WO2007138468A2 - Processes for the preparation of lansoprazole - Google Patents

Processes for the preparation of lansoprazole Download PDF

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Publication number
WO2007138468A2
WO2007138468A2 PCT/IB2007/001437 IB2007001437W WO2007138468A2 WO 2007138468 A2 WO2007138468 A2 WO 2007138468A2 IB 2007001437 W IB2007001437 W IB 2007001437W WO 2007138468 A2 WO2007138468 A2 WO 2007138468A2
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WO
WIPO (PCT)
Prior art keywords
formula
lansoprazole
och
compound
less
Prior art date
Application number
PCT/IB2007/001437
Other languages
English (en)
French (fr)
Other versions
WO2007138468A3 (en
Inventor
Mohammed Jaweed Mukarram Siddiqui
Dilip Ganesh Kulkarni
Praveen Raosaheb Supekar
Prakash Sakharam Shinde
Vikas Vitthalrao Deshmukh
Original Assignee
Wockhardt 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 Wockhardt Ltd filed Critical Wockhardt Ltd
Publication of WO2007138468A2 publication Critical patent/WO2007138468A2/en
Publication of WO2007138468A3 publication Critical patent/WO2007138468A3/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the field of the invention relates to processes for the preparation of benzimidazole sulphinyl compounds. More particularly, it relates to the preparation of pure lansoprazole and pharmaceutical compositions that include the pure lansoprazole.
  • Benzimidazole sulphinyl compounds of Formula I are known for gastric proton pump inhibitors.
  • lansoprazole H
  • omeprazole Ri and R 3 OCH 3
  • R 2 and R 4 CH 3 and its (S)-enantiomer esomeprazole
  • Lansoprazole is known to have excellent gastric acid secretion inhibiting action and gastric mucous membrane protecting action. It is chemically, 2-[[[3-Methyl-4- (2,2,2-trifluoro-ethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole having structure of Formula l-a.
  • U.S. Patent No. 4,689,333 discloses a process of making lansoprazole by reaction of 2-mercaptobenzimidazole with 2-chloromethyl 3-methyl-4-(2,2,2- trifluoroethoxy) pyridine derivative in presence of a base and solvent.
  • U.S. Patent No. 6,002,011 discloses a process of crystallizing benzimidazole compounds with aqueous alcohol. The process includes isolating the water alcohol solvate and desolvating by suspending the solvate in warm water.
  • U.S. Patent No. 6,423,846 discloses a process of crystallization in acetone water. The process includes further purification by column chromatography.
  • U.S. Patent Application No. 20040138466 discloses a process for the preparation of benzimidazole sulphinyl compounds by reacting a thioether with tert-butyl hydroperoxide (TBHP) in the presence of a vanadium catalyst.
  • U.S. Patent Application No. 20040215021 discloses a purification process for benzimidazole compounds using organic solvents or mixture of organic solvents and water in the presence of a weak basic gas like ammonia and methylamine.
  • European Patent No. 302,720 discloses a process wherein the benzimidazole compound is crystallized from water and ethanol.
  • PCT Patent Application No. 2002074766 discloses a process for making lansoprazole by reacting 2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy) pyridine or its salt with 2-mercaptobenzimidazole in the presence of a halogenating agent and oxidizing the obtained thioethers compound with hydrogen peroxide in presence of benzene seleseninic acid.
  • Ri is H, OCH 3 or OCHF 2 ;
  • R 2 is CH 3 or OCH 3 ;
  • R 3 is OCH 3 , OCH 2 CF 3 or O(CH 2 ) 3 OCH 3 ;
  • R 4 is H or CH 3 .
  • the process includes the steps of: a) oxidizing a thioether of Formula Il in presence of oxygen scavenger with a suitable oxidizing agent in one or more organic solvents,
  • Embodiments of the process may include one or more of the following features.
  • the oxidation may be carried out in the presence of one or more suitable oxidizing agents.
  • suitable oxidizing agents may include one or more of m-chloroperbezoic acid, peracids, sodium hypohalides, magnesium monoperoxyphalate, hydrogen peroxide, benzeneseleseninic acid or Vanadium catalyst.
  • the process may include carrying out the oxidation reaction in the presence of an oxygen scavenger.
  • the oxygen scavenger may include one or more of dimethylsulphoxide, N-methylmorpholine or sulphur containing heterocycles.
  • Suitable organic solvents may include one or more of lower alkanols, halogenated hydrocarbons or mixtures thereof.
  • the lower alkanol may include one or more of methanol, ethanol, isopropanol, n-propanol, n-butanol, and iso- butanol.
  • the halogenated hydrocarbon may include one or more of dichloromethane, dibromomethane, chloroform and ethylene dichloride.
  • the process includes the steps of: a) reacting a compound of Formula III,
  • the base may be, for example one or more of inorganic bases or organic bases.
  • the inorganic base may include one or more of alkali metal and alkaline earth metal hydroxides, hydrides, carbonates, bicarbonates and alkoxides and their solution in water.
  • the organic base may include one or more of ammonia, primary, secondary or tertiary amines.
  • Ri is H, OCH 3 or OCHF 2 ;
  • R2 is CH 3 or OCH 3 ;
  • R3 is OCH 3 , OCH 2 CF 3 or O(CH 2 ) 3 OCH 3 ;
  • R 4 is H or CH 3 , the process comprising: a) dissolving the compound of Formula I in aqueous alkali to get a solution; b) purging carbon dioxide into the solution; and c) isolating the compound of Formula I.
  • Embodiments of the process may include one or more of the following features.
  • the aqueous alkali may include one or more of sodium hydroxide, potassium hydroxide, water, and mixtures thereof.
  • a pure lansoprazole In one general aspect there is provided a pure lansoprazole. In another general aspect there is provided a process for preparing lansoprazole containing less than about 100 ppm residual solvent. The process includes dissolving lansoprazole in aqueous alkali to get a solution; purging carbon dioxide into the solution; and isolating the lansoprazole containing less than about 100 ppm residual solvent.
  • the process may include further drying of the product obtained.
