilylation of compound of formula-VII gave the tryptopol derivative of formula- VIII. Tryptopol derivative of formula- VIII was converted to

Scheme-II rizatriptan via mesylate formation. Overall yield of rizatriptan by this route is about 30%. Purity of rizatriptan is 89% only. Conversion of rizatriptan base to its benzoate salt gave a 95% quality product.

Main drawback in this process is handling of corrosive iodine monochloride, hazardous and costly butyl lithium. Palladium acetate is very expensive. Also, 3-butyn-l-ol, used in the process is expensive and not readily available on commercial scale. Purity of rizatriptan base is 89% only. Conversion of this base to benzoate salt gave 95% quality product. Therefore rizatriptan benzoate produced by this process as such is not acceptable for pharmaceutical formulations. Also, the overall yield of rizatriptan has not increased compared to the prior art process. Therefore, the process is not viable for commercial production of rizatriptan.

Keeping in view of the difficulties in commercialization of the above-mentioned process for the preparation of rizatriptan, we aimed to develop a simple and economical process for commercial production of rizatriptan.

We observed that a promising approach for a process for the preparation of rizatriptan will be to (a) avoid the usage of costly and hazardous reagents like n-butyl lithium, iodine monochloride, 3-butyl-l-ol, palladium acetate (b) avoid the column chromatography to purify the intermediates or final product (c) avoid harsh conditions such as 90- 100⁰C during indolyzation to minimize the polymeric material formation.

Accordingly, the main objective of the present invention is to provide an improved process for the preparation of rizatriptan, which is commercially applicable.

Another objective of the present invention is to provide an improved process for the preparation of rizatriptan avoiding the usage of costly and hazardous reagents thereby making the process simple and economical.

Yet another objective of the present invention is to provide an improved process for the preparation of rizatriptan avoiding the column chromatography purification technique for isolating rizatriptan thereby making the process further simpler and economical.

Still another objective of the present invention is to provide an improved process for the preparation of rizatriptan wherein the overall yield is consistent during scale-up operations. Still another objective of the present invention is to provide an improved process for the preparation of solid crystalline rizatriptan of the formula-I which is directly obtained from the reaction mass by simple crystallization techniques.

During our studies (pending Indian patent application No. 1195/CHE/04) on Fischer indolization process for making sumatriptan on a commercial scale we observed that the temperature of reaction is very critical to avoid the polymeric material formation. Also, if one minimizes the formation of polymeric impurities, required indole derivative can be easily crystallized from reaction mass thereby avoiding the usage of column chromatography. Keeping this in mind we aimed to develop a process for the preparation of rizatriptan based on the original process disclosed in EP 573221.

The present invention has been developed _^based on our finding that the above Fischer indolization process is very sensitive to temperature and rate of heating of reaction mass. We also found that one major impurity formed in the indolyzation step is a dimeric impurity of formula-X,

X

Under the prior art (EP 573221, Preparation 1) conditions (15min at 90-93⁰C) formation of. above impurity is more than 20%. Physico-chemical properties (solubility of base or salts in organic solvents) of this impurity make it difficult to separate from the rizatriptan by conventional crystallization techniques. Therefore, only column chromatography technique is useful in separating this impurity from rizatriptan. ^c

During the studies on above Fischer indolization process for making rizatriptan on a commercial scale we observed that the indolization takes place even while making the precursor hydrazone at 25-30 °C. This indicates that the reflux temperature (90-93°C) is not required to make rizatriptan. A careful investigation on rate of reaction versus temperature indicated that with increasing temperature reaction proceeded fast. But, simultaneously formation of impurity of formula-X also increased with increasing temperature. To optimize the formation of rizatriptan and to reduce the formation of impurity of formula-X, reaction was conducted at different temperatures. Optimum percentage (ca. 70%) of rizatriptan formation (by HPLC) was observed at 50-70 ⁰C. Formation of the impurity of formula-X is below 3% and its removal became easy. After usual work-up of the reaction mass rizatriptan was isolated by crystallizing from an organic solvent. Alternatively, the crude rizatriptan can be converted into its benzoate salt. Purity of isolated solid rizatriptan is > 95% and that of benzoate salt is >98%. One recrystallization of rizatriptan base or benzoate salt from a suitable solvent gave >99% quality product.

