EP1368338A1 - Verfahren zur herstellung von lansoprazol und dessen zwischenprodukt - Google Patents

Verfahren zur herstellung von lansoprazol und dessen zwischenprodukt

Info

Publication number
EP1368338A1
EP1368338A1 EP02700866A EP02700866A EP1368338A1 EP 1368338 A1 EP1368338 A1 EP 1368338A1 EP 02700866 A EP02700866 A EP 02700866A EP 02700866 A EP02700866 A EP 02700866A EP 1368338 A1 EP1368338 A1 EP 1368338A1
Authority
EP
European Patent Office
Prior art keywords
methyl
trifluoroethoxy
compound
reaction
benzimidazole
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.)
Withdrawn
Application number
EP02700866A
Other languages
English (en)
French (fr)
Other versions
EP1368338A4 (de
Inventor
Wan Joo Kim
Kyoung Soo Kim
Myung Hwa Kim
Yong Gu Baek
Jong Yek Park
Jung Min Jang
Jae Won Choi
Yong Sang Yoo
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.)
Hansol Chemience Co Ltd
Original Assignee
Chemtech Research Inc
Hansol Chemience 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 Chemtech Research Inc, Hansol Chemience Co Ltd filed Critical Chemtech Research Inc
Publication of EP1368338A1 publication Critical patent/EP1368338A1/de
Publication of EP1368338A4 publication Critical patent/EP1368338A4/de
Withdrawn legal-status Critical Current

