WO2010068049A2 - Procédé pour préparer du (r)-(+)-lansoprazole et intermédiaire utilisé dans celui-ci - Google Patents

Procédé pour préparer du (r)-(+)-lansoprazole et intermédiaire utilisé dans celui-ci Download PDF

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Publication number
WO2010068049A2
WO2010068049A2 PCT/KR2009/007389 KR2009007389W WO2010068049A2 WO 2010068049 A2 WO2010068049 A2 WO 2010068049A2 KR 2009007389 W KR2009007389 W KR 2009007389W WO 2010068049 A2 WO2010068049 A2 WO 2010068049A2
Authority
WO
WIPO (PCT)
Prior art keywords
lansoprazole
mixture
ethanediol
triphenyl
formula
Prior art date
Application number
PCT/KR2009/007389
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English (en)
Other versions
WO2010068049A3 (fr
Inventor
Sun Young Jang
Tai Won Kim
Sungbum Kim
Byung-Ku Kim
Chang-Ju Choi
Cheol Kyung Kim
Tae Hee Ha
Kwee Hyun Suh
Gwan Sun Lee
Original Assignee
Hanmi Pharm. Co., 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 Hanmi Pharm. Co., Ltd. filed Critical Hanmi Pharm. Co., Ltd.
Publication of WO2010068049A2 publication Critical patent/WO2010068049A2/fr
Publication of WO2010068049A3 publication Critical patent/WO2010068049A3/fr

