WO2006003946A1 - ベンズイミダゾール誘導体塩沈殿物の製造方法 - Google Patents
ベンズイミダゾール誘導体塩沈殿物の製造方法 Download PDFInfo
- Publication number
- WO2006003946A1 WO2006003946A1 PCT/JP2005/011969 JP2005011969W WO2006003946A1 WO 2006003946 A1 WO2006003946 A1 WO 2006003946A1 JP 2005011969 W JP2005011969 W JP 2005011969W WO 2006003946 A1 WO2006003946 A1 WO 2006003946A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- methoxypropoxy
- benzimidazole
- methylpyridine
- dichloromethane
- organic solvent
- Prior art date
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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 present invention is useful as a drug such as a gastric acid secretion inhibitor, an anti-ulcer agent or the like, or a production intermediate of the drug.
- YL ⁇ Methyl sulfiel] 1H-benzimidazole ' relates to a method for producing a precipitate of an alkali metal salt.
- freeze-drying method requires a large amount of equipment in actual production, and is not necessarily excellent in terms of workability, operability, and energy saving.
- Patent Document 1 U.S. Pat.No. 5,045,552
- Patent Document 2 JP-A-7-278141
- Patent Document 3 International Publication Pamphlet WO03Z101452
- the object of the present invention is to provide 2-[ ⁇ 4- (3-methoxypropoxy) 3 methylpyridine 2yl ⁇ methylsulfier] 1H benzimidazole alkali metal salt useful as an antiulcer agent.
- the purpose is to provide a manufacturing method that does not require large-scale equipment and is excellent in workability, operability, and energy saving.
- the present invention provides:
- the present invention relates to 2-[ ⁇ 4- (3-methoxypropoxy) —3-methylpyridine-2-yl ⁇ methylsulfier] 1H benzimidazole, which is a pharmaceutical or a pharmaceutical production intermediate.
- Lucari metal salt (1) is a useful production method because it does not require large-scale equipment and can be produced by an excellent method in terms of workability, operability and energy saving.
- the manufacturing method according to the present invention comprises:
- the first organic solvent to be used is not particularly limited as long as it dissolves the compound represented by the formula (2) (hereinafter simply referred to as “compound (2)”).
- compound (2) Preferred are, for example, alcohols such as methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, particularly preferably methanol or ethanol. It is.
- the second organic solvent to be used is not particularly limited as long as it is difficult to dissolve the salt represented by the formula (1) (hereinafter simply referred to as “compound (1) or salt (1)”).
- ethers such as, for example, jetyl ether, diisopropyl ether, tert-butyl (methyl) ether, tetrahydrofuran, dioxane, dimethoxyethane, and particularly preferred is tert-butyl (methyl).
- Ether or diisopropyl ether is particularly preferred.
- the amount of the first organic solvent used is usually 0.9 to 1.5 ml with respect to the compound (2) lg.
- the amount of the second organic solvent used is usually 10 to 11 Oml with respect to the compound (2) lg.
- the alkali metal hydroxide used is, for example, sodium hydroxide, potassium hydroxide, or the like, and preferably sodium hydroxide.
- the amount of the alkali metal hydroxide to be used is not particularly limited as long as the purity of the compound (1) obtained as a precipitate is not significantly reduced, but is preferably relative to the compound (2). 0. 99 to 1 equivalent.
- the temperature at which the compound (2) is dissolved in the first organic solvent or the first organic solvent in which the alkali metal hydroxide is dissolved is the compound (2) or the salt (1). If it is within the range where does not decompose, there is no particular limitation, but it is usually 0 to 30 ° C.
- the temperature at which the alkali metal hydroxide is added to the first organic solvent solution of the compound (2) is particularly within the range where the compound (2) or the salt (1) is not decomposed. There is no limit, but it is usually 0-30 ° C.
- the conversion from the compound (2) to the salt (1) is usually performed instantaneously.
- the second organic solvent when the second organic solvent is added to the first organic solvent solution of the salt (1), the second organic solvent is not added all at once, but gradually or It is preferable to divide and add.
- the obtained salt (1) precipitate means an amorphous substance, a crystalline substance or a mixture thereof.
