WO2012147020A1 - Procédé amélioré pour la préparation de frovatriptan - Google Patents

Procédé amélioré pour la préparation de frovatriptan Download PDF

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Publication number
WO2012147020A1
WO2012147020A1 PCT/IB2012/052020 IB2012052020W WO2012147020A1 WO 2012147020 A1 WO2012147020 A1 WO 2012147020A1 IB 2012052020 W IB2012052020 W IB 2012052020W WO 2012147020 A1 WO2012147020 A1 WO 2012147020A1
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WO
WIPO (PCT)
Prior art keywords
frovatriptan
racemic
salt
acetate
free base
Prior art date
Application number
PCT/IB2012/052020
Other languages
English (en)
Inventor
Buchi Reddy Reguri
Sampathkumar Upparapalli
Thirumurugan Kunchithapatham
Thiyagarajan Sambashivam
Suresh MUNUSAMY
Original Assignee
Orchid Chemicals And Pharamceuticals 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 Orchid Chemicals And Pharamceuticals Limited filed Critical Orchid Chemicals And Pharamceuticals Limited
Publication of WO2012147020A1 publication Critical patent/WO2012147020A1/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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds

Definitions

  • the present invention relates to an improved process for the preparation of Frovatriptan of formula (I) and its enantiomers, particularly R-enantiomer.
  • Frovatriptan (I) chemically named as R-(+)-6-carboxamido-3-methylamino- 1,2,3,4 tetrahydrocarbazole, is currently marketed as the monosuccinate salt monohydrate (II) under the brand name Frova® for the treatment of migraine.
  • This product was hydrolyzed with sodium hydroxide to give 3-hydroxy-6-cyano-l, 2,3,4- tetrahydrocarbazole, which was further treated with tosyl chloride in the presence of pyridine to yield corresponding tosylated tetrahydrocarbazole.
  • the tosyloxy group was removed by treatment with methylamine in a sealed tube at 100°C to yield 3- methylamino-6-cyano-l,2,3,4-tetrahydrocarbazole, which was isolated after column chromatography.
  • WO 94/014772 discloses the process for preparation of ( ⁇ )-6-Carboxamido- 3-N-methylamino-l,2,3,4-tetrahydrocarbazole which involves the basification of the solution of ( ⁇ )-6-carboxamido-3-N-methylamino-l,2,3,4-tetrahydrocarbazole hydrochloride salt in water with 5M aqueous sodium hydroxide to pH 10.5 followed by the extraction with of the resultant mixture with butan-l-ol. These extractions were combined and evaporated to give the racemic Frovatriptan free base as dark oil. This oil containing about 40% butanol was taken as such for resolution using chiral acid.
  • WO 94/14772 discloses enantiomers of Frovatriptan, further it discloses various methods for the preparation of optically pure enantiomer of Frovatriptan;
  • the primary objective of the invention is to provide an improved process for the preparation of Frovatriptan formula (I) with good purity which is easy to implement on commercial scale and avoids chromatographic methods.
  • Another objective of the present invention is to provide an improved process for the preparation of Frovatriptan formula (I) i.e racemic Frovatriptan as a solid form.
  • One more objective of the present invention is to provide a novel chiral resolution process for the preparation of optically pure Frovatriptan particularly R- isomer of Frovatriptan (R-(+)-6-carboxamido-3-methylamino-l,2,3,4 tetrahydrocarbazole) using optically active acids.
  • Still more objective of the present invention is to provide a novel Frovatriptan Di-p-toluoyl-D-(+)-tartaric acid (DPTTA) salt.
  • the present invention provides an improved process for the preparation of R-isomer of Frovatriptan or its salt, the said process comprising the steps of:
  • racemic Frovatriptan optionally treating the racemic Frovatriptan with an organic solvent; c. optionally isolating racemic Frovatriptan as a solid by filtration;
  • the present invention also provides an improved process for the preparation of Frovatriptan of formula (I);
  • Figure- 1 Powder XRD pattern of crystalline form of racemic Frovatriptan free base obtained by the present invention.
  • Figure-2 Powder XRD pattern of Frovatriptan DPTTA salt obtained by the present invention.
  • the present invention provides a simple crystallization method for the isolation of racemic Frovatriptan as a solid form.
  • the said process involves treating the residue of racemic Frovatriptan with an organic solvent.
  • the organic solvent employed for the crystallization of racemic Frovatriptan is selected from acetone, methyl isobutyl ketone, methylethyl ketone, tetrahydrofuran, methyl acetate, ethyl acetate, n-butyl acetate, t-butyl acetate, isobutyl acetate , methyl t- butyl ether, isopropyl ether, n-hexane, n-heptane, cyclohexane, and the like or mixtures thereof, however, other organic solvents which do not adversely affect the crystallization can also be present or used; preferably ethyl acetate, acetone and cyclohexane.
  • the residue of racemic Frovatriptan may be in the form of oil or gummy paste that may optionally contain small amount of solvent are obtained from the reaction mass directly.
  • the use of said chiral acid has several advantages like high chiral purity, good stability and high yield.
  • Di-p- toluoyl-(D)-(+)-tartaric acid can be added directly in to the reaction mass or in the form of solution.
  • the unwanted isomer from filtrate can be racemized and can be recycled by using conventional technique for example treating with base or an acid.
  • the solvent used for resolution in step (d) is selected from methanol, ethanol, 1-propanol, isopropanol, butanol, methylt-butyl ether (MTBE), acetone, water and the like or mixtures thereof.
  • Frovatriptan DPTTA salt if required, can be purified using a solvent system including but not limited to methanol, ethanol, isopropanol, acetone, water and the like or mixtures thereof by crystallization method or by using dissolution and anti-solvent precipitation method etc.
  • a solvent system including but not limited to methanol, ethanol, isopropanol, acetone, water and the like or mixtures thereof by crystallization method or by using dissolution and anti-solvent precipitation method etc.
  • the present invention provides purification process of racemic frovatriptan which involves treating the racemic frovatriptan with Copper sulfate (CuSO 4 ) or its hydrate to reduce the undesired hydrazine impurity.
  • CuSO 4 Copper sulfate
  • Applicant of the present invention observed that the presence of hydrazine impurity affects the resolution process.
  • use of CuSO 4 or its hydrate in the purification of racemic frovatriptan reduces the hydrazine impurity namely 4-carboxamido-phenylhydrazine, which ultimately enhances the efficiency of resolution of racemic Frovatriptan.
  • the present invention removes hydrazine impurity from 5% to 0.75% preferably less than 0.2%.
  • the obtained novel optically active Frovatriptan salts can be converted to (R)-(+)-Frovatriptan or its pharmaceutically acceptable solvate by the conventional method.
  • Racemic Frovatriptan used in the present invention can be obtained by following the procedure disclosed in prior art or by following the reference example provided in the specification or by following the scheme provided below ;
  • the chiral salt of the present invention can be converted to Frovatriptan succinate by any suitable conventional method or by the methods reported in the prior art.
  • 1,4 cyclohexane dione (200 grams) was dissolved in MDC. To this con sulfuric acid was added followed by the addition of neopentyl glycol in dichloromethane. After completion of the reaction, sodium bicarbonate was added and stirred. Organic layer was filtered and the filtrate was distilled under vacuum then work up carried out using petroleum ether to filter the by-products. To the reaction mass methanol was added and un-dissolved material was filtered. To the filtrate, methanol was added followed by the addition of methanolic methylamine. This solution was charged with Pd/C and was hydrogenated. The reaction mass filtered and to the filtrate IPA was added, it was distilled to reach 2V.
  • Cost of resolution of process is less when compared to prior art process.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé pour la préparation et l'épuration de frovatriptan de formule (I) et ses énantiomères, en particulier l'énantiomère R, comprenant la formation de sel de l'acide di-p-toluoyltartarique de frovatriptan.
PCT/IB2012/052020 2011-04-25 2012-04-23 Procédé amélioré pour la préparation de frovatriptan WO2012147020A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1412CH2011 2011-04-25
IN1412CHE2011 2011-04-25

