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A kind of synthetic method for the key intermediate of synthetic bet protein inhibitor

A synthesis method and reagent technology, which are applied in the field of synthesis of key intermediates used to synthesize BET protein inhibitors, can solve the problems of cumbersome purification, harsh reaction conditions, and low yields, and achieve simple reaction operations, convenient post-processing, The effect of increasing selectivity

Active Publication Date: 2017-10-13
SHANGHAI HAOYUAN MEDCHEMEXPRESS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In summary, currently reported BET protein inhibitors 5-aryltriazoloazepine The synthetic route of the key intermediate II of derivative I has harsh reaction conditions, low yield, cumbersome purification and other factors that restrict its scale-up production

Method used

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  • A kind of synthetic method for the key intermediate of synthetic bet protein inhibitor
  • A kind of synthetic method for the key intermediate of synthetic bet protein inhibitor
  • A kind of synthetic method for the key intermediate of synthetic bet protein inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Embodiment 1: the preparation of compound 6

[0044]

[0045] Compound 5 (700g, 3.66mol) was dissolved in DMAC (7L), potassium carbonate (1kg, 7.32mol) was added, and methyl iodide (230ml) was slowly added dropwise under ice-water bath conditions. After the dropwise addition, the reaction system was raised to Stir overnight at room temperature. After the reaction was detected by TLC, the reaction solution was filtered and added to EA, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 2.5 kg of a yellow solid crude product, which was directly carried out to the next step without purification.

[0046] 1 H NMR (400MHz, CDCl 3 ):δ7.80-7.75(m,1H),7.55-7.49(m,1H),7.21-7.14(m,2H),3.00-2.94(m,2H),2.77-2.72(m,2H),2.48 (s,3H).

Embodiment 2

[0047] Embodiment 2: the preparation of compound 7

[0048]

[0049] Dissolve compound 6 obtained in the previous step in ethanol (7.5 L), add acetylhydrazide (820 g), and stir at room temperature until the reaction is detected by TLC. A large amount of white solids are precipitated from the reaction system. After the reaction solution is filtered, the filter cake is washed with ethanol successively. , ether, and vacuum-dried to obtain white solid compound 7 (785 g, purity 97%, two-step yield 90%). Without further purification, the next reaction can be carried out directly.

[0050] 1 H-NMR(400MHz,DMSO):δ11.24(s,1H),9.82(s,1H),7.75-7.65(m,1H),7.60-7.45(m,2H),7.15-7.05(m,1H ),2.90-2.80(m,2H),2.75-2.63(m,2H),1.99(s,3H).

Embodiment 3

[0051] Embodiment 3: the preparation of compound 8

[0052]

[0053] Compound 7 obtained in the previous step was dissolved in glacial acetic acid (8 L), and stirred overnight at 100° C., and TLC detected that the reaction of compound 7 was complete. Concentrate the reaction liquid under vacuum conditions, after cooling down to room temperature, add a mixed solvent of methyl tert-butyl ether and petroleum ether, a large amount of light yellow solid precipitates, filter, and recrystallize the obtained filter cake under the condition of isopropanol to obtain the light yellow solid target Compound 8 weighed 553g (purity 99%) after drying the solid, concentrated the crystallization mother liquor, and recrystallized from isopropanol to obtain the light yellow solid target compound 8, weighed 105g (purity 93%) after solid drying , The total yield is 89%.

[0054] 1 H NMR (400MHz, CDCl 3 ):δ7.84-7.80(dd,1H),7.76-7.70(dt,1H),7.59-7.53(dt,1H),7.33-7.28(dd,1H),3.28-3.22(m,2H),3.09...

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Abstract

The invention relates to a method for synthesizing a key intermediate of a BET protein inhibitor, in particular to a synthetic method for the key intermediate of 5-aryl triazoloazepine inhibiting BRD4. The method comprises the steps that a methylation reaction is conducted on a compound 1, condensation and ring closing are conducted, and a compound II is obtained; a preparation method of a compound 4 is changed, and the selectivity of a hydrazide reaction is improved by introducing methylthio; compared with the prior art, the reaction condition of a new route is mild, reaction operation is easy, aftertreatment is simple and convenient, purification is not needed during the process, and the three-step yield is up to 80%; compared with the prior art, a purification method of the compound II is changed, the key intermediate II is purified through a crystallization and recrystallization method, the purity is up to 99%, aftertreatment is simplified, resources are saved, and the cost is reduced. The method for synthesizing the key intermediate of the BET protein inhibitor is a brand new industrialized synthetic route, and the method has good methodology significance in developing a new BET protein inhibitor. Please see the formula in the description.

Description

technical field [0001] The present invention relates to a kind of 5-aryltriazoloazepine used for synthesizing BET protein inhibitor, especially inhibiting BRD4 The synthetic method of the key intermediate of , further speaking is 1-R 2 Substituted-4,5-dihydro-6H-[1,2,4]triazolo[4,3-a][1]benzazepine The synthetic method of -6-ketone, the invention belongs to the field of organic synthesis. Background technique [0002] The BET protein family is the second class of the BRD protein family, including BRD2, BRD3, BRD4, and BRDT. Studies have shown that BET proteins bind to acetylated lysines of histones and regulate the transcription of genes related to the cell cycle and cell growth. The occurrence of many human diseases is closely related to the BET protein. Studies have found that in models of hematopoietic tumors including AML, Burkitt lymphoma, multiple myeloma and B-cell acute lymphoblastic leukemia, by interfering with BRD4 and the oncogene MYC The combination of MYC...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 许维嘉孙昱飞周治国高强郑保富
Owner SHANGHAI HAOYUAN MEDCHEMEXPRESS CO LTD
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