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WO2009037718A2 - Procédé de préparation de 3-(2-(diméthylamino)éthyl)-n-méthyl-1h-indole-5-méthanesulfonamide et produit associé - Google Patents

Procédé de préparation de 3-(2-(diméthylamino)éthyl)-n-méthyl-1h-indole-5-méthanesulfonamide et produit associé Download PDF

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Publication number
WO2009037718A2
WO2009037718A2 PCT/IN2008/000592 IN2008000592W WO2009037718A2 WO 2009037718 A2 WO2009037718 A2 WO 2009037718A2 IN 2008000592 W IN2008000592 W IN 2008000592W WO 2009037718 A2 WO2009037718 A2 WO 2009037718A2
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WO
WIPO (PCT)
Prior art keywords
sumatriptan
acid
base
process according
acid addition
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.)
Ceased
Application number
PCT/IN2008/000592
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English (en)
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WO2009037718A8 (fr
WO2009037718A3 (fr
Inventor
O. D. Tyagi
Purendhar Koilkonda
Jitendra Sharma
R. V. N. Vikas Chandradev
R. Sridhar
Saswata Lahiri
A. V. Mouneshwar
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.)
Mylan Laboratories Ltd
Original Assignee
Matrix Laboratories 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 Matrix Laboratories Ltd filed Critical Matrix Laboratories Ltd
Publication of WO2009037718A2 publication Critical patent/WO2009037718A2/fr
Publication of WO2009037718A8 publication Critical patent/WO2009037718A8/fr
Publication of WO2009037718A3 publication Critical patent/WO2009037718A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines

