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Processes for the preparation of ahu‑377 intermediates and intermediates and processes for the preparation of intermediates

A technology of AHU-377 and intermediates, applied in the field of medicinal chemistry synthesis, can solve the problems of reduced yield and purity, difficult removal of diastereomers, etc.

Active Publication Date: 2017-10-03
ZHEJIANG YONGNING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

A major disadvantage of the described method is that the hydrogenation step is not very selective, the ratio of the target product to its diastereomer is 80:20, and the diastereomer is not easily removed, resulting in a loss of yield and purity. reduce

Method used

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  • Processes for the preparation of ahu‑377 intermediates and intermediates and processes for the preparation of intermediates
  • Processes for the preparation of ahu‑377 intermediates and intermediates and processes for the preparation of intermediates
  • Processes for the preparation of ahu‑377 intermediates and intermediates and processes for the preparation of intermediates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Synthesis of compound (Ⅲ-a)

[0067]

[0068] Dissolve (R)-4-phenyl-2-oxazolidinone (16.3g, 1 equivalent) in 180ml of dichloromethane, add triethylamine (15.2g, 1.5 equivalent) under stirring in an ice bath at 0°C, and 4- Dimethylaminopyridine (DMAP) (366 mg, 0.03 equivalents), then added propionyl chloride (9.2 g, 1 equivalents) dropwise, kept stirring at 0°C for 1 hour, diluted with dichloromethane, washed with water, washed with saturated sodium bicarbonate, organic The phase was dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain the target compound (Ⅲ-a) (20.1 g, yield 92%).

Embodiment 2

[0070] Synthesis of compound (Ⅲ-b)

[0071]

[0072] Dissolve (R)-4-benzyl-2-oxazolidinone (20 g, 1 equivalent) in 200 ml of dichloromethane, add triethylamine (17.1 g, 1.5 equivalents) while stirring in an ice bath at 0°C, and 4-di Aminopyridine (414 mg, 0.03 eq), then propionyl chloride (10.4 g, 1 eq) was added dropwise, kept stirring at 0°C for 1 hour, diluted with dichloromethane, washed with water, washed with saturated sodium bicarbonate, and the organic phase was washed with anhydrous Na2SO4 dried. The solvent was removed by evaporation under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain the target compound (Ⅲ-b) (24.3 g, yield 93%).

Embodiment 3

[0074] Synthesis of compound (Ⅲ-c)

[0075]

[0076] Dissolve (R)-4-isopropyl-2-oxazolidinone (14.3 g, 1 equivalent) in 150 ml of dichloromethane, and add triethylamine (15.2 g, 1.5 equivalents) under stirring in an ice bath at 0° C., 4 -Dimethylaminopyridine (366mg, 0.03 equivalents), then added propionyl chloride (9.2g, 1 equivalents) dropwise, kept stirring at 0°C for 1 hour, diluted with dichloromethane, washed with water, washed with saturated sodium bicarbonate, and the organic phase was washed with Dry over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain the target compound (Ⅲ-c) (18.3 g, yield 92%).

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Abstract

The invention relates to the field of medicinal chemical synthesis, in particular to a preparation method of an AHU-377 intermediate and the preparation method of the intermediate and the intermediate. The preparation method of the AHU-377 intermediate represented by the formula (I), the method comprises the compound represented by the formula (II) and the compound represented by the formula (III) through a substitution reaction and then hydrolyzed to prepare the compound represented by the formula (I). The intermediate of AHU-377, the hydrolysis reaction is carried out in the presence of hydrogen peroxide and hydrated lithium hydroxide: another object of the present invention is to provide a new compound, the structure is shown in formula (II): The present invention In the new route, since the compound of formula (II) and the compound of formula (III) are used to prepare a new compound of formula (IV), the selectivity is very good, and the diastereomers generated during the reaction are These very small amounts of diastereomers can be removed by simple post-treatment.

Description

technical field [0001] The invention relates to the field of chemical synthesis of medicines, in particular to a preparation method of an AHU-377 intermediate, an intermediate, and a preparation method of the intermediate. Background technique [0002] LCZ696 is a dual-acting angiotensin receptor neprilysin inhibitor developed by Novartis, which was approved by the FDA on July 7, 2015, and developed for the treatment of patients with heart failure with reduced ejection fraction (HFrEF). LCZ696, a complex of AHU-377 and Novartis' high blood pressure drug Diovan (generic name: valsartan), has a unique mode of action thought to reduce strain on failing hearts, where AHU-377 blocks the threatening The mechanism of action of the 2 peptides responsible for lowering blood pressure, Diovan improves vasodilation and stimulates the body to excrete sodium and water. [0003] AHU-377 is a prodrug whose chemical name is: 4-(((2S,4R)-1-([1,1'-diphenyl]-4-yl)-5-ethoxy- 4-Methyl-5-oxo-2-p...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C271/16C07C269/06C07C309/66C07C303/28C07D263/26
Inventor 叶天健陆修伟郁光亮刘婷
Owner ZHEJIANG YONGNING PHARMA
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