WO2010073253A1 - Procédé de préparation de frovatripan optiquement actif - Google Patents

Procédé de préparation de frovatripan optiquement actif Download PDF

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Publication number
WO2010073253A1
WO2010073253A1 PCT/IN2008/000854 IN2008000854W WO2010073253A1 WO 2010073253 A1 WO2010073253 A1 WO 2010073253A1 IN 2008000854 W IN2008000854 W IN 2008000854W WO 2010073253 A1 WO2010073253 A1 WO 2010073253A1
Authority
WO
WIPO (PCT)
Prior art keywords
methylamino
tetrahydrocarbazole
formula
cyano
iii
Prior art date
Application number
PCT/IN2008/000854
Other languages
English (en)
Inventor
Kompella Amala
Sreenivas Rachakonda
Bhujanga Rao Adibhatla Kali Satya
Nannapaneni Venkaiah Chowdary
Original Assignee
Natco Pharma Limited
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 Natco Pharma Limited filed Critical Natco Pharma Limited
Priority to PCT/IN2008/000854 priority Critical patent/WO2010073253A1/fr
Publication of WO2010073253A1 publication Critical patent/WO2010073253A1/fr

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Classifications

    • 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
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system

Definitions

  • Frovatriptan succinate is a 5HTl receptor agonist. It is marketed under the name FROVA ® for the treatment of migraine.
  • WO 93/00086 discloses a group of tetrahydrocarbazole derivatives, which have activity as 5HTl receptor agonists, and are therefore useful in the treatment of migraines.
  • a specific compound disclosed therein is 3-methylamino-6-carboxamido- 1,2,3,4-tetrahydrocarbazole hydrochloride prepared by a six stage process, and 3- methylamino-6-cyano- 1 ,2,3,4-tetrahydrocarbazole, via 3-methylamino-6-cyano-l ,2,3 » 4- tetrahydrocarbazole, involving a number of protection and deprotec ⁇ on steps.
  • WO 94/14772 discloses enantiomers of certain carbazole derivatives, including the aforementioned compound (R)-(+)-6-carboxamido-3-N-methylamino- 1 ,2,3 ,4- tetrahydrocarbazole, salts and solvates thereof.
  • WO 94/14772 further discloses various methods by which single enantiomers can be prepared; one of which involves:
  • WO 99/54302 discloses novel process for the preparation of (R)-(+)-6-carboxamido-3-N- methylamino-l,2,3,4-tetrahydrocarbazole which involves : i. Resolving a mixture of enantiomers of an indole nitrile of the formula(I) using L-pyroglutamic acid.
  • the main objective of the present invention is to provide an improved process for the preparation of optically active Frovatriptan overcoming the difficulties of hitherto known processes
  • the resolution of cyano indole enantiomers(I) with the optically active acid D-pyroglutamic acid can be carried out as follows :
  • Step 1 mixture of solvents are preferably alcohol and acetone more preferably methanol and acetone.
  • Step 4 The solvents preferred for dissolution are isopropyl acetate or ethyl acetate more preferably Ethyl acetate.
  • Step 5 The alcohol preferred for dissolution are ethanol or methanol more preferably methanol
  • Step 8 Heating temperature is 100- 130 0 C more preferably 110-12O 0 C
  • Step 9 The solvent preferred for extraction is n-Butanol
  • Step 10 The solvents preferred for precipitation are isopropyl acetate or ethyl acetate more preferably Ethyl acetate.
  • the resulting compound (IV) from step 10 can easily be converted to a pharmaceutically acceptable salt for example succinate salt by reaction of succinic acid in methanol medium.
  • present invention provides the use of D-pyroglutamic acid in resolving the racemic mixture of 6-cyano-3-N-methylamino-l,2,3,4- tetrahydrocarbazole of the formula(I).
  • (+)6-cyano-3-N-methylamino-l,2,3,4-tetrahydrocarbazole HCl (0.46mol, 12Og) obtained from Example-l was suspended in phosphoric acid(l lmol, 1.08kg) .
  • the reaction mass was heated to 110-115 0 C and maintained at the same temperature for 3hours.
  • the reaction mass was brought to room temperature and quenched into crushed ice(4kgs) . It was basified with50% sodium hydroxide solution(2L) and extracted with n-butanol (2x2L). Organic layer was separated and distilled under vacuum . The residue was suspended in 300ml Ethyl acetate at room temperature and maintained at the same temperature for 1-2 hours.
  • the process can be used for commercial preparation of fro vatriptan salts of pharmaceutical grade.
  • the process is suitable for operation on industrial scale runs.