Links

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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • the present invention relates to a novel process for preparing 2-[3-methyl-4- (2,2,2-trifluoroethoxy)-2-pyridyl]methylsulfinyl- 1 H-benzimidazole (hereinafter also called “lansoprazole”), which is an anti-ulcer agent having an excellent gastric acid secretion inhibiting action and a gastric mucous membrane protecting action, and its intermediate.
  • lansoprazole 2-[3-methyl-4- (2,2,2-trifluoroethoxy)-2-pyridyl]methylsulfinyl- 1 H-benzimidazole
  • the present invention relates to a process for preparing lansoprazole which comprises the steps of 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 additives to obtain 2-[3-methyl-4-(2,2,2- trifluoroethoxy)-2-pyridyl]methylthio-l H-benzimidazole in good yield (not less than 96%), and oxidizing the reaction product with hydrogen peroxide in the presence of a benzeneseleninic acid catalyst to obtain lansoprazole.
  • 2-[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylsulfmyl-lH- benzimidazole, also called lansoprazole, having the following formula (I), is well known as a major component of an anti-ulcer agent having excellent gastric acid secretion inhibiting action and gastric mucous membrane protecting action.
  • lansoprazole (I) or its intermediate, 2-[3-methyl-4-(2,2,2- trifluoroethoxy)-2-pyridyl]methylthio-l H-benzimidazole having the following structural formula ⁇ IT), are disclosed in European Patent Nos.
  • the intermediate, 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylthio- 1 H-benzimidazole (II) is prepared by reacting 2-mercaptobenzimidazole of the formula (IV) with 3-methyl-4-(2,2,2-trifluoroethoxy)pyridine derivative of the formula (V), or by reacting benzimidazole derivative of the formula (VI) with 2-mercaptomethyl-3- methyl-4-(2,2,2-trifluoroethoxy)pyridine of the formula (VII), as shown in the following Reaction Scheme 1 (U.S. Patent No. 4,689,333).
  • X is a leaving group such as a halogen atom, arylsulfonyloxy, C 1 . 4 alkylsulfonyloxy, or organic phosphoryloxy group.
  • base such as alkali metal, alkali metal hydride, alkali metal carbonate, sodium alcoholate, or organic amines, and reaction solvent such as alcohol or dimethylformamide are used to enhance the reactivity.
  • reaction solvent such as alcohol or dimethylformamide
  • X of the compound (V) is a chlorine atom
  • additional isolation or purification steps are needed to remove the remaining thionyl chloride after 2- hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine (III) is reacted with thionyl chloride.
  • lansoprazole (I) is prepared by oxidizing 2-[3-methyl-4- (2,2,2-trifluoroethoxy)-2-pyridyl]methylthio-lH-benzimidazole (II) as shown in the following Reaction Scheme 2.
  • This oxidation reaction may be summarized to two processes as follows:
  • the first process is disclosed in U.S. Patent No. 4,689,333, in which lansoprazole (I) is prepared by oxidizing 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridyl]methylthio-lH-benzimidazole (II).
  • the oxidizing agent used in this process is exemplified by peracid, sodium bromite, sodium hypochlorite, or hydrogen peroxide, and the reaction solvent is halogenated hydrocarbon, ether, amide, alcohol, or water.
  • the above first process has the following disadvantages. Firstly, 2-[3-methyl- 4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylsulfinyl-lH-benzimidazole N-oxide (VIII) produced by the oxidation of nitrogen of the pyridine ring in the object compound (I), is obtained in a considerable amount as a by-product during the oxidation reaction of the above process.
  • the second process for preparing the compound (I) is disclosed in European Patent No. 0 302 720 and is more improved than the first process, hi this process, 2-(3- methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl)methylsulfinyl-lH-benzimidazole (I) is prepared by oxidizing 2-(3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl)methylthio-lH- benzimidazole (II) with an inexpensive oxidizing agent, i.e. hydrogen peroxide, instead of an expensive oxidizing agent (m-chloroperbenzoic acid), in the presence of vanadium compound as a catalyst.
  • an inexpensive oxidizing agent i.e. hydrogen peroxide
  • m-chloroperbenzoic acid instead of an expensive oxidizing agent (m-chloroperbenzoic acid
  • the second process has drawbacks in that the amount of the vanadium compound should be increased to enhance the low reactivity, and the production rate of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylsulfinyl-lH- benzimidazole N-oxide (VIH) is still high (approximately 4%).
  • the present inventors have developed a novel process, by which 2- [3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylthio- lH-benzimidazole (II) may be obtained in good yield from 2-hydroxymethyl-3-methyl-4-(2,2,2- trifluoroethoxy)pyridine (III) by using a more simple process, and lansoprazole (I) may be then obtained in good yield from the compound (II).
  • the present inventors have developed the process comprising the steps of reacting 2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine (III) or its salt with 2-mercaptobenzimidazole in the presence of a halogenating agent, without using any base to obtain 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridyljmethylthio-lH-benzimidazole (II) in good yield, and then oxidizing the resulting compound (II) with hydrogen peroxide in the presence of benzeneseleninic acid as a catalyst to obtain lansoprazole (I).
  • the reaction may be carried out effectively without using any base, and 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridyl]methylthio-lH-benzimidazole (II) may be obtained only in one step with a better yield than the prior art which is subjected to additional isolation or concentration.