  • the process may produce the pure lansoprazole having purity more than 99.2% as determined by HPLC. In particular, it may produce the lansoprazole having purity more than 99.2% and residual solvent less than 50 ppm.
  • composition that includes a therapeutically effective amount of pure lansoprazole having less than 50 ppm residual solvent; and one or more pharmaceutically acceptable carriers, excipients or diluents.
  • sulphone is formed as an impurity during the synthesis of benzimidazole compounds.
  • the sulphone impurity is formed during the oxidation step. It was also noticed that the known processes for the oxidation involve the use of expensive and/or toxic catalyst, which are not selective.
  • the known reagents for oxidation result in over oxidation of the benzimidazole sulphinyl compound to sulphone impurity, removal of which is extremely difficult from the finished product.
  • the sulphone impurity rapidly imparts color to the product during storage and handling.
  • the inventors have now developed a controlled oxidative process, which employs the use of oxygen scavengers to prevent the further oxidation of desired benzimidazole sulphinyl compounds to sulphone impurities.
  • the sulphone impurity could be kept under control during reaction by using a combination of solvents for example, lower alkanols and halogenated hydrocarbons.
  • solvents for example, lower alkanols and halogenated hydrocarbons.
  • the use of such solvents for the preparation of lansoprazole sulphide of Formula ll-a results in a product having moisture content more than the required limit, which requires rigorous drying to get moisture content of the product in limit. The recovery of solvent is also insufficient. The drying of the lansoprazole sulphide to get the desired moisture results in increased impurity content.
  • the inventors have now developed an efficient process for the preparation of lansoprazole sulphide of Formula ll-a wherein the process does not require extensive drying of the intermediate and provide very efficient recovery of the solvent.
  • the inventors have developed a process to desolvate the benzimidazole compound that employs the use of carbon dioxide to produce the bezimidazoles which are solvent and water free.
  • the inventors have developed processes for the preparation of anti-ulcerative agents for example, lansoprazole, pantoprazole, omeprazole, esomeprazole, laminoprazole and rabeprazole having a compound of Formula I,
  • R 1 is H, OCH 3 or OCHF 2 ;
  • R2 is CH 3 or OCH 3 ;
  • R 3 is OCH 3 , OCH 2 CF 3 or O(CH 2 ) 3 OCH 3 ;
  • R 4 is H or CH 3 .
  • the thioethers of Formula Il and ll-a can be prepared by, methods known in the literature. In particular, these may be prepared by the methods described in U.S. Patent No. 4,628,098 and U.S. Patent No. 6,423,846.
  • the thioether may be suspended in a suitable organic solvent and the mass may be oxidized using one or more oxidizing agents while maintaining the pH of the reaction mass in range of about 4 to about 7 using a buffer optionally in the presence of an oxygen scavenger.
  • Suitable solvents include one or more of lower alkanol, halogenated hydrocarbon, ketone or ester.
  • the lower alkanol may include one or more of methanol, ethanol, isopropanol, n-propanol, n-butanol, and isobutanol.
  • the halogenated hydrocarbon may include one or more of dichloromethane, dibromomethane, chloroform, ethylene dichloride, and the like.
  • the oxidizing agent may include one or more of m-chloroperbezoic acid, peracids, sodium hypohalides, magnesium monoperoxyphalate, hydrogen peroxide, benzeneseleseninic acid or Vanadium catalyst.
  • the oxygen scavenger may include one or more of dimethylsulphoxide, N-methylmorpholine or sulphur containing heterocycles
  • the buffering effect can be obtained by using a mixture of sodium acetate and acetic acid. After completion of the reaction, the pH of the reaction mass can be raised and the organic phase can be separated. The organic layer so obtained can be extracted with an aqueous alkali from which the product can be isolated by acidification.
  • the compounds of Formula III and IV may be prepared by the methods known in the literature. In particular, these may be prepared by the methods described in U.S. Patent No. 4,628,098 and German Patent No. 4,230,923.
  • the compound of Formula III may be reacted with a compound of Formula IV in aqueous acetone in the presence of a base.
  • the base may include one or more of inorganic bases or organic bases.
  • Inorganic bases may include alkali metal and alkaline earth metal hydroxides, hydrides, carbonates, bicarbonates and alkoxides.
  • Organic bases may include ammonia, primary, secondary or tertiary amines.
  • the compound of Formula Il and ll-a may be subjected to oxidation using oxidizing agent to get benzimidazole sulphinyl compounds of Formula I.
  • the benzimidazole sulphinyl of Formula I may be dissolved in aqueous alkali such as sodium hydroxide, potassium hydroxide, and the like.
  • aqueous alkali such as sodium hydroxide, potassium hydroxide, and the like.
  • the pH of the reaction mixture may be adjusted to about 8 and carbon dioxide may be purged into the solution.
  • the separated benzimidazole compound of Formula I may be isolated.
  • the isolation may include filtration, filtration under vacuum, centrifugation, and decantation.
  • the product obtained may be further or additionally dried to achieve the desired moisture values.
  • the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.
  • the pure lansoprazole has a purity of more than 99.2%. More particularly, the lansoprazole has a purity of more than 99.2% and less than 100 ppm residual solvent, for example less than 50 ppm residual solvent.
  • the compound of formula I is purified by any process know in art, which may optionally include crystallization and chromatographic purification.
  • Lansoprazole (750 gm) was dissolved in 10% aqueous ethyl alcohol (6 Lit, 1:9) by portion wise addition of solid sodium carbonate (20 gm). The reaction mixture was heated to 60-70 0 C to get a clear solution. The solution was filtered hot and the filtrate was cooled to 5°C gradually to crystallize out the product. The solid was filtered.
  • Residual solvent Not detected (less than 50 ppm)

