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Synthesis method of anacetrapib chiral intermediate

A kind of technology of anseltrapib and synthetic method, applied in the field of medicine, achieves the effects of high selectivity, improved yield and purity, and low production cost

Active Publication Date: 2018-03-13
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] The technical problem to be solved by the present invention is to avoid the use of ruthenium metal complex catalysts and provide a cheap and easy-to-obtain catalyst. The preparation method of the present invention has high catalytic selectivity, mild reaction conditions, single product, and the obtained anseltrapib intermediate High optical purity and high yield, low production cost, environmentally friendly, more suitable for industrial production

Method used

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  • Synthesis method of anacetrapib chiral intermediate
  • Synthesis method of anacetrapib chiral intermediate
  • Synthesis method of anacetrapib chiral intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Preparation of (1R,2S)-1-(3,5-bis(trifluoromethyl)phenyl)-2-Boc-amino-propanol

[0034] Under the protection of argon, add 300ml of petroleum ether to the reaction bottle, cool down to -5~0℃, add 3ml (0.01mol) of (R)-2-methyl-CBS-oxazoborane, borane dimethyl sulfide Complex 15ml (0.25mol), stirring for 30min; control 5 ~ 10 ℃ dropwise containing the petroleum ether solution containing 65g (0.162mol) of the compound of formula (Ⅲ); after dropping, stir and react for 1h at 5 ~ 10 ℃, the reaction is complete; cool down To -5 ~ 0 ℃, add methanol dropwise, stir for 30min, add 1mol / L sulfuric acid, stir for 30min. Stand to separate and collect the organic phase; the organic phase is washed once with 1mol / L sulfuric acid, 5% sodium bicarbonate solution and purified water respectively, the obtained organic phase is dried by adding anhydrous sodium sulfate, filtered, and the filtrate is concentrated to dryness under reduced pressure 62.3 g of the crude product was obtained, and...

Embodiment 2

[0036] Preparation of (1R,2S)-1-(3,5-bis(trifluoromethyl)phenyl)-2-Boc-amino-propanol

[0037] Under the protection of argon, add 300ml of acetone to the reaction bottle, cool down to -5~0℃, add 6ml (0.02mol) of (R)-2-methyl-CBS-oxazoborane, borane dimethyl sulfide complex Compound 30ml (0.5mol), stirring for 30min; control 5 ~ 10 ℃ dropwise acetone solution containing 65g (0.162mol) of compound of formula (Ⅲ); after dropping, stir and react for 1h at 5 ~ 10 ℃, the reaction is complete; cool down to - 5~0℃, add ethanol dropwise, stir for 30min, add 1mol / L hydrochloric acid, stir for 30min. Stand to separate and collect the organic phase; the organic phase was washed once with 1mol / L hydrochloric acid, 5% sodium bicarbonate solution and purified water respectively, the obtained organic phase was dried by adding anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure 63.2 g of the crude product was obtained, and the (R, S) / (R, R) ...

Embodiment 3

[0039] Preparation of (1R,2S)-1-(3,5-bis(trifluoromethyl)phenyl)-2-Boc-amino-propanol

[0040] Under the protection of argon, add 300ml of chloroform into the reaction bottle, cool down to -5~0℃, add 10ml (0.034mol) of (R)-2-methyl-CBS-oxazoborane, borane dimethyl sulfide Ether complex 30ml (0.5mol), stirred for 30min; controlled 5 ~ 10 ℃ dropwise containing chloroform solution containing 65g (0.162mol) of the compound of formula (Ⅲ); after dropping, stirred and reacted for 1h at 5 ~ 10 ℃, the reaction was complete ; Cool down to -5~0°C, add methanol dropwise, stir for 30 minutes, add 1mol / L sulfuric acid, and stir for 30 minutes. Stand for stratification, collect the organic phase; wash the organic phase with 1mol / L sulfuric acid, 5% sodium bicarbonate solution and purified water successively, add anhydrous magnesium sulfate to the obtained organic phase, dry, filter, and concentrate the filtrate to dryness under reduced pressure 63.5 g of the crude product was obtained, and...

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Abstract

The present invention relates to a method for synthesizing an anacetrapib intermediate (1R,2S)-1-(3,5-bis(trifluoromethyl)phenyl)-2-Boc-amino-propanol. The method comprises: adding (R)-2-methyl-CBS-oxazaborolidine and a borane-dimethyl sulfide complex to 1-(3,5-bis(trifluoromethyl)phenyl)-2-Boc-amino-acetone in a certain solvent at a certain temperature, and carrying out a reducing reaction. According to the present invention, the chiral catalytic reaction does not use the expensive metallic ruthenium catalyst, the catalytic selectivity is high, the reaction condition is mild, the product is single, the obtained intermediate has the high optical purity and the high yield, the production cost is low, and the method is environment is environmentally friendly, and is suitable for Industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a method for synthesizing a chiral intermediate of anseltrapib. Background technique [0002] Cardiovascular and cerebrovascular diseases have become one of the main causes of death in developed countries and my country's urban and rural population, and atherosclerosis is the main pathological basis of cardiovascular and cerebrovascular diseases. Systematic etiology studies have shown that atherosclerosis is a pathological development process. The main pathogenic factors are hyperlipidemia and lipoprotein metabolism disorders. Cholesterol ester transfer protein (CETP) promotes lipid exchange and transport between plasma lipoproteins in plasma. The result of high expression of CETP is that the amount of cholesterol ester of high-density lipoprotein (HDL-C) decreases, and the amount of cholesterol ester of very low-density lipoprotein and low-density lipoprotein (VLDL-...

Claims

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Application Information

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IPC IPC(8): C07C269/06C07C269/08C07C271/16C07B53/00B01J31/22
CPCB01J31/226B01J2231/643C07B53/00C07B2200/07C07C269/06C07C269/08C07C271/16
Inventor 张贵民臧超许建国夏明军
Owner LUNAN PHARMA GROUP CORPORATION
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