  • lansoprazole (I) may be produced in good quality with a good yield by oxidizing the said compound (II) with hydrogen peroxide in the presence of a benzeneseleninic acid catalyst.
  • the present process leads to low production of by-product such as 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridyl]methylsulfinyl-l H-benzimidazole N-oxide (VIII) by a simple and economic oxidation method. It is a feature of the present invention to provide a novel process for the preparation of lansoprazole, which is an anti-ulcer agent having an excellent gastric acid secretion inhibiting action and a gastric mucous membrane protecting action.
  • I lansoprazole
  • the present invention relates to a process for preparing lansoprazole and its intermediate.
  • the process comprises the steps of reacting 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy)pyridine (III) or its salt with 2-mercaptobenzimidazole (IN) in reaction solvent in the presence of a halogenating agent, and oxidizing 2-[3-methyl-4- (2,2,2-trifluoroethoxy)-2-pyridyl]methylthio-lH-benzimidazole (II) obtained from the above step with hydrogen peroxide in reaction solvent in the presence of benzeneseleninic acid as a catalyst to obtain lansoprazole as shown in the Reaction Scheme 3.
  • Reaction Scheme 3 Reaction Scheme 3
  • Step 1 Preparation of 2-[3-methyl-4-(2,2,2-trifluoroethoxyV2-pyridyl]methyl thio-lH- benzimidazole (IT)
  • the reaction solvent is preferably halogenated hydrocarbon such as dichloromethane, chloroform, or carbon tetrachloride; or ether such as tetrahydrofuran, or dioxane, more preferably dichloromethane or chloroform.
  • 2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine (III) may be prepared from 2,3-lutidine as disclosed in U.S. Patent No.4,689,333, and the compound
  • (III) may be used in the form of its salts combined with acid, for example, its hydrochloride, hydrobromide, or hydroiodide.
  • the amount of 2-mercaptobenzimidazole (IV) used is usually one or more equivalent of 2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine (III), preferably 1 to 4 equivalents, more preferably 1 to 1.5 equivalents of the compound
  • the reaction temperature is usually from about 0 ° C to the boiling point of the reaction solvent, preferably about 20 to 85 ° C, more preferably about 35 to 60 ° C.
  • the reaction time is usually between initial start of the reaction and 24 hours, preferably about 10 minutes to 3 hours. If a halogenating agent and 2-mercaptobenzimidazole (IV) are sequentially added, the preferable time interval is between just after introducing the halogenating agent and 8 hours, more preferably about 5 minutes to 3 hours.
  • the halogenating agent used in the reaction includes phosphorus halide, for example phosphorous tribromide (PBr ), phosphorous trichloride (PC1 ), phosphorous pentabromide (PBr 5 ), phosphorous pentachloride (PC1 5 ), phosphorous oxybromide (POBr 3 ), phosphorous oxychloride (POCl 3 ), or mixtures thereof, preferably phosphorous trihalide.
  • the amount of the halogenating agent is usually 1 (1/3 as a molar ratio) to 15 equivalents (5 as a molar ratio), preferably 2 to 3 equivalents of the compound (HI).
  • Thiosulfate compound as an additive allows the yield of the product to enhance about 2%.
  • Such thiosulfate compound includes sodium thiosulfate (Na 2 S O 3 ), potassium thiosulfate (K 2 S 2 O 3 ), calcium thiosulfate (CaS 2 O ), or tetrabutylammonium thiosulfate ((Bu 4 N) 2 S 2 O 3 ), and sodium thiosulfate is preferred among these compounds.
  • the amount of thiosulfate compound is usually 0.001 to 0.5 equivalent, preferably 0.01 to 0.2 equivalent of the compound (HI).
  • the intermediate of lansoprazole (II) produced by the reaction described above may be collected by filtrating it to an organic layer by basification after cooling the reaction medium, followed by concentration, and then be further purified by conventional methods, e.g. by using ethyl acetate or hexane.
  • 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridyl]methylthio-lH-benzimidazole (II) may be prepared in high purity and good yield of not less than about 96% from reacting 2-hydroxymethyl-3-methyl-4-(2,2,2- trifluoroethoxy)pyridine (III) or its salt.
  • the present invention is characterized in that 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylthio-lH- benzimidazole (II) may be prepared only in one step under the same acidic condition as the reaction solution without adding any base, and also without carrying out an additional concentration or purification process an intermediate, 2-halomethyl-3- methyl-4-(2,2,2-trifluoroethoxy)pyridine of the formula (V).
  • X is a halogen atom, e.g. bromine and chlorine.
  • reaction solvent in the second step is halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride; or ether such as tetrahydrofuran, dioxane; or water, preferably dichloromethane or chloroform.
  • the catalyst used is benzeneseleninic acid (PhSeO H), and the amount of the catalyst is usually 0.0001 to 0.2 equivalent, preferably 0.001 to 0.1 equivalent, more preferably, 0.002 to 0.01 equivalent of the compound (H).
  • Hydrogen peroxide is used as its aqueous solution of about 20 to 50 %, but not limited thereto.
  • the amount of hydrogen peroxide is usually 0.95 to 2.0 equivalents, preferably 0.95 to 1.4 equivalents, more preferably, 1.0 to 1.1 equivalents of the compound (IT).
  • the reaction temperature is usually about 0 to 50 ° C, preferably about 5 to
  • reaction time is usually about 5 minutes to 48 hours, preferably about 30 minutes to 10 hours, more preferably about 1 to 6 hours.
  • the resulting product thus obtained may be subject to terminate its oxidation reaction with a conventional method for decomposing excess hydrogen peroxide (for example, by adding an aqueous solution of sodium thiosulfate), and then to extract with solvent such as dichloromethane, followed by concentrating, and finally to crystallize by using an aqueous solution of acetonitrile or ethanol.