- the precipitate of the salt (1) obtained by the above method can be isolated by filtration and drying under reduced pressure or normal pressure.
- the isolated precipitate can be used for the desired preparation as it is or by appropriate pulverization.
- the production method according to the present invention preferably includes:
- the compound (2) used as a starting material is the method described in Patent Document 1 or a known improvement method of the method (for example, Japanese Patent Laid-Open Publication No. — 71370, JP-A 2000-143659, International Publication Pamphlet WO 01Z68594, European Patent Publication EP1, 2705, 55, etc.).
- Compound (2) can be produced by the following method.
- compound (3) The compound represented by the above formula (3) (hereinafter simply referred to as “compound (3)”. Furthermore, the compounds represented by the formulas (4) and (5) are also represented in the same manner) or compound. (5) is a known compound.
- This step is a step for producing a crude compound (4) comprising reacting a compound (3) with a chlorinating agent in an inert solvent and concentrating the resulting reaction mixture.
- This step differs from the method described in Patent Document 1 in that the reaction mixture is simply concentrated and no other work-up is performed.
- the inert solvent used in this step is not particularly limited as long as it can dissolve the raw material compound to some extent and does not inhibit this reaction, but preferably, for example, benzene, toluene, Aromatic hydrocarbons such as xylene, organic acid esters such as methyl acetate and ethyl acetate, ethers such as jetyl ether, diisopropyl ether, tetrahydrofuran, dioxane and dimethoxyethane, methylene chloride, black mouth form, Halogenated hydrocarbons such as carbon tetrachloride and dichloroethane can be used, particularly preferably toluene, ethyl acetate, dimethoxyethane or dichloromethane.
- Aromatic hydrocarbons such as xylene, organic acid esters such as methyl acetate and ethyl acetate, ethers such as jetyl ether, diisopropyl ether, te
- chlorinating agent used in this step for example, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, salt thiol, etc. can be used. In Those that can be removed by distillation together with the solvent are preferred.
- the reaction temperature in this step varies depending on the solvent, raw material compound, chlorinating agent and the like to be used, but it is usually -20 to 50, preferably 0 to 20 ° C.
- the reaction time in this step varies depending on the solvent, raw material compound, chlorinating agent, reaction temperature, etc. used, and is usually 30 minutes to 6 hours, preferably 1 to 2 hours.
- reaction mixture can be concentrated to dryness under reduced pressure or normal pressure and used as it is in the second step without being purified.
- This step is a step for producing compound (5) by reacting compound (4) obtained in step 1 with 2-benzimidazolethiol in the presence of a base in an inert solvent.
- the inert solvent used in this step is not particularly limited as long as it can dissolve the raw materials and compounds to some extent and does not inhibit this reaction, but preferably, for example, methanol, ethanol, propanol Alcohols such as isopropanol, butanol and tert-butanol can be used, and ethanol is particularly preferably used.
- the base used in this step is not particularly limited as long as it is soluble to some extent in a solvent, but preferably an alkali metal hydride such as sodium hydroxide or potassium hydroxide is preferably used. Particularly preferred is sodium hydroxide.
- the reaction temperature in this step varies depending on the solvent, raw material compound, base, etc. to be used, but it is usually 20 ° to 70 ° ⁇ and is suitable. is there.
- reaction time in this step varies depending on the solvent, raw material compound, base, reaction temperature and the like to be used, it is generally 30 min to 6 hr, preferably 1 to 2 hr.
- the compound (5) can be isolated from the reaction mixture according to a conventional method. For example, after completion of the reaction, the reaction mixture is concentrated under reduced pressure, then extracted with water and an organic solvent immiscible with water (eg, dichloromethane, ethyl acetate, etc.), and the organic layer is washed with aqueous sodium hydroxide and water. Thereafter, the compound (5) can be produced by concentration.
- an organic solvent immiscible with water eg, dichloromethane, ethyl acetate, etc.
