Synthesis method of furan [3, 2-b] pyridine derivative

A synthesis method, the technology of 2-b, applied in the direction of organic chemistry, etc., can solve the problems of high cost, unsuitable for industrial production, complicated operation, etc., and achieve the effects of low cost, high synthesis cost and simple operation

Active Publication Date: 2022-03-22
GUANGZHOU GAOLING PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The purpose of the present invention is to provide a kind of furo[3,2-b] and to solve the existing defects of high cost of heterocyclic compound synthesis of furo[3,2-b]pyridine, complicated operation and unsuitability for industrial production. The method for synthesizing pyridine derivatives has the advantages of convenient operation, simple process, simple and easy-to-obtain raw materials, low cost, and is suitable for both small-scale preparation in laboratories and industrial production

Method used

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  • Synthesis method of furan [3, 2-b] pyridine derivative
  • Synthesis method of furan [3, 2-b] pyridine derivative
  • Synthesis method of furan [3, 2-b] pyridine derivative

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Embodiment 1

[0031] see image 3 , the present embodiment provides a method for synthesizing furo[3,2-b]pyridine derivatives, including:

[0032] a) Under nitrogen protection, add 84 g of compound 2-chloromethyl-3,4-dimethoxypyridine represented by formula (I) into a 2000 mL three-necked flask, add 117 g of triphenylphosphine, then add 800 mL of toluene, and heat up. Reflux (108~115°C), stirred for 16 hours, cooled to less than 35°C, suction filtered, the filter cake was rinsed with 100 mL of toluene, and dried to obtain 162.9 g of the compound phosphine salt represented by formula (II), with a yield of 81.1%;

[0033] b) Under nitrogen protection, add 50 g of the compound phosphine salt represented by the formula (II) and 300 mL of tetrahydrofuran into a 1000 mL three-necked flask, stir and cool down to 0-5 °C, add 13.8 g of potassium tert-butoxide in batches, and stir for 1 hour after adding , 32 g of ethyl formate was added dropwise, then the temperature was raised to 25-35° C., and th...

Embodiment 2

[0036] see image 3 , the present embodiment provides a method for synthesizing furo[3,2-b]pyridine derivatives, including:

[0037] a) Under nitrogen protection, add 84 g of compound 2-chloromethyl-3,4-dimethoxypyridine represented by formula (I) into a 2000 mL three-necked flask, add 140 g of triphenylphosphine, then add 800 mL of toluene, and heat up. Reflux (108~115 ℃) and stirring for 16 hours, cooling to less than 35 ℃, suction filtration, the filter cake was rinsed with 100 mL of toluene, and dried to obtain 191.4 g of the compound phosphine salt represented by formula (II), with a yield of 95.3%;

[0038] b) Under nitrogen protection, add 50 g of the compound phosphine salt represented by the formula (II) into a 1000 mL three-necked flask, add 200 mL of DMSO, stir to cool down to 15-25 °C, add 13.8 g of potassium tert-butoxide in batches, and stir for 1 32 g of ethyl formate was added dropwise, the temperature was heated to 35-45 °C and stirred for 3 hours, then 250 m...

Embodiment 3

[0041] see image 3 , the present embodiment provides a method for synthesizing furo[3,2-b]pyridine derivatives, including:

[0042] a) Under nitrogen protection, add 84 g of compound 2-chloromethyl-3,4-dimethoxypyridine represented by formula (I) into a 2000 mL three-necked flask, add 128.7 g of triphenylphosphine, and then add 1000 mL of toluene, The temperature was raised and refluxed (108-115°C), stirred for 16 hours, cooled to within 35°C, suction filtered, the filter cake was rinsed with 100 mL of toluene, and dried to obtain 181.6 g of the compound phosphine salt represented by formula (II), with a yield of 90.4%;

[0043] b) Under nitrogen protection, add 60 g of the compound phosphine salt represented by formula (II) into a 1000 mL three-necked flask, add 240 mL of DMSO, stir to cool down to 15-25 °C, add 14.0 g of sodium tert-butoxide in batches, and stir for 1 48.0 g of ethyl formate was added dropwise, the temperature was raised to 35-45 °C and stirred for 3 hours...

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Abstract

The invention discloses a synthesis method of a furan [3, 2-b] pyridine derivative, which comprises the following steps: refluxing a substance as shown in a formula (I) and triphenylphosphine in a solvent, cooling and filtering to obtain a compound as shown in a formula (II); carrying out Wittig reaction on the compound shown in the formula (II) and formate under the action of alkali to obtain a compound shown in a formula (III); and performing cyclization reaction on the compound represented by the formula (III) under an acidic condition to obtain a compound represented by a formula (IV). The method disclosed by the invention is convenient to operate, simple in process, simple and easily available in raw materials and low in cost, and is suitable for small-scale preparation in a laboratory and industrial production.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing a heterocyclic compound of furo[3,2-b]pyridine. Background technique [0002] Heterocyclic compounds of furo[3,2-b]pyridines are an important class of pharmaceutical intermediates. It can be used for the synthesis of highly selective JAK1 inhibitors for the treatment of rheumatoid arthritis (WO2018067422). For the preparation of furo[3,2-b]pyridine, there are few reports at home and abroad so far. At present, it has been reported that such compounds are synthesized by the reaction of 2-bromo-3-acetoxypyridine and substituted alkynes by palladium-catalyzed Sonogashira coupling (WO200551304). The reaction requires the participation of precious metals, and the cost is high, which is not suitable for industrial production. There are also reports using 3-hydroxypyridine-2 carboxylic acid derivatives to prepare this type of compounds through multi-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/048
CPCC07D491/048Y02P20/55
Inventor 陆国彪殷宏飞金煜东廖思敏
Owner GUANGZHOU GAOLING PHARMA CO LTD
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