Accordingly, the present invention provides an improved process for the preparation of rizatriptan benzoate of the formula-I,

I which comprises:

(i) Addition of 4-dimethylaminobutyraldehyde diethyl acetal to an aqueous sulfuric acid solution of phenylhydrazine of formula-Ill,

III at a temperature of 15-30 °C (ii) Maintenance of reaction mass at 15-30 °C for 3-6hr (iii) Heating of reaction mass to 50-70 °C and maintenance of reaction mass at 50-

70 °C for 2-4hr

(iv) Cooling of reaction mass to 25-30 °C and neutralization to pH 6-7 with a base (v) Removal of liberated impurities from the reaction mass by extraction into an organic solvent

(vi) Carbon treatment to aqueous layer and pH adjustment to 8-9 with a weak base

(vii) Extraction of crude rizatriptan base into an organic solvent

(viii) Distillation of solvent and formation of crude rizatriptan benzoate salt in an organic solvent (ix) Isolation of crude rizatriptan benzoate salt by filtration

(x) Dissolution of crude rizatriptan benzoate salt in water medium and neutralization with a base

(xi) Extraction of pure rizatriptan base into a solvent

(xii) Partial distillation of solvent and crystallization of rizatriptan base from same solvent

(xiii) Isolation of pure rizatriptan base by filtration

(xiv) Formation of rizatriptan benzoate by dissolution of pure rizatriptan base in a solvent and addition of benzoic acid (xv) Isolation of pure rizatriptan benzoate by filtration

In a preferred embodiment of the present invention preferred temperature of reaction mass in step (iii) is 60-70 ⁰C, more preferably 60-65°C. It is observed that during the maintenance time attempts to consume all starting hydrazone led to the increased formation of impurity of formula-X. Therefore preferred maintenance time is 2-3 hours, more preferably 2.0-2.5hr. The base used for neutralization in step (iv) is selected from an organic base such as ammonia or an inorganic base such as sodium or potassium carbonate, bicarbonate, etc., preferably ammonia.

Organic solvent used in step (v), (vii), and (xi) is selected from esters like ethyl acetate, and hydrocarbon solvents such as toluene, or halogenated solvents such as methylene chloride, preferably toluene or ethyl acetate. Weak base used in step (vi) is selected from ammonia or alkylamines such as triethylamine, preferably ammonia. Solvent used for extraction of crude rizatriptan base includes esters like ethyl acetate, and hydrocarbon solvents such as toluene, or halogenated solvents such as methylene chloride, chloroform, preferably toluene or ethyl acetate.

During benzoate salt formation in step (viii) and (xiv) preferred solvents are ketones like acetone, methyl ethyl ketone, alcohols like methanol, ethanol, isopropanol, esters like ethyl acetate or nitriles like acetonitrile can be used, preferable acetone, methanol, or ethanol. Purity of crude rizatriptan benzoate obtained in step (ix) is more than 95% by HPLC. Purity of pure rizatriptan base obtained in step (xii) is more than 99%. Quality of final pharma grade rizatriptan benzoate obtained according to this process is more than 99.7% and impurity of formula -X is less than 0.1%.

The details of the process of the invention are provided in the Examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

Example 1

Preparation of l-(4-NitrophenylmethyI)-l,2,4-triazole (i) Preparation of sodium triazole dihydrate

Into a IOOL glass flask were charged 50L of isopropanol and 2.9kg of sodium hydroxide flakes. The reaction mass was heated to 70°C. After maintaining for 30min at same temperature lH-l,2,4-triazole (5.0kg) was added to the reaction mass. The reaction mass was maintained at reflux temperature for lhr. Slowly cooled the reaction mass to 30°C and maintained for 3hr. The reaction mass was filtered and the wet cake washed with 5L of isopropanol. The wet material was dried at 60⁰C until a constant weight is reached. Yield of sodium 1,2,4-triazole is 6.5kg.

(ii) Preparation of l-(4-Nitrophenylmethyl)-l,2,4-triazoIe Into a 50L-glass flask were charged 1OL of methanol, 2kg of 4-nitrobenzyl chloride, and 1.57kg of sodium 1,2,4-triazole. The resultant solution was heated to reflux temperature and maintained at reflux temperature for 2hr. Methanol was distilled out from the reaction mass under mild vaccum. Methanol (5L) was added to the residue and maintained at 30⁰C for lhr. Reaction mass was further cooled to 0°C and maintained for lhr before filtration. The wet cake was washed with 500ml of chilled methanol. The wet material thus obtained was taken into 50L glass flask and charged 5L of water. After stirring for lhr at 30°C, reaction mass was filtered and the wet solid washed with IL water. The wet material was dried at 50°C to get 1.5kg of the title compound.

