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Preparation method of 2-(hydroxyl-(methyl cyclopropyl) phenylamino)-1-piperazinyl ethanone derivative

A methylcyclopropyl, phenylamino technology, applied in the field of organic compound synthesis, can solve the problems of heterogeneity of reaction system, low yield, poor atom economy and the like

Active Publication Date: 2020-01-17
SHANGHAI HAOYUAN MEDCHEMEXPRESS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the prior art, the synthesis of ARS-853 is shown in the above formula. Compound 1 is prepared by dehydration, ring formation, and deprotection reactions to obtain compound 4; compound 4 is prepared by two steps of reductive amination and hydrolysis to obtain compound 7. Two steps Although the reaction is a conventional reaction in this field, the yield is very low, only 33%; compound 7 is prepared by coupling reaction with compound 8 and then deprotected to obtain compound 9
WO2014152588 pointed out that compound ARS-853 was prepared from compound 9 to synthesize a similar compound of reference example 17, but the yield of the two-step reaction of deprotection and docking with acryloyl chloride was only 10%. Under the action of boron tribromide at -60°C The yield of demethylation reaction is only 5%. The yields of acryloyl and demethylation on other similar structures in WO2014152588 are very low, and the atom economy is very poor. The total yield from compound 1 to ARS-853 is only 0.5‰
[0007] The inventors will detect a large number of aromatic ring-linked amino-substituted by-products and di-substituted by-products with a molecular weight greater than 54 when repeating the above-mentioned method to prepare compound 12; During deprotection, the reaction system is very heterogeneous, and there are a large number of ring-opening by-products, it is difficult to separate the compound ARS-853

Method used

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  • Preparation method of 2-(hydroxyl-(methyl cyclopropyl) phenylamino)-1-piperazinyl ethanone derivative
  • Preparation method of 2-(hydroxyl-(methyl cyclopropyl) phenylamino)-1-piperazinyl ethanone derivative
  • Preparation method of 2-(hydroxyl-(methyl cyclopropyl) phenylamino)-1-piperazinyl ethanone derivative

Examples

Experimental program
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Embodiment 1

[0099]Example 1 1-(3-(4-(2-((4-chloro-2-hydroxyl-5-(1-methylcyclopropyl)phenyl)amino)acetyl)piperazin-1-yl) Preparation of azetidin-1-yl)prop-2-en-1-one (compound M-1, ARS-853)

[0100]

[0101] The preparation process is shown in the above formula and includes the following steps:

[0102] Step a-1: Dissolve compound A-1 (its synthesis reference is from WO2014152588, 300g, 1.164mol) in dichloromethane (15L), cool down to 0°C, and slowly add boron tribromide (336.5 mL, 3.492mol) of dichloromethane solution (2.5L) was raised to room temperature, and reacted until all the raw materials disappeared under TLC monitoring. Under ice-bath conditions, slowly add MeOH (1.2L) to the reaction solution, then add 8L of water, separate the organic phase, extract the aqueous phase with DCM / MeOH (10:1, 8L) once, combine the organic phases, and concentrate A yellow solid crude product (270g) was obtained, and the crude product was slurried with DCM (1L) to obtain a white solid compound B-...

Embodiment 2

[0112] Example 2 Referring to the preparation method of step a-1 in Example 1, the difference is that in step a-1, under ice bath conditions, a dichloromethane solution (2L) of boron tribromide (224mL, 2.33mol) was dropped Add compound A-1 (300 g, 1.164 mol) to a toluene (12 L) solution, gradually warm up to room temperature, and react until TLC monitors that all the reaction materials disappear. Refer to the post-treatment method of step a-1 of Example 1 to obtain a pure white solid compound B-1 (223.2 g, yield: 85%) by dichloromethane beating.

Embodiment 3

[0113] Example 3 Refer to the preparation method of step a-1 in Example 1, the difference is that in step a-1, hydrobromic acid / acetic acid solution (33%, 38g, 155.21mmol) was added dropwise to compound A-1 (10g , 38.8mmol) in acetic acid (100ml) solution, during the dropwise addition, the reaction temperature was controlled to be less than 5°C, and after the dropwise addition was completed, it was raised to room temperature, and reacted until TLC monitored that the reaction materials all disappeared. Refer to the post-treatment method of step a-1 of Example 1 to obtain a pure white solid compound B-1 (7.53 g, yield: 86%) by beating dichloromethane.

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PUM

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Abstract

The invention relates to the field of organic compound synthesis, in particular to a preparation method of a 2-((2-hydroxy-5-(1-methylcyclopropyl) phenyl) amino)-1-(piperazine-1-yl) ethanone derivative capable of being used as a KRAS G12C covalent inhibitor. The preparation method comprises the following steps: a, dehydrating and demethylating a compound A to prepare a compound B; b, protecting the compound B under the action of an organic alkali to prepare a compound C; c, carrying out cyclopropanation reaction on the compound C to prepare a compound D; d, carrying out deprotection on the compound D under an acidic condition to prepare a compound E; e, performing reductive amination on the compound E and a compound F to prepare a compound G; f, hydrolyzing the compound G to prepare a compound H; g, performing a coupling reaction on the compound H and a compound I to prepare a compound J; h, carrying out deprotection on the compound J to prepare a compound K; and i, reacting the compound K with a compound L under the action of an organic alkali and a buffer solution to prepare a compound M.

Description

technical field [0001] The present invention relates to the field of organic compound synthesis, in particular to the preparation method of 2-(hydroxyl-(methylcyclopropyl)phenylamino)-1-piperazinyl ethyl ketone derivatives, the 2-(hydroxyl-( Methylcyclopropyl) phenylamino)-1-piperazinyl ethyl ketone derivatives are 2-((2-hydroxy-5-(1-methylcyclopropyl)phenyl)amino)-1-(piperazine Azin-1-yl) ethanone derivatives. Background technique [0002] KRAS (kirsten rat sarcoma viral oncogene, a murine sarcoma virus oncogene) is a member of the RAS family. The currently known RAS family has three genes: KRAS, NRAS and HRAS. In human tumors, KRAS mutations are the most common, accounting for about 85%, NRAS and HRAS account for 12% and 3%, respectively. KRAS mutations are one of the most common forms of mutation in lung cancer and are very common in several other cancer types as well. G12C (glycine-12 to cysteine) is a recurrent mutation of the K-Ras gene. This mutation has been foun...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D205/04C07D211/58C07D295/185
CPCC07D205/04C07D211/58C07D295/185
Inventor 郑保富高强宗成龙岳庆磊周治国李莹
Owner SHANGHAI HAOYUAN MEDCHEMEXPRESS CO LTD