WO2007088557A1 - Procédé d'obtention de base cristaline de granisétron de haute pureté - Google Patents

Procédé d'obtention de base cristaline de granisétron de haute pureté Download PDF

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Publication number
WO2007088557A1
WO2007088557A1 PCT/IN2007/000018 IN2007000018W WO2007088557A1 WO 2007088557 A1 WO2007088557 A1 WO 2007088557A1 IN 2007000018 W IN2007000018 W IN 2007000018W WO 2007088557 A1 WO2007088557 A1 WO 2007088557A1
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WO
WIPO (PCT)
Prior art keywords
granisetron
base
crystalline
preparation
high purity
Prior art date
Application number
PCT/IN2007/000018
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English (en)
Inventor
Ramanadham Jyothi Prasad
Bollepalli Nageshwar Rao
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
Publication of WO2007088557A1 publication Critical patent/WO2007088557A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/14—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof

Definitions

  • the present invention relates to an improved process for the preparation of high purity crystalline base of Granisetron, and its pharmaceutically acceptable salts. More particularly the present invention provides an improved process for the preparation of high purity (>99.9%) crystalline base of Granisetron and its pharmaceutically acceptable hydrochloride salt.
  • Granisetron base and its pharmaceutically acceptable salts are well known antiemetic drug.
  • Granisetron is currently being used in the anticancer chemotherapy. It is l-methyl-N-[(3- er ⁇ cfo)-9-methyl-9-azabicyclo[3.3. l]non-3-yl]- lH-indazole-3-carboxamide having the structural formula (1) as given below:
  • Granisetron was first developed and disclosed by Beecham group (GB), in their European Patent Application EP 200444; corresponding to US 4886808.
  • Granisetron of the formula (1) can be prepared by reacting a solution of 1- methyl indazole-3-carboxylic acid chloride in dichloromethane with a solution of endo-9- methyl-9-azabicyclo[3.3.1]nonan-3-amine and triethyl amine in dichloromethane. After the normal work-up and subsequent evaporation of the solvent, Granisetron base was obtained as an oil. This oil was purified by using column chromatography and reacted with hydrogen chloride to give the desired compound, Granisetron Hydrochloride (mp: 290-2°C).
  • R is a nitrogen- protecting group which does not significantly reduce the nucleophilicity of a secondary amino group and optionally forming a pharmaceutically acceptable salt.
  • Example (5) of the above said patent gives the Granisetron base purity as 84.7% and that of hydrochloride as 96%.
  • the Example (6) gives the Granisetron base purity as 86% and that of hydrochloride salt as 97%.
  • the Granisetron base obtained by the process disclosed in the above said patent WO 03/080606 was having a maximum purity of 86% and that of hydrochloride was 97% only, which is not acceptable for pharmaceutical use as an Active Pharmaceutical Ingredient (API).
  • the main objective of the present invention is to provide an improved process for the preparation of crystalline and highly pure (>99.9%) Granisetron base of the formula (1),
  • Another objective of the present invention is to provide an improved process for the manufacture of salts of Granisetron, preferably the hydrochloride, in which the crystalline and highly pure (>99%) granisetron base is used.
  • the crystalline base of Granisetron prepared according to the present invention has a melting point between 148 - 152 0 C, more preferably between 150 - 152°C. Whereas its purity is more than 99.6%, preferably more than 99.8%, most preferably more than 99.9% by HPLC (% area) and the following identified and pharmacoepial listed impurities are in the range of 0 to 0.05% (% area) (i) endo-N- (9-methyl-9-azabicyclo [3.3.1] non-3-yl)-2-methyl-2H-indazole-3- carboxamide
  • the present invention provides a process for the preparation of high purity(>99.9% by HPLC) crystalline Granisetron base of the formula (1),
  • (1) which comprises, (i) suspending the crude base of granisetron in a protic solvent or a mixture of protic solvents, such as alcohols, at 25-35 0 C, cooling to a temperature in the range of 0 to 15°C, preferably 0 to 5°C and stirring for a period in the range of one to three hours. (ii) filtering the crystals so formed in the alcoholic solvent medium used in step (ii), by conventional techniques, washing the crystals with the same solvent and if necessary drying the crystalline Granisetron base formed under vacuum and if desired,
