WO2008075163A2

WO2008075163A2 - An improved process for the preparation of rizatriptan

Info

Publication number: WO2008075163A2
Application number: PCT/IB2007/003896
Authority: WO
Inventors: Joseph Prabahar Koilpillai; Magesh Subramanian; Uppalaiah Mallela; Venkata Balaji Boddu; Ramesh Dandala; Sivakumaran Meenakshisunderam
Original assignee: Aurobindo Pharma Limited
Priority date: 2006-12-15
Filing date: 2007-12-10
Publication date: 2008-06-26
Also published as: EP2121663A2; WO2008075163A3

Abstract

The present invention relates to an improved process for preparing N,N-dimethyl-5-(1H-1,2,4-triazol-1-ylmethyl)-1H-indole-3-ethanamine of Formula (I) and its pharmaceutically acceptable salts.

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF RIZATRIPTAN

FIELD OF THE INVENTION

The present invention relates to an improved process for preparing N,N-dimethyl-5-( 1 H- 1 ,2,4-triazol- 1 -ylmethyl)- 1 H-indole-3-ethanamine of Formula I

Formula I

and its pharmaceutically acceptable salts. BACKGROUND OF THE INVENTION

Rizatriptan benzoate is chemically known as, N,N-dimethyl-5-(lH-l,2,4-triazol-l- ylmethyl)-l H-indole-3-ethanamine monobenzoate of Formula I, which is used as an antimigraine drug. Rizatriptan benzoate is being marketed under the proprietary name MAXALT as an oral tablet.

Rizatriptan is an orally active serotonin 5-HT(I) receptor agonist that potently and selectively binds to 5-HT(lB/lD) subtypes. Rizatriptan is used in the treatment of migrane and associated conditions like cluster headache, chronic paroxysmal hemicrains, headache associated with vascular disorders, tension headache and pediatric migrane.

US 5,298,520 discloses a method of preparing rizatriptan comprising reacting 4- nitrobenzylbromide with 1,2,4-triazole sodium salt in anhydrous dimethylformamide to yield l-(4-nitrophenyl)methyl- 1,2,4-triazole. This l-(4-nitrophenyl)methyl- 1,2,4- triazole was hydrogenated using 10% PaVC in ethanol and hydrochloric acid to give l-(4-aminophenyl)niethyl- 1,2,4-triazole. Subsequently the l-(4-aminophenyl)methyl- 1,2,4-triazole was treated with sodium nitrite in the presence of concentrated hydrochloric acid and SnCl₂ dihydrate to give l-(4-hydrazinophenyl)methyl- 1,2,4- triazole dihydrochloride, which on further condensation with 4- (dimethylamino)butanal dimethylacetal in aqueous sulphuric acid yielded Rizatriptan. Rizatriptan base was converted to its benzoate salt using benzoic acid in diethyl ether. The process is as summarized below:

Benzoic acid in diethyl ether

The main disadvantage of this process is generation of large quantity of isomeric Rizatriptan due to 4-substituted triazole. Further, the above process has another disadvantage of reduction of diazonium salt with SnCl₂ dihydrate in concentrated hydrochloric acid. Tin salts are notoriously toxic giving rise to significant disposal problems, and the replacement of SnCl₂ dihydrate by sodium sulphite is therefore plainly beneficial from the environmental viewpoint, especially when the process is adapted for full-scale manufacture. Moreover, tin salts are persistent, and trace amounts thereof is frequently observed to be carried through to the final stages of the synthetic sequence unless rigorous chromatographic purification is under taken.

US 5,567,819 claims a process to prepare Rizatriptan, by reacting 4-nitrobenzylhalide with 4-amino-l,2,4-triazole to yield 4-amino-l-(4-nitrophenyl)methyl- 1,2,4- triazolium halide which was further deaminated in the presence of nitrous acid to yield l-(4-nitrophenyl)methyl-l,2,4-triazole. This l-(4-nitrophenyl)methyl- 1,2,4- triazole was subsequently hydrogenated using transfer hydrogenation in the presence of hydrogen donor to give l-(4-aminophenyl)methyl-l,2,4-triazole and then treated with nitrous acid and then with alkali metal sulphite followed by acidification to give l-(4-hydrazinophenyl)methyl-l,2,4-triazole and insitu condensed with 4- (dimethylamino)butanal dimethylacetal to yield rizatriptan. The process is as summarized below:

enation

wherein D represents a halogen atom. Hydrogenation catalyst is palladium on carbon- and hydrogenation donor is ammonium formate, sodium hypophosphite, triethylammonium formate or potassium formate. The disadvantage of the above process is that heating the reaction mass of hydrazine compound with acetal derivative at 90⁰C, results in the formation of rizatriptan dimeric impurities. Further, the residue of rizatriptan base is subjected to column chromatography to give pure Rizatriptan base. The process is not feasible on industrial scale operations.

