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Synthesis method of JAK1 inhibitor Filgotinib

A compound and catalyst technology, applied in the field of synthesis of JAK1 inhibitor Filgotinib, can solve the problems of ineffective correction of rheumatoid arthritis and osteoarthritis diseases, and achieve the effects of simple reaction operation, high yield and cheap raw materials

Active Publication Date: 2019-09-06
四川伊诺达博医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there are currently no effective drugs for the correction of rheumatoid arthritis and osteoarthritis disease

Method used

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  • Synthesis method of JAK1 inhibitor Filgotinib
  • Synthesis method of JAK1 inhibitor Filgotinib

Examples

Experimental program
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Embodiment 1

[0062] Embodiment 1, the synthesis of compound Filgotinib

[0063] According to the following synthetic route, compound Filgotinib is prepared:

[0064]

[0065] 1, Synthesis of 6-(4-methylphenyl)-2-aminopyridine (compound 1)

[0066] Add 2-amino-6-bromopyridine (50g, 0.29mol), p-tolylboronic acid (47g, 0.35mol), 1,4-dioxane (750ml) and water (250ml) into the reaction flask, Potassium acetate (85 g, 0.87 mol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl) were added 2 , 12.7g, 0.0174mol). Nitrogen was introduced, heated to reflux for 13 hours, and the reaction was monitored by TLC. Cool down to room temperature, add 2N hydrochloric acid to PH>3, precipitate solid, filter, dissolve the filter cake with 2N aqueous sodium hydroxide solution, extract with ethyl acetate (300mlX3), concentrate the organic phase to obtain the product 6-(4-methylphenyl )-2-aminopyridine (compound 1) 144.7g, yield 83.6%.

[0067] 2. Synthesis of [6-(4-methylphenyl)p...

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Abstract

The invention provides a preparing method of Filgotinib. The preparing method comprises the following steps that (1), 2-amino-6-bromopyridine reacts with a p-methylbenzene derivative to prepare a compound 1; (2), the compound 1 reacts with ethoxycarbonyl isothiocyanate to prepare a compound 2; (3), the compound 2 reacts with hydroxylamine hydrochloride and N,N-diisopropylethylamine to prepare a compound 3; (4), the compound 3 reacts with cyclopropanecarbonyl chloride to obtain a compound 4; (5), the compound 4 reacts with N-bromosuccinimide and azodiisobutyronitrile to obtain a compound 5; (6), the compound 5 reacts with thiomorpholine-1,1-dioxide to obtain the Filgotinib. According to the synthesis route of the Filgotinib, firstly, coupling is conducted, then ring closing is conducted, the raw materials are cheap, the reaction operation is simple, and the product is easy to purify, high in yield and suitable for large-scale commercial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for synthesizing JAK1 inhibitor Filgotinib. Background technique [0002] Cartilage degeneration is a hallmark of many diseases, of which rheumatoid arthritis and osteoarthritis are the most important. Rheumatoid arthritis (RA) is a chronic joint degenerative disease characterized by inflammation and destruction of joint structures. When the disease is unchecked, loss of joint functionality results in substantial disability and pain, and even premature death. However, there are currently no effective drugs for correcting rheumatoid arthritis and osteoarthritic diseases. [0003] Janus kinases (JAKs) are cytoplasmic tyrosine kinases that transduce cytokine signals from membrane receptors to STAT transcription factors. Four JAK family members have been described in the prior art: JAK1, JAK2, JAK3 and TYK2. When cytokines bind to their receptors, JAK family members autopho...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 万华斯涛周平吴夏霍欢徐国燕岳利剑
Owner 四川伊诺达博医药科技有限公司
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