Preparation method of 6-bromo-4-methoxypyrazolo [1, 5-a] pyridine-3-formonitrile

A technology of methoxypyrazole and methoxypyridine, which is applied in the field of preparation of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile, can solve the unsatisfactory Industrial production needs and other issues

Pending Publication Date: 2022-04-12
PHARMABLOCK SCIENCES (NANJING) INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] Aiming at the problem that the number of reaction steps or the yield in the prior art cannot meet the needs of industrialized production, the present invention provides a 6-bromo-4-methoxypyrazolo[1,5-a] with high yield The preparation method of pyridine-3-carbonitrile, the reaction yield can reach more than 90%

Method used

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  • Preparation method of 6-bromo-4-methoxypyrazolo [1, 5-a] pyridine-3-formonitrile
  • Preparation method of 6-bromo-4-methoxypyrazolo [1, 5-a] pyridine-3-formonitrile
  • Preparation method of 6-bromo-4-methoxypyrazolo [1, 5-a] pyridine-3-formonitrile

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Embodiment 1

[0039]

[0040] Put 4-hydroxy-2,2,6,6-tetramethylpiperidinyloxy (876g, 5.10mol, 2.05eq.) and acetonitrile (3900g, 3.9V) into the reaction kettle, and stir at 15-25°C for 2h. Add 1-amino-3-bromo-5-methoxypyridin-1-ium 2,4,6-trimethylbenzenesulfonate (1000g, 2.48mol, 1eq.) under temperature control at 10-20°C, 2 -Chloroacrylonitrile (238g, 2.72mol, 1.1eq.), triethylamine (527g, 5.21mol, 2.1eq.), and the reaction solution was stirred for 6h. Add sodium sulfite (75.6g) to quench the reaction, filter and dry to give 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile (566g, yield 91%, purity ≥ 96% ). MS(m / z)=251.97[M+H] +1 . 1 H NMR (400 MHz, DMSO) δ 8.938 (t, 1H); 8.589 (s, 1H); 7.24 (t, 1H); 4.038 (s, 3H).

Embodiment 2

[0042]

[0043] Put 2,2,6,6-tetramethylpiperidine oxide (811g, 5.20mol, 2.1eq.) and acetonitrile (5000g, 5V) into the reaction kettle, and stir at 15-25°C for 2h. Add 1-amino-3-bromo-5-methoxypyridin-1-ium 2,4,6-trimethylbenzenesulfonate (1000g, 2.48mol, 1eq.) under temperature control at 10-20°C, 2 -Chloroacrylonitrile (326g, 3.72mol, 1.5eq.), DBU (830g, 5.46mol, 2.2eq.), the reaction solution was stirred for 8h. Add sodium sulfite (75.6g) to quench the reaction, filter and dry to give 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile (541g, yield 87%, purity ≥ 96% ).

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Abstract

The invention relates to a preparation method of 6-bromine-4-methoxy pyrazolo [1, 5-a] pyridine-3-formonitrile, and the 6-bromine-4-methoxy pyrazolo [1, 5-a] pyridine-3-formonitrile is prepared from 1-amino-3-bromine-5-methoxy pyridine-1-onium 2, 4, 6-trimethyl benzene sulfonate and 2-chloroacrylonitrile in the presence of an organic solvent, an alkaline reagent and an oxidizing agent. The route yield is greatly improved and can reach 90%, the product purity is 96% or above, the reaction operation is simple and convenient, the condition is mild, and the method is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of synthesis of pharmaceutical intermediates, in particular to a preparation method of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile. Background technique [0002] Pyrazolopyridine compounds as relatively novel drug fragments have received more and more attention in the field of medicinal chemistry, among which pyrazolo[1,5-a]pyridine derivatives, especially 6-bromo-4-methoxy Pyrazolo[1,5-a]pyridine-3-carbonitriles have been used in the synthesis of several kinase inhibitor compounds. For example, WO2010017047A1 is used to prepare PDK1 kinase inhibitors, WO2017011776A1 & WO2018071447A1 is used to prepare RET kinase inhibitors, and WO2020131627A1 is used to prepare FGFR tyrosine kinase inhibitors. [0003] [0004] WO2010017047A1 discloses that 2,4,6-trimethylbenzenesulfonyl hydroxylamine and 3-bromo-5-methoxypyridine are used as raw materials to form a salt, and 6-bromo-4-methoxypyridine is obtained thro...

Claims

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Application Information

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IPC IPC(8): C07D471/04
Inventor 梁雪伟高鹋尹鸿宇邓鹿江赵庆
Owner PHARMABLOCK SCIENCES (NANJING) INC
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