Definitions

  • This invention in general relates to a process for preparing an indole derivative. More particularly, but without restriction to the particular embodiments herein after described in accordance with the best mode of practice, the present invention provides an improved process for the preparation of 3-(2- (dimethylamono)ethyl)-N-methyl-lH-indole-5-methanesulfonamide (sumatriptan) acid addition salts, a crystalline form of sumatriptan base and product thereof.
  • sumatriptan 3-(2- (dimethylamono)ethyl)-N-methyl-lH-indole-5-methanesulfonamide
  • the indole derivatives are used in the treatment of migraine. It has been suggested that the pain of migraine may be associated with excessive dilatation of the cranial vasculature.
  • the indole derivatives are selective 5HT 1 -IUCe receptors agonists and exhibit selective vasoconstrictor activity, which have been described in the art as useful in the treatment of migraine.
  • reaction mass is diluted with water and then the reaction mass pH is adjusted 10.0 to 11.0 and product is extracted into chloroform. Chloroform layer is concentrated under reduced pressure to give the residue, which is subjected to column chromatography purification to give sumatriptan oil. It is further subjected to crystallization to give sumatriptan base.
  • the prior art process required chlorinated solvents such as chloroform and sumatriptan is purified through column chromatography. Further, the obtained oil base is subjected to crystallization in different solvents to give the crystalline sumatriptan base. This process involves the column purification, which is not commercially feasible, in addition to this, process needed more time cycle.
  • WO 2006/054311 publication reveals the process for the preparation of sumatriptan, wherein 4, 4-dimethoxy-N, N-dimethylbutanamine is reacted with 4- hydrazino-N-methyl benzene methanesulfonamide hydrochloride in diluted hydrochloric acid. After completion of the condensation reaction, the reaction mass pH is adjusted to 9.0-9.5 with sodium carbonate, the resulting solution is extracted with chloroform and -the organic layer is concentrated to give the residue.
  • the said prior art process needed more number of solvents like chloroform, ethyl acetate, acetonitrile and methanol for reaction and crystallization of sumatriptan base.
  • the sumatriptan base is subjected to repeated crystallizations in different solvents. It needs number of solvents for reaction and recrystallisation of sumatriptan.
  • the recovery and reuse of the solvents in the same process requires more time cycle in the plant level. Finally, it leads to additional cost on the final product.
  • US publication No. 2007/0054953 discloses process for the preparation of sumatriptan.
  • the crude sumatriptan is dissolved in acetone at reflux temperature, treated with carbon and filtered to give pure sumatriptan base. It is further reacted with different acids such as citric acid, ascorbic acid and oxalic acid to give corresponding sumatriptan acid addition salts.
  • sumatriptan base is also crystallized in a solvent, then converting sumatriptan base into acid addition salt.
  • the sumatriptan acid addition salt is set free by treating sodium or potassium carbonate to give sumatriptan base, which is subjected to crystallization to give pure sumatriptan base.
  • sumatriptan base is converted into acid addition salts by conventional method.
  • an improved process for preparing sumatriptan acid addition salts comprising adsorbing crude sumatriptan base on stationary phase, leaching/ treating stationary phase with acid and isolating the resultant acid addition salt of sumatriptan, wherein said stationary phase is silica gel enabling the reduction of purification steps and resulting a pure and improved yield of acid addition salt of sumatriptan.
  • an improved process for preparing sumatriptan acid addition salts comprising adsorbing crude sumatriptan base on stationary phase, leaching/ treating stationary phase with solvent, followed by adding acid to the solvent and isolating the resultant acid addition salt of sumatriptan, wherein said stationary phase is silica gel enabling the reduction of purification steps and resulting a pure and improved yield of acid addition salt of sumatriptan.
  • a process for preparing crystalline form of sumatriptan base comprises of suspending the sumatriptan acid addition salt in a water or mixture of water and water miscible organic solvents, adjusting pH of the resultant solution to basic with base and isolating the crystalline form of sumatriptan base.
  • a novel crystalline sumatriptan base wherein said crystalline form is characterized by having a X-ray powder diffraction pattern having peaks at about 9.97 ( ⁇ ) 0.2, 17.29 ( ⁇ ) 0.2, 21.68 ( ⁇ ) 0.2, two-theta.
  • a novel crystalline sumatriptan base wherein said crystalline form is characterized by having a differential scanning calorimetry thermogram (DSC) peak at about 67 ° C, about 106 ° C and 174° C ( ⁇ ) 0.1% at 10° C/ minute.
  • DSC differential scanning calorimetry thermogram
  • FIG. 1 is X-ray powder diffractogram for the sumatriptan base isolated from water.
  • FIG.2 is X-ray powder diffractogram for the sumatriptan base crystallized from Isopropyl alcohol.
  • FIG. 3 is X-ray powder diffractogram for the sumatriptan base crystallized from acetone.
  • FIG. 4 is X-ray powder diffractogram for the sumatriptan benzoate.
  • FIG. 5 is X-ray powder diffractogram for the sumatriptan succinate.
  • FIG. 6 is a DSC curve for the sumatriptan base isolated from water.
  • the disclosed embodiment of the present invention provides a cost effective and industrial feasible process for preparing sumatriptan acid addition salts, a novel crystalline form of sumatriptan base and product thereof, wherein the process is improved upon prior arts in view of reducing process steps, avoiding repeated crystallizations and purification of the resultant.
  • the resulting solution is further extracted with solvent, preferably dichloromethane and the resultant combined organic layer is washed with water. Then the solvent is removed under reduced pressure to give residue, which is further diluted with organic solvents selected from dichloromethane, dichloroethane, chloroform, preferably in dichloromethane. and the process further involves cooling the obtained reaction mass between -10° C to 25° C, preferably 0° C to 5° C. Polyphosphoric acid ester which is diluted with dichloromethane, is added to the reaction mass and temperature is maintained between 20-60° C. After completion of the cyclization reaction, reaction mass is cooled to 0-5° C. Further the resultant reaction mass is diluted with water followed by separating the organic and aqueous layer obtained therein.
  • solvent preferably dichloromethane
  • chloroform preferably in dichloromethane
  • aqueous layer pH is adjusted to 9.0 to 12.0 with base wherein base is selected from sodium hydroxide, potassium hydroxide, ammonia .
  • base is selected from sodium hydroxide, potassium hydroxide, ammonia .
  • water immiscible organic solvents which are selected from dichloromethne, dichloroethane, chloroform, toluene, ethyl acetate.
  • the preferred water immiscible organic solvent is ethyl acetate.
  • silica gel is added to the resultant ethyl acetate layer obtained from above process steps at ambient temperature and stir for 1- 2 hours.
  • the sumatriptan product is adsorbed on the silica gel and the impurities are not adsorbed on silica gel.
  • Sumatriptan base is completely adsorbed on acidic silica gel due to sumatriptan base having the basic nature.
  • the acidic impurities not adsorbed on silica gel are removed by simple filtration, without performing any purification steps such as column chromatography, or repeated crystallization methods in different solvents.
  • the resultant silica gel containing sumatriptan is filtered and isolated as pure sumatriptan base. Further, the obtained sumatriptan base is treated with pharmaceutically acceptable acids to prepare corresponding pharmaceutically acceptable acid addition salts with improved yield.
  • silica gel containing pure sumatriptan is filtered and suspended in a solvent selected from methanol, ethanol, isopropyl alcohol.
  • Silica gel is suspended in alcoholic solvent and stirred for 1 to 2 hours, then filtered and washed with solvent.
  • the sumatriptan base is soluble in alcohol and the filtrate is containing the sumatriptan base, which is concentrated under reduced pressure to give sumatriptan base.
  • the preferred solvent is methanol.
  • sumatriptan base is isolated, as a solid without performing purification techniques like column chromatography or crystallization process subjecting to apply external heating and cooling.
  • the resultant sumatriptan base is optionally dissolved in a solvent and treated with pharmaceutically acceptable acids to give corresponding pharmaceutically acceptable acid addition salts with improved yield.
  • the pharmaceutically acceptable acid used according to the present invention is selected from hydrochloric acid, hydrobromic acid, phosphoric acid, benzoic acid, methanesulfonic acid, oxalic acid, succinic acid or any other acid suitable to give corresponding pharmaceutically acceptable acid addition salts.
  • Another embodiment of present invention is isolation of novel crystalline sumatriptan base, wherein the above isolated sumatriptan acid addition salt is dissolved in water or a mixture of water and water miscible organic solvents to give clear solution.
  • the water miscible organic solvent is selected from methanol, ethanol, isopropyl alcohol; acetone.
  • the preferred water miscible organic solvent is methanol.
  • Sumatriptan Base The resulting solution pH is adjusted to 8.0 to 11.0 with base in the presence of anti oxidant such as sodium dithionite, butylated hydroxy toluene or butylated hydroxyl anisole to precipitate the crystalline sumatriptan base.
  • the base is like alkali/alkaline earth hydroxides carbonate sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate.
  • the precipitated crystalline solid is filtered and washed and dried to give crystalline sumatriptan base, which is having powder diffraction pattern having peaks at about 9.97 ( ⁇ ) 0.2, 17.29 ( ⁇ ) 0.2, 21.68 ( ⁇ ) 0.2, two-theta.
  • the precipitated crystalline solid is filtered and washed and dried to give crystalline sumatriptan base, which is having powder diffraction pattern having peaks at about 9.97 ( ⁇ ) 0.2, 13.3 ( ⁇ ) 0.2, 15.88 ( ⁇ ) 0.2, 21.09 ( ⁇ ) 0.2, 21.64 ( ⁇ ) 0.2, 22.76 ( ⁇ ) 0.2, two-theta
  • DSC Differential scanning calorimetry thermogram
  • sumatriptan base is crystallized from isopropyl alcohol, acetone, acetonitrile etc.
  • the sumatriptan crystallized from isopropyl alcohol and acetone are having the similar PXRD pattern, where as sumatriptan base isolated from the water or mixture of water and water miscible organic solvent is having the different PXRD pattern, which is not known in the prior art.
  • crystalline sumatriptan base isolated from water or a mixture of water and water miscible organic solvents, having different
  • the isolated pure crystalline sumatriptan base is converted to pharmaceutically acceptable salt by conventional method without subjecting extra purification steps.
  • the following examples will further illustrate certain specific aspects and embodiments of the invention in greater detail and are not to be construe as limiting the scope of the invention.
  • Example-2A 3-(2-Dimethylamino)-N-methyl-lH- indole-5-methane sulphonamide was taken in 300 ml methanol. 38.65 ml of concentrated. HCl was added slowly at 25-30°C. The solution was cooled to 10-15 0 C and filtered. The product weight was 80-85 gm.
  • the dichloromethane layer and 1000 gm polyphosphoric ester in 600ml dichloromethane was stirred at 35-40°C for 2 hours and then 2 litres water was added.
  • the organic layer was separated and aqueous layer was basified with sodium hydroxide solution and the product was extracted with ethyl acetate.
  • the organic layer was treated with silica gel 60-100 mesh and then filtered.
  • Silica gel washed with ethyl acetate 1000X3 ml.
  • the absorbed product on silica gel was eluted with methanol 1000X2 ml. Filtrate methanol was distilled off completely under vacuum and 500 ml acetone was added.

