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A kind of preparation method of ezetimibe and intermediate thereof

A technology of ezetimibe and an intermediate, which is applied in the field of drug synthesis, can solve the problems of complicated production process, increase production cost, increase the difficulty of operation, etc., and achieve the effects of high economic value, improved stability and reduced cost

Active Publication Date: 2018-12-14
HEADING NANJING PHARMTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Such repetition leads to complicated production procedures, which is very unfavorable for large-scale drug production, virtually increases the difficulty of operation, and greatly increases production costs

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] The preparation of embodiment 1 4-benzyloxybenzaldehyde

[0039]

[0040] 5L four-necked flask, then stirred, added p-hydroxybenzaldehyde (100g, 1eq), benzyl chloride (124.4g, 1.2eq), potassium carbonate (135.81g, 1.2eq), N,N-dimethylformamide ( 1000ml, 10V), stirred overnight at room temperature, and monitored the end of the reaction. Filtrate, concentrate, add 1000ml of ethyl acetate and 400ml of water, extract and separate, filter and concentrate to dryness to obtain a white solid with a yield of about 97% and a purity of >99%.

Embodiment 2

[0041] The preparation of embodiment 2 compound SM2

[0042]

[0043] Take a 2L three-necked flask, stir it mechanically, add raw materials (173.7g, 1eq), p-fluoroaniline (100g, 1.1eq), isopropanol (1730ml, 10V), stir and heat to 40°C, a large amount of light yellow crystalline solids are gradually precipitated , Stir at 40°C for 2h, and monitor the end of the reaction. Stop heating and naturally stir to cool down to room temperature, filter with suction, rinse the filter cake with cold isopropanol, and dry to obtain light yellow crystal SM2 with a mass of 238 g, a yield of 95%, and a purity of 99%.

Embodiment 3

[0044] Preparation of compound (trimethylsilyl protecting group and benzyl protecting group) shown in embodiment 3 formula (III)

[0045]

[0046] 2L three-necked flask, mechanically stirred, under the protection of nitrogen, add SM2 (64.1g, 1.5eq), SM1 (50g, 1.0eq), dichloromethane (500ml, 10V), put it in a low temperature tank and stir to cool down to -5°C, Dropwise addition of DIPEA (45.3g, 2.5eq) was started and the solution gradually cleared. Slowly add TMSCl (22.8g, 1.5eq), keep the internal temperature between -5°C and 5°C, stir the reaction for 2-3h, monitor the end of the reaction, keep cooling down to -30°C to -40°C, add TiCl dropwise 4 (29.2g, 1.1eq), after the dropwise addition was completed, the current temperature was maintained for 1 hour, and the reaction was completed by liquid phase monitoring. Add dichloromethane (350ml / 350ml) dropwise at the current temperature, control the exothermic temperature below -30°C, stir for 2h, then add NaHSO 3 (250ml) solut...

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Abstract

The invention relates to a preparation method of a cholesterol reducing drug ezetimibe. The method comprises the following steps: generating an intermediate protected by a trimethylsilyl group and a benzyl group, and carrying out deprotection to obtain ezetimibe. The preparation method solves the problem of easy falling of protection groups of the intermediate in present production technologies, and obviously improves the stability of the intermediate in order to greatly simplify the technologic operation. The method also greatly improves the yield and the purity of the above target product; and the protection groups adopted in the invention are cheap and easily available, so the production cost of the method provided by the invention is obviously lower than the production cost in the prior art, thereby the method provides a very good production technology for amplified production of ezetimibe.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for preparing cholesterol-lowering drug Ezetimibe. Background technique [0002] Ezetimibe, English name Ezetimibe, also known as Ezetimibe, Ezetimibe, is the first selective cholesterol absorption inhibitor jointly developed by Schering-Plough and Merck, and also the first to obtain Selective inhibitors of cholesterol absorption approved by the US FDA. The chemical structure of ezetimibe is shown in formula (I). [0003] [0004] In the preparation method patent US 6207822B1 of Schering-Plough and Merck, the synthesis route is as follows: [0005] [0006] Two of these intermediates are: [0007] [0008] The content of the process is to mix 004 and 001 together, then treat them with TMSCl and DIPEA, the resulting intermediates are 006 and 007, and then react with TiCl4 at low temperature to produce 005 (OTMS), but after the reaction treatment, there is a large...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D205/08C07D263/26
CPCY02P20/55
Inventor 李文森
Owner HEADING NANJING PHARMTECH CO LTD
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