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to a process for the preparation of (R)-(+)-lansoprazole having a high optical purity, and a novel intermediate used therein.
  • Lansoprazole 2-[[3-methyl-4-(2,2,2,-trifluoroethoxy)-2-pyridinyl]methyl] sulfinyl- lH-benzimidazole disclosed in EP Patent No. 0 174 726 Bl, is a proton pump inhibitor, which suppresses gastric acid secretion to prevent ulcer.
  • Lansoprazole molecule has a chiral center at the sulfur atom, and thus, two enantiomers thereof exist: dextrorotatory (R)-(+)-lansoprazole and levorotatory (S)-(-)-lansoprazole as disclosed in WO 1992/08716.
  • WO 1996/02535 and WO 1997/02261 describe enantioselective synthesis of a single enantiomer by catalytic asymmetric oxidation
  • CN 1,329,003 proposes an optical resolution of racemic lansoprazole by using (R)-(+)-BINOL.
  • Such methods are mainly divided into following categories: 1) isolating an enantiomer by chromatography using a chiral column; 2) preparing an enantiomer by catalytic asymmetric oxidation of the corresponding prochiral sulfide to sulfoxide; and 3) optically resolving racemic lansoprazole using a suitable optical resolving agent.
  • the present invention also provides the complex of (R)-(+)-lansoprazole and (R)-(+)-l,l,2-triphenyl-l,2-ethanediol of formula (I), which is used as an intermediate in the preparation of the compound of formula (II).
  • step (1) racemic lansoprazole is allowed to react with (R)-(+)- l,l,2-triphenyl-l,2-ethanediol to produce a complex of (R)-(+)-lansoprazole and (R)-C + )- 1 > 1 ,2-triphenyl- 1 ,2-ethanediol.
  • step (1) of the present invention racemic lansoprazole and (R)-(+)-l,l,2-triphenyl-l,2-ethanediol are completely dissolved in an organic solvent selected from the group consisting of chloroform, methanol, ethanol, isopropanol, acetone, acetonitrile, and a mixture thereof under a reflux condition, and the resulting mixture is cooled to induce the precipitation of the complex of formula (I) which is composed of (R)-(+)-lansoprazole and (R)-(+)- 1 , 1 ,2-triphenyl- 1 ,2-ethanediol in an equivalent ratio of about 1 :2.
  • an organic solvent selected from the group consisting of chloroform, methanol, ethanol, isopropanol, acetone, acetonitrile, and a mixture thereof under a reflux condition
  • the solvent (1 st solvent) used in the step (1) selected from the group consisting of chloroform, methanol, ethanol, isopropanol, acetone, acetonitrile, and a mixture thereof may be employed alone or it may be used as a mixed solvent with a 2 nd solvent selected from the group consisting of hexane, diisopropyl ether, and water (with the proviso that the mixed solvent is not a mixture of chloroform and water).
  • the preferable 1 st organic solvent to 2 nd solvent mix ratio is 1 : 1 to 10: 1 by volume, the volume of 2 nd solvent is not over 50% of the volume of the mixture.
  • a mixed solvent of diisopropyl ether and an organic solvent selected from the group consisting of methanol, ethanol, isopropanol, acetone, and acetonitrile is preferred.
  • a mixed solvent of water and an organic solvent selected from the group consisting of methanol, ethanol, isopropanol, acetone, and, acetonitrile is preferred.
  • the solvent or mixed solvent may be used in an amount of 10 niL to 50 mL, preferably 15 mL to 40 mL, per 1 g of racemic lansoprazole.
  • (R)-(+)-l,l,2-triphenyl-l,2-ethanediol may be used in an amount of 1.5 to 3 equivalents, preferably 1.8 to 2.5 equivalents based on racemic lansoprazole, and preferably has an optical purity of not less than 99.5%ee.
  • Crystallization of the compound of formula (I) is accomplished by dissolving racemic lansoprazole and (R)-(+)-l,l,2-triphenyl-l,2-ethanediol by maintaining the mixture at a temperature in the range of room temperature to the boiling point of the solvent, and slowly cooling the resulting homogenous solution to 0 0 C to room temperature.
  • the complex of formula (I) obtained in accordance with above method carries (R)-(+)-lansoprazole moiety whose optical purity is not less than 90%ee.
  • the method of the present invention may comprise a further recrystallization step prior to step (2).
  • the optical purity of (R)-(+)-lansoprazole may increase to not less than 99.0%ee when the solvent for this step is carefully controlled.
  • the solvent for the recrystallization a 1 st organic solvent or a mixture of a 1 st organic solvent and a 2 nd solvent may be used, the volume of the 2 nd solvent being preferably 75% based on the volume of the mixture.
  • step (2) the complex of (R)-(+)-lansoprazole and (R)-(+)-l,l,2-triphenyl-l,2-ethanediol obtained in step (1) is allowed to partition between an organic solvent and a basic aqueous solution. Then, the aqueous layer is isolated and neutralized with an acid to obtain (R)-(+)-lansoprazole of formula (II).
  • step (2) of the present invention added to the complex of (R)-(+)-lansoprazole and (R)-(+)-l,l,2-triphenyl-l,2-ethanediol obtained in step (1), is an organic solvent and a basic aqueous solution and the resulting mixture is kept at room temperature.
  • the aqueous layer of the reaction mixture is then isolated, and neutralized to pH in the range of 5 to 7 using an acid such as acetic acid and hydrochloric acid.
  • the precipitated solid is filtered or the precipitate is extracted with ethyl acetate or dichloromethane to obtain (R)-(+)-lansoprazole.
  • the organic solvent used in the step (2) may be selected from the group consisting of methyl acetate, ethyl acetate, isopropyl acetate, ethyl ether, dichloromethane, chloroform, and a mixture thereof, and may be used in an amount of 10 to 30 niL, preferably 15 to 20 mL per 1 g of the complex of (R)-(+)-lansoprazole and (R)-(+)- 1 , 1 ,2-triphenyl- 1 ,2-ethanediol .
  • the basic aqueous solution is preferably an aqueous solution containing sodium hydroxide or potassium hydroxide, in an amount of 1 to 5 equivalents, preferably 2 to 2.5 equivalents based on the compound of formula (I).
  • solid residue obtained by concentrating the organic layer isolated from the aqueous layer in the step (2) is recrystallized by using a mixture of ethyl acetate and hexane to obtain (R)-(+)-l,l,2-triphenyl-l,2-ethanediol in a yield of more than 85%.
  • the present invention may further comprise the step of recycling (R)-(+)-l,l,2-triphenyl-l,2-ethanediol used in the preparation of the compound of formula (I).
  • Example 1 40.0 g (108.3 mmol) of racemic lansoprazole and 62.9 g (216.6 mmol: optical purity 99.7%ee) of (R)-(+)-l,l,2-triphenyl-l,2-ethanediol were suspended in 640 niL of chloroform, and refluxed until they were dissolved. The resulting mixture was slowly cooled to room temperature, stirred for 4 hours, and the precipitate formed was isolated by filtering, washed with cold chloroform, and dried at 40 0 C, to obtain 41.1 g (80%) of the compound of formula (I) as a white crystalline powder (step A).
  • the compound of formula (I) was obtained by repeating the procedure of Example 4, except for conducting under the condition of Table 1 using 1 g of racemic lansoprazole. ⁇ Table 1>
  • the compound of formula (I) was obtained by repeating the procedure of Example 7, except for conducting under the condition of Table 2 using 1 g of racemic lansoprazole. ⁇ Table 2>
  • IR (KBr, cm “1 ): 3631, 3363, 3072, 2976, 1645, 1583, 1475, 1443, 1315, 1262, 1249, 1200, 1110, 1079, 1033, 973, 917, 828, 743.
  • the aqueous layer was isolated therefrom, 200 mL of ethylacetate was added thereto, and the resulting mixture was adjusted to pH 7.0 using hydrochloric acid.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé pour la préparation de (R)-(+)-lansoprazole ayant une pureté optique élevée et un nouvel intermédiaire utilisé dans celui-ci. Le procédé de l'invention produit du (R)-(+)-lansoprazole ayant une pureté optique élevée par résolution optique de lansoprazole racémique.
PCT/KR2009/007389 2008-12-12 2009-12-10 Procédé pour préparer du (r)-(+)-lansoprazole et intermédiaire utilisé dans celui-ci WO2010068049A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2008-0126478 2008-12-12
KR1020080126478A KR101001646B1 (ko) 2008-12-12 2008-12-12 (ｒ)-(+)-란소프라졸의 제조방법 및 이에 사용되는 중간체

