Synthesis method of key intermediate of anacetrapib

A technology of anseltrapib and synthetic methods, applied in the direction of organic chemistry, etc., can solve problems such as difficult to meet cholesterol ester transfer protein, and achieve the effect of improving drug purity, high selectivity, and low production cost

Inactive Publication Date: 2014-07-16
汕头经济特区鮀滨制药厂
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  • Abstract
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Problems solved by technology

[0016] From the above, the current existing technology is not easy to meet the preparation of high-purity synthetic cholesteryl ester transfer protein (CETP) inhibitors such as anacetrapib (Anacetrapib) intermediates, so it is necessary to develop a new technology to overcome the above shortcomings

Method used

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  • Synthesis method of key intermediate of anacetrapib
  • Synthesis method of key intermediate of anacetrapib
  • Synthesis method of key intermediate of anacetrapib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Step a:

[0050]

[0051] Ph 3 Preparation of PEtBr

[0052] Triphenylphosphine (200g, 0.76mol), dissolved in toluene (600mL), added bromoethane (200mL, 2.66mol), then stirred and reacted at 70°C for 48 hours, the resulting solid was washed with petroleum ether, and dried in vacuo to obtain a white Solid (240g, 85%);

[0053] Preparation of I-2

[0054] Weigh the above-prepared triphenylethylphosphine bromide (74.25g, 0.20mol) and dissolve it in 375mL of anhydrous tetrahydrofuran, cool to 0°C, add potassium tert-butoxide (24g, 0.21mol) to avoid violent exotherm. Inverted at room temperature and stirred for 0.5 hours to obtain a dark red solution. Add 250 mL of anhydrous THF solution containing 3,5-bis(trifluoromethyl)benzaldehyde (I-1) (36.3 g, 0.15 mol) dropwise under stirring. 40 minutes. Under cooling, the reaction was quenched with 200 mL of water until the reaction did not exotherm violently. Extracted with 500 mL×3 ethyl acetate, combined the organic lay...

Embodiment 2

[0084] Step a:

[0085]

[0086] Ph 3 Preparation of PEtBr

[0087] Triphenylphosphine (150g, 0.57mol), dissolved in toluene (450mL), added bromoethane (150mL, 2.0mol), then stirred and reacted at 70°C for 48 hours, the resulting solid was washed with petroleum ether, and dried under vacuum to obtain a white Solid (200g, 94%);

[0088] Preparation of I-2

[0089] Weigh the above-prepared triphenylethylphosphine bromide (37.1g, 0.10mol) and dissolve it in 200mL of anhydrous tetrahydrofuran, cool to 0°C, add potassium tert-butoxide (13.5g, 0.12mol) to avoid violent exotherm . Inverted at room temperature and stirred for 50 minutes to obtain a dark red solution. Add dropwise 121 mL of anhydrous THF solution containing 3,5-bis(trifluoromethyl)benzaldehyde (I-1) (24.2 g, 0.10 mol) under stirring. 30 minutes. Under cooling, the reaction was quenched with 150 mL of water until the reaction was not exothermic violently. Extract with 200 mL×3 ethyl acetate, combine the organ...

Embodiment 3

[0114] Step a:

[0115]

[0116] Ph 3 Preparation of PEtBr

[0117] Triphenylphosphine (300g, 1.14mol), dissolved in toluene (900mL), added bromoethane (300mL, 4.0mol), then stirred and reacted at 70°C for 48 hours, the resulting solid was washed with petroleum ether, and dried in vacuo to obtain a white Solid (370g, 87%);

[0118] Preparation of I-2

[0119] Weigh the above-prepared triphenylethylphosphine bromide (74.25g, 0.20mol) and dissolve it in 1100mL of anhydrous tetrahydrofuran, cool to 5°C, add potassium tert-butoxide (29g, 0.26mol) to avoid violent exotherm. Inverted at room temperature and stirred for 1.0 hour to obtain a dark red solution. Add dropwise 322 mL of anhydrous tetrahydrofuran solution containing 3,5-bis(trifluoromethyl)benzaldehyde (I-1) (32.2 g, 0.133 mol) under stirring. 60 minutes. Under cooling, the reaction was quenched with 200 mL of water until the reaction did not exotherm violently. Extracted with 500 mL×3 ethyl acetate, combined the...

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Abstract

The invention discloses a synthesis method of a key intermediate of anacetrapib. The synthesis method comprises the steps: making 3,5-bi(trifluoromethyl) benzaldehyde as a raw material perform a witting reaction with ethyltriphenylphosphonium bromide to obtain a mixture, performing inversion of configuration on the mixture under the illumination in the presence of an iodine elementary substance of a catalytic amount to obtain a transform product (I-2); performing Shi-dissymmetry epoxidation on the transform product (I-2) to obtain a compound (I-3); performing hydrolysis and ring opening on the compound (I-3) under an acidic condition, and then reacting under an alkaline condition to obtain a transform product (I-4); substituting the compound (I-4) by sodium azide, and performing inversion of configuration, performing hydrogenation reduction in the presence of Pd / C into an amino group, salifying with a feasible acid to obtain a compound (I-5); and performing ring closing on the compound (I-5) and triphosgene to obtain the key intermediate of anacetrapib. The synthesis method has the advantages of simplicity in operation, availability in raw materials, no need of purification of the intermediate, high yield, and environmental friendliness, and is easy to post-process, and suitable for large-scale production.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, in particular to a method for synthesizing anacetrapib and its intermediates. Background technique [0002] Ancetrapib, English name: Anacetrapib, chemical name is (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[[2-(4-fluoro-2- Methoxy-5-propan-2-ylphenyl)-5-(trifluoromethyl)phenyl]methyl]-4-methyl-1,3-oxazolidin-2-one), (CAS No: 875446-37-0), molecular formula: C 30 h 25 f 10 NO 3 , molecular weight: 637.51, the structural formula is as follows: [0003] [0004] Anacetrapib (Anacetrapib) is an orally effective small-molecule oxazolidinone selective CETP inhibitor developed by Merck & Co. for the treatment of atherosclerosis and coronary heart disease. Clinical studies on healthy volunteers and patients with hyperlipidemia have shown that Anacetrapib can safely and effectively regulate lipid levels in patients with coronary heart disease and high-risk patients with coronary hea...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D263/22
CPCC07D263/22
Inventor 冯汝洁吴毅武贝荣丙陈海龙施涯邻
Owner 汕头经济特区鮀滨制药厂
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