Publications (1)

Publication Number Publication Date
WO2012147020A1 true WO2012147020A1 (fr) 2012-11-01

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014202717A1 (fr) * 2013-06-20 2014-12-24 Duke Chem, S.A. Procédé de préparation du frovatriptan et de son énantiomère
CN104402798A (zh) * 2014-10-21 2015-03-11 杭州瑞德化工有限公司 一种3-氨基-1,2,3,4-四氢咔唑的拆分方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994014772A1 (fr) * 1992-12-21 1994-07-07 Smithkline Beecham Plc Enantiomeres de derives du carbazole utilises comme agonistes similaires a la 5-ht1
US5618948A (en) * 1995-05-26 1997-04-08 Smithkline Beecham P.L.C. Process for preparing an enantiomer of a carbazole derivative

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994014772A1 (fr) * 1992-12-21 1994-07-07 Smithkline Beecham Plc Enantiomeres de derives du carbazole utilises comme agonistes similaires a la 5-ht1
US5618948A (en) * 1995-05-26 1997-04-08 Smithkline Beecham P.L.C. Process for preparing an enantiomer of a carbazole derivative

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ELIEL E.L. ET AL., STEREOCHEMISTRY OF ORGANIC COMPOUNDS, 1994, NEW YORK, pages 322 - 344 *
GUO, R. ET AL.: "`Improved synthesis of frovatriptan", CHINESE JOURNAL OF MEDICINAL CHEMISRY., vol. 21, February 2011 (2011-02-01), pages 44 - 46, 56 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014202717A1 (fr) * 2013-06-20 2014-12-24 Duke Chem, S.A. Procédé de préparation du frovatriptan et de son énantiomère
EP2816030A1 (fr) 2013-06-20 2014-12-24 Duke Chem, S. A. Procédés de préparation de frovatriptan et ses énantiomères
CN104402798A (zh) * 2014-10-21 2015-03-11 杭州瑞德化工有限公司 一种3-氨基-1,2,3,4-四氢咔唑的拆分方法

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