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Synthesis method of Lorlatinib intermediate 2-amino-5-bromo-3-hydroxypyridine

A technology for the synthesis of hydroxypyridine, which is applied in the field of 2-amino-5-bromo-3-hydroxypyridine synthesis, can solve problems such as drug resistance, and achieve the effects of increasing the rate, improving product quality, and increasing the reaction yield

Pending Publication Date: 2020-11-17
XIHUA UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Yet recalcitrant tumors quickly developed resistance to these new inhibitors

Method used

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  • Synthesis method of Lorlatinib intermediate 2-amino-5-bromo-3-hydroxypyridine
  • Synthesis method of Lorlatinib intermediate 2-amino-5-bromo-3-hydroxypyridine
  • Synthesis method of Lorlatinib intermediate 2-amino-5-bromo-3-hydroxypyridine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Example 1: Synthesis of 3H-oxazol[4,5-b]pyridin-2-one

[0036] 2-Amino-3-hydroxypyridine (4.0g, 36.3mmol) was dissolved in THF (120 mL), and after it was completely dissolved, CDI (8.8g, 54.3mmol) was added after stirring for a while, and the CDI solid gradually dissolved, and the solution was Yellowish-brown clear shape, stirred at room temperature for 1.5 hours, added BTC (6.5g, 21.9mmol) in batches under ice bath conditions, after the addition was completed, heated to reflux, reacted for 1 hour, after the reaction was completed, filtered, washed the filter cake with water, and dried Dry to obtain 4.75 g of light yellow powder 3H-oxazol[4,5-b]pyridin-2-one with a yield of 96.1%. The crude product can be directly used in the next bromination reaction without purification. Intermediate structure identification requires further separation and purification by column chromatography, 1H NMR (400 MHz, DMSO) δ 12.43 (s, 1H), 8.04 (dd, J =5.3, 1.2 Hz, 1H), 7.64 (dd, J = 7.9, ...

Embodiment 2

[0037] Example 2: Synthesis of 6-bromo-3H-oxazolo[4,5-b]pyridin-2-one

[0038] The crude oxazol[4,5-b]pyridin-2(3H)-one (2.50 g, 18.35 mmol) obtained in the aforementioned ring-closing step, 30 mL of anhydrous N,N-dimethylformamide (DMF), Add in the quartz glass three-necked bottle successively, then add 25 mg photoinitiator 2-hydroxyl-2-methyl-1-phenyl-1-propanone, adopt the 23 watts ultraviolet lamp that has standard lampshade to irradiate reaction bottle, control The temperature of the reaction solution is at 0-5°C, and the DMF solution containing liquid bromine (2.94g, 18.35 mmol) is slowly added dropwise. After the reaction is complete, pour the reaction solution into a certain amount of ice-water mixture, stir, filter, wash the filter cake with water, and dry to obtain a yellow solid 6-bromo-3H-oxazolo[4,5-b]pyridine- The crude product of 2-ketone was 3.93g, the molar yield of the crude product in the photocatalytic bromination single-step reaction was 86.4%, and the re...

Embodiment 3

[0039] Example 3: Synthesis of 2-amino-5-bromo-3-hydroxypyridine

[0040] The 6-bromo-3H-oxazolo[4,5-b]pyridin-2-one intermediate (5.0g, 23.3mmol) prepared according to the photocatalytic bromination reaction method was added to the three-necked flask, Then add 40 mL of aqueous sodium hydroxide solution with a concentration of 10% by mass, and heat up to reflux for 14 hours. Monitor the reaction process by thin-layer chromatography. After the reaction raw material 6-bromo-3H-oxazolo[4,5-b]pyridin-2-one is completely converted, cool to room temperature and add 5% dilute hydrochloric acid dropwise to adjust the pH value of the solution. to 6-7, extracted three times with ethyl acetate, collected the organic layer, dried the organic layer by adding anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 3.96 g of the crude product of 2-amino-5-bromo-3-hydroxypyridine as gray-brown solid, The single-step reaction of hydrolysis has a molar yield of 90%, and ...

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Abstract

The invention relates to synthesis of an important intermediate, namely 2-amino-5-bromo-3-hydroxypyridine, of an anti-tumor drug Lorlatinib (PF-06463922). 2-amino-3-hydroxy pyridine is used as a starting raw material, and subjected tothree steps of reactions including ring closing, bromination and hydrolysis to finally prepare 2-amino-5-bromo-3-hydroxypyridine, wherein in the ring closing step, bis(trichloromethyl) carbonate (BTC) and N,N'-carbonyl diimidazole (CDI) are combined for use; in the bromination step, 2-hydroxy-2-methyl-1-phenyl-1-acetone is used as a photoinitiator, and liquid bromine is used as a brominating agent. Compared with the prior art, the method is more environment-friendly and economical.

Description

technical field [0001] The invention relates to the synthesis of 2-amino-5-bromo-3-hydroxypyridine, in particular to the synthesis method of 2-amino-5-bromo-3-hydroxypyridine by adopting the steps of ring closure, photocatalytic bromination, hydrolysis and the like. Background technique [0002] Lorlatinib (PF-06463922), English name: (R)-26-amino-55-fluoro-11,4,7-trimethyl-6-oxo-11H-3-oxa-7-aza- 2(3,5)-pyridina-1(4,3)-pyrazola-5(1,2)-benzocyclooctaphane-15-carbonitrile, CAS number: 14548 46-35-5, molecular formula: C 21 h 19 FN 6 o 2 , molecular weight: 406.4. Lorlatinib is a third-generation ALK (anaplastic lymphoma kinase) inhibitor. The first-generation ALK inhibitor, Crizotinib, is an ATP-competitive multi-target protein kinase inhibitor. The US FDA approved Crizotinib in 2016 for the treatment of advanced (metastatic) patients with ROS-1 gene mutations. Patients with non-small cell lung cancer (NSCLC). Unfortunately, most patients developed resistance to crizoti...

Claims

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Application Information

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IPC IPC(8): C07D213/73
CPCC07D213/73Y02P20/584
Inventor 刘家琴刘凯赖鑫悦陈国凤朱雨晗杨维清
Owner XIHUA UNIV
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