EP2121663A2 - Procédé perfectionné pour la fabrication de rizatriptan - Google Patents

Procédé perfectionné pour la fabrication de rizatriptan

Info

Publication number
EP2121663A2
EP2121663A2 EP07859030A EP07859030A EP2121663A2 EP 2121663 A2 EP2121663 A2 EP 2121663A2 EP 07859030 A EP07859030 A EP 07859030A EP 07859030 A EP07859030 A EP 07859030A EP 2121663 A2 EP2121663 A2 EP 2121663A2
Authority
EP
European Patent Office
Prior art keywords
acid
formula
rizatriptan
compound
formula iii
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07859030A
Other languages
German (de)
English (en)
Inventor
Joseph Prabahar Koilpillai
Magesh Subramanian
Uppalaiah Mallela
Venkata Balaji Boddu
Ramesh Dandala
Sivakumaran Meenakshisunderam
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aurobindo Pharma Ltd
Original Assignee
Aurobindo Pharma Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Aurobindo Pharma Ltd filed Critical Aurobindo Pharma Ltd
Publication of EP2121663A2 publication Critical patent/EP2121663A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • 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
  • 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.
  • the main disadvantage of this process is generation of large quantity of isomeric Rizatriptan due to 4-substituted triazole.
  • the above process has another disadvantage of reduction of diazonium salt with SnCl 2 dihydrate in concentrated hydrochloric acid. Tin salts are notoriously toxic giving rise to significant disposal problems, and the replacement of SnCl 2 dihydrate by sodium sulphite is therefore plainly beneficial from the environmental viewpoint, especially when the process is adapted for full-scale manufacture.
  • 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.
  • 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:
  • 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 90 0 C, 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:
  • 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 :
  • 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.
  • 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,
  • 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.
  • 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.
  • 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.
  • 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.
  • the reaction mixture was cooled to 0-5°C and pH adjusted to 10.5-11.0 using aqueous sodium hydroxide.
  • 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.
  • Fischer-Indole cyclization of compound of Formula III with compound of Formula IV could proceed at lower temperature in the range of 30-60 0 C, 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.
  • 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.
  • 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.
  • Rizatriptan benzoate appears as an oily mass and hence difficult to crystallize.
  • Rizatriptan benzoate is obtained as a solid without chromatographic purification.
  • the obtained Rizatriptan benzoate salt is purified by crystallizing in ethanol.
  • 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.
  • 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 Rizatriptan base was dissolved in acetone (200 ml) and stirred with benzoic acid (22.69 g, 0.186 mol) at 0-5 0 C for 3 h.
  • the solid precipitated was filtered and stirred in a mixture of ethanol (50 ml) and acetone (25 ml) at 60-65 0 C for 1 h.
  • the resulting slurry was cooled to 5-1O 0 C 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%)

Landscapes

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

Abstract

La présente invention porte sur un procédé perfectionné de fabrication de N,N-diméthyl-5-(1H-1,2,4-triazol-1-ylméthyl)-1H-indole-3-éthanamine de Formule I et de ses sels pharmaceutiquement acceptables.
EP07859030A 2006-12-15 2007-12-10 Procédé perfectionné pour la fabrication de rizatriptan Withdrawn EP2121663A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2336CH2006 2006-12-15
PCT/IB2007/003896 WO2008075163A2 (fr) 2006-12-15 2007-12-10 Procédé perfectionné pour la fabrication de rizatriptan

Publications (1)

Publication Number Publication Date
EP2121663A2 true EP2121663A2 (fr) 2009-11-25

Family

ID=39265610

Family Applications (1)

Application Number Title Priority Date Filing Date
EP07859030A Withdrawn EP2121663A2 (fr) 2006-12-15 2007-12-10 Procédé perfectionné pour la fabrication de rizatriptan

Country Status (2)

Country Link
EP (1) EP2121663A2 (fr)
WO (1) WO2008075163A2 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103387570A (zh) * 2013-08-20 2013-11-13 余鲜红 一种苯甲酸利扎曲普坦的制备方法
CN103664900B (zh) * 2013-11-25 2016-02-24 四川大学 一种制备苯甲酸利扎曲坦的方法
CN103664901B (zh) * 2013-11-25 2016-04-13 四川大学 一种苯甲酸利扎曲坦制备方法
CN108892648A (zh) * 2018-07-13 2018-11-27 山东贵邦药业有限公司 一种苯甲酸利扎曲普坦中间体固相合成工艺

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Publication number Priority date Publication date Assignee Title
WO2006053116A2 (fr) * 2004-11-10 2006-05-18 Dr. Reddy's Laboratories Ltd. Procede de preparation de rizatriptan

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2008075163A3 *

Also Published As

Publication number Publication date
WO2008075163A3 (fr) 2008-09-25
WO2008075163A2 (fr) 2008-06-26

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