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Preparation method of PIM kinase inhibitor and intermediate of PIM kinase inhibitor

A volume and catalyst technology, applied in the direction of organic chemistry, etc., can solve the problems of easy decomposition, unstable raw material compound B1, unsuitable for industrial production, etc.

Inactive Publication Date: 2018-05-22
SHANGHAI FANGYU HEALTH PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The method is to use compound II as the starting material, first carry out substitution reaction with compound B1, then carry out condensation reaction with compound VI, and finally generate 5-(2,6-difluorophenyl)-N-(4 -(piperidine-4-methoxy)pyrimidine-5-)thiophene-2-carboxamide hydrochloride, raw material compound B1 is very unstable in this route, easy to decompose, not suitable for industrialized production

Method used

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  • Preparation method of PIM kinase inhibitor and intermediate of PIM kinase inhibitor
  • Preparation method of PIM kinase inhibitor and intermediate of PIM kinase inhibitor
  • Preparation method of PIM kinase inhibitor and intermediate of PIM kinase inhibitor

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Embodiment 1

[0107] Embodiment 1: the preparation of the compound shown in formula I of the present invention

[0108] (1) Preparation of compound shown in formula IV

[0109] 4-(Hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (compound shown in formula II) (2.15g, 10mmol), tetrahydrofuran (20ml) and sodium hydrogen (0.48g, 20mmol) were added to the reaction flask , stirred for 2h, added 4,6-dichloro-5-aminopyrimidine (compound represented by formula III) (1.49g, 9.1mmol), raised the temperature to 50-60°C for 2-3h, cooled to 0-5°C in an ice bath , drop 5ml of methanol, then use acetic acid to adjust the pH to 6-7, reduce the pressure to -0.09Mpa at 40°C, evaporate the above solvent to dryness, add 20ml of ethyl acetate and 20ml of water to the obtained residue, stir for 5 minutes, and let it stand Place and separate the layers, add 5g of anhydrous sodium sulfate to the obtained ethyl acetate layer and dry for 1h, filter, reduce the pressure to -0.09Mpa at 50°C and evaporate ...

Embodiment 2

[0119] Embodiment 2: the preparation of the compound shown in formula I of the present invention

[0120] (1) Preparation of compound shown in formula IV

[0121] Add tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (compound represented by formula II) (2.15g, 10mmol) and 20ml of acetonitrile into the reaction flask, stir for 3h, then cool down with dry ice ethanol solution To below -20°C, slowly add 15ml of 2mol / L n-butyl lithium and tetrahydrofuran solution (30mmol) dropwise, the temperature does not exceed 0°C during the dropwise addition, stir at 0-5°C for 2h after the dropwise addition, add 4,6 - Dichloro-5-aminopyrimidine (compound shown in formula III) (3.28g, 20mmol), heat up to 30-40°C for 2-3h, cool down to 0-5°C in an ice bath, add 5ml of methanol dropwise, and then use Adjust the pH to 6-7 with acetic acid, and evaporate the solvent under reduced pressure to -0.09Mpa at 40°C. Add 20ml of ethyl acetate and 20ml of water to the obtained residue, stir for 5 min...

Embodiment 3

[0125] Embodiment 3: the preparation of the compound shown in formula I of the present invention

[0126] (1) Preparation of compound shown in formula IV

[0127]Add 4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (compound shown in formula II) (2.15g, 10mmol) and 20ml of 1,4-dioxane into the reaction flask, dry ice ethanol Cool the solution below -20°C, slowly add 2.5ml of 2mol / L n-butyllithium and tetrahydrofuran solution (5mmol) dropwise, the temperature does not exceed 0°C during the dropwise addition, stir at 0-5°C for 2h after the dropwise addition, add 0.82 g of 4,6-dichloro-5-aminopyrimidine (compound shown in formula III) (5mmol), heated up to 70-80°C for 2h, cooled to 0-5°C in an ice bath, dropped into 5ml of methanol, and then Adjust the pH to 6-7 with acetic acid, evaporate the solvent under reduced pressure to -0.09Mpa at 40°C, add 20ml of ethyl acetate and 20ml of water to the obtained residue, stir for 5 minutes, let stand, and separate the liq...

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Abstract

The invention relates to a preparation method of a PIM kinase inhibitor and an intermediate of PIM kinase inhibitor. The invention provides a preparation method of a compound as shown in a formula I or pharmaceutical salt thereof, or a compound as shown in a formula V. The preparation method comprises the following steps. The method has the characteristics of simplicity and convenience in production, low production cost, high production efficiency, excellent product quality, stable quality, low pollution, high safety and the like, can effectively solve the problems of reaction impurity uncontrollability and yield reduction caused by raw material instability, and is convenient for industrialized enlargement production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of a PIM kinase inhibitor and an intermediate thereof. Background technique [0002] Anticancer drug research is a very challenging and significant field in life science today. In recent years, with the in-depth study of the pathogenic mechanism of tumors, the basic process of signal transduction pathway changes in tumor cells has been gradually elucidated. Using key kinases in some cell signal transduction pathways as drug screening targets to discover new targeted drugs with high efficiency, low toxicity and strong specificity has become one of the effective ways for anticancer drug research today. At present, among all pharmacological targets, it is estimated that more than 1 / 4 of the targets are protein kinases, and it is as high as 75% in the field of anti-tumor. Among them, PIM (Provirus Integration site for Moloney leukemia) ki...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/14
CPCC07D417/14
Inventor 俞雄张袁伟袁西伦孙鹏
Owner SHANGHAI FANGYU HEALTH PHARMA TECH CO LTD
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