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Process for producing optically active sulfoxide devivative'

A compound and substituent technology, applied in the field of optically active sulfoxide derivatives, can solve the problems of low yield and low optical purity of sulfoxide

Inactive Publication Date: 2003-06-25
TAKEDA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] Conventional production methods involve the following problems: generation of sulfone which is difficult to remove; low optical purity (enantiomeric excess) of target optically active sulfoxide; therefore, basically purification by column chromatography etc.; low yield

Method used

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  • Process for producing optically active sulfoxide devivative'

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0108] The preparation of embodiment 1 (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole (1) Under a nitrogen protection atmosphere, 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]thio]benzimidazole (50.0 g, 0.14 mol, containing 16.7 mg of water), toluene (250 ml), water (283 mg, 0.016 mol, total moisture content 0.017 mol) and (+)-diethyl tartrate (10.6 ml, 0.062 mol) were mixed , and the mixture was stirred at 50-55°C for 30 minutes. Under a nitrogen protective atmosphere, titanium(IV) isopropoxide (8.29 mL, 0.028 mol) was added, and the mixture was stirred at 50-55°C for 1 hour. Under a nitrogen protective atmosphere and cooling, diisopropylethylamine (8.13 ml, 0.047 mol) was added to the resulting mixture, and then cumene hydroperoxide (76.50 ml, content 82% , 0.43 mol). The mixture was stirred at -10 to 10°C for 4.5 hours.

[0109] Analysis of the reaction mixture by high performance liquid chromatography (condition (A)) rev...

Embodiment 2

[0112] Example 2 Preparation of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole (1) Under nitrogen protection gas flow, 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]thio]benzimidazole (900 g, 2.55 mol, containing 80 mg of water), toluene (4500 ml), water (5.4 g, 0.300 mol, total moisture content 0.304 mol) and (+)-diethyl tartrate (192 ml, 1.12 mol) were mixed , and the mixture was stirred at 50-56°C for 30 minutes. Under nitrogen gas flow, titanium(IV) isopropoxide (149 ml, 0.505 mol) was added, and the mixture was stirred at 53-56°C for 1 hour. Under nitrogen protection flow, the mixture was cooled to room temperature, diisopropylethylamine (147 ml, 0.844 mol) was added to the resulting mixture, and then cumene hydroperoxide (1380 ml, content 82 %, 7.70 moles). The mixture was stirred at -5 to 5°C for 2 hours.

[0113] The resulting reaction mixture was analyzed by high performance liquid chromatography (condition (A)). As...

Embodiment 3

[0115] Example 3 Preparation of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole

[0116] 2-[[[3-Methyl 4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfanyl]benzimidazole (25.0 g, 0.071 mole, containing 13.4 mg water), toluene (122 mL), water (137 mg, 0.0076 mol, total moisture content 0.0083 mol) and (+)-diethyl tartrate (5.32 mL, 0.031 mol). To the mixture was added titanium(IV) isopropoxide (4.15 ml, 0.014 mol) at 50-60°C, and the mixture was stirred at 50-55°C for 1 hour. To the resulting mixture was added diisopropylethylamine (4.07 ml, 0.023 mol) at room temperature, and then cumene hydroperoxide (38.2 ml, content 82%, 0.22 mol) was added at -5 to 5°C. The mixture was stirred at -5 to 5°C for 1.5 hours.

[0117] The resulting reaction mixture was analyzed by high performance liquid chromatography (condition (A)). As a result, it was found that 0.60% of thioether and 1.76% of sulfone existed as analogs in the reaction mixture, and no o...

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Abstract

A process for producing an optically active isomer of a compound represented by the formula (II) (wherein ring A represents an optionally substituted benzene ring; R<1> represents hydrogen, an optionally substituted hydrocarbon group, acyl, or acyloxy; R<2>, R<3>, and R<4> each represents hydrogen, optionally substituted alkyl, optionally substituted alkoxy, or optionally substituted amino; X represents nitrogen or CH; Y represents nitrogen or CH; and * indicates an asymmetric center) or of a salt of the compound, characterized by reacting a compound represented by the formula (I) (wherein the symbols have the same meanings as the above) or a salt thereof with an excess of an oxidizing agent in the presence of a catalyst for asymmetry induction. This process is a simple process by which an optically active sulfoxide derivative can be efficiently and industrially mass-produced in high yield while attaining an extremely high enantiomer excess.

Description

technical field [0001] The invention relates to a production method of an optically active sulfoxide derivative with antiulcer activity. Background technique [0002] Optically active sulfoxide derivatives with antiulcer activity can be obtained by asymmetric oxidation of prochiral sulfide derivatives. Typically, the above reactions produce sulfones, which are an overreaction product. As a result, the obtained sulfoxide derivatives include unreacted sulfide derivatives in the form of analogs and sulfone derivatives as over-reaction products. [0003] As a method for producing an optically active sulfoxide derivative, for example, WO96 / 02535 (Japanese Published Patent Application published in PCT: Hei-504290) discloses a method comprising using a sulfide derivative and an oxidizing agent in an organic solvent in hand In the presence of a neutral titanium complex and a base, the optically active sulfoxide compound is obtained. [0004] For example, in Example 22 of the pres...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4439A61P1/04C07D209/30C07D235/28C07D277/74C07D277/76C07D401/12C07D417/12
CPCC07D277/74C07D401/12C07D209/30A61K31/4439C07D235/28C07D417/12C07D277/76A61P1/04
Inventor 桥本秀雄浦井征
Owner TAKEDA PHARMA CO LTD
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