A kind of preparation method of ezetimibe intermediate

A technology of ezetimibe and an intermediate, which is applied in the field of drug synthesis, can solve problems such as troublesome reaction products, and achieve the effects of short reaction route, high yield and convenient operation

Active Publication Date: 2018-10-26
JIANGSU HANSYN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The total yield of this scheme is only about 60%, and in the first step Friedel-Crafts reaction, due to the addition of a large amount of metal compounds such as catalyst aluminum trichloride, it causes great trouble to the separation of reaction products, which is also reported in the patent CN103694111A The defect of this method has been identified, and it is necessary to improve the dispersibility of the catalyst in the organic phase by grinding and sieving the catalyst aluminum trichloride

Method used

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  • A kind of preparation method of ezetimibe intermediate
  • A kind of preparation method of ezetimibe intermediate
  • A kind of preparation method of ezetimibe intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1 Preparation of ((1-(4-fluorophenyl)vinyl)oxy)trimethylsilane

[0037] The structural formula is as follows:

[0038]

[0039] In a 500ml three-necked flask, add 20g (0.145mol, 1eq.) of 1-(4-fluorophenyl) ethyl ketone, 22g (0.217mol, 1.5eq) of triethylamine, and 18.90g (0.174mol, 1.2eq) and 100ml of N,N-dimethylformamide, the reaction was stirred under nitrogen protection, heated to 100°C for 10 hours, then cooled to room temperature (25°C), the reaction solution was diluted with 150ml petroleum ether, and the precipitate precipitated The triethylamine hydrochloride was removed by suction filtration with a Buchner funnel, the filtrate was collected, and the organic phase was washed with 200 ml of ice 10% (wt) sodium bicarbonate solution, and the organic phase was washed twice with 200 ml of water and distilled off under reduced pressure. Solvent, 27.1 g of solid was obtained, with a yield of 90%.

Embodiment 2

[0040] Example 2 Preparation of ((1-(4-fluorophenyl)vinyl)oxy)trimethylsilane

[0041] The structural formula is as follows:

[0042]

[0043] In a 500ml three-necked flask, add 20g (0.145mol, 1eq.) of 1-(4-fluorophenyl)ethanone, 26.18g (0.203mol, 1.4eq) of diisopropylethylamine, and 19.69g of trimethylchlorosilane (0.181mol, 1.25eq) and 100ml of toluene, the reaction was stirred under nitrogen protection, the temperature was raised to 100°C for 8 hours, then cooled to room temperature, the reaction solution was diluted with 150ml petroleum ether, and the precipitated triethylamine hydrochloride was used The Buchner funnel was removed by suction, the filtrate was collected, and the organic phase was washed with 200 ml of ice 10% (wt) sodium bicarbonate solution. The organic phase was washed twice with 200 ml of water. The solvent was distilled off under reduced pressure to obtain 25.59 g of solid. Rate 85%).

Embodiment 3

[0044] Example 3 Preparation of ((1-(4-fluorophenyl)vinyl)oxy)trimethylsilane

[0045] The structural formula is as follows:

[0046]

[0047] In a 500ml three-necked flask, add 20g (0.145mol, 1eq.) of 1-(4-fluorophenyl)ethanone, 26.18g (0.203mol, 1.4eq) of diisopropylethylamine, and 27.70g of bromotrimethylsilane (0.181mol, 1.25eq) and 100ml of toluene, the reaction was stirred under nitrogen protection, the temperature was raised to 100°C for 12 hours, then cooled to room temperature, the reaction solution was diluted with 150ml petroleum ether, and the precipitated triethylamine hydrochloride was used The Buchner funnel was suction filtered to remove, the filtrate was collected, and the organic phase was washed with 200 ml ice 10% (wt) sodium bicarbonate solution, and the organic phase was washed twice with 200 ml water. The solvent was distilled off under reduced pressure to obtain 26.50 g of solid. The rate is 88%.

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Abstract

The invention discloses a preparation method of an ezetimibe intermediate, which is (S)-1-(4-fluorophenyl)-5-(2-oxygen-4-phenyloxazolidine- 3-yl)pentane-1,5-dione, from 1-(4-fluorophenyl)ethanone and silane protecting agent to form ((1-(4-fluorophenyl)vinyl)oxy)trimethyl In addition, acryloyl chloride and (S)-4-phenyloxazolidin-2-one are reacted and condensed to obtain (S)-3-acryloyl-4-phenyloxazolidin-2-one, and then obtained by ( Condensation of (1‑(4‑fluorophenyl)vinyl)oxy)trimethylsilane and (S)‑3‑acryloyl‑4‑phenyloxazolidin‑2‑one. The process route adopts a converging route, the total yield can reach more than 80%, the raw materials used in the process are cheap and easy to obtain, the solvent types are small, the toxicity is small, the production cycle is short, the production cost is low, the production unit is simple to operate, safe and environmentally friendly, and is very suitable for Industrial production.

Description

Technical field [0001] The invention relates to a preparation method of an ezetimibe intermediate, belonging to the technical field of medicine synthesis. Background technique [0002] The chemical name of Ezetimube is: 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4( S)-(4-hydroxyphenyl)-2-azetidine (azetidine) ketone, the structural formula is as follows: [0003] [0004] Ezetimibe is the first and only selective cholesterol absorption inhibitor approved for clinical use. Since its birth in 1987, the first cholesterol-lowering drug with a new mechanism can selectively inhibit intestinal cholesterol transporter and effectively reduce intestinal Cholesterol absorption in the tract reduces plasma cholesterol levels and liver cholesterol storage. [0005] There have been a large number of reports on the synthesis method of ezetimibe. We reported in the journal "Chinese Journal of Pharmaceutical Industry" 2004,35(4),251-253) the synthesis diagram of ezetimibe and "C...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D263/26
CPCC07D263/26
Inventor 王希林丁尊良吴华峰王喆陈志宽
Owner JIANGSU HANSYN PHARMA
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