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
PCT/IB2007/001437 2006-06-01 2007-05-31 Processes for the preparation of lansoprazole WO2007138468A2 (en)

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
IN838MU2006 2006-06-01
IN846MU2006 2006-06-01
IN837/MUM/2006 2006-06-01
IN837MU2006 2006-06-01
IN846/MUM/2006 2006-06-01
IN835MU2006 2006-06-01
IN838/MUM/2006 2006-06-01
IN854MU2006 2006-06-01
IN854/MUM/2006 2006-06-01
IN835/MUM/2006 2006-06-01

Publications (2)

Publication Number Publication Date
WO2007138468A2 true WO2007138468A2 (en) 2007-12-06
WO2007138468A3 WO2007138468A3 (en) 2009-04-23

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010095144A3 (en) * 2009-02-04 2010-11-04 Msn Laboratories Limited Process for preparation of proton pump inhibitors
CN102558148A (zh) * 2010-12-15 2012-07-11 山东方明药业股份有限公司 一种兰索拉唑重要中间体的合成工艺
CN102617555A (zh) * 2012-03-20 2012-08-01 西藏易明西雅生物医药科技有限公司 一种兰索拉唑的制备方法
CN104327048A (zh) * 2014-04-04 2015-02-04 苏州东瑞制药有限公司 一种兰索拉唑硫醚晶型及其制备方法与应用
CN104483403A (zh) * 2014-12-05 2015-04-01 广东东阳光药业有限公司 一种检测右兰索拉唑原料药有关物质的方法
CN104530006A (zh) * 2015-01-06 2015-04-22 江苏奥赛康药业股份有限公司 兰索拉唑的制备方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6245913B1 (en) * 1999-06-30 2001-06-12 Wockhardt Europe Limited Synthetic procedure for 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-IH-benzimidazole hydrochloride and its conversion to omeprazole
MXPA04000433A (es) * 2001-07-16 2004-03-18 Janssen Pharmaceutica Nv Procedimiento mejorado para preparar compuestos tipo bencimidazol.

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010095144A3 (en) * 2009-02-04 2010-11-04 Msn Laboratories Limited Process for preparation of proton pump inhibitors
CN102558148A (zh) * 2010-12-15 2012-07-11 山东方明药业股份有限公司 一种兰索拉唑重要中间体的合成工艺
CN102617555A (zh) * 2012-03-20 2012-08-01 西藏易明西雅生物医药科技有限公司 一种兰索拉唑的制备方法
CN102617555B (zh) * 2012-03-20 2014-05-21 北京易明康元医药科技有限公司 一种兰索拉唑的制备方法
CN104327048A (zh) * 2014-04-04 2015-02-04 苏州东瑞制药有限公司 一种兰索拉唑硫醚晶型及其制备方法与应用
CN104483403A (zh) * 2014-12-05 2015-04-01 广东东阳光药业有限公司 一种检测右兰索拉唑原料药有关物质的方法
CN104530006A (zh) * 2015-01-06 2015-04-22 江苏奥赛康药业股份有限公司 兰索拉唑的制备方法
CN104530006B (zh) * 2015-01-06 2018-05-11 江苏奥赛康药业股份有限公司 兰索拉唑的制备方法

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