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Ezetimibe intermediate and synthesis method of ezetimibe

A technology of ezetimibe and synthesis method, applied in organic chemistry, bulk chemical production, etc., can solve the problems of low yield and purity, harsh reaction conditions, etc.

Active Publication Date: 2015-09-09
SHANDONG CHUANGXIN PHARMA RES & DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The whole route has harsh reaction conditions and low yield and purity

Method used

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  • Ezetimibe intermediate and synthesis method of ezetimibe
  • Ezetimibe intermediate and synthesis method of ezetimibe
  • Ezetimibe intermediate and synthesis method of ezetimibe

Examples

Experimental program
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Effect test

Embodiment 1

[0056] Embodiment 1: Preparation of ezetimibe intermediate;

[0057] Add the above-mentioned compound 1 (53.85Kg), compound 2 (64.86Kg), dichloromethane (372.4kg) into a 1000L enamel reaction kettle, control the temperature at -5°C, add DIPEA (139L) dropwise, and complete the dropwise addition within 20min. Start to add trimethylchlorosilane (72.5 L) dropwise, and half an hour later, the dropwise addition is completed, and the stirring is continued for 3 hours, which is recorded as reaction solution A.

[0058] Add titanium tetrachloride (19.83L) into a 200L reaction kettle containing 85L of dichloromethane, cool down to -15°C, add titanium tetraisopropoxide (18.01L), stir for 20min, milky white suspension, cool down to -10°C °C, transfer the above system to a 3000L enamel reaction kettle, add the reaction solution A dropwise, the temperature does not exceed -25 °C, the dropwise addition is completed after 1h, and vigorously stirred for 3h. Add 500L of isopropanol dropwise, a...

Embodiment 2

[0060] Embodiment 2: Preparation of ezetimibe;

[0061] Compound 6 (47.7Kg), dichloromethane (250L), and BSA (81.6L) were put into a 1000L enamel reaction kettle, heated to reflux, and stirred for 3h. Return to normal temperature, add TBAF (1.4Kg), the turbidity becomes light yellow and transparent, and react for 2 hours. Compound 5 disappeared and transformed into Compound 7. After the reaction was completed, the organic phase was distilled off, and 135 L of isopropanol and lithium fluoride (2.1 kg) were added, and stirred at room temperature for 1 h; the isopropanol was distilled off at 30° C., and 135 L of dichloromethane and 135 L of purified water were added. , transferred to a 500L layered crystallization tank, stirred for 5min, and separated and extracted. Add 170 L of water to the organic phase, stir at 0°C under temperature control, solid precipitates, filter after 30 min, and wash with water to obtain 28.7 Kg. Dry at 40°C for 12 hours to obtain 31.5Kg of crude prod...

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Abstract

The invention relates to an ezetimibe intermediate and a synthesis method of ezetimibe, and mainly solves the technical problems of low yield, low purity, severe conditions and the like in existing methods. According to a technical scheme of the invention, the preparation method includes: subjecting a compound 1 to Aldol condensation reaction under the condition of a self-made isopropoxy titanium trichloride catalyst to generate a compound 2, controlling the Aldol condensation temperature below -5DEG C, in terms of dropwise adding of the catalyst, adding a system A into a catalyst system, conducting ring closing on a compound 2 under the catalysis of TBAF, and removing silicon protecting group under the fluoride salt condition to generate ezetimibe. The synthesis route has mild conditions, the obtained intermediate and end product have high yield, and the purity is high.

Description

Technical field: [0001] The invention belongs to the technical field of chemical synthesis, and relates to an ezetimibe intermediate and a new ezetimibe synthesis method. Background technique [0002] Ezetimibe is the first selective cholesterol absorption inhibitor jointly developed by Schering-Plough and Merck, and Schering-Plough was acquired by Merck in 2009. In 2002 and 2004, the FDA approved the Ezetimibe tablets launched by Schering-Plough and Merck under the trade name Ezetrol and the Ezetimibe tablet launched under the trade name Vytorin. Zetimibe Simvastatin Tablets. Different from statins inhibiting the cholesterol synthesis pathway in the liver, ezetimibe, as the first selective cholesterol absorption inhibitor, works by selectively inhibiting the absorption of cholesterol in the intestine. [0003] At present, Schering-Plough has patented ezetimibe compound and process synthesis (CN100475829C, CN1130342C, US5767115). Patent US5767115 discloses a synthetic met...

Claims

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Application Information

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IPC IPC(8): C07D263/26C07D205/08
CPCY02P20/55C07D263/26C07D205/08
Inventor 江鸿付长华魏娟
Owner SHANDONG CHUANGXIN PHARMA RES & DEV
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