  • a conventional purification method such as recrystallization by ethanol or water may be used.
  • lansoprazole (I) can be obtained from 2- [3 -methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylthio-l H-benzimidazole (II) in good yield (approximately 90% or more) and high quality. Furthermore, the yield of by-products such as 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylsulfiny_- 1 H-benzimidazole N-oxide may be reduced to 1.5% or less. A conventional purification process as disclosed in Examples 7 and 8 may be further carried out, if necessary, and thus the amount of the resulting by-products can be reduced to about 0.1% or less.
  • Example 1 23g (0.10 mole) of 2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy) pyridine was dissolved in 1L of dichloromethane, cooled at 4 ° C, to which was sequentially added 9.9ml (O.lOmole) of phosphorous tribromide (PBr 3 ), 15.6g (O.lOmole) of 2-mercaptobenzimidazole, and 3.3g (0.02 mole) of sodium thiosulfate at a temperature of below 10 ° C, and then allowed to reflux for 2.5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, to which was added 4N-sodium hydroxide to make the pH of the reaction mixture 13.5 to 14.
  • PBr 3 phosphorous tribromide
  • 2-mercaptobenzimidazole 2-mercaptobenzimidazole
  • Example 2 23g (0.10 mole) of 2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy) pyridine was dissolved in 1L of dichloromethane, cooled at 4 ° C, to which was gradually added 9.9ml (O.lOmole) of phosphorous tribromide (PBr 3 ) at a temperature of below 10°C, and then allowed to reflux for 1 hour. The temperature of reaction solution was cooled to room temperature, to which was added 15.6g (O.lOmole) of 2- mercaptobenzimidazole, and 3.3g (0.02 mole) of sodium thiosulfate, and then allowed to reflux for 2.5 hours.
  • PBr 3 phosphorous tribromide
  • Example 4 lOg (0.0452 mole) of 2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy) pyridine was dissolved in 400ml of dichloromethane, cooled at 4 ° C, to which was gradually added 3.94ml (0.0452mole) of phosphorous trichloride (PC1 3 ) at a temperature of below 10 ° C, and then allowed to reflux for 1 hour. The temperature of the reaction mixture was cooled to room temperature, to which was added 6.79g (0.0452mole) of 2-mercaptobenzimidazole, and 1.43g (0.00904mole) of sodium thiosulfate, and then allowed to reflux for 2.5 hours.
  • PC1 3 phosphorous trichloride
  • reaction mixture was cooled to room temperature, and then was added 4N-sodium hydroxide to make the pH of the reaction mixture 13.5 to 14.
  • the reaction mixture was stirred vigorously for about 20 minutes, and an organic layer was then separated. The organic layer thus separated was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the residue was crystallized with a mixture of ethyl acetate-hexane (1:6, 56ml) to yield 2.69g of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridyl]methylthio-l H-benzimidazole as a off-white crystal. The yield of the crystal was 84.3%.
  • Example 6 Preparation of lansoprazole 1.5g (4.24mmole) of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl thio-1 H-benzimidazole obtained in Example 2 was suspended in 30ml of dichloromethane, to which was added 2.01mg (0.0106mmole) of bezeneseleninic acid (PhSeO 2 H), and then cooled to 10 ° C .
  • lansoprazole 1.5g (4.24mmole) of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl thio-1 H-benzimidazole obtained in Example 2 was suspended in 30ml of dichloromethane, to which was added 2.01mg (0.0106mmole) of bezeneseleninic acid (PhSeO 2 H), and then cooled to 10 ° C .
  • reaction mixture 2ml of tert-butanol and 0.376ml (4.46mmole) of 35.7% hydrogen peroxide were added at a temperature of below 10 ° C.
  • the reaction mixture was stirred for 5 hours with the temperature maintaining at 15 to 20 ° C.
  • the reaction mixture was cooled to 5 ° C , gradually added dropwise an aqueous solution of sodium thiosulfate (0.4g/20ml) at a temperature of below 10 ° C, and then stirred vigorously for about 30 minutes at a temperature of about 10 ° C .
  • the organic layer was separated from the mixture, and it was washed with 20ml of water.
  • the dichloromethane layer was washed with water (30ml), and dried with magnesium sulfate, and then concentrated under reduced pressure and dissolved in about 5ml of ethanol before a crystal is crystallized out, and then crystallized with reconcentration.
  • the crystals thus obtained were dried under vacuum to give 1.63g of a light brown-violet color object compound (the yield of the products: 93.0%).
  • the organic layer thus separated was dried with magnesium sulfate, and then concentrated under reduced pressure and dissolved in about 5ml of ethanol before a crystal was crystallized out, and then recrystallized with reconcentration.
  • the crystals thus obtained were dried under vacuum to give 1.6 lg of an object compound as a violet color (the yield of the products: 103%).
  • Example 6 Each resulting product obtained in Example 6 according to the present invention and Reference Examples 1 and 2 according to prior art process (European Patent No. 0 302 720) was analyzed by High Performance Liquid Chromatography (HPLC) and the yield and content of resulting product and the results of analysis were shown in the following Table 1.
  • HPLC High Performance Liquid Chromatography
  • HPLC HPLC
  • the crystal thus obtained was added again 11.8ml of ethanol, and then heated at 45 to 50°C to dissolve thoroughly the crystal.
  • the insoluble matters were removed by hot filtration, and 1.69ml of water was added, and then gradually cooled at 5 ° C .
  • the resulting crystal was collected by filtration and washed with a mixture of ethanol-water (7:1) of 5 ° C .
  • the crystal was dried under reduced pressure to obtain 1.4 lg of lansoprazole as a white crystal.
  • the yield of the crystal was 95.0%».