- a highly purified compound (5) can be produced as crystals by using the following organic solvent: Ethers such as jetyl ether, diisopropyl ether, tert butyl (methyl) ether, tetrahydrofuran, dioxane, dimethoxyethane (especially diisopropyl ether or tert butyl (methinole) etherol),
- Ethers such as jetyl ether, diisopropyl ether, tert butyl (methyl) ether, tetrahydrofuran, dioxane, dimethoxyethane (especially diisopropyl ether or tert butyl (methinole) etherol
- -Tolyls such as acetonitrile (especially acetonitrile),
- Aromatic hydrocarbons such as benzene, toluene and xylene (especially toluene), alcohols such as methanol, ethanol, propanol and isopropanol (especially isopropanol),
- Ketones such as acetone and methyl ethyl ketone (especially acetone),
- Organic acid esters such as methyl acetate, ethyl acetate, dimethyl carbonate, and jetyl carbonate (especially ethyl acetate and jetyl carbonate) or
- a mixed solvent of at least two of these solvents is provided.
- the amount of solvent used for crystallization varies depending on the type of solvent, but is 3 to 40 ml with respect to compound (5) lg.
- This step is a step for producing compound (2) by reacting compound (5) with an oxidizing agent in an inert solvent.
- the inert solvent used in this step is not particularly limited as long as it can dissolve the raw materials and compounds to some extent and does not inhibit this reaction.
- Halogenated hydrocarbons such as dichloromethane, carbon tetrachloride and dichloroethane can be used, and dichloromethane is particularly preferably used.
- oxidizing agent used in this step hydrogen peroxide, peracetic acid, m-cloperbenzoic acid, sodium periodate, etc. can be used, but m-cloperbenzoic acid is preferably used. To do.
- the reaction temperature in this step varies depending on the solvent, raw material compound, oxidizing agent and the like to be used, but is usually 50 to 0 ° C., preferably ⁇ 30 to 10 ° C.
- the reaction time in this step varies depending on the solvent, raw material compound, oxidizing agent, reaction temperature and the like to be used, but is usually 30 minutes to 6 hours, preferably 1 to 2 hours.
- the compound (2) can be isolated from the reaction mixture according to a conventional method. For example, the following operations are sequentially performed:
- a basic aqueous solution for example, an aqueous solution of an alkali metal hydroxide, particularly an aqueous solution of sodium hydroxide and sodium hydroxide
- a basic aqueous solution for example, an aqueous solution of an alkali metal hydroxide, particularly an aqueous solution of sodium hydroxide and sodium hydroxide
- the highly purified compound (2) can be produced as crystals by crystallization using the following organic solvent after concentration:
- Ethers such as jetyl ether, diisopropyl ether, tert-butyl (methyl) ether, tetrahydrofuran, dioxane, dimethoxyethane (especially jetyl ether),
- -Tolyls such as acetonitrile (especially acetonitrile),
- Aromatic hydrocarbons such as benzene, toluene and xylene (especially toluene), alcohols such as methanol, ethanol, propanol, isopropanol and isobutyl alcohol (especially isopropanol),
- Ketones such as acetone and methyl ethyl ketone (especially acetone),
- Organic acid esters such as methyl acetate, ethyl acetate, dimethyl carbonate, and jetyl carbonate ( In particular ethyl acetate) or
- mcpba Metaclochrome perbenzoic acid
- HPLC High performance liquid chromatography.
- Example 3 26.5 ml of ethanol was added to 1.65 g (41.3 mmol) of sodium hydroxide and dissolved. Then, 2-[ ⁇ 4-((3-methoxypropoxy))-3-methylpyridine-2-yl ⁇ methylsulfier] — 1H benzimidazole 15.0 g (41.7 mmol) was added to confirm dissolution. Later, 160 ml of tert-butyl methyl ether was slowly added and precipitated to give 2-[ ⁇ 4 (3-methoxypropoxy) -3-methylpyridine-2-yl ⁇ methylsulfier]-1H-benzimidazole 'sodium Obtained 19.9 g of salt (100% yield).
- the present invention relates to 2-[ ⁇ 4- (3-methoxypropoxy) —3-methylpyridine-2-yl ⁇ methylsulfier] 1H-benzimidazole, which is a pharmaceutical or an intermediate for producing pharmaceuticals.