WO 2006/0531 16 A2 discloses a process to prepare Rizatriptan. The process comprises; condensation of l-(4-hydrazinophenyl)methyl-l,2,4-triazole dihydrochloride with 4-(dimethylamino)butanal dimethylacetal in the presence of hydrochloric acid yielded crude rizatriptan. This crude rizatriptan was passed through silica gel to give pure Rizatriptan that was further converted to benzoate salt of rizatriptan. The process is as shown below:

The disadvantage of the above process is use of silica gel column to purify the rizatriptan base. Hence, the process will not be economical.

We have now found an improved process to prepare Rizatriptan, which is industrially feasible, with good yields and good quality. Further, the Rizatriptan benzoate product is substantially free of Rizatriptan dimeric impurities such as Rizatriptan- 1,2-dimer Rizatriptan 2,2-dimer and Rizatriptan 2,5-dimer represented by the following formulae :

OBJECTIVE

The objective of the present invention is to develop a new improved process for the preparation of Rizatriptan and its pharmaceutically acceptable salts without requiring laborious purification to remove oligomeric/dimeric impurities that in turn can be used as Active Pharmaceutical Ingredient.

The objective of the present invention is to provide an improved process for preparing Rizatriptan. In yet another objective of the present invention is to provide an improved process for the preparation of substantially pure Rizatriptan benzoate, which is simple, industrially applicable and economically viable.

SUMMARY OF THE INVENTION

The present invention relates to an improved process for preparation of N, N- dimethyl-5-(lH-l,2,4-triazol-l-ylmethyl)-lH-indole-3-ethanarnine of Formula I

Formula I

and its pharmaceutically acceptable salts which comprises: a) reacting 4-(lH-(l,2,4-triazole-l-ylmethyl)benzamine of Formula II,

Formula II with sodium nitrite in the presence of an acid and alkali metal sulphite to give 4- (lH-(l,2,4-triazole-l-ylmethyl)phenylhydrazinesulfonic acid of Formula III,

Formula III

b) isolating the 4-(lH-l,2,4-triazol-l-ylmethyl)phenylhydrazine sulfonic acid of Formula III and c) cyclizing with a compound of Formula IV

Formula IV

wherein Ri and R₂ are independently Ci_-4 alkyl in the presence of acid to give rizatriptan of Formula I followed by conversion to its pharmaceutically acceptable salts.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for the preparation of Rizatriptan followed by further conversion to Rizatriptan benzoate in moderately high yield and better quality.

The conversion of compound Formula II to compound Formula III is achieved by converting compound II into corresponding diazonium salt using nitrous acid that on further reaction with alkali metal sulfite in presence of acid like hydrochloride and sulfuric acid afforded compound of Formula III. The compound of Formula III is a stable addition product and is isolated in good yield. The alkali metal sulfite employed suitably is selected from sodium sulfite or potassium sulfite more preferably sodium sulfite. In the prior art, Formula II is first converted to corresponding diazonium salt which on further reduction with sodium sulfite yielded the benzyltriazolehydrazine (compound 5) and this hydrazine product is isolated as dihydrochloride salt in poor yield. In general, the reduction of diazonium compound with sodium sulfite could proceed through a sodium sulfite addition intermediate complex which on in-situ digestion in acidic medium yields the hydrazine product and this intermediate sulfite addition product could not be isolated from the reaction mass. Instead the inventors surprisingly isolated addition product of Formula III as a stable compound. Further it was observed that it could be advantageous to isolate the compound Formula III. This compound III could be easily crystallized from the reaction mass and purified by acid base treatment.

The compound of Formula III is a novel compound and forms an aspect of the present invention. The Fischer-Indole synthesis for the preparation of Rizatriptan of Formula I comprising condensation of compound of Formula HI with compound of Formula IV can be efficiently carried out in the presence of acid selected from hydrochloric acid, phosphoric acid, sulfuric acid, formic acid, /7-toluenesulfonic acid, methane sulfonic acid, more preferably sulfuric acid at a temperature of about 35-45°C for 9 hrs. Upon completion, the reaction mixture was cooled to 0-5°C and pH adjusted to 10.5-11.0 using aqueous sodium hydroxide. The product was extracted with ethyl acetate and extract concentrated under reduced pressure to obtain Rizatriptan base as an oily mass. This particular temperature conditions employed in the condensation of the compound of Formula III and IV yielded pure Rizatriptan with Rizatriptan-2,5-dimer impurity less than 0.5 %. The major advantage realized by this reaction conditions set forth in this invention is the elimination of chromatography as compared to prior-art procedures wherein extensive chromatographic separation is carried out.