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

Abstract

La présente invention concerne un procédé amélioré pour la préparation du sel d'addition d'acide du 3-(2-(diméthylamino)éthyl)-N-méthyl-1H-indole-5-méthanesulfonamide (sumatriptan) et de la base avec un rendement et une pureté accrus. La présente invention concerne également une nouvelle forme cristalline de sumatriptan base.
PCT/IN2008/000592 2007-09-17 2008-09-16 Procédé de préparation de 3-(2-(diméthylamino)éthyl)-n-méthyl-1h-indole-5-méthanesulfonamide et produit associé Ceased WO2009037718A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2078CH2007 2007-09-17
IN2078/CHE/2007 2007-09-17

Publications (3)

Publication Number Publication Date
WO2009037718A2 true WO2009037718A2 (fr) 2009-03-26
WO2009037718A8 WO2009037718A8 (fr) 2009-05-28
WO2009037718A3 WO2009037718A3 (fr) 2010-01-21

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PCT/IN2008/000592 Ceased WO2009037718A2 (fr) 2007-09-17 2008-09-16 Procédé de préparation de 3-(2-(diméthylamino)éthyl)-n-méthyl-1h-indole-5-méthanesulfonamide et produit associé

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102212027A (zh) * 2011-05-04 2011-10-12 苏州莱克施德药业有限公司 一种舒马曲坦的制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060106227A1 (en) * 2002-06-13 2006-05-18 Dr Reddy's Laboratories Limited 3-'2-(Dimethylamino) ethyl!-n-methyl-1h-indole-5-methanesulfonamide and the succinate thereof
WO2004076403A1 (fr) * 2003-02-24 2004-09-10 Transform Pharmaceuticals, Inc. Formes cristallines du sumatriptan, compositions pharmaceutiques et procedes
US20070054953A1 (en) * 2003-05-12 2007-03-08 Potluri Ramesh B A novel process for preparation of indole derivatives
WO2007070504A2 (fr) * 2005-12-13 2007-06-21 Morton Grove Pharmaceuticals, Inc. Compositions orales liquides de sumatriptan stables et de gout agreable

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102212027A (zh) * 2011-05-04 2011-10-12 苏州莱克施德药业有限公司 一种舒马曲坦的制备方法

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WO2009037718A8 (fr) 2009-05-28
WO2009037718A3 (fr) 2010-01-21

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