  • a protic solvent or a mixture of protic solvents such as alcohols
  • step (iii) converting the Granisetron base obtained in step (ii) above into its pharmaceutically acceptable salts thereof by conventional techniques.
  • the alcoholic solvent used in step (i) may be selected from, isopropyl alcohol, ethyl alcohol, methyl alcohol, isobutyl alcohol, etc., preferably, isopropyl alcohol.
  • Granisetron base prepared according to the present invention was found to be a stable crystalline solid with very high melting point (150 - 152°C) and high purity (> 99.9% by HPLC area %).
  • the melting point observed by us is nearly 30°C higher than the prior art melting point.
  • This process for preparation of high purity Granisetron crystals is novel and simple. It avoids the cumbersome column chromatography purification disclosed in prior art method.
  • the granisetron base (wet or dry) as obtained in step (ii) above can be further converted into its pharmaceutically acceptable salts, such as hydrochloride in a commercially simple and viable process.
  • the present invention also provides a process for the preparation of high purity (>99.8%) hydrochloride salt of Granisetron from the crystalline Granisetron base of formula (1),
  • step (a) suspending the crystalline Granisetron base (wet or dry) obtained in step (ii) of the process defined above in aqueous or non-aqueous alcoholic solvent or a mixture thereof
  • the starting compound namely endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-l- methyl-lH-indazole-3-carboxamide may be prepared by any known conventional methods, for example, by the method described in Example 6 of EP 200444.
  • the aqueous or non-aqueous alcoholic solvent used in step (a) is selected from the methanol, ethanol, isopropanol, n-butanol, preferably isopropanol.
  • the polar solvent used in step (d) is selected from water; alcohols like methanol, ethanol, isopropanol, n- butanol, preferably isopropanol; amides like N,N-dimethylformamide; nitriles like acetonitrile; esters like ethyl acetate, isopropyl acetate or a mixture thereof.
  • the decolorizing agent used in step (e) is for example activated charcoal.
  • the process of the present invention for preparing hydrochloride salt of Granisetron is very high yielding (>90%), commercially feasible with pharmaceutically acceptable quality.
  • isopropyl alcohol (5L) added and cooled to 0-5°C and stirred for about 2 hr to make good slurry and centrifuged and washed the cake with chilled isopropyl alcohol. Dried the material under vacuum to get a very nice crystalline solid.
  • the methylene chloride layer containing l-methyl-indazole-3-carbonyl chloride [prepared from 2Kg of l-methyl-indazole-3-carboxylic acid, according to the process described in the Example- 1] was transferred into an all glass reactor under nitrogen atmosphere and cooled to 15-20°C. To this a mixture of endo-3-amino-9-methyl-9- azabicyclo[3.3.1]nonane (2Kg) and triethylamine (1.45Kg) was slowly added in about 1 Vz hr and maintained the reaction mass for V 2 hr at the same temperature and checked the completion of the reaction by HPLC.
  • Granisetron hydrochloride is passing in all aspects as per the specifications of EP 5.1.
  • Example 9 Preparation of Granisetron HCl (Pharma Grade) from Methyl alcohol Into a three-necked round-bottomed flask equipped with a mechanical stirrer, thermometer pocket, condenser, etc. charged 10OmL of methanol, followed by lO.Og granisetron HCl (Tech) prepared by the process described in Example 3 and raised the temperature to 60+2°C, and maintained for about 15 min to get clear solution. Then 2.Og activated carbon added, filtered and washed the carbon cake with 15mL of methanol. Then distilled off methanol around 5OmL from the filtrate and cooled to the reaction mass to 25-35 0 C and maintained for 90min and filtered the mass. Washed the cake with 20 ml of methanol and dried the material at 70-75 0 C till constant weight is obtained. Dry weight : 7.Og
  • Granisetron hydrochloride is passing in all aspects as per the specifications of EP 5.1.
  • Granisetron hydrochloride is passing in all aspects as per the specifications of EP 5.1.
  • Granisetron base prepared by the present process is of high purity (>99.9%).
  • the high purity Granisetron base prepared according to the present invention can be converted to pharmaceutically acceptable salts such as hydrochloride salt with pharmaceutically acceptable grade.

