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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 few separation steps

Active Publication Date: 2016-05-04
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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  • 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 the protection of nitrogen, the temperature was raised to 100°C for 10 hours, and then cooled to room temperature (25°C), the reaction solution was diluted with 150ml of 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. The solvent was distilled off under reduced pressure. , 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. The intermediate is (S)-1-(4-fluorophenyl)-5-(2-oxo-phenyloxazolidinyl-3-yl)pentane-1, 5-dione. The preparation method comprises that 1-(4-fluorophenyl)ethanone and a silane protective agent undergo a reaction to produce ((1-(4-fluorophenyl)vinyl)oxo)trimethylsilane, (S)-4-phenyloxazolidin-2-one and acryloyl chloride undergo a condensation reaction to produce (S)-3-acrylyl-4-phenyloxazolidin-2-one, and the ((1-(4-fluorophenyl)vinyl)oxo)trimethylsilane and the (S)-3-acrylyl-4-phenyloxazolidin-2-one undergo a condensation reaction to produce the ezetimibe intermediate. The preparation method utilizes a convergent type route, has the total yield of 80% or more, utilizes cheap and easily available raw materials, utilizes less types of solvents, produces small toxicity, has a short production period, utilizes simple production units operated easily, is 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] Ezeimibe is the first and only selective cholesterol absorption inhibitor approved for clinical use. It is the first cholesterol-lowering drug with a new mechanism since its birth in 1987. It 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 ezetimib...

Claims

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Application Information

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Patent Type & Authority Applications(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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