WO2012147020A1 - Procédé amélioré pour la préparation de frovatriptan - Google Patents
Procédé amélioré pour la préparation de frovatriptan Download PDFInfo
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- frovatriptan
- racemic
- salt
- acetate
- free base
- Prior art date
Links
- 0 *OC(CC1)Cc2c1[n]c(cc1)c2cc1C#N Chemical compound *OC(CC1)Cc2c1[n]c(cc1)c2cc1C#N 0.000 description 1
- LXOOHYOLZHTOHL-UHFFFAOYSA-N CCCCOC(N(C)C(CC1)Cc(c2c3)c1[nH]c2ccc3C#N)=O Chemical compound CCCCOC(N(C)C(CC1)Cc(c2c3)c1[nH]c2ccc3C#N)=O LXOOHYOLZHTOHL-UHFFFAOYSA-N 0.000 description 1
- WPDCBQPOJXEMKM-UHFFFAOYSA-N CNC(CC1)Cc(c2c3)c1[nH]c2ccc3C#N Chemical compound CNC(CC1)Cc(c2c3)c1[nH]c2ccc3C#N WPDCBQPOJXEMKM-UHFFFAOYSA-N 0.000 description 1
- XPSQPHWEGNHMSK-UHFFFAOYSA-N CNC(CC1)Cc(c2c3)c1[nH]c2ccc3C(N)=O Chemical compound CNC(CC1)Cc(c2c3)c1[nH]c2ccc3C(N)=O XPSQPHWEGNHMSK-UHFFFAOYSA-N 0.000 description 1
- YDMUHFDMRBTSAB-UHFFFAOYSA-N N#Cc(cc1)cc2c1[nH]c(CC1)c2CC1OCc1ccccc1 Chemical compound N#Cc(cc1)cc2c1[nH]c(CC1)c2CC1OCc1ccccc1 YDMUHFDMRBTSAB-UHFFFAOYSA-N 0.000 description 1
- DZUUSHCOMPROCJ-UHFFFAOYSA-N NNc(cc1)ccc1C#N Chemical compound NNc(cc1)ccc1C#N DZUUSHCOMPROCJ-UHFFFAOYSA-N 0.000 description 1
- FFGVIYUANJAFJS-UHFFFAOYSA-N O=C(CC1)CCC1OCc1ccccc1 Chemical compound O=C(CC1)CCC1OCc1ccccc1 FFGVIYUANJAFJS-UHFFFAOYSA-N 0.000 description 1
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.
Landscapes
- 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.
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 |
Family
ID=47071654
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2012/052020 WO2012147020A1 (fr) | 2011-04-25 | 2012-04-23 | Procédé amélioré pour la préparation de frovatriptan |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2012147020A1 (fr) |
Cited By (2)
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)
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 |
-
2012
- 2012-04-23 WO PCT/IB2012/052020 patent/WO2012147020A1/fr active Application Filing
Patent Citations (2)
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)
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)
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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