Landscapes

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

Abstract

La présente invention concerne un procédé de préparation de frovatriptan optiquement actif ou d'un sel consistant : (i) à combiner le 6-cyano-3-N-méthylamino- 1,2,3,4- tétrahydrocarbazole racémique de formule (I) avec de l'acide D-pyroglutamique comme agent de résolution dans un solvant de résolution et à faire cristalliser à partir dudit mélange le sel diastéréomérique du composé de formule (II) avec de l'acide D- pyroglutamique optiquement pur; (ii) à séparer le (+)-6-cyano-3-N-méthylamino-l,2,3,4- tétrahydrocarbazole voulu de formule (III) du sel diastéréomérique (II) à l'aide d'une simple technique de filtration; (iii) à hydrolyser le composé de formule (III) avec de l'acide phosphorique pour obtenir du R-(+)-6-carboxamido-3-N-méthylamino-l,253,4-tétrahydrocarbazole (frovatriptan) de formule (IV).
PCT/IN2008/000854 2008-12-22 2008-12-22 Procédé de préparation de frovatripan optiquement actif WO2010073253A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/IN2008/000854 WO2010073253A1 (fr) 2008-12-22 2008-12-22 Procédé de préparation de frovatripan optiquement actif

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2008/000854 WO2010073253A1 (fr) 2008-12-22 2008-12-22 Procédé de préparation de frovatripan optiquement actif

Publications (1)

Publication Number Publication Date
WO2010073253A1 true WO2010073253A1 (fr) 2010-07-01

Family

ID=40591893

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2008/000854 WO2010073253A1 (fr) 2008-12-22 2008-12-22 Procédé de préparation de frovatripan optiquement actif

Country Status (1)

Country Link
WO (1) WO2010073253A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021163676A1 (fr) * 2020-02-16 2021-08-19 Ayala Pharmaceuticals Inc. Procédés de préparation de dérivés chiraux de benzodiazépinone

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993000086A1 (fr) * 1991-06-26 1993-01-07 Smithkline Beecham Plc Utilisation de derives de tetrahydrocarbazone comme agonistes de recepteurs du type 5-ht¿1?
WO1994014772A1 (fr) * 1992-12-21 1994-07-07 Smithkline Beecham Plc Enantiomeres de derives du carbazole utilises comme agonistes similaires a la 5-ht1
WO1999054302A1 (fr) * 1998-04-16 1999-10-28 Vernalis Limited Procede de production de r-(+)-6-carboxamido-3-n-methylamino-1,2,3,4-tetrahydrocarbazole

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993000086A1 (fr) * 1991-06-26 1993-01-07 Smithkline Beecham Plc Utilisation de derives de tetrahydrocarbazone comme agonistes de recepteurs du type 5-ht¿1?
WO1994014772A1 (fr) * 1992-12-21 1994-07-07 Smithkline Beecham Plc Enantiomeres de derives du carbazole utilises comme agonistes similaires a la 5-ht1
WO1999054302A1 (fr) * 1998-04-16 1999-10-28 Vernalis Limited Procede de production de r-(+)-6-carboxamido-3-n-methylamino-1,2,3,4-tetrahydrocarbazole

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KHAN M ET AL: "A validated chiral CE method for Frovatriptan, using cyclodextrin as chiral selector", JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, NEW YORK, NY, US, vol. 41, no. 4, 16 June 2006 (2006-06-16), pages 1447 - 1452, XP025145954, ISSN: 0731-7085, [retrieved on 20060616] *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021163676A1 (fr) * 2020-02-16 2021-08-19 Ayala Pharmaceuticals Inc. Procédés de préparation de dérivés chiraux de benzodiazépinone

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