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

Abstract

L'invention porte sur un procédé commercial amélioré de préparation de base cristalline de haute pureté (>99,9%) de granisétron (1-méthyl-N-[(3-endo)-9-méthyl-9-azabicyclo[3.3.1]non-3-yl]-1H-indazole-3-carboxamide)de formule (1), et sur des utilisations dans les processus de fabrication de sels d'hydrochlorure pharmacocompatibles.
PCT/IN2007/000018 2006-02-01 2007-01-18 Procédé d'obtention de base cristaline de granisétron de haute pureté WO2007088557A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN166/CHE/2006 2006-02-01
IN166CH2006 2006-02-01

Publications (1)

Publication Number Publication Date
WO2007088557A1 true WO2007088557A1 (fr) 2007-08-09

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WO (1) WO2007088557A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008117282A1 (fr) * 2007-03-27 2008-10-02 Chemagis Ltd. Forme polymorphe de base de granisétron et son procédé de production
WO2010022052A1 (fr) * 2008-08-19 2010-02-25 Scinopharm Taiwan, Ltd. Forme polymorphe du chlorhydrate de granisétron et procédés de fabrication
CN103319396A (zh) * 2012-03-21 2013-09-25 黑龙江福和华星制药集团股份有限公司 一种1-甲基吲哚-3-羧酸的制备方法
CN115372487A (zh) * 2021-05-18 2022-11-22 成都倍特药业股份有限公司 盐酸格拉司琼中杂质e的hplc测定方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0200444A2 (fr) * 1985-04-27 1986-11-05 Beecham Group Plc Azabicyclononyl-indazole carboxamide ayant une activité antagoniste de la 5-HT
WO1995023799A1 (fr) * 1994-03-03 1995-09-08 Smithkline Beecham Plc Procede de preparation d'un derive d'indazole-3-carboxamide
WO1997030049A1 (fr) * 1996-02-13 1997-08-21 Smithkline Beecham Plc Procede de production de granisetron
WO2003080606A1 (fr) * 2002-03-26 2003-10-02 Laboratorios Vita, S.A. Procede de preparation d'un compose pharmaceutiquement actif (granisetron)

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0200444A2 (fr) * 1985-04-27 1986-11-05 Beecham Group Plc Azabicyclononyl-indazole carboxamide ayant une activité antagoniste de la 5-HT
WO1995023799A1 (fr) * 1994-03-03 1995-09-08 Smithkline Beecham Plc Procede de preparation d'un derive d'indazole-3-carboxamide
WO1997030049A1 (fr) * 1996-02-13 1997-08-21 Smithkline Beecham Plc Procede de production de granisetron
WO2003080606A1 (fr) * 2002-03-26 2003-10-02 Laboratorios Vita, S.A. Procede de preparation d'un compose pharmaceutiquement actif (granisetron)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008117282A1 (fr) * 2007-03-27 2008-10-02 Chemagis Ltd. Forme polymorphe de base de granisétron et son procédé de production
WO2010022052A1 (fr) * 2008-08-19 2010-02-25 Scinopharm Taiwan, Ltd. Forme polymorphe du chlorhydrate de granisétron et procédés de fabrication
US20100048613A1 (en) * 2008-08-19 2010-02-25 Scinopharm Taiwan Ltd. Polymorphic form of granisetron hydrochloride and methods of making the same
US8193217B2 (en) 2008-08-19 2012-06-05 Scinopharm Taiwan Ltd. Polymorphic form of granisetron hydrochloride and methods of making the same
CN102131506B (zh) * 2008-08-19 2013-07-24 台湾神隆股份有限公司 盐酸格拉司琼的多晶型和其制备方法
CN103319396A (zh) * 2012-03-21 2013-09-25 黑龙江福和华星制药集团股份有限公司 一种1-甲基吲哚-3-羧酸的制备方法
CN115372487A (zh) * 2021-05-18 2022-11-22 成都倍特药业股份有限公司 盐酸格拉司琼中杂质e的hplc测定方法
CN115372487B (zh) * 2021-05-18 2023-10-10 成都倍特得诺药业有限公司 盐酸格拉司琼中杂质e的hplc测定方法

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