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Method for synthesizing upadacitinib intermediate and the intermediate

A synthetic method, the technology of upadatinib, applied in the field of drug synthesis, can solve the problems of difficult synthesis, difficult application, and only about 20% yield

Active Publication Date: 2019-05-03
ZHEJIANG NORMAL UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The patent document (WO2017066775) reported the synthesis method of asymmetric hydrogenation of one of the intermediates. During the research, it was found that when the method synthesized chiral alkenes III, the trifluoromethanesulfonate was under high temperature and alkaline conditions. Under very easy hydrolysis, cause triflate overwhelming majority to all be decomposed into raw material II, cause the productive rate of this step to only have about 20%, be far below the crude product yield of 91% described in literature, in addition in synthetic For intermediate V, the chiral catalyst used in the literature is the S-segphosRu complex, and the synthesis of the ligand S-segphos is difficult and expensive, and it is in the patent protection period, so it is difficult to apply

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  • Method for synthesizing upadacitinib intermediate and the intermediate
  • Method for synthesizing upadacitinib intermediate and the intermediate
  • Method for synthesizing upadacitinib intermediate and the intermediate

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Embodiment Construction

[0061] 1. Synthesis of Intermediate 3

[0062]

[0063] Add 10mmol of compound 1 and 1mmol of trifluoroacetic acid to 20mL of dichloromethane. After cooling the reactor to 20°C, add 20mmol of compound 2 and stir for 50min. Slowly add water to stop the reaction. The reaction mixture is separated and the water layer is used The dichloromethane was extracted twice, the combined dichloromethane was dried, and the dichloromethane was recovered to obtain the crude product. The crude product was purified with ethyl acetate petroleum ether (ethyl acetate: petroleum ether = 1:10) mixed solvent column chromatography to obtain the product compound 3: 2.2g, yield 86%. 1 H-NMR (400MHz, CDCl 3 ): δ1.07-1.09(t,3H),1.28-1.30(t,3H),2.62-2.64(m,2H),3.62-3.64(m,2H),3.73-3.76(m,2H),3.80 (s, 2H), 4.18-4.22 (m, 2H) 7.29-7.40 (m, 5H). MS(ESI): 260.5.

[0064] 2. Synthesis of Intermediate 4

[0065]

[0066] Intermediate 3 10mmol was dissolved in methanol 5mL, added 10% NaOH solution 6mL, stirred at room...

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Abstract

The invention discloses a method for synthesizing upadacitinib intermediate. The method includes performing a ring-forming reaction with 2-pentynoate and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine under a catalyst A to prepare a compound (3), by which the compound (7) or the compound (8) can be obtained in various manners. The method especially the first and the third technical schemes,is high in yield and purity and is high in overall yield. The method is simple in post-treatment and is suitable for industrial large-scale production.

Description

Technical field [0001] The invention relates to the technical field of drug synthesis, and relates to a method for synthesizing an upatinib intermediate by adopting a chiral catalytic method. Background technique [0002] Upatinib is an oral JAK1 inhibitor used to treat rheumatoid arthritis, psoriatic arthritis and other diseases. JAK (just another kinase or janus kinase) kinase is a family of non-receptor tyrosine kinases. Four members have been found, namely JAK1, JAK2, JAK3 and TYK1. The substrate of JAK is STAT, that is, signal transducer and activator of transcription (STAT). STAT is phosphorylated by JAK and then dimerizes, and then passes through the nuclear membrane and enters the nucleus to regulate the expression of related genes. This signaling pathway is called the JAK-STAT pathway. Therefore, JAK plays an important role in the pathophysiological process of immune-mediated diseases. It can be used to treat some autoimmune diseases, such as atopic dermatitis, rheumat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/22C07D207/16
Inventor 李新生陈雪珂陈修华罗红敏
Owner ZHEJIANG NORMAL UNIVERSITY
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