Preparation method of benzimidazole complex

A technology of benzimidazole and complexes, applied in the field of medicinal chemistry, can solve the problems of difficult to meet optical purity requirements and high cost, and achieve the effects of easy scale-up of production, simple reaction steps and operations, and low cost of solvents

Inactive Publication Date: 2018-02-16
拉萨泰达医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Omeprazole, lansoprazole, pansoprazole and rabeprazole all have single optical purity medicines on the market, but the method of prior art, its racemate is resolved into the method for single isomer Difficult to meet optical purity requirements, or high cost

Method used

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  • Preparation method of benzimidazole complex
  • Preparation method of benzimidazole complex
  • Preparation method of benzimidazole complex

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Omeprazole benzimidazole complex 1 49.4 g (0.103 mol) was dispersed in 250 ml of ethanol, and 43 g of 10% aqueous sodium hydroxide solution (0.115 mol, 1.04 times) was added dropwise at 20°C, and stirred for 2 hours , ethanol was evaporated to dryness under reduced pressure, 250 milliliters of tetrahydrofuran was added, the layers were separated, the organic layer was dried with 20 grams of anhydrous sodium sulfate, filtered, and the filtrate was added with 20.5 grams of (S)-2-hydroxyl-2-phenylacetyl chloride (170.59, 0.12 mole , 1.16 times), reacted at 20°C for 6 hours, evaporated THF to dryness, slowly added isopropanol, and raised the temperature to 65°C, stopped adding isopropanol after dissolving, slowly cooled to 5°C, and maintained for 4 hours , filtered, and dried to obtain 45.2 g (0.08755) of omeprazole benzimidazole complex 2 (516.01), with a yield of 85% and an isomer purity of 99.8%.

Embodiment 2

[0047] Omeprazole benzimidazole complex 1 49.4 grams (0.103 moles) is dispersed in 220 milliliters of isopropanols, and 35 grams of 10% sodium hydroxide aqueous solution (0.115 moles, 1.04 times) is added dropwise at 20 ℃, stirs After 3 hours, evaporate the isopropanol to dryness under reduced pressure, add 250 milliliters of tetrahydrofuran, separate the layers, dry the organic layer with 20 grams of anhydrous sodium sulfate, filter, and add 20 grams of (S)-2-hydroxyl-2-phenylacetyl chloride to the filtrate ( 170.59, 0.12 moles, 1.16 times), reacted at 20°C for 4 hours, evaporated THF to dryness, slowly added ethanol, and raised the temperature to 50°C, stopped adding ethanol dropwise after dissolving, slowly cooled down to 10°C, and maintained for 4 hours , filtered, and dried to obtain 39.3 grams (0.07622) of omeprazole benzimidazole complex 2 (516.01), with a yield of 74% and an isomer purity of 99.6%.

Embodiment 3

[0049] Lansoprazole benzimidazole complex 1 50 grams (0.135 moles) was dispersed in 220 milliliters of isopropanol, and 35 grams of 10% aqueous sodium hydroxide solution was added dropwise at 20°C, stirred for 3 hours, and evaporated to dryness under reduced pressure Isopropanol, add 250 ml of THF, separate the layers, dry the organic layer with 20 g of anhydrous sodium sulfate, filter, add 20 g of (S)-2-hydroxyl-2-phenylacetyl chloride (170.59, 0.12 mol, 0.88 times ), react at 20°C for 4 hours, evaporate THF to dryness, slowly add ethanol, and heat up to 50°C, stop adding ethanol dropwise after dissolving, slowly cool down to 10°C, and maintain for 4 hours, filter, and dry to obtain 38.8 grams Lansoprazole benzimidazole complex 2, yield 72%, isomer purity 99.4%.

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Abstract

The invention discloses a preparation method of benzimidazole complex 2 with high optical purity. The method comprises the following steps: forming benzimidazole complex 1 by using (L)-malic acid andbenzimidazole compound, obtaining the benzimidazole compound with higher (S) configuration rate after the desalting process, forming a crude product of the benzimidazole complex 2 by the benzimidazolecompound and (S)-2-hydroxy-2-phenylacetyl chloride, crystallizing the crude product of the benzimidazole complex 2 to obtain the benzimidazole complex 2 with high optical purity. The method is mild in reaction condition, the operation is simpler, the environmental pollution is small, and a product with high optical purity which meets the quality requirements of the current art can be obtained.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to drug synthesis, in particular to a preparation method of an optically active benzimidazole complex. Background technique [0002] Benzimidazole compounds are weakly basic, and they can affect the H of the gastric parietal cell membrane + , K + -ATP enzyme system has inhibitory effect and prevents gastric acid secretion, thereby confirming the status of benzimidazole compounds as proton pump inhibitors. [0003] After long-term research, it has been found that drugs that inhibit H+ / K+-ATPase must have three structural parts: pyridine ring, SO group and benzimidazole ring. Most of the currently marketed PPIs are benzimidazole derivatives, which enhance their ability to inhibit gastric acid through different modifications to the pyridine ring or benzimidazole ring. [0004] Swedish Haessel Company developed temoprazole (timoprazole) and picoprazole (picoprazole) in 1974 and 1976 r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D235/28C07D401/12
CPCC07B57/00C07B2200/07C07D235/28C07D401/12
Inventor 杨胜喜谈红利
Owner 拉萨泰达医药科技有限公司
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