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Process method suitable for amplification preparation of 4-(6-aminopyridin-3-yl) substituted piperidine

A technology of base piperidone and piperidine, which is applied in the field of amplifying the preparation of 4-substituted piperidines, can solve the problems of difficult purification and removal of impurities, low synthesis process yield, poor economic benefits and the like, and achieves short route steps and optimized preparation. Craftsmanship, universal effect

Active Publication Date: 2019-12-06
SHANGHAI ZAIQI BIO TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] This method uses pyrrole to protect the amino group, and then removes it after coupling. In actual operation, the steps of debenzylation and reduction need to be completed step by step, and impurities are difficult to purify and remove.
[0013] Therefore, on the whole, the existing synthesis process has low yield, is difficult to purify, and has poor economic benefits. It is necessary to improve the existing process scale-up, adopt cheaper and easily available raw materials, and develop a process suitable for industrial scale-up

Method used

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  • Process method suitable for amplification preparation of 4-(6-aminopyridin-3-yl) substituted piperidine
  • Process method suitable for amplification preparation of 4-(6-aminopyridin-3-yl) substituted piperidine
  • Process method suitable for amplification preparation of 4-(6-aminopyridin-3-yl) substituted piperidine

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041]

[0042] Step 1: Preparation of 6-amino-3',6'-dihydro-2'-hydrogen-[3,4']bipyridyl-1'-formyl tert-butyl ester

[0043] Add N-tert-butoxycarbonyl-4-piperidone (1.45g), p-toluenesulfonyl hydrazide (1.35g), and dioxane (31.2g) into the bottle, and replace nitrogen three times under stirring conditions. The temperature was raised to 75°C and the reaction was stirred for 5h. Spot plate monitoring shows that after the point of N-tert-butoxycarbonyl-4-piperidone disappears, distill off 20 g of solvent, and under nitrogen protection, add Xphos (0.11 g), [1,1'-bis(diphenyl Phosphinoyl)ferrocene]palladium dichloride (0.029g), sodium tert-butoxide (1.34g), 2-amino-5-bromopyridine (1g), heated to 110°C for 8h, cooled, filtered, added 5ml of methyl tert-butyl ether, beat for 10 minutes, filter the obtained solid and dry it to obtain 6-amino-3',6'-dihydro-2'-hydrogen-[3,4']bipyridyl-1' - Formyl tert-butyl ester 1.30 g, purity: 99.1%, yield: 82%. 1 H-NMR (400MHz, DMSO-d 6):7.94...

Embodiment 2

[0048]

[0049] Add N-benzylpiperidone (1.38g), p-toluenesulfonyl hydrazide (1.35g), and dioxane (31.2g) into the bottle, replace nitrogen three times under stirring conditions, and heat up to 75°C and stir Reaction 5h. Spot plate monitoring showed that after the N-benzylpiperidone point disappeared, 20 g of solvent was evaporated, and under nitrogen protection, tricyclohexylphosphine (0.064 g), tris(dibenzylideneacetone) dipalladium (0.0106 g) were added successively in the bottle. g), cesium carbonate (1.34g), 2-amino-5-bromopyridine (1g), heated to 110°C for 8h, filtered to obtain 6-amino-3',6'-dihydro-2'-hydrogen-[ 3,4']bipyridyl-1'-benzyl solution, external standard content 5.1%. Add Boc anhydride (1.1g) to the reaction solution, add 5% palladium carbon (0.06g), and pump hydrogen three times under stirring. Finished with diatomaceous earth filtration and concentration to obtain a paste, beating with 20ml methyl tert-butyl ether, filtered and dried to obtain solid 4-(...

Embodiment 3

[0051]

[0052] In the reaction flask, add 1-Cbz-4-piperidone (1.70g), p-toluenesulfonyl hydrazide (1.35g), dioxane (31.2g), replace nitrogen three times under stirring conditions, and heat up The reaction was stirred at 75°C for 5h. After spot plate monitoring showed that the 1-Cbz-4-piperidone point disappeared, the solvent was evaporated and 10 g of dioxane was added. Under nitrogen protection, 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (0.13g), [1,1'-bis(diphenylphosphino)ferrocene ] Palladium dichloride dichloromethane complex (0.047g), potassium carbonate (2.3g), 2-amino-5-bromopyridine (1g), heated to 110 ° C for 8h, filtered to obtain 6-amino-3' , 6'-dihydro-2'-hydrogen-[3,4']bipyridyl-1'-CBZ solution, external standard content 5.0%, content yield: 83%. MS(m / z)310.3(M+H) + .In this solution, add isopropanol (25mL), add Boc anhydride (1.1g), add 10% palladium carbon (0.05g) under the protection of nitrogen, and replace the hydrogen three times under stirring, a...

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Abstract

The invention discloses a process method suitable for amplification preparation of 4-(6-aminopyridin-3-yl) substituted piperidine, and belongs to the synthesis field of a medicine intermediate. N-substituted piperidone, aryl sulfohydrazide and 2-amino-5-bromopyridine are subjected to a coupling reaction under a palladium catalyst, and then are subjected to a hydrogenation to obtain 4-(6-aminopyridin-3-yl) substituted piperidine. According to the process, the raw materials in pyridine do not need to be protected; the condensation and the coupling are carried out in the same reaction kettle, sothat the operation cost is reduced, the steps of performing protection at first and then performing protection removal as in documents can be avoided, and production cost of the existing biological, medicine and chemical intermediates is greatly reduced; and the process is subjected to amplification verification in kilogram-scale, and the verification proves that the yield and the product purity are basically equal to those of gram-scale, so that the method can be used as a process for industrial scale production.

Description

technical field [0001] The invention belongs to the field of synthesis of pharmaceutical intermediates, and in particular relates to a process suitable for the scale-up preparation of 4-(6-aminopyridin-3-yl)-substituted piperidines. Background technique [0002] In recent years, major pharmaceutical companies in the world have developed a variety of selective CDK4 / CDK6 inhibitors, such as palbociclib developed by Pfizer / Onyx, abemaciclib developed by Eli Lilly, ribociclib developed by Novartis, for the treatment of cancer, cardiovascular Disorders and inflammatory diseases. [0003] WO2014183520 discloses a selective CDK4 / CDK6 inhibitor with a new structure, and found that the compound with this structure exhibits excellent effects and effects, especially excellent pharmacokinetic absorption activity, and has the following structure: In this inhibitor, 4-(6-aminopyridin-3-yl) substituted piperidine is an important structural fragment, for example: tert-butyl 4-(6-aminopyri...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCC07D401/04Y02P20/55
Inventor 孙鹏边奕澄田贝贝李超张欣魏菱李涛
Owner SHANGHAI ZAIQI BIO TECH
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