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Novel method for producing chiral sulfoxide derivant

A derivative and chiral technology, applied in drug combination, organic chemistry, digestive system, etc., can solve the problems of peroxidation oxidation yield, purification difficulty, yield and ee value reduction, etc., to achieve mild reaction and simple preparation process Effect

Inactive Publication Date: 2009-05-13
YANGTZE RIVER PHARM GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] However, in these oxidation processes, there are generally problems of peroxidation and low oxidation yields. As a result, a mixture of sulfoxide derivatives, sulfones, and thioethers is obtained. Because their properties are relatively close, purification is difficult, resulting in low yields and low yields. ee value decreased

Method used

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  • Novel method for producing chiral sulfoxide derivant
  • Novel method for producing chiral sulfoxide derivant
  • Novel method for producing chiral sulfoxide derivant

Examples

Experimental program
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Effect test

Embodiment 1

[0020] Synthesis of (-)5-difluoromethoxy-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole, (S)-pantrop Larazole

[0021] 5-Difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methyl]thio-1H-benzimidazole (183.5g, 0.50mol) was suspended in 1000ml of toluene, Add D-diethyl tartrate (62.4g, 0.30mol), tetraisopropyl titanate (42.6g, 0.15mol), H 2 O (1.15ml, 0.064mol). Raise the temperature to 60-65°C, heat and stir for 1 hour to form a transparent solution, cool down to 0-5°C, add diisopropylethylamine (25.5ml), and slowly add dicumyl hydroperoxide dropwise within 3 hours ( DCHP, 294g, 47%, 0.71mol), insulation reaction for 20 hours, HPLC detection containing pantoprazole 97.7%, thioether 0.7%, add 500ml10% sodium hydroxide, stir for half an hour, layering, organic layer with 10% Extract with sodium hydroxide (250ml×3), discard the organic layer, combine the lye, add 750ml of methanol and 10g of activated carbon, stir for half an hour, filter, adjust the pH of the filtrate ...

Embodiment 2

[0023] Synthesis of (+)5-difluoromethoxy-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole, (R)-pantrop Larazole

[0024] 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methyl]thio-1H-benzimidazole (11.1g, 30.0mmol) was suspended in 60ml of toluene, Add L-diethyl tartrate (3.12ml, 18.2mmol), tetraisopropyl titanate (2.64ml, 9.0mmol), H 2 O (69 μl, 0.038 mmol). Raise the temperature to 60-65°C, heat and stir for 1 hour to form a transparent solution, cool down to 0-5°C, add diisopropylethylamine (1.53ml), and slowly add dicumyl hydroperoxide dropwise within 3 hours ( DCHP, 6.9g, 70%, 0.71mol), react at room temperature for 48 hours, add 60ml of 10% sodium hydroxide, stir for half an hour, separate layers, extract the organic layer with 10% sodium hydroxide (30ml×3), discard the organic layer , combined the lye, adjusted the pH to 7.5-8.0 with acetic acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pres...

Embodiment 3

[0026] (-) Synthesis of 2-[[(3,5-dimethyl-4-methoxyl-2-pyridyl)methyl]sulfinyl]-5-methoxyl-1H-benzimidazole, ( S)-Omeprazole

[0027] Suspension of 2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]thio]-5-methoxy-1H-benzimidazole (1.63 g, 5 mmol) In 10ml of toluene, add D-diethyl tartrate (0.62g, 3.03mmol), tetraisopropyl titanate (0.43g, 1.5mmol), H 2 O (11.5 μl, 0.64 mmol). Raise the temperature to 60-65°C, heat and stir for 1 hour to form a transparent solution, cool down to 0-5°C, add diisopropylethylamine (0.26ml), slowly add dicumyl hydroperoxide (DCHP, 2.94g , 47%, 7.1mmol), insulation reaction overnight, HPLC detection containing 95.4% omeprazole, 0.3% thioether, add 5ml10% sodium hydroxide, stir for half an hour, separate layers, and extract the organic layer with 10% sodium hydroxide (10ml×3), the organic layer was discarded, the lye was combined, 1g of activated carbon was added, stirred for half an hour, filtered, the filtrate was adjusted to pH=7.5-8 with acetic ac...

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Abstract

The invention discloses a novel method for producing a chiral sulphoxide derivative. The method comprises the following steps: an oxidant is utilized to selectively oxidize a corresponding prochiral thioether compound in the presence of a chiral titanium complex. The method has high yield and few byproducts, and the obtained product has higher optical purity and chemical purity.

Description

technical field [0001] The invention relates to a new method for preparing the S-isomer or R-isomer of imidazole sulfoxide anti-ulcer active compounds. Background technique [0002] Imidazole sulfoxide compounds (representative compound structures are as follows) or their alkali metal salts and alkaline earth metal salts are proton pump (H+ / K+-ATPase) inhibitors, which have a strong inhibitory effect on gastric acid secretion and can effectively inhibit gastric acid secretion. For the treatment of diseases related to gastric acid secretion disorders, such as gastric ulcer, duodenal ulcer, reflux esophagitis and Zoller-Ellard syndrome [Bioorg.Med.Chem.2007, 15, 1181-1205]. [0003] [0004] Sulfoxides [0005] All imidazole sulfoxide compounds have a chiral center——sulfur atom, so they are a pair of enantiomers, namely, the left-handed body (-)- and the right-handed body (+)-or called S-type and R-type racemic mixture. Enantiomers often have different physiological acti...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07D495/04C07D235/28A61P1/04
Inventor 孙田江陆宏国周斌张正艮孟霆刘昕朱爱林何慧丽蔡瞻杨玉社
Owner YANGTZE RIVER PHARM GRP CO LTD
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