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Preparation method of (R)-2-[[[3[methyl-4-nitro-2-pyridyl]methyl]sulfinyl]benzimidazole

A technology of benzimidazole and sulfinyl, applied in the preparation of (R)-2-[[[3-methyl-4-nitro-2-pyridyl]methyl]sulfinyl]benzimidazole It can solve the problems of unsolved compound purification, long reaction time, difficult separation and purification, etc., and achieve the effect of easy industrial production, low cost and good yield

Inactive Publication Date: 2012-10-17
SHANGHAI INST OF PHARMA IND CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

According to the reaction conditions, the reaction cannot be terminated on the sulfoxide product, and side reactions easily occur to obtain further oxidation of sulfoxide to sulfone, and the physical and chemical properties of the two are very similar, so it is difficult to separate and purify them
[0009] WO0183473 has improved this method, by reducing the reaction temperature, increasing the amount of oxidant to improve the reaction yield and the optical purity of enantiomers, but the reaction time is longer, and still can not solve the purification of the compound shown in formula (III) question

Method used

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  • Preparation method of (R)-2-[[[3[methyl-4-nitro-2-pyridyl]methyl]sulfinyl]benzimidazole
  • Preparation method of (R)-2-[[[3[methyl-4-nitro-2-pyridyl]methyl]sulfinyl]benzimidazole
  • Preparation method of (R)-2-[[[3[methyl-4-nitro-2-pyridyl]methyl]sulfinyl]benzimidazole

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Experimental program
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Effect test

Embodiment 1

[0039] Under nitrogen protection atmosphere, 400.0g (1.32mol) 2-[[[3-methyl-4 nitro-2-pyridyl] methyl] sulfenyl] benzimidazole, 4L toluene, 146.4g (0.72mol ) L-(+)-diethyl tartrate, 3.6ml of water, stirred at 50-55°C for 30min. 104.8 g (0.37 mol) of titanium isopropoxide were added, and the mixture was stirred at 50-55° C. for 1 h. Cool to 20°C, add 60.0g (0.48mol) of diisopropylethylamine, dropwise add 300.0g (1.68mol) of cumene hydroperoxide, stir and react at 25-30°C for 1.5h, and obtain 396.4g of solid. The yield was 94.1%. Melting point 113-114°C (decomposition).

[0040] [α] D =+251.5° (c=1, CH 3 OH), the enantiomeric excess of the title compound was 99.2% ee.

Embodiment 2

[0042]Under nitrogen protection atmosphere, 50.0g (0.17mol) 2-[[[3-methyl-4 nitro-2-pyridyl] methyl] sulfenyl] benzimidazole, 500ml toluene, 18.5g (0.09mol) ) L-(+)-diethyl tartrate and 0.45ml of water were mixed, and stirred at 50-55°C for 30min. 13.1 g (0.046 mol) titanium isopropoxide was added, and the mixture was stirred at 50-55° C. for 1 h. Cool to 20°C, add 8.00g (0.062mol) of diisopropylethylamine, dropwise add 38.0g (0.25mol) of cumene hydroperoxide, stir and react at 20-40°C for 1h, and obtain 49.8g of solid. The yield is 95%. Melting point 112-113°C (decomposition).

[0043] [α] D =+240° (c=1, CH 3 OH), the enantiomeric excess of the title compound was 97.5% ee.

Embodiment 3

[0045] Under nitrogen protection atmosphere, 20.0g (0.07mol) 2-[[[3-methyl-4 nitro-2-pyridyl] methyl] sulfenyl] benzimidazole, 200ml toluene, 7.4g (0.036mol ) L-(+)-diethyl tartrate and 0.2ml of water were mixed and stirred at 50-55°C for 30min. 5.2 g (0.018 mol) of titanium isopropoxide were added, and the mixture was stirred at 50-55° C. for 1 h. Cool to 20°C, add 3.00g (0.023mol) of diisopropylethylamine, dropwise add 15.0g (0.084mol) of cumene hydroperoxide, stir and react at 40-50°C for 0.5h, and obtain 17.2g of solid. The yield was 93.2%. Melting point 112-113°C (decomposition).

[0046] [α] D =+241.0° (c=1, CH 3 OH), the enantiomeric excess of the title compound was 97.8% ee.

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Abstract

The invention discloses a preparation method of (R)-2-[[[3[methyl-4-nitro-2-pyridyl]methyl]sulfinyl]benzimidazole. The preparation method is characterized in that the preparation method comprises a step that 2-[[[3[methyl-4-nitro-2-pyridyl]methyl]thio]benzimidazole or its salt reacts with an excess oxidant in a solvent in the presence of an asymmetric induction effect catalyst, and the molar ratio of the 2-[[[3[methyl-4-nitro-2-pyridyl]methyl]thio]benzimidazole or its salt to the oxidant is 1:1-1:2.0. The optical purity and the yield of (R)-2-[[[3[methyl-4-nitro-2-pyridyl]methyl]sulfinyl]benzimidazole prepared through the method of the invention are extremely high.

Description

technical field [0001] The invention relates to a preparation method of an intermediate optically active sulfoxide derivative of drug D-lansoprazole with anti-ulcer activity. Background technique [0002] Dexlansoprazole (III) is a proton pump inhibitor with significant antiulcer activity. [0003] [0004] The optically active compound (I) of the following formula is the key intermediate for the preparation of proton pump inhibitor dexlansoprazole, and its chemical name is (R)-2-[[[3-methyl-4-nitro- 2-pyridyl]methyl]sulfinyl]benzimidazole. [0005] [0006] There are mainly two kinds of preparation methods about D-lansoprazole (III) reported in the literature at present, one is the resolution method, including chemical resolution, biological enzyme method and inclusion resolution. DE 403545 has described chemical resolution method and prepared dexlansoprazole (III), this method adopts stereoselective nitrogen derivatization to resolve lansoprazole, the lansoprazole ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
Inventor 王哲烽刘启皓王小梅隋强益兵谢智乾钟静芬时惠麟
Owner SHANGHAI INST OF PHARMA IND CO LTD
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