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Preparation method of sacubitril

A technology of sacubitril and compounds, which is applied in the field of preparation of sacubitril and its intermediates and chiral prosthetic groups, can solve the problems of high waste liquid treatment cost, low ratio of diastereoisomers, high production cost, etc. question

Active Publication Date: 2021-09-14
SHENZHEN CATALYS SCI & TECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The chiral auxiliary reported in this patent is the same as the patent CN 105085322, which has the problem of high production cost
At the same time, the subsequent reaction uses reagents such as hydrogen peroxide, which is dangerous in large quantities, and the cost of waste liquid treatment is high
[0015] In summary, in the existing preparation methods, the preparation of sacubitril is limited by raw materials, reaction reagents, post-treatment process, etc. on the one hand, and on the other hand, the synthesis route is long, the ratio of diastereoisomers is low, and the environment Problems such as unfriendliness lead to high production cost, cumbersome operation, and are not conducive to industrialization
Constructing a carbon chiral center through a chiral prosthetic group, the method reported in the current patent still has many problems that are not conducive to industrialization

Method used

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  • Preparation method of sacubitril
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  • Preparation method of sacubitril

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0109] Embodiment 1: Preparation of (1R, 2S, 5R)-2-isopropyl-5-methylcyclohexyl propionate (formula VIa)

[0110]

[0111] Add L-Menthol (20g, formula Xa), DMAP (80mg) in the round bottom flask (100mL), stir at room temperature, then add propionic anhydride (18.3g), continue to stir for 10 hours. Distillation under reduced pressure gave the compound of formula VIa (26.5 g, 98%).

[0112] Tested: 1 H NMR (400MHz, CDCl 3 )δ (ppm) 0.76 (d, J = 7.0Hz, 3H), 0.88 (d, J = 2.2Hz, 3H), 0.92 (d, J = 1.6Hz, 3H), 0.99-1.05 (m, 2H), 1.06-1.10(m,1H),1.14(t,J=7.6Hz,3H),1.35-2.00(m,6H),2.31(q,J=7.6Hz, 2H),4.70(dd,J=10.8, 4.4Hz, 1H).

Embodiment 2

[0113] Example 2: Preparation of (1S, 2R, 5S)-2-isopropyl-5-methylcyclohexyl propionate (formula VIb)

[0114]

[0115] Add D-Menthol (20g, formula Xb), DMAP (80mg) in the round bottom flask (100mL), stir at room temperature, then add propionic anhydride (18.3g), continue to stir for 10 hours. Distillation under reduced pressure gave the compound of formula VIb (26.4 g, 97%).

Embodiment 3

[0116] Embodiment 3: Preparation of (1R, 2S)-2-phenylcyclohexyl propionate (formula VId)

[0117]

[0118] Add (1R,2S)-2-phenylcyclohexyl-1-alcohol (20g, formula Xd), DMAP (80mg) in the round bottom flask (100mL), stir at room temperature, then add propionic anhydride (16g), continue to stir for 10 Hour. Distillation under reduced pressure gave the compound of formula VId (24.2 g, 92%).

[0119] Tested: 1 H NMR (400MHz, CDCl 3 )δ (ppm) 0.85 (t, J = 7.5Hz, 3H), 1.30-1.66 (m, 4H), 1.72-2.10 (m, 6H), 2.66 (dt, J = 4.4, 11.4Hz, 1H), 4.95 (dt, J=4.4, 10.5Hz, 2H), 7.11-7.25 (m, 5H).

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Abstract

The invention discloses a sacubitril, and a method for preparing the sacubitril form sacubitril intermediates and chiral prosthetic groups. The method comprises steps 1-11 in a synthesis route shown in the specification. In the synthesis route, ROH (formula X) is chiral alcohol and an analogue thereof, PG is a hydroxyl protecting group, and a compound of formula VI and a compound of formula V are the chiral prosthetic groups provided by the invention. Cheap and easily available propionic anhydride and chiral alcohol ROH (formula X) are used for preparing chiral prosthetic compounds of formula VI and formula V, high diastereomeric excess sacubitril intermediates of formula XI and formula IV are efficiently prepared through chiral prosthetic groups, and the sacubitril disclosed by the invention can be prepared through three simple operation steps of the formula IV. The whole route is simple in process, safe, environment-friendly, free of special requirements on equipment, low in production cost, high in yield, high in enantiomer selectivity and suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis, and in particular relates to the preparation method of sacubitril (AHU-377) and its intermediate and chiral prosthetic group. The method has short steps, simple operation, efficient construction of a chiral carbon center by induction of a chiral auxiliary group, low cost, and great industrial application value. Background technique [0002] Sacubitril (AHU-377), chemical name: (2R,4S)-5-(biphenyl-4-yl)-4-[(3-carboxypropionyl)amino]-2-methylpentanoic acid Ethyl ester, CAS: 149709-62-6, molecular formula: C24H29NO5, molecular weight: 411.49, structural formula: [0003] [0004] Sacubitril (AHU-377) is one of the main components of LCZ696 (CAS: 936623-90-4), an anti-heart failure drug developed by Novartis. The drug is a supramolecular complex (complex) formed by non-covalent bonding of valsartan and AHU-377, which has dual effects of angiotensin receptor blocking and neutral e...

Claims

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Application Information

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IPC IPC(8): C07C233/47C07C231/10C07D207/404C07C67/08C07C69/24C07D453/02C07F7/18C07C67/31C07C69/732
CPCC07C231/10C07D207/404C07C67/08C07D453/02C07F7/1804C07F7/188C07C67/31C07B2200/07C07C2601/14C07C2603/74C07C233/47C07C69/24C07C69/732Y02P20/55
Inventor 郑勇鹏赵金辉
Owner SHENZHEN CATALYS SCI & TECH CO LTD
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