Example 2

Preparation of l-(4-NitrophenyImethyI)-l,2,4-triazole

(i) Preparation of l-(4-Nitrophenylmethyl)-4-amino-4H-l,2,4-triazolium chloride Into a 50L glass reactor are charged n-butanol (10L), 4-amino- 1,2,4-triazole (560 g), 4- nitrobenzyl chloride (1.2kg), and tetra-n-butylammonium bromide (22.5 g) at 25-30°C. The reaction mass was heated to reflux temperature and maintained for 5h. The reaction mass was cooled to 25 °C and filtered. The wet cake was washed with IL of n-butanol. The wet solid was dried at 60-65⁰C to get 1.3kg of title compound as white solid. Melting point: 186-188°C. IR (KBr): 3242.0, 3106.0, 3031.1, 1613.9, 1542.1, 1491.5, 1411.9, 1350.0, 1292.8, 1194.1, 1173.7, 1153.5, 1143.0, 1104.5, 1066.5, 1046.3, 994.0, 952.3, 929.3, 904.1, 871.8, 859.0, 814.2, 784.8, 730.4, 706.7, 696.2, 670.8, 639.7, 629.6, 614.9, 526.8, 483.9, 462.4, and 426.9cm^"1.

(ii) Preparation of l-(4-Nitrophenylmethyl)-l,2,4-triazole

Into a clean glass flask are charged water (42L) and l-(4-Nitrophenylmethyl)-4-amino- 4H-l,2,4-triazolium chloride (6.0kg) prepared in step (i) at 25-30⁰C. Concentrated hydrochloric acid (4L) was added to the reaction mass at 25-30⁰C. The reaction mass was stirred for 10-15min at 25-30 ⁰C and cooled to -5 to 0 °C. A solution of sodium nitrite in water (1.55kg in 6.5L) was added to the reaction mass in 60-90min keeping the temperature below 0⁰C. After completion of maintenance at 0-5 ⁰C for lhr the reaction mass was allowed to reach 20-25°C over a period of lhr. A clear solution will form. Aq. ammonia was added to the reaction mass to get a pH of 9.0-9.5 keeping the temperature below 3O⁰C. The reaction mass was cooled to 0-5°C and maintained for lhr at 0-5°C. The reaction mass was filtered and the cake washed with 3L of DM water. The white solid thus obtained was dried in the oven at 60-70°C to get 4.2kg of title compound.

Example 3

Preparation of rizatriptan benzoate (i) Preparation of l-(4-aminophenylmethyl)-l,2,4-triazoIe

Methanol (350L) and l-(4-nitrophenylmethyl)-l,2,4-triazole (35kg) were charged into a clean and dry stainless steel hydrogenation kettle at 25-30°C. Wet Raney nickel (7kg) was added to the reaction mass and passed hydrogen (40-50 psi) at 25-30°C. After feeding hydrogen for 5hr reaction was found to be over by TLC. Hydrogen was replaced with nitrogen in the kettle and filtered the reaction mass. Methanol was partially distilled of from the filtrate and cooled the residue to 20-25°C. The reaction mass was filtered and the cake washed with 2OL of methanol. Drying of the wet cake at 40-50°C gave the title compound (30kg) as pure white solid. Purity by HPLC is 99.3%.

(ii) Preparation of crude rizatriptan benzoate

Into a clean IOOL glass reactor were charged water (20L) cone. HCl (8.5L), and l-(4- aminophenylmethyl)-l,2,4-triazole (5.0Kg). The reaction mass was stirred for 20-30min at 25-30 °C and cooled to 0-5 °C. Aqueous sodium nitrite (2.1Kg in 3.0Lof water) was added to the reaction mass below 5°C over a period of 2hr. The reaction mass was maintained below 5⁰C for lhr.

Into a clean, 200L glass reactor were charged water (30 L) and sodium sulfite (9.0 Kg) under nitrogen atmosphere at 25-30 °C. The resulting solution was cooled to below 10 °C. Above diazonium salt solution was added to the reaction mass in 20-30 min period keeping the temperature below 10 °C. The reaction mass was slowly heated to 65-7O⁰C over a period of 2.5-3. Ohr. After maintaining at this temperature for 2hr sulfuric acid (7.2L) was added to the reaction mixture and continued the maintenance at same temperature for 2.0-2.5 hr. The reaction mass was cooled to reach 20-25 ⁰C.