The inventors were able to achieve the formation of Rizatriptan from Fischer-Indole reaction of benzyltriazolehydrazinesulfonic acid of Formula III with 4- (dimethylamino)butanal diethyl acetal of Formula IV, the inventors have further established that the present invention does not proceed as assumed from the prior art reaction route in which, first compound of Formula III is hydrolyzed to yield the intermediate, benzyltriazolehydrazine (compound 5) and thereafter the benzyltriazolehydrazine undergoes Fischer-Indole cyclization with Formula IV to yield rizatriptan. Rather the benzenetriazolesulfonic acid of Formula HI reacts directly with 4-(dimethylamino)butanal diethyl acetal to undergo Fischer-Indole cyclization to afford Rizatriptan.

In another embodiment, the inventors found that Fischer-Indole cyclization of compound of Formula III with compound of Formula IV could proceed at lower temperature in the range of 30-60 ⁰C, more particularly 35-45 °C which is contrary to the prior art procedures wherein Fischer-Indole reaction leading to Rizatriptan was carried out at higher temperature i.e >90°C. During the Fischer-Indole synthesis, acid catalyzed oligomerization/dimerization of Rizatriptan could occur when the reaction was done at higher temperature. Since the Fischer-Indole reaction of compound of Formula III with compound of Formula IV was carried out at lower temperature, the formation of dimeric impurities was advantageously controlled in this process.

More specifically, the present invention furnishes Rizatriptan that contains no greater than 0.5 % of all dimers as determined by high performance chromatography (HPLC).

The Fischer-Indole cyclization of compound of Formula III with compound of Formula IV to prepare Rizatriptan is normally associated with the formation of large amounts of the oligomeric/dimeric impurities Viz Rizatriptan-2,5-dimer, Rizatriptan 2,2-dimer and Rizatriptan- 1,2 dimer that are difficult to remove. The inventors were able to modify the reaction conditions so as to reduce the formation of the dimer impurities to the acceptable regulatory limits. Also in the process of the present invention, the formation of the dimer impurities was reduced by carrying out the reaction with the compound of Formula III. Since it was found that in earlier published procedures benzyltriazolehydrazine intermediate (compound 5) when condensed with compound of Formula IV produced rizatriptan in very low yield coupled with large amounts of the above mentioned dimeric/oligomeric impurities.

Also, the prior-art process containing high amounts of oligomers and polymers makes the Rizatriptan benzoate appear as an oily mass and hence difficult to crystallize. However, with the present process of the invention, it is noteworthy to mention that Rizatriptan benzoate is obtained as a solid without chromatographic purification. The obtained Rizatriptan benzoate salt is purified by crystallizing in ethanol. Also the condensation of the sulfonic acid of compound of Formula III with compound of Formula IV leading to the formation of rizatriptan base proceeds very fast when compared with the condensation of simple benzyltriazolehydrazine (compound 5) under similar reaction conditions thus imparting high throughput capability to the process.

The compound of Formula II is prepared by known methods in the literature.

The compound of Formula I is further converted to rizatriptan benzoate involving the reaction of free base with benzoic acid in a suitable solvent, optionally followed by purification of benzoate salt. Suitable solvents that can be used for the preparation of solution of benzoic acid include, without limitation, acetone, ethanol, isopropanol, n- propanol and n-butanol. Acetone has been found to be an excellent choice for the preparation of benzoate salt. Also another advantage with acetone is that the oligomeric impurities could almost be eliminated in the acetone filtrate during the isolation of the rizatriptan benzoate product.

Suitable solvents for recrystallization of the crude benzoate salt include, without limitation, acetone, ethanol, isopropanol, n-propanol and n-butanol.

The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.

Example 1

Preparation of 4-(lH-l,2,4-triazol-l-ylmethyl)phenylhydrazinesulfonic acid

A solution of 4-(lH-l,2,4-triazol-ϊ-ylmethyl)benzenamine (50 g, 0.287 mol) in aqueous hydrochloric acid (-17% w/w, 300 ml) was cooled to -5 to -1O⁰C. To this chilled solution, a solution of sodium nitrite (25.74 g, 0.373 mol) in water (50 ml) was added slowly at -5 to -1O⁰C to obtain a solution of diazonium salt. In a separate flask, sodium sulfite (90.40 g, 0.717 mol) was taken in water (300 ml) and cooled to 0-5⁰C. To this sodium sulfite solution, above diazonium salt solution was added rapidly at 0-5° C and continued to stir the reaction mixture at 0-5° C for 30 min. Thereafter, the temperature of the reaction mixture was raised to 25-3O⁰C and continued to stir at 25- 3O⁰C for 2 h to allow the title product to crystallize out. The isolated solid was filtered and dissolved in water (250 ml) by adjusting the pH to 6.5-7.0 using aqueous ammonia. Thereafter, the aqueous solution was washed with methylene chloride and the aqueous layer pH was readjusted to 2.0-2.2 to isolate the product. The product was filtered and dried at 45-50⁰C under reduced pressure to constant weight. YIELD: 56 g

