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A kind of preparation method of nep inhibitor intermediate

An intermediate and inhibitor technology, applied in the field of industrial production and preparation, can solve the problems of expensive reagents, unfavorable industrial scale-up production, and difficulty in ligand synthesis.

Active Publication Date: 2017-03-15
苏州楚凯药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this method increases the ratio of diastereoisomers, the synthesis of ligands is difficult, the reagents are relatively expensive, and industrial scale-up production is not used.

Method used

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  • A kind of preparation method of nep inhibitor intermediate
  • A kind of preparation method of nep inhibitor intermediate
  • A kind of preparation method of nep inhibitor intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1: Add (R,E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methanol to the autoclave in sequence Base-2-pentenoic acid 381g, ethanol 3.5kg, bis(dicyclopentadiene) rhodium tetrafluoroborate 99mg and phosphine ligand CK-01 221mg, replace hydrogen, pressure 15 kg, temperature 40 ℃, stir until LC control After the reaction was complete, it was filtered, and the filtrate was spin-dried to obtain the crude product. The two isomers II:III=82:18 were analyzed by chiral analysis. The crude product was washed with ethyl acetate and petroleum ether, and then recrystallized with ethanol to obtain the product (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxy Carbonyl)amino)-2-methylpentanoic acid 307g.

[0039]

Embodiment 2

[0040] Example 2: Add (R,E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methanol to the autoclave in sequence Base-2-pentenoic acid 381g, ethanol 3.5kg, bis(dicyclopentadiene) rhodium tetrafluoroborate 99mg and phosphine ligand CK-02 230mg, replace hydrogen, pressure 15 kg, temperature 40 ℃, stir until LC control After the reaction was complete, it was filtered, and the filtrate was spin-dried to obtain the crude product. The two isomers II:III=85:15 were analyzed by chiral analysis. The crude product was slurried with ethyl acetate and petroleum ether, then recrystallized with ethanol, and the crude product was slurried with ethyl acetate and petroleum ether to obtain the product (2R,4S)-5-([1,1'-biphenyl]-4- Base)-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid 280g.

[0041]

Embodiment 3

[0042] Example 3: Add (R,E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methanol to the autoclave in sequence Base-2-pentenoic acid 381g, ethanol 3.5kg, bis(dicyclopentadiene) rhodium tetrafluoroborate 99mg and phosphine ligand CK-04 279mg, replace hydrogen, pressure 15 kg, temperature 40 ℃, stir until LC control After the reaction was complete, it was filtered, and the filtrate was spin-dried to obtain the crude product. The two isomers II:III=90:10 were analyzed by chiral analysis. The crude product was slurried with ethyl acetate and petroleum ether, and then recrystallized with ethanol, and the crude product was slurried with ethyl acetate and petroleum ether to obtain the product (2R,4S)-5-([1,1'-biphenyl]-4- Base)-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid 340g.

[0043]

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Abstract

The invention discloses a preparation method of an NEP (neutral endopeptidase) inhibitor intermediate, further discloses a selective reduction preparation method of the NEP inhibitor intermediate (2R, 4S)-5-([1,1'-biphenyl]-4-yl)-4-((t-butyloxycarboryl)amino)-2-methylpentanoic acid in presence of a chiral ligand, and particularly discloses a diastereoselective hydrogenation synthetic method with hydrogen under the condition of presence of a transition metal catalyst and the chiral ligand. The metal catalyst used in the method is cheap, the chiral ligand is obtained easily, high yield is realized, a high-purity product is produced preferably, and the product with the proportion of diastereoisomers being 90:10 is produced preferably.

Description

technical field [0001] The present invention relates to a kind of preparation method of NEP inhibitor intermediate, be specifically related to a kind of method that is used in the presence of transition metal catalyst and chiral ligand under the situation of using hydrogen diastereoselective hydrogenation synthesis (2R, 4S)- The industrial production preparation method of 5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid. Background technique [0002] With the acceleration of the pace of modern life and the increase of life pressure, the incidence of cardiovascular diseases is increasing year by year. Hypertension is one of the most common cardiovascular diseases, which leads to congestive heart failure, stroke death, coronary heart disease, The main risk factors for the incidence of renal failure and aortic aneurysm, which seriously threaten human health. Nearly 20 million people die from cardiovascular and cerebrovascular diseases caused by hy...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C269/06C07C271/22B01J31/22
Inventor 刘现军戴益思张中剑余飞飞黄文飞
Owner 苏州楚凯药业有限公司