Publications (2)

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WO2010068049A2 true WO2010068049A2 (fr) 2010-06-17
WO2010068049A3 WO2010068049A3 (fr) 2010-10-28

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KR (1) KR101001646B1 (fr)
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011098938A1 (fr) * 2010-02-11 2011-08-18 Orchid Chemicals And Pharmaceuticals Limited Nouveau solvate du dexlansoprazole
CN110873767A (zh) * 2018-09-04 2020-03-10 天津药物研究院有限公司 一种右兰索拉唑合成中间体及其有关物质的快速检测方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5929244A (en) * 1995-07-03 1999-07-27 Astra Aktiebolag Process for the optical purification of enantiomerically enriched benzimidazole derivatives
WO2003051867A1 (fr) * 2001-12-18 2003-06-26 Astrazeneca Ab Procede de preparation d'enantiomeres enrichis au niveau optique au moyen d'une chromatographie a lit mobile simule
WO2007140608A1 (fr) * 2006-06-09 2007-12-13 Apotex Pharmachem Inc. Procédé de préparation de l'ésoméprazole et de ses sels
US20080275245A1 (en) * 2004-10-11 2008-11-06 Neela Praveen Kumar Processes for the Preparation of Substituted Sulfoxides

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5929244A (en) * 1995-07-03 1999-07-27 Astra Aktiebolag Process for the optical purification of enantiomerically enriched benzimidazole derivatives
WO2003051867A1 (fr) * 2001-12-18 2003-06-26 Astrazeneca Ab Procede de preparation d'enantiomeres enrichis au niveau optique au moyen d'une chromatographie a lit mobile simule
US20080275245A1 (en) * 2004-10-11 2008-11-06 Neela Praveen Kumar Processes for the Preparation of Substituted Sulfoxides
WO2007140608A1 (fr) * 2006-06-09 2007-12-13 Apotex Pharmachem Inc. Procédé de préparation de l'ésoméprazole et de ses sels

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BORNER, K. ET AL.: 'Separation of Lansoprazole Enantiomers in Human Serum by HPLC.' CHROMATOGRAPHIA. vol. 47, no. 3/4, 1998, pages 171 - 175 *
KIM, KYOUNG-AH ET AL.: 'Enantioselective disposition of lansoprazole in extensive and poor metabolizers of CYP2C19.' CLINICAL PHARMACOLOGY & THERAPEUTICS. vol. 72, 2002, pages 90 - 99 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011098938A1 (fr) * 2010-02-11 2011-08-18 Orchid Chemicals And Pharmaceuticals Limited Nouveau solvate du dexlansoprazole
CN110873767A (zh) * 2018-09-04 2020-03-10 天津药物研究院有限公司 一种右兰索拉唑合成中间体及其有关物质的快速检测方法
CN110873767B (zh) * 2018-09-04 2022-03-11 天津药物研究院有限公司 一种右兰索拉唑合成中间体及其有关物质的快速检测方法

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Publication number Publication date
KR101001646B1 (ko) 2010-12-17
KR20100067886A (ko) 2010-06-22
WO2010068049A3 (fr) 2010-10-28

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