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (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)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
EP02700866A 2001-02-21 2002-02-20 Verfahren zur herstellung von lansoprazol und dessen zwischenprodukt Withdrawn EP1368338A4 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
KR2001008677 2001-02-21
KR10-2001-0008677A KR100430575B1 (ko) 2001-02-21 2001-02-21 란소프라졸 및 그 중간체의 제조방법
PCT/KR2002/000261 WO2002074766A1 (en) 2001-02-21 2002-02-20 Method of preparing lansoprazole and its intermediate

Publications (2)

Publication Number Publication Date
EP1368338A1 true EP1368338A1 (de) 2003-12-10
EP1368338A4 EP1368338A4 (de) 2004-09-15

Family

ID=19706059

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02700866A Withdrawn EP1368338A4 (de) 2001-02-21 2002-02-20 Verfahren zur herstellung von lansoprazol und dessen zwischenprodukt

Country Status (4)

Country Link
EP (1) EP1368338A4 (de)
JP (1) JP2004525927A (de)
KR (1) KR100430575B1 (de)
WO (1) WO2002074766A1 (de)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100758600B1 (ko) 2006-01-05 2007-09-13 주식회사 대웅제약 란소프라졸 결정형 ａ의 제조방법
KR100771655B1 (ko) * 2006-04-24 2007-10-30 주식회사 카이로제닉스 라베프라졸 및 그 중간체의 제조방법
CN102180866B (zh) * 2011-05-23 2013-03-13 中山大学 兰索拉唑晶型及其制备方法和应用
CN103012369B (zh) * 2011-05-23 2014-04-23 中山大学 兰索拉唑n晶型及其制备方法和应用
CN103724325B (zh) * 2013-12-10 2016-04-13 南京工业大学 制备亚磺酰基-1-氢-苯并咪唑衍生物的方法
CN103864695A (zh) * 2014-03-19 2014-06-18 连云港市亚晖医药化工有限公司 三氯苯达唑亚砜的制备方法
CN114163419A (zh) * 2021-12-24 2022-03-11 辰欣药业股份有限公司 一种兰索拉唑的制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0302720A1 (de) * 1987-08-04 1989-02-08 Takeda Chemical Industries, Ltd. Herstellung von 2-(2-Pyridylmethylsulfinyl)-benzimidazol-Verbindungen