Example 2

Preparation of N,N-dimethyl-5-(lH-l,2,4-triazol-l-ylmethyl)-lH-indoIe-3- ethanamine benzoate

A mixture of 4-(lH-l,2,4-triazol-lylmethyl)phenylhydrazinesulfonic acid (50 g, 0.186 mol) and 4-(dimethylamino)butanal diethyl acetal (45.70 g, 0.242 mol) was stirred in 15 % w/w aqueous sulfuric acid (500 ml) at 35-4O⁰C for 9 h. The reaction mixture was then cooled to 0-5⁰C and pH was adjusted to 10.5-11.0 using aqueous sodium hydroxide solution. The product was extracted with ethyl acetate and the solvent was removed by distillation under reduced pressure to obtain the Rizatriptan base as an oily mass. The Rizatriptan base was dissolved in acetone (200 ml) and stirred with benzoic acid (22.69 g, 0.186 mol) at 0-5⁰C for 3 h. The solid precipitated was filtered and stirred in a mixture of ethanol (50 ml) and acetone (25 ml) at 60-65⁰C for 1 h. The resulting slurry was cooled to 5-1O⁰C and filtered to obtain crude Rizatriptan benzoate product. This crude Rizatriptan benzoate was crystallized from ethanol to obtain pure Rizatriptan benzoate. YIELD: 16 g (HPLC PURITY: >99.6%) Example 3

Preparation of N,N-dimethyl-5-(lH-l,2,4-triazol-l-ylmethyl)-lH-indole-3- ethanamine benzoate

A mixture of 4-(lH-l,2,4-triazol-lylmethyl)phenylhydrazinesulfonic acid (50 g, 0.186 mol) and 4-(dimethylamino)butanal diethyl acetal (45.70 g, 0.242 mol) was stirred in 15 % w/w aqueous sulfuric acid (500 ml) at 38-42⁰C for 9 h. The reaction mixture was then cooled to 0-5⁰C and pH was adjusted to 10.5-11.0 using aqueous sodium hydroxide solution. The product was extracted with ethyl acetate and the solvent was removed by distillation under reduced pressure to obtain the Rizatriptan base as an oily mass. The Rizatriptan base was dissolved in acetone (200 ml) and stirred with benzoic acid (22.69 g, 0.186 mol) at 0-5⁰C for 3 h. The solid precipitated was filtered and stirred in a mixture of ethanol (50 ml) and acetone (25 ml) at 60-65⁰C for 1 h. The resulting slurry was cooled to 5-1O⁰C and filtered to obtain crude Rizatriptan benzoate product. This crude Rizatriptan benzoate was crystallized from ethanol to obtain pure Rizatriptan benzoate. YIELD: 16 g (HPLC PURITY: >99.6%)

Claims

WE CLAIM

1. An improved process for the preparation of N,N-dimethyl-5-(lH-l,2,4-triazol-l- ylmethyl)-lH-indole-3-ethanamine of Formula I

Formula I

and its pharmaceutically acceptable salts which comprises : a) reacting a compound of Formula III

Formula III

with a compound of Formula IV

Formula IV wherein Ri and R₂ are independently C_1-4 alkyl in the presence of an acid to give compound of Formula I.

2. The process according to claim 1, wherein the acid used is selected from hydrochloric acid, phosphoric acid, acetic acid, sulfuric acid, formic acid, p- toluenesulfonic acid, methanesulfonic acid, more preferably sulfuric acid.

3. A process for the preparation of 4-(lH-l,2,4-triazol-l-ylmethyl)phenylhydrazine sulfonic acid of compound of Formula III

Formula III

which comprises : a) reacting 4-( 1 H-( 1 ,2,4-triazole- 1 -ylmethyl)benzamine of Formula II,

Formula II with sodium nitrite in the presence of an acid and alkali metal sulphite to give 4-(lH-(l,2,4-triazole-l-ylmethyl)phenylhydrazinesulfonic acid of Formula HI, b) isolating the 4-(lH-l,2,4-triazol-l-ylmethyl)phenylhydrazine sulfonic acid of Formula III.

4. The process according to claim 3, wherein the acid employed is selected from hydrochloric acid, sulfuric acid, more preferably hydrochloric acid.

5. The process according to claim 3, wherein the alkali metal sulphite employed is selected from sodium sulfite, potassium sulfite, more preferably sodium sulfite.

6. The process according to claim 3, wherein the reaction is conducted at below 50⁰C.

7. The compound of Formula III

_NH- NH-_SO3H Formula III

8. Use of compound of Formula III in the preparation of Rizatriptan of Formula I.