Aldehyde group compounds, as well as preparation method and application thereof

A technology of compounds, aldehyde groups, applied in the fields of medicinal chemistry and pharmacotherapeutics

Active Publication Date: 2017-07-07
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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  • Aldehyde group compounds, as well as preparation method and application thereof
  • Aldehyde group compounds, as well as preparation method and application thereof
  • Aldehyde group compounds, as well as preparation method and application thereof

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preparation example Construction

[0090] The preparation of formula (I) compound

[0091] The present invention also provides a synthetic method for a compound of general formula I, specifically, said compound of formula I is prepared by the following processes:

[0092]

[0093] Step a: Dissolve dimethyl tert-butoxycarbonyl glutamate in a solvent, add alkali at -78°C and stir, then add bromoacetonitrile, and continue stirring to obtain compound I a , the solvent is tetrahydrofuran or dioxane; the base is lithium hexamethyldisilazide or lithium diisopropylamide;

[0094] Step b: put I a Dissolve in a solvent, add a catalytic amount of platinum dioxide, stir until the raw materials are completely reacted, filter, add alkali, and stir under reflux to obtain compound I b ; The alkali is sodium carbonate or sodium acetate; The solvent is a mixed solvent of methanol and chloroform;

[0095] Step c: put I b Dissolve in the solvent, stir until the reaction is complete, and spin the solvent to obtain compound I...

Embodiment 1

[0121] Embodiment 1: the synthesis of compound 1

[0122]

[0123] synthetic route:

[0124]

[0125] Synthesis of Compound 1-3:

[0126] Under the protection of argon, N-tert-butoxycarbonyl-L-glutamic acid dimethyl ester (1-1) (6 g, 21.8 mmol) was dissolved in 60 mL of anhydrous tetrahydrofuran, and LiHMDS ( 1M in THF) in tetrahydrofuran (47mL, 47mmol), the temperature was kept stable at -78°C during the dropwise addition for about 1 hour. After the dropping, the mixture was stirred at -78°C for 1 hour. Bromoacetonitrile (2.79 g, 23.3 mmol) was dissolved in 20 ml of tetrahydrofuran, and then the solution was slowly dropped into the reaction system, and the dropping process lasted for 1 to 2 hours. The temperature was controlled at -78°C, and the reaction was continued for 20 hours. THL monitoring (alkaline potassium permanganate color development) After the reaction is complete, add 3 mL of methanol and 22.7 mL of a mixed solution of glacial acetic acid and tetrahyd...

Embodiment 2

[0149] Embodiment 2: the synthesis of compound 2

[0150]

[0151] Compound 1-11 was used to replace acid 1-13 in Example 1, and the synthesis method was referred to the synthesis of compound 1 to obtain compound 2. 1 H NMR (400MHz, CDCl3): δ9.32-9.26(m,1H),7.81(m,1H),7.54-7.18(m,8H),7.13-6.91(m,1H),6.44-6.08(m, 1H),5.15-4.90(m,1H),4.65(m,2H),4.47-4.04(m,2H),3.45-3.03(m,4H),2.54-2.30(m,1H),2.24-2.16( m,1H),2.12-1.54(m,3H).ESI-MSm / z 496.15[M+H] + .

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Abstract

The invention relates to the fields of medicinal chemistry and pharmacotherapeutics, in particular to compounds of a general formula (I), whichserve as an enterovirus protease inhibitor. The compounds have remarkable inhibition activity on coronavirus [SRAS (severe acute respiratory syndromes)] main proteinase and can be used for treating related diseases. The invention also relates to a preparation method of the compounds, a medicinal composition of the compounds, and medicinal salt, enantiomeric form and diastereoisomer as well as racemic compounds. (The formula I is as shown in the description).

Description

technical field [0001] The present invention relates to the fields of medicinal chemistry and pharmacotherapeutics, in particular to aldehyde-based compounds used as enterovirus protease or coronavirus main protease inhibitors, their preparation methods, pharmaceutical compositions containing such compounds and uses. Background technique [0002] Infectious diseases caused by enteroviruses are more common in children. Its clinical features are fatigue, fatigue, and low-grade fever in mild patients. In severe patients, systemic infection can damage the brain, heart, liver, spinal cord and other important organs. The prognosis is poor and there are sequelae. These diseases are distributed all over the world, and the incidence is high in humid, warm, poor sanitation and densely populated areas. Some virus infections often occur in epidemics, and the epidemics in different years can be caused by different types of viruses, and the epidemics of some virus infections are periodic...

Claims

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Application Information

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IPC IPC(8): C07D405/12C07D413/12C07D403/12C07D401/12C07D471/04C07D409/12A61K31/4025A61K31/422A61K31/403A61K31/4155A61K31/4439A61K31/437A61K31/498A61K31/416A61K31/4184A61K31/4709A61P31/12A61P31/14A61P1/00A61P11/00A61P17/00A61P25/00
CPCC07D401/12C07D403/12C07D405/12C07D409/12C07D413/12C07D471/04A61K31/4025
Inventor 柳红年永李建饶福·希尔根菲尔德林岱宗刘海龙周宇蒋华良陈凯先
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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