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JAK (Janus kinase) inhibitor and preparation method and use thereof

A kind of technology of solvate and compound, applied in the field of JAK enzyme inhibitor and preparation thereof

Active Publication Date: 2018-07-31
SHANGHAI LONGWOOD PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The development of inhibitors with high selectivity for JAK1 has been difficult due to the fact that JAK1 and JAK3 are components of the common γ-chain cytokine receptor complex

Method used

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  • JAK (Janus kinase) inhibitor and preparation method and use thereof
  • JAK (Janus kinase) inhibitor and preparation method and use thereof
  • JAK (Janus kinase) inhibitor and preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0151] Embodiment 1: the synthesis of compound 1a

[0152]

[0153] Under the protection of argon, 4-chloropyrrolopyridine (308g, 2.0mol, SM-1) was dissolved in 1.5L of anhydrous DMAc, cooled to 10°C in an ice-water bath, and NaH (104g, 2.6mol, 60%) was added in batches Maintain the temperature at 10-15°C, and stir at this temperature for 1 h after the dropwise addition is complete. A tetrahydrofuran solution of methyl pivalate (390 g, 2.6 mol dissolved in 1.5 L anhydrous THF, SM-2) was slowly added dropwise, keeping the temperature below 20° C., and the addition was completed after 1 h. The reaction solution was raised to room temperature for 2 h, and TLC showed that the reaction was complete. Water was added dropwise in an ice-water bath to quench the reaction, and extracted with methyl tert-butyl ether. Concentration of the organic phase afforded 1a (530 g) as a white solid.

Embodiment 2

[0154] Embodiment 2: the synthesis of compound 2a

[0155]

[0156] Compound 1a (309g, 1.16mol), 1-(1-ethoxyethyl)-4-pyrazoleboronic acid pinacol ester (339g, 1.28mol, SM-3), cesium fluoride (352g , 2.32mol), n-butanol (1.5L), water (1.5L). After evacuating argon three times, tetrakis(triphenylphosphine)palladium (10 g, 12 mmol) was added. After the argon was replaced again, the temperature was raised to reflux, and the reaction was carried out for 16 hours. HPLC showed that the reaction was complete. After cooling down, the liquid was separated, extracted with ethyl acetate, concentrated and directly proceeded to the next step (containing n-butanol).

Embodiment 3

[0157] Embodiment 3: the synthesis of compound 3a

[0158]

[0159] Compound 2a was dissolved in 500 mL of tetrahydrofuran, 4N hydrochloric acid solution (800 mL) was added dropwise, and reacted overnight at room temperature. HPLC showed that the reaction of the raw materials was complete, and the purity of the target compound was 73.1%. Slowly add 10% sodium hydroxide solution dropwise under ice-water bath until pH = 7-8, a lot of solids are formed. After filtering, the filter cake was washed with water and dried in an oven to obtain solid 3a (193 g), with a purity of 92% and a two-step yield of 56%.

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PUM

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Abstract

The invention provides a novel JAK (Janus kinase) selective inhibitor and a preparation method thereof and use thereof, in particular, the invention discloses a compound having the structure represented by the formula I or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, hydrate or solvate thereof which can be used as the JAK kinase inhibitor.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular, the invention relates to a JAK enzyme inhibitor and its preparation method and application. Background technique [0002] Protein kinases, also known as protein phosphorylases (Protein Phosphokinase), are a class of enzymes that catalyze protein phosphorylation reactions and are key factors in regulating cell signals, including cell proliferation and cell differentiation. [0003] Currently, there are four known mammalian JAK family members: JAK1 (also known as Janus kinase-1), JAK2 (also known as Janus kinase-2), JAK3 (also known as JAKL or L-JAK, leukocyte Janus kinase; and Janus Kinase-3) and TYK2 (also known as protein-tyrosine kinase 2). [0004] Blockade of signal transduction at the level of JAK kinases holds promise for the development of treatments for inflammatory diseases, autoimmune diseases, myeloproliferative diseases and cancer. Inhibition of JAK kinases is also helpf...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519A61P29/00A61P37/00A61P35/00A61P17/00A61P17/06
CPCC07D487/04A61P17/00A61P17/06A61P29/00A61P35/00A61P37/00A61K31/519
Inventor 王喆范国钦杨赛曾志宏
Owner SHANGHAI LONGWOOD PHARMA
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