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A kind of synthesis method of p53-mdm2 binding inhibitor dihydroxyisoquinoline derivative

A compound and alkyl technology, applied in the field of organic synthesis, can solve the problems of high cost and increased synthesis cost, and achieve the effects of convenient post-processing, easy operation and high yield

Active Publication Date: 2017-05-10
SHANGHAI HAOYUAN MEDCHEMEXPRESS CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This synthetic route needs to use the high-cost compound 9-2 preferentially, which greatly increases the synthetic cost of compound 10

Method used

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  • A kind of synthesis method of p53-mdm2 binding inhibitor dihydroxyisoquinoline derivative
  • A kind of synthesis method of p53-mdm2 binding inhibitor dihydroxyisoquinoline derivative
  • A kind of synthesis method of p53-mdm2 binding inhibitor dihydroxyisoquinoline derivative

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] The preparation of embodiment 1 compound 13

[0066]

[0067] Dissolve compound 1 (100g, 774.0mmol) in ethanol (1.5L), add N-tert-butoxycarbonyl-(methylamino)acetaldehyde (134.06g, 774.0mmol), stir for 10 minutes, add acetic acid (14.0g, 232.2mmol), stirred at room temperature for 1 hour, cooled to 0°C and added sodium triacetoxyborohydride (328.1g, 1548.0mmol), and slowly raised to room temperature for 20 hours. Concentrate the reaction solution and dissolve it with dichloromethane (800mL), add water (800mL) and stir, separate the layers, and wash the aqueous phase with dichloromethane (800mL×2). The resulting aqueous phase was adjusted to pH=8-9 with sodium carbonate, extracted by adding dichloromethane (800mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give brown oil 13 (210g, purity 85% , yield 80.5%).

[0068] 1 H NMR (400MHz, CDCl 3 ):δ3.48-3.43(d,2H,J=6.4Hz),3.40-3.25(m,2H),2.87(s,3H),2.86-2.72(m...

Embodiment 2

[0069] The preparation of embodiment 2 compound 14

[0070]

[0071] Potassium carbonate (171.12g, 1.24mol) was added to compound 13 (209g, 85%, 620.0mmol) in acetonitrile (1.8L) solution, after stirring for 40 minutes, methyl bromoacetate (94.84g, 620.0mmol) was added and Potassium iodide (2.06 g, 12.4 mmol), stirred overnight at room temperature until the reaction of detection compound 13 was complete. The reaction solution was filtered, concentrated, and separated by column chromatography (dichloromethane:methanol=50:1) to obtain light yellow oil 14 (206.0 g, yield 92.7%).

[0072] 1 H NMR (400MHz, CDCl 3 ):δ3.69(s,3H),3.45-3.42(d,2H, J=6.0Hz),3.38(s,2H),3.24-3.22(m,2H),2.87(s,3H),2.73( m,2H),2.59-2.51(m,1H),1.91-1.79(m,4H),1.44(s,9H),1.36-1.32(m,1H),1.23-1.12(m,2H),1.04- 0.90(m,2H).

Embodiment 3

[0073] The preparation of embodiment 3 compound 15

[0074]

[0075] Dimethyl sulfoxide (8.7 g, 111.7 mmol) was slowly added dropwise to a solution of oxalyl chloride (8.66 mL, 101.5 mmol) in dichloromethane (100 mL) at -60°C. After stirring for 0.5 hours, dichloromethane (50 mL) of compound 14 (18.2 g, 50.8 mmol) was added dropwise to the reaction solution, and the temperature of the reaction system was kept at -65 ° C. After stirring for 1 hour, dichloromethane was added at -60 ° C Isopropylethylamine (39 mL, 223.4 mmol), the reaction system was slowly raised to room temperature within 5 hours, and continued to stir overnight. Wash the reaction solution with 10% citric acid, extract with dichloromethane (200 mL), combine the organic phases, and wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and column chromatography (petroleum ether: ethyl acetate=10 : 1) Separation and concentration gave light brown oily compound 15 (17.2 g, yield 95%...

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Abstract

The invention discloses a synthetic method for preparing a non-peptide p53-MDM2-binding inhibitor dyhydroxyl quinoline derivative. The method comprises the following steps of: carrying out reductive amination on a compound 1 and a compound 2 to obtain a compound 3; and carrying out substitution, oxidization, reductive amination and deprotection amidation reaction to prepare a compound I. The synthetic method adopts a brand-new synthesis route, is simple and convenient to operate, high in yield, good in safety, environmentally-friendly, low in cost, and beneficial for technical production. FORMULA as shown in the specification.

Description

technical field [0001] The invention relates to a synthetic method for preparing a class of non-peptide p53-MDM2 binding inhibitor dihydroxyisoquinoline derivatives, which belongs to the field of organic synthesis. Background technique [0002] The p53 protein is one of the tumor suppressor proteins most relevant to human malignant tumors, and it refers to all genes named TP53, p53, TP73, p73, TP63, TP73L, p63 and / or their encoded proteins. Strict regulation of p53 is necessary for the survival of mammalian cells. Excessive expression or inappropriate activation of p53 leads to cell death, while reduced expression or inactivation leads to tumorigenesis. Under stress conditions such as DNA damage, hypoxemia, heat shock, RNA depletion or metabolic changes, the p53 tumor suppressor protein is activated, leading to cell growth arrest and apoptosis directly or indirectly through other transcription factors. The p53 protein is controlled by its negative feedback regulatory protei...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 夏军伟郇恒桥王业发周治国高强郑保富
Owner SHANGHAI HAOYUAN MEDCHEMEXPRESS CO LTD
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