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6150978A (ja) * 1984-08-16 1986-03-13 Takeda Chem Ind Ltd ピリジン誘導体およびその製造法
CA1327010C (en) * 1986-02-13 1994-02-15 Tadashi Makino Stabilized solid pharmaceutical composition containing antiulcer benzimidazole compound and its production
KR100359256B1 (ko) * 1999-10-06 2002-11-04 한미약품공업 주식회사 란소프라졸의 개선된 제조방법

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0302720A1 (de) * 1987-08-04 1989-02-08 Takeda Chemical Industries, Ltd. Herstellung von 2-(2-Pyridylmethylsulfinyl)-benzimidazol-Verbindungen

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO02074766A1 *

Also Published As

Publication number Publication date
KR100430575B1 (ko) 2004-05-10
JP2004525927A (ja) 2004-08-26
KR20020068592A (ko) 2002-08-28
EP1368338A4 (de) 2004-09-15
WO2002074766A1 (en) 2002-09-26

Similar Documents

Publication Publication Date Title
EP0868423B1 (de) Verfahren zur herstellung einer benzimidazolverbindung
CA2289409C (en) Sulfoxide compounds and acetone complexes, and a process for producing the same
JP5355893B2 (ja) パントプラゾールナトリウムの製造方法
CN116969976A (zh) 去泛素化酶抑制剂及其应用
EP1368338A1 (de) Verfahren zur herstellung von lansoprazol und dessen zwischenprodukt
KR20230026411A (ko) 방향족 에터 화합물의 제조 방법
US6423846B1 (en) High-yield method for preparing lansoprazole
KR100551926B1 (ko) 시로스타졸의 제조 방법
CA2323422A1 (en) Chemical process for the production of sulphinyl derivatives by oxidation of the corresponding co-derivatives with perborates
EP2022789A1 (de) Verfahren zur Herstellung eines Magensäuresekretionshemmers
EP1116710B1 (de) Verfahren zum Herstellen von Pivaloylessigsäureester
US20220220072A1 (en) Method for producing cis-(-) flocinopiperidol
KR100359256B1 (ko) 란소프라졸의 개선된 제조방법
JP3107834B2 (ja) １−アリール−４−オキソピロロ［３，２−ｃ］キノリン誘導体の製造方法
JP3029901B2 (ja) 新規なメトキシ基導入法による２−ヒドロキシメチル−４−メトキシ−３，５−ジメチルピリジンの製造法
KR100771655B1 (ko) 라베프라졸 및 그 중간체의 제조방법
JP5205971B2 (ja) テトラヒドロピラン化合物の製造方法
KR20110097058A (ko) 새로운 중간체를 이용하는 피타바스타틴 헤미칼슘의 신규한 제조방법
KR100771659B1 (ko) 판토프라졸 및 그 중간체의 제조방법
KR100783020B1 (ko) 2-메틸클로라이드 피리딘 유도체 및 이를 이용한 벤즈이미다졸 유도체의 제조 방법
CN117658986A (zh) Ar拮抗剂trc-253的制备方法
WO2019230864A1 (ja) ジアリールメタン化合物の製造方法
MXPA00008482A (en) Chemical process for the production of sulphinyl derivatives by oxidation of the corresponding co-derivatives with perborates
KR20050020162A (ko) 카르복실 벤조트리아졸 알킬에스테르의 제조방법
BG60588B1 (en) Method for the preparation of quinoline derivatives

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20030829

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: HANSOL CHEMIENCE CO., LTD.

Owner name: CHEMTECH RESEARCH INCORPORATION

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: HANSOL CHEMIENCE CO., LTD.

A4 Supplementary search report drawn up and despatched

Effective date: 20040804

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20060901