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Preparation method of sacubitril

A technique of sacubiqu and preparation steps, which is applied in the field of preparation of neprilysin inhibitor sacubiqu, can solve problems such as difficult industrialization, difficult industrialization, and numerous reaction steps, and achieves environmentally friendly, economical and simple process , the effect of promoting development

Active Publication Date: 2015-04-29
广州博览咨询服务有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Although there are certain differences in the use of starting materials, the method of forming chirality and the sequence of unit reactions in the synthetic routes of the above two documents, there are difficulties in obtaining chiral raw materials, numerous reaction steps, and chiral catalytic reduction. The disadvantages of expensive catalysts and repeated use of carboxyl or aminobutyl for protection and deprotection make it difficult to successfully realize the industrialization of the above synthetic route
[0010] It can be seen from this that, on the one hand, the existing preparation scheme does not solve the preparation of the chiral amino group of the target compound well;

Method used

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  • Preparation method of sacubitril

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Under nitrogen atmosphere at 0-5°C, (4S,1'R)-4,5-dihydro-2-(1-methyl-3-butenyl)-4-(1-methylethyl) Oxazole (16.7g, 0.1mol) was added in hydrochloric acid (10%w / w, 250mL), heated to boiling water, stirred for 3 hours, cooled to room temperature, extracted three times with dichloromethane, recovered solvent under normal pressure, and reduced Pressure distillation afforded 2R-methyl-4-ene-pentanoic acid as a yellow liquid. The obtained yellow oil was dissolved in 250 mL of dichloromethane, cooled to -78°C, and ozone was introduced, the color of the solution gradually changed to dark green, and the reaction ended after about 15 minutes. Use nitrogen to remove excess ozone, raise to room temperature, wash with 5% sodium thiosulfate aqueous solution and pure water successively, dry over anhydrous sodium sulfate, recover solvent to obtain light yellow oil 2R-methyl-4-oxo-butanol Acid (III) 7.9g, yield 68.1%; FAB-MSm / z: 117[M+H] + .

Embodiment 2

[0027] Add (S)-1-(α-aminobenzyl)-2-naphthol (II) (7.5g, 30mmol), 2R-methyl-4-oxo-butanoic acid (III) (3.7 g, 31.5mmol) and toluene 100mL, heated up to 40-50°C, stirred and reacted for 36 hours, and TLC detected that the reaction was complete. Cool down and remove insoluble matter by filtration. Concentrate to recover toluene, and the resulting oil is recrystallized with isopropyl ether and dried in vacuo to obtain a white solid (7aR, 9R, 12S)-9-methyl-10-oxo-12-phenyl-7a,8,9,10- Tetrahydro-12H-naphtho[1,2-e]pyrrolecyclo[2,1-b][1,3]oxazine (IV) 7.2g, yield 72.9%; 1H NMR (CDCl 3)δ7.72-765 (m, 2H), 7.35-7.28 (m, 1H), 7.24-7.13 (m, 7H), 7.10 (d, 1H), 5.84 (s, 1H), 5.65-5.54 (m, 1H), 2, 43-2.67(m, 1H), 2.24-2.57(m, 2H), 1.16(d, 3H); FAB-MSm / z: 330[M+H] + .

Embodiment 3

[0029] At room temperature and under a nitrogen atmosphere, add a small amount of bromoethane (initiator), magnesium powder (1.0 g, 40 mmol) and 10 mL of dry tetrahydrofuran into a dry reaction flask. After the reaction is initiated, add 4-bromomethyl-1,1 '-biphenyl (4.92g, 20mmol) in 100mL of dry tetrahydrofuran solution, after the dropwise addition, continue to stir for 3-4 hours to prepare the Grignard reagent (1,1'-biphenyl-4-yl-methyl) bromide magnesium oxide. Cool down to -78°C, add dropwise (7aR,9R,12S)-9-methyl-10-oxo-12-phenyl-7a,8,9,10-tetrahydro-12H-naphtho[1,2 -e] A solution of pyrrocyclo[2,1-b][1,3]oxazine (IV) (4.9g, 15mmol) in 100mL of dry tetrahydrofuran was maintained at the temperature for 2-3 hours, and the reaction was detected by TLC. The reaction was quenched with 50 mL of saturated ammonium chloride, raised to room temperature, extracted three times with dichloromethane, and the organic phases were combined and dried over anhydrous magnesium sulfate. C...

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Abstract

The invention discloses a preparation method of one of components of a novel antihypertensive drug LCZ696, namely, sacubitril (sacubitril, AHU-377, I). The method comprises the following preparation steps: carrying out cyclization, addition, debenzylation, ring opening, esterification, amidation and the like on a chiral induciton reagent (S)-1-(alpha-aminobenzyl)-2-naphthol (S-betti Base) and 2R-methyl-4-oxo-butyric acid to prepare the sacubitril (I). The preparation method is available in raw materials, concise in process, economic and environmentally friendly, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and in particular relates to a preparation method of Sacubitril, an enprilysin inhibitor. Background technique [0002] LCZ696 is a new antihypertensive drug developed by Novartis, which combines Novartis' Diovan (generic name: valsartan) and experimental drug Sacubitril (AHU-377) and other two components Among them, valsartan can improve vasodilation and stimulate the body to excrete sodium and water, while Sacubitri can block the mechanism of action of two polypeptides that threaten to lower blood pressure. Therefore, LCZ696 is called the combination of angiotensin II receptor and enkephalinase. dual inhibitors. The unique mode of action clinically demonstrated, the antihypertensive effect superior to standard drugs, and the efficacy of reducing heart failure have enabled the drug to obtain the fast-track review qualific...

Claims

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Application Information

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IPC IPC(8): C07C233/47C07C231/02
CPCC07C231/02C07C233/47C07C231/22
Inventor 许学农
Owner 广州博览咨询服务有限公司
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