4-Dimethylaminobutyraldehyde diethyl acetal (7.8 kg) was added to the reaction mass in 30-45min keeping the temperature at 25-30 °C. The reaction mass was maintained at this temperature for 4-5hr. TLC of the reaction mass indicated the absence of starting material. The reaction mass was heated to 35-40⁰C and maintained for lhr. Temperature of the reaction mass was further raised to 60-65°C and maintained for 3.5hr. The reaction mass was cooled to 20-30°C and adjusted the pH of reaction mass to 6.5-7.0 with ammonia solution. Ethyl acetate (15L) was added to the reaction mass and stirred for 15- 20min and separated the organic layer. Aqueous layer pH was adjusted to 8.5-9.0 with ammonia solution. Aqueous layer was extracted with ethyl acetate (3 x 35L). Combined ethyl acetate layer was treated with activated carbon (lkg) and distilled of solvent under reduced pressure to get 4.7kg crude rizatriptan base as oil.

The above crude rizatriptan base was dissolved in 18L of acetone at 25-30 ⁰C. Benzoic acid (2.1kg) was added to the reaction mass at 25-30 °C. After stirring for 45-60min at 25-30 °C the reaction mixture was cooled to below 0 °C and maintained for 10-12hr. The reaction mass was allowed to reach 20-25 ⁰C and maintained for 2.5hr- before filtration. The wet cake was washed with 3.5L of acetone. Drying at 50-60 °C gave 3kg of rizatriptan benzoate.

(iii) Recrystallization of rizatriptan benzoate

The above prepared rizatriptan benzoate (3kg) was added to 5% aqueous methanol (12L) and heated to reflux temperature. Activated carbon was added to the reaction mass and filtered. Filtrate was slowly allowed to reach 25 ⁰C and maintained for lOhr. The reaction mass was cooled to below 5°C and maintained for 2hr. Filtration of the reaction mass and washing of the wet cake with 5% aqueous methanol (IL) and drying at 60 °C gave 2.5kg of pure rizatriptan benzoate as white solid. HPLC purity is 99.60% and the single impurity is 0.22%. Example 4

Preparation of rizatriptan benzoate

(i) Preparation of crude rizatriptan benzoate: Into a clean IOOL glass reactor were charged water (30L)₅ cone. HCl (15kg), and l-(4- aminophenylmethyl)-l,2,4-triazole (7.5Kg). The reaction mass was stirred for 20-30min at 25-30 ⁰C and cooled to below 0 °C. Aqueous sodium nitrite (3.2Kg in 5Lof water) was added to the reaction mass below 5°C over a period of 2hr. The reaction mass was maintained below 5°C for lhr.

Into a clean, 200L glass reactor were charged water (45 L) and sodium sulfite (13.5 Kg) under nitrogen atmosphere at 25-30 °C. The resulting solution was cooled to below 10 ⁰C. The above prepared diazonium salt solution was added to the reaction mass in 20-30 min period keeping the temperature below 10 °C. The reaction mass was slowly heated to 65-70°C over a period of 2.5-3.Ohr. After maintaining at this temperature for 2hr sulfuric acid (19.8kg) was added to the reaction mixture and continued the maintenance at same temperature for 2.0-2.5 hr. The reaction mass was cooled to reach 20-25 ⁰C.

4-Dimethylaminobutyraldehyde diethyl acetal (11.7 kg) was added to the reaction mass in 30-45min keeping the temperature at 25-30 ⁰C. The reaction mass was maintained at this temperature for 4-5hr. TLC of the reaction mass indicated the absence of starting material. The reaction mass was heated to 35-40°C and maintained for lhr. Temperature of the reaction mass was further raised to 60-65°C and maintained for 3.5hr. The reaction mass was cooled to 20-30°C and adjusted the pH of reaction mass to 6.5-7.0 with ammonia solution. Ethyl acetate (15L) was added to the reaction mass and stirred for 15-

20min and separated the organic layer. Aqueous layer pH was adjusted to 8.8-9.2 with ammonia solution. Aqueous layer was extracted with ethyl acetate (3 x 45L). Combined ethyl acetate layer was treated with activated carbon (1.5kg) and distilled of solvent under reduced pressure to get 7.5kg of crude rizatriptan base as oil. The above crude rizatriptan base was dissolved in 3OL of acetone at 25-30 ⁰C. Benzoic acid (3.5kg) was added to the reaction mass at 25-30 °C. After stirring for 45-60min at 25-30 °C the reaction mixture was cooled to below 0 °C and maintained for 10-12hr. The reaction mass was allowed to reach 20-25 °C and maintained for 2.5hr before filtration. The wet cake was washed with 5L of acetone. Drying at 50-60 ⁰C gave 4.5kg of rizatriptan benzoate.

