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Preparation method of olmesartan medoxomil key intermediate

A technology for olmesartan medoxomil and an intermediate, which is applied in the field of pharmaceutical synthesis and can solve the problems of many impurities, high toxicity of selenium dioxide, expensive starting materials and the like

Active Publication Date: 2021-08-06
山东四君子集团汉邦生物医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The preparation method of DMDO-OH mainly contains following two kinds: the first route is to be starting material with DMDO, obtain under the effect of selenium dioxide, the by-product is the mixture of elemental selenium and selenium dioxide in the second route, and two Selenium oxide is more toxic, and the yield is lower, and the yield is 60%; the second route is to use DMDO-Cl as the starting material, through formate esterification, and then use alkyd acid hydrolysis to obtain, the starting material of this route The price is expensive, and there are many impurities, the product is not easy to purify, and it is difficult to meet the large demand of the market

Method used

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  • Preparation method of olmesartan medoxomil key intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0014]

[0015] Add 250Kg of solid phosgene to a 2000L enamel reaction kettle at 0°C under slight negative pressure, pump 1000Kg of dichloromethane, keep the temperature, stir for 1 hour, after the solid phosgene is completely dissolved, add 70Kg of 3-hydroxybutanone Slowly add the mixed solution of 280Kg of dichloromethane into a 2000L reactor, and it takes 3 hours to complete the addition, then keep stirring at 0°C for 1 hour, then raise the temperature to reflux, keep the heating rate at 0.5°C / min, continue to react for 2 hours, and then cool down to 0°C, transfer to a 3000L reaction kettle, add 700Kg saturated sodium bicarbonate solution, stir, measure the pH value, keep the system between pH=7-8, if pH≤7, you need to add solid sodium bicarbonate until , the pH value of the solution=7-8, let stand, and separate layers. Distill 1200Kg of dichloromethane from the lower organic phase, add 500Kg mixed solvent (isopropanol:cyclohexane=1:1v / v) while hot, add slowly when addin...

Embodiment 2

[0018]

[0019] In a reaction device with an ultraviolet irradiation device, 65Kg of chlorotriazine is dissolved in 390Kg of dichloromethane, and pumped into a 500L high-level tank for use. Add 115Kg DMDO into a 2000L reactor, pump in 800Kg of dichloromethane, add 1.65Kg of azoisobutyronitrile, irradiate with 254nm ultraviolet light, heat to reflux, and start to drop the mixture of chlorotriazine and dichloromethane , maintain reflux, keep the dropping rate at 1-2Kg / min, and finish dropping within 1 hour. After keeping the reflux for 2 hours, turn off the ultraviolet irradiation, cool down, keep the cooling rate at 2°C / min, drop to -20°C, shake off the filter (centrifuge room, keep the temperature -10°C), and rinse the filter cake with 200Kg dichloromethane to obtain The s-triazine is packed into bags directly while it is cold, and is quickly transferred to a cold storage for storage. The organic phase was concentrated under normal pressure and distilled to obtain 145Kg of...

Embodiment 3

[0021]

[0022] In the reaction device with ultraviolet irradiation device, 81.3Kg of trichloroisocyanuric acid was dissolved in 400Kg of dichloromethane, and pumped into a 1000L high-level tank for use. Add 115Kg DMDO into a 3000L reactor, pump 1000Kg of dichloromethane, add 1.65Kg of azoisobutyronitrile, 254nm ultraviolet light, under irradiation, heat to reflux, start to drop trichloroisocyanuric acid and dichloromethane Keep the mixed solution under reflux, keep the dropping rate at 1-2Kg / min, and finish dropping within 1 hour. After keeping the reflux for 2 hours, turn off the ultraviolet irradiation, cool down, keep the cooling rate at 2°C / min, drop to -20°C, shake off the filter (centrifuge room, keep the temperature -10°C), and rinse the filter cake with 200Kg dichloromethane to obtain Isocyanuric acid is packed in bags while it is cold, and quickly transferred to cold storage for storage. The organic phase was concentrated under normal pressure and distilled to ob...

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Abstract

The invention discloses a preparation method of an olmesartan medoxomil key intermediate, and belongs to the technical field of medicine synthesis. The key points of the technical scheme are as follows: triphosgene with relatively low toxicity is adopted to replace gaseous phosgene, so that the problems of storage and transportation are solved; and a molecular distillation technology is utilized to treat the crude product, so that the occurrence of a polymer at high temperature is avoided, and a high-yield product is obtained.

Description

Technical field [0001] The invention belongs to the technical field of drug synthesis, and specifically relates to a preparation method of a key intermediate of olmesartan medoxomil. Background technique [0002] 4,5-Dimethyl-1,3-dioxole-2-one (DMDO) and its derivatives (4-chloromethyl-5-methyl-1,3-dioxole -2-one (DMDO-Cl) or 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one (DMDO-OH)) is an AT1 subtype angiotensin II receptor. The key intermediate of the body antagonists (ARB) olmesartan medoxomil and azilsartan medoxomil. Compared with the highest approved dose of the commonly used ARB prescription drug olmesartan medoxomil (40mg / day), azilsartan medoxomil EDARBI (80 mg / day) has statistically significant advantages in reducing clinical systolic blood pressure (SBP) and 24-hour average SBP. [0003] At present, the main methods for preparing DMDO are as follows: the first route uses 3-hydroxy-2-butanone as the starting material and reacts with phosgene to generate 4,5-dimethyl-1,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D317/40
CPCC07D317/40
Inventor 吴斗灿马矜烁郑康威李彦灵杨金昌
Owner 山东四君子集团汉邦生物医药有限公司
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