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1-(pyrimidine-4-yl)-3-aminopiperdine derivative and its preparation method and use

A technology of aminopiperidine and its derivatives, applied in the field of 1-3-aminopiperidine derivatives and its preparation

Active Publication Date: 2016-08-10
CHENGDU ZENITAR BIOMEDICAL TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since JAK3 and the same family of JAK1 and JAK2 kinases have very high homology and are very similar in structure and function, all existing JAK3 inhibitors have side effects of inhibiting JAK1 and JAK2

Method used

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  • 1-(pyrimidine-4-yl)-3-aminopiperdine derivative and its preparation method and use
  • 1-(pyrimidine-4-yl)-3-aminopiperdine derivative and its preparation method and use
  • 1-(pyrimidine-4-yl)-3-aminopiperdine derivative and its preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0090] Example 1 Synthesis of (R)-tert-butyl (1-(9H-purin-6-yl)piperidin-3-yl) carbamate (Compound 1)

[0091]

[0092] At room temperature, 6-chloropurine (1 mmol) and R-3-Boc aminopiperidine (1.2 mmol) were added to methanol. After stirring for 5 minutes, the temperature was slowly raised to 50 degrees Celsius. After stirring for 7 hours, a precipitate precipitated and the reaction was stopped. After cooling to room temperature, the reaction solution was filtered, the filter cake was washed with a little methanol, the filter cake was collected and drained to obtain a crude product. The crude product was purified by column chromatography to obtain the final target compound 1, yield: 42%.

[0093] 1 H NMR(400MHz, DMSO-d6): δ12.98(s,1H), 8.20(s,1H), 8.11(s,1H), 6.94(d,1H,J=6.4Hz), 5.16-5.04(m , 2H), 3.34 (s, 1H), 3.23-3.05 (m, 2H), 1.90-1.79 (m, 2H), 1.50 (t, 2H, J=4.2 Hz), 1.39 (s, 9H). MS(ESI),m / z:317.4[M-H] - .

Embodiment 2

[0094] Example 2 Synthesis of (R)-N-(1-(9H-purin-6-yl)piperidin-3-yl)acetamide (Compound 2)

[0095]

[0096] Compound 1 (1 mmol) was added to dichloromethane (2 mL) and trifluoroacetic acid (2 mL), stirred at room temperature for 4 hours, and the reaction was monitored by thin layer chromatography. When the reaction is complete, the reaction solution is spin-dried, and ether is added to precipitate a precipitate, which is filtered to obtain the trifluoroacetate intermediate of compound 1. Add the trifluoroacetate (1mmol) of compound 1 to tetrahydrofuran, add triethylamine (3mmol), slowly add acetyl chloride (1.2mmol) under an ice bath, and react at room temperature. After the reaction is complete, spin dry the solution at low temperature. Add methanol to dissolve and purify by column chromatography to obtain compound 2, yield: 40%.

[0097] 1 H NMR (400MHz, DMSO-d6): δ10.01 (s, 1H), 8.19 (s, 1H), 8.10 (s, 1H), 7.91 (d, 1H, J = 8.0 Hz), 5.34-4.66 (m ,2H),3.72-3.71(m,1H),3.43-3.36...

Embodiment 3

[0098] Example 3 Synthesis of (R)-N-(1-(9H-purin-6-yl)piperidin-3-yl)palmitamide (Compound 3)

[0099]

[0100] Compound 1 (1 mmol) was added to dichloromethane (2 mL) and trifluoroacetic acid (2 mL), stirred at room temperature for 4 hours, and the reaction was monitored by thin layer chromatography. When the reaction is complete, the reaction solution is spin-dried, and ether is added to precipitate a precipitate, which is filtered to obtain the trifluoroacetate intermediate of compound 1. Add the trifluoroacetate (1mmol) of compound 1 to tetrahydrofuran, add triethylamine (3mmol), slowly add pivaloyl chloride (1.2mmol) under ice bath, and react at room temperature. After the reaction is complete, spin dry the solution at low temperature , Adding methanol to dissolve and purifying by column chromatography to obtain compound 3, yield: 35%.

[0101] 1 H NMR (400MHz, DMSO-d6): δ8.37 (s, 1H), 7.98 (s, 1H), 6.16 (d, 1H, J = 4.2Hz), 4.64-4.28 (m, 2H), 4.23-4.01 (m,3H),2.00-1.89(m,2H)...

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Abstract

The invention relates to the field of chemical medicines and concretely relates to a 1-(pyrimidine-4-yl)-3-aminopiperdine derivative and its preparation method and use. The invention provides the 1-(pyrimidine-4-yl)-3-aminopiperdine derivative. The 1-(pyrimidine-4-yl)-3-aminopiperdine derivative has a structure shown in the formula IV. The invention also provides a preparation method and a use of the 1-(pyrimidine-4-yl)-3-aminopiperdine derivative. The 1-(pyrimidine-4-yl)-3-aminopiperdine derivative can selectively inhibit JAK3 and provide a novel choice for treating JAK3-related diseases such as rheumatoid arthritis, asthma, chronic obstructive pulmonary diseases and tumors.

Description

Technical field [0001] The invention belongs to the field of chemistry and medicine, and specifically relates to 1-(pyrimidin-4-yl) 3-aminopiperidine derivatives, and a preparation method and application thereof. Background technique [0002] Tyrosine protein kinase (TPK) is a type of kinase that catalyzes the transfer of γ-phosphate from ATP to protein tyrosine residues. It can catalyze the phosphorylation of protein tyrosine residues on various substrates. The signal transduction pathway occupies a very important role, regulating a series of physiological and biochemical processes such as cell growth, differentiation and death. Tyrosine kinases are divided into receptor type and non-receptor type. Receptor tyrosine kinase is a single-pass transmembrane protein, and non-receptor tyrosine kinase is a cytoplasmic protein. They play an important role in the process of signal transduction from extracellular to intracellular. The dysfunction of protein tyrosine kinase will cause a ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D473/34C07D473/16C07D473/40A61P19/02A61P11/06A61P11/00A61P35/00
CPCC07D473/16C07D473/34C07D473/40C07D487/04
Inventor 陈俐娟魏于全
Owner CHENGDU ZENITAR BIOMEDICAL TECH CO LTD
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