- Lucari metal salt (1) is industrially applicable because it does not require large-scale equipment and can be manufactured by a method that is excellent in terms of workability, operability, and energy saving.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2006528754A JP4884967B2 (ja) | 2004-06-30 | 2005-06-29 | ベンズイミダゾール誘導体塩沈殿物の製造方法 |
US11/597,743 US7557217B2 (en) | 2004-06-30 | 2005-06-29 | Process for production of benzimidazole derivative salt precipitate |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2004192715 | 2004-06-30 | ||
JP2004-192715 | 2004-06-30 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2006003946A1 true WO2006003946A1 (ja) | 2006-01-12 |
Family
ID=35782753
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2005/011969 WO2006003946A1 (ja) | 2004-06-30 | 2005-06-29 | ベンズイミダゾール誘導体塩沈殿物の製造方法 |
Country Status (3)
Country | Link |
---|---|
US (1) | US7557217B2 (ja) |
JP (1) | JP4884967B2 (ja) |
WO (1) | WO2006003946A1 (ja) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102993179B (zh) * | 2012-12-14 | 2015-09-09 | 江苏奥赛康药业股份有限公司 | 一种高纯度雷贝拉唑钠的制备方法 |
WO2022148868A1 (en) * | 2021-01-11 | 2022-07-14 | Xellia Pharmaceuticals Aps | Synthesis process |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS646270A (en) * | 1986-11-13 | 1989-01-10 | Eisai Co Ltd | Pyridine derivative and remedy for ulceration containing the same |
JPH0769888A (ja) * | 1992-08-21 | 1995-03-14 | Eisai Co Ltd | 抗菌剤 |
JP2001039975A (ja) * | 1999-07-26 | 2001-02-13 | Eisai Co Ltd | スルホキシド誘導体の結晶およびその製造法 |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FI90544C (fi) * | 1986-11-13 | 1994-02-25 | Eisai Co Ltd | Menetelmä lääkeaineina käyttökelpoisten 2-pyridin-2-yyli-metyylitio- ja sulfinyyli-1H-bensimidatsolijohdannaisten valmistamiseksi |
JPH0414381Y2 (ja) | 1987-06-27 | 1992-03-31 | ||
JPH07278141A (ja) | 1994-01-12 | 1995-10-24 | Eisai Co Ltd | 光学活性ベンズイミダゾール誘導体の製造法および中間体 |
JP3926936B2 (ja) * | 1998-11-16 | 2007-06-06 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | スルホキシド誘導体・アセトン錯体およびその製造法 |
ES2166269B1 (es) | 1999-07-14 | 2003-04-01 | Sint Quimica Sa | Nuevo procedimiento de obtencion de derivados de 2-(2-piridinilmetilsulfinil)-1h-benzimidazol. |
FR2827564A1 (fr) | 2001-07-17 | 2003-01-24 | Michelin Soc Tech | Chenilles en caoutchouc pour vehicules |
EP1487820A1 (en) * | 2002-03-26 | 2004-12-22 | Dr. Reddy's Laboratories Ltd. | Crystalline forms of rabeprazole sodium |
WO2003101452A1 (en) * | 2002-06-03 | 2003-12-11 | Aurobindo Pharma Ltd. | Process for the preparation of highly pure rabeprazole sodium salt |
-
2005
- 2005-06-29 JP JP2006528754A patent/JP4884967B2/ja not_active Expired - Fee Related
- 2005-06-29 US US11/597,743 patent/US7557217B2/en not_active Expired - Fee Related
- 2005-06-29 WO PCT/JP2005/011969 patent/WO2006003946A1/ja active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS646270A (en) * | 1986-11-13 | 1989-01-10 | Eisai Co Ltd | Pyridine derivative and remedy for ulceration containing the same |
JPH0769888A (ja) * | 1992-08-21 | 1995-03-14 | Eisai Co Ltd | 抗菌剤 |
JP2001039975A (ja) * | 1999-07-26 | 2001-02-13 | Eisai Co Ltd | スルホキシド誘導体の結晶およびその製造法 |
Also Published As
Publication number | Publication date |
---|---|
JPWO2006003946A1 (ja) | 2008-04-17 |
US7557217B2 (en) | 2009-07-07 |
US20070225502A1 (en) | 2007-09-27 |
JP4884967B2 (ja) | 2012-02-29 |
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