(ii) Preparation of pure rizatriptan base:

Water (10L) was taken into a glass flask and charged the crude rizatriptan benzoate (5kg) obtained in step (i) above. After stirring for about 20min saturated potassium carbonate was added to the reaction mass to get a pH of 9.0-10.0. Reaction mass was extracted with 1 x 30L, 2 x 15L, and 1 x 1OL of ethyl acetate. Combined organic layer was washed with 1OL of water. The organic layer was dried with sodium sulfate and treated with 0.7kg of carbon. After filtering of the carbon ethyl acetate was distilled of under reduced pressure to leave about 4-5L in the reaction. The reaction mass was cooled to 10-15 °C and maintained for 2hr. Filtration of reaction mass and washing of the wet cake with IL chilled ethyl acetate gave 2.5kg of rizatriptan base as white solid. Melting point is

Purity by HPLC is 99.3% with 0.1% of impurity of formula-X.

Recrystallization of a small sample from ethyl acetate gave 99.8% quality rizatriptan base with 85% recovery.

(iii) Preparation of rizatriptan benzoate

Into a IOOL glass flask were charged 75L of acetone and 7.5kg of rizatriptan base. The reaction mass was stirred for 30min. To the resultant solution was added 3.5kg of benzoic acid. Immediately formation of crystalline rizatriptan benzoate was observed. The reaction mass was stirred at 30 ⁰C for 4hr. The reaction mass was filtered and the wet cake washed with 5L of acetone.

(iv) Recrystallization of rizatriptan benzoate

Into a IOOL glass flask were charged 7OL of ethanol and the above obtained wet rizatriptan benzoate. The reaction mass was heated to reflux temperature to get a clear solution, the solution was treated with carbon (lkg) and filtered. The filtrate was cooled below 5°C and maintained for 2hr. the reaction mass was filtered and washed the set material with 2L of ethanol. Drying of the wet material at 60⁰C gave 9.5kg of pure rizatriptan benzoate as white crystalline solid. Purity by HPLC is 99.85%.

Example 5

Preparation of 3-[2-(dimethylamino)ethyl]-2-[[3-[2-(dimethylamino)ethyl]-lH-indol- 5-yl]methyl]-5-(lH-l,2,4-triazol-l-ylmethyl)indole of formula-X Into a IL single necked RB flask were charged 500ml of mother liquors of crude rizatriptan benzoate obtained in step (ii) of Example 3. Acetone was distilled of from the mass under vaccum and the residue suspended in 500ml of water. Reaction mass pH was adjusted to 9.0-9.5 with potassium carbonate and extracted with 3 x 300ml of ethyl acetate. Combined ethyl acetate layer was washed with brine, dried and distilled of solvent under vaccum to get 30g of syrup. Column chromatography of this syrup gave 5g of the title compound as off-white solid. M. P. is 146-150°C. IR (KBr): 3296.6, 3119.0, 3033.9, 2943.3, 2824.0, 2774.0, 1623.8, 1507.7, 1465.0, 1440.6, 1373.8, 1350.2, 1324.4, 1274.0, 1255.0, 1229.4, 1197.0, 1167.2, 1138.9, 1105.5, 1046.1, 1014.4, 1004.8, 965.8, 934.4, 860.2, 800.4, 764.5, 744.0, 683.6, 660.1, 640.0, and 579.8cm-¹. ¹H-NMR (300MHz, CDCl₃): δ 8.10 (s, IH, exch. with D₂O, NH); 7.96 (s, IH, triazole H); 7.95 (s, IH, triazole H); 7.78 (s, IH, exch. with D₂O, NH); 7.51 (s, IH, aromatic H); 7.47 (s, IH, aromatic H); 7.29 (d, J = 8.30Hz, IH, aromatic H); 7.15 (d, J = 8.30Hz, IH, aromatic H); 7.05 (d, J = 1.95Hz, IH, aromatic H); 7.01 (dd, J = 1.71, 3.66Hz, IH, aromatic H); 6.99 (dd, J = 1.71, 3.91Hz, IH, aromatic H); 5.40 (s, 2H, triazolyl CH₂); 4.22 (s, 2H, indolyl CH₂); 2.99 (t, J = 8.30Hz, 2H, CH₂CH₂N); 2.91 (t, J = 8.30Hz, 2H, CH₂CH₂N); 2.62 (t, J = 8.30Hz, 2H, CH₂CH₂N); 2.56 (t, J = 8.30, 2H, CH₂CH₂N); 2.36 (s, 6H, 2 x NCH₃); 2.32 (s, 6H, 2 x NCH₃). ¹³C-NMR (75MHz, CDCl₃): δ 151.58, 142.69, 136.36, 135.45, 135.26, 128.79, 127.71, 124.46, 122.72, 122.34, 121.37, 118.55, 113.69, 111.58, 109.72, 60.41, 60.14, 54.57, 45.30, 32.47, 23.50, and 22.70ppm. Mass (EI-MS): 470.2 (M + 1), 425.1, 401.2, 356.1, 344.2, 313.2, 301.1, 201.1, 158.1. Advantages of Present Invention:

