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A kind of preparation method of Shakubiqu

A technology of Shakubitqu and compounds, which is applied in the field of preparation of Shakubitqu, can solve the problems of difficult source of starting raw materials, inapplicability to industrial production, etc.

Active Publication Date: 2021-06-08
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] The route (S)-1-(α-aminobenzyl)-2-naphine and 2R-methyl 4-oxo-butanoic acid are starting materials, through cyclization reaction, Grignard reagent addition reaction, benzyl A total of six steps including group removal reaction, ring-opening reaction, esterification reaction and amidation reaction to obtain the target compound. Although there are fewer reaction steps in this route, the source of starting materials in this route is difficult, and it is not suitable for industrial production.

Method used

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  • A kind of preparation method of Shakubiqu
  • A kind of preparation method of Shakubiqu
  • A kind of preparation method of Shakubiqu

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0094] Embodiment 1: the preparation of formula 1 compound

[0095] Step A: Preparation of compounds of formula 1-2:

[0096]

[0097] LiAlH 4 (1.1eq) was dissolved in anhydrous THF, and under ice-bath conditions, the THF solution of the compound of formula 1-1 (biphenyl-4-carboxylic acid, 1.0eq) was slowly added. hour, end the reaction, add 15% NaOH solution to quench the reaction, the resulting mixed solution is extracted with ethyl acetate, the organic phases are combined, dried, filtered, concentrated and then column chromatographed to obtain white flaky crystals, which are formula 1-2 Compound, yield 70%.

[0098] Tested: 1 H NMR (400MHz, CDCl 3 ): δ7.59-7.55(m, 4H), 7.46-7.42(m, 2H), 7.36-7.31(m, 3H), 3.91(q, J=8.0Hz, 2H), 2.92(t, J=8.0 Hz, 2H), 1.48 (t, J = 4.0Hz, 1H).

[0099] Step B: Preparation of compounds of formula 1-3:

[0100]

[0101] Dissolve the compound of formula 1-2 (1.0eq) in dichloromethane, and slowly add Dess-Martin oxidant (2.5eq) under i...

Embodiment 2

[0123] Embodiment 2: the preparation of formula 3 compound

[0124]

[0125] Dissolve the compound of formula 1 (1.0eq) in THF, under the condition of ice bath, add the compound of formula 2 (succinimide, 3.0eq) and PPh3 (3.0eq), stir evenly, slowly add DIAD (3.0eq) dropwise , reacted at room temperature for 12 hours, ended the reaction, added water to quench the reaction, extracted the reaction solution with ethyl acetate, combined the organic phases, dried the organic phases with anhydrous sodium sulfate, filtered, and concentrated to obtain the compound of formula 3, which was directly used in Next reaction.

Embodiment 3

[0126] Embodiment 3: the preparation of formula 4 compound

[0127]

[0128] Dissolve the compound of formula 3 (1.0eq) in THF, add TBAF solution (1.0M in THF, 2.0eq), stir the reaction at room temperature for 12 hours, end the reaction, add saturated ammonium chloride to quench the reaction, and the reaction solution is washed with ethyl acetate Extract, combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography to obtain the compound of formula 4 with a two-step yield of 80%.

[0129] Tested: 1 H NMR (400MHz, CDCl 3 ):δ7.56-7.47(m,4H),7.42-7.39(m,2H),7.33-7.20(m,3H),4.59-4.55(m,1H),3.31-3.25(m,1H),3.07 -3.02 (m, 1H), 2.72-2.26 (m, 8H), 2.15-2.02 (m, 1H), 1.23 (d, J=8.0Hz, 3H).

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Abstract

The invention discloses a preparation method of Shakubitqu, comprising steps a to e in the following synthetic route: wherein R is a hydroxyl protecting group. In the present invention, the readily available compound of formula 1 and formula 2 is used as the starting material, and the Shakubiqu described in the present invention can be prepared through 5 steps of reaction. The whole route is simple to operate, safe and pollution-free, and has no special requirements for equipment , low production cost, high yield, suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of sacubitril, which belongs to the technical field of chemical drug synthesis. Background technique [0002] Heart failure is a life-threatening debilitating disease. The blood pumped by the patient's heart is insufficient to supply the whole body, resulting in the slow emergence of symptoms such as dyspnea, fatigue and fluid retention, which may affect the quality of life in severe cases. Entresto (also known as LCZ696), pioneered by Novartis, combines the angiotensin IIAT1 receptor antagonist valsartan (Diovan) and the neprilysin receptor inhibitor sacubitril (Sacubitril, Also known as AHU-377), it can enhance the body's natural defense against heart failure, increase the levels of natriuretic peptides and other endogenous vasoactive peptides, and inhibit the renin-angiotensin-aldosterone system (RAAS), Thought to reduce the strain on a failing heart. In view of the higher safety and better efficacy of...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C231/10C07C233/47
CPCC07C29/147C07C45/30C07C67/343C07C231/10C07D207/404C07D307/58C07F7/188C07C233/47C07C33/20C07C47/228C07C69/732C07C33/26Y02P20/55
Inventor 张国柱张瀚文陈斌许美晨李善勇
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI