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Preparation method and intermediate of AHU-377 intermediate and preparation method of intermediate

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

Active Publication Date: 2015-11-25
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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  • Preparation method and intermediate of AHU-377 intermediate and preparation method of intermediate

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 chemical synthesis of medicines and in particular relates to a preparation method and intermediate of an AHU-377 intermediate and a preparation method of the intermediate. The preparation method of the AHU-377 intermediate shown in a formula (I) in the description comprises the following steps: performing a substitution reaction on a compound shown in a formula (II) in the description and a compound shown in a formula (III) in the description and then carrying out hydrolysis to prepare the AHU-377 intermediate shown in the formula (I), wherein the hydrolysis reaction is carried out in the presence of hydrogen peroxide and lithium hydroxide hydrate. The invention also aims to provide a new compound with a structure shown in the formula (II). In the new route, as a new compound shown in a formula (IV) in the description is prepared through reaction of the compound in the formula (II) and the compound in the formula (III), the selectivity is quite good, and a few diastereoisomers are generated in the reaction process and can be removed only through simple aftertreatment.

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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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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