1. Process for preparation of rizatriptan base or its benzoate salt does not require column chromatography.

2. Process is suitable for commercial scale with consistent yield and quality of rizatriptan base or benzoate salt.

3. Process produces very little (<3%) impurity of formula-X, which makes it suitable for isolation of rizatriptan base or benzoate salt by simple crystallization techniques.

4. Overall yield of rizatriptan base is 5-10% more than the prior art yield.

Claims

Claims:

1. Improved process for the preparation of rizatriptan benzoate of the formula-I,

which comprises:

> (i) Addition of 4-dimethylaminobutyraldehyde diethyl acetal to an aqueous sulfuric acid solution of phenylhydrazine of formula-Ill,

III at a temperature of 15-30 ⁰C

(ii) Maintenance of reaction mass at 15-30 °C for 3-6hr

(iii) Heating of reaction mass to 50-70 °C and maintenance of reaction mass at 50- 70 °C for 2-4hr

(vii) Extraction of crude rizatriptan base into an organic solvent

(viii) Distillation of solvent and formation of crude rizatriptan benzoate salt in an organic solvent

(ix) Isolation of crude rizatriptan benzoate salt by filtration

(xi) Extraction of pure rizatriptan base into a solvent (xii) Partial distillation of solvent and crystallization of rizatriptan base from same solvent

(xiii) Isolation of pure rizatriptan base by filtration

(xiv) Formation of rizatriptan benzoate by dissolution of pure rizatriptan base in a solvent and addition of benzoic acid

(xv) Isolation of pure rizatriptan benzoate by filtration

2. A process according to claim 1 wherein the temperature of reaction mass in step (iii) is 60-70 ⁰C, more preferably 60-65°C.

3. A process according to claims 1 & 2 wherein the base used for neutralization in step (iv) is selected from an organic base such as ammonia or an inorganic base such as sodium or potassium carbonate, bicarbonate, etc., preferably ammonia.

4. A process according to claims 1-3 wherein the organic solvent used in step (v), (vii), or (xi) is selected from esters like ethyl acetate, and hydrocarbon solvents such as toluene, or halogenated solvents such as methylene chloride, preferably toluene or ethyl acetate.

5. A process according to claims 1-4 wherein the weak base used in step (vi) is selected from ammonia or alkylamines such as triethylamine, preferably ammonia.

6. A process according to claim 1-5 wherein the solvent used for crystallization of rizatriptan benzoate in step (viii) or (xiv) is selected from alcohols like methanol, ethanol, isopropanbol, ketones like acetone, methyl ethyl

like acetonitrile with or without a combination of water.

7. A process according to claims 1-6 wherein the amount of water used in crystallization step (viii) or (xiv) is 5-10%.

8. A process according to claim 1-7 wherein the base used in step (x) is selected from sodium or potassium hydroxide, carbonate or bicarbonate, preferably sodium or potassium carbonate.

9. Purity of crude rizatriptan benzoate obtained according to the process of present invention is more than 95% with the impurity of formula-X in less than 1.5%.

X

10. Purity of the pure rizatriptan base obtained according to the process of present invention is more than 99.5% with the impurity of formula-X in less than 0.2%, preferably 0.15% and the purity of rizatriptan benzoate is more than 99.5%, preferably more than 99.7% with the impurity of formula-X in less than 0.15%, preferably 0.10%.