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Preparation method of 2-(4-phenoxyphenyl)-6-(N-substituted oxycarbonyl piperidine-4-) yl nicotinamide

A technology of phenoxyphenyl and base carbonyl piperidine is applied in the field of preparation of 2--6-yl nicotinamide, and achieves the effects of low cost, cheap and easily available raw materials, and easy operation of the technological process

Active Publication Date: 2021-10-29
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] At present, there is no relevant patent report about the preparation of 2-(4-phenoxyphenyl)-6-(N-substituted oxycarbonylpiperidin-4-)yl nicotinamide (I), and a 2-( The low-cost green preparation process of 4-phenoxyphenyl)-6-(N-substituted oxycarbonylpiperidin-4-)yl nicotinamide is of great significance for the production of obrutinib. For this reason, this paper is proposed invention

Method used

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  • Preparation method of 2-(4-phenoxyphenyl)-6-(N-substituted oxycarbonyl piperidine-4-) yl nicotinamide
  • Preparation method of 2-(4-phenoxyphenyl)-6-(N-substituted oxycarbonyl piperidine-4-) yl nicotinamide
  • Preparation method of 2-(4-phenoxyphenyl)-6-(N-substituted oxycarbonyl piperidine-4-) yl nicotinamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Example 1: Preparation of 2-(4-phenoxybenzoyl)-5-nitro-n-pent-2-enamide (Ⅳ)

[0059] Add 250 grams of cyclohexane, 20.6 grams (0.2 moles) of 3-nitropropanal, 51.0 grams (0.2 moles) of 3-( 4-phenoxyphenyl)-3-oxopropionamide, 0.6 g of p-toluenesulfonic acid, refluxed with water under stirring at 80-82°C for 3 hours until completely watered. The solvent was recovered by distillation under reduced pressure at 40°C, and 200 g of 90% methanol aqueous solution was added to the residue, recrystallized by heating, filtered, and dried to obtain 63.0 g of 2-(4-phenoxybenzoyl)-5-nitro The yield of n-pent-2-enamide (IV) is 92.6%, and the liquid phase purity is 99.9%.

Embodiment 2

[0060] Example 2: Preparation of 2-(4-phenoxybenzoyl)-5-nitro-n-pent-2-enamide (Ⅳ)

[0061] Add 250 grams of ethanol, 20.6 grams (0.2 moles) of 3-nitropropanal, 51.0 grams (0.2 moles) of 3-(4-phenoxybenzene base)-3-oxopropionamide, 0.5 g of 98% sulfuric acid, and stirred at 60-65° C. for 3 hours. Cool to 10-15°C, filter, and dry to obtain 61.5 grams of 2-(4-phenoxybenzoyl)-5-nitro-n-pent-2-enamide (Ⅳ), yield 90.4%, liquid phase purity 99.7%.

Embodiment 3

[0062] Example 3: Preparation of 2-(4-phenoxybenzoyl)-5-nitro-n-pent-2-enamide (Ⅳ)

[0063] Add 250 grams of 2-methyltetrahydrofuran, 20.6 grams (0.2 moles) of 3-nitropropanal, and 51.0 grams (0.2 moles) of 3 -(4-phenoxyphenyl)-3-oxopropionamide, 0.6 g of p-toluenesulfonic acid, reflux with water under stirring at 75-80°C for 3 hours until completely watered. The solvent was recovered by distillation under reduced pressure at 40°C, and 200 grams of 90% methanol aqueous solution was added to the residue, recrystallized by heating, filtered, and dried to obtain 62.1 grams of 2-(4-phenoxybenzoyl)-5-nitro The yield of n-pent-2-enamide (IV) is 91.3%, and the liquid phase purity is 99.7%.

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Abstract

The invention provides a preparation method of 2-(4-phenoxyphenyl)-6-(N-substituted oxycarbonyl piperidine-4-)-yl nicotinamide, which comprises the following steps of: under the action of an acid catalyst, carrying out a first condensation reaction on 3-nitropropionaldehyde and 3-(4-phenoxyphenyl)-3-oxo-propionamide, and obtaining the 2-(4-phenoxy benzoyl)-5-nitryl n-pentyl-2-alkenyl amide; then carrying out a second condensation reaction with N-substituted oxycarbonylpiperidin-4-ketone under the action of an alkali to obtain 2-(4-phenoxybenzoyl)-5-nitro-5-(N-substituted oxycarbonyl-4-hydroxy-4-yl) piperidinyl n-pentyl-2-enamide, adding ammonium salt and a catalyst, and under programmed temperature, carrying out a reduction-cyclization reaction and an isomerization reaction to obtain the 2-(4-phenoxyphenyl)-6-(N-substituted oxycarbonyl piperidine-4-) yl nicotinamide. The method has the advantages of cheap and easily available raw materials, easy operation of the process, low cost of the target product, high yield and purity, and suitableness for industrial production.

Description

technical field [0001] The invention relates to a preparation method of 2-(4-phenoxyphenyl)-6-(N-substituted oxycarbonylpiperidin-4-)yl nicotinamide, which belongs to the technical field of medicine and chemical industry. Background technique [0002] 2-(4-phenoxyphenyl)-6-(N-substituted oxycarbonylpiperidin-4-)ylnicotinamide (I) is an important pyridine derivative, which can be used to prepare Orelabrutinib ). Obrutinib, CAS No. [1655504-04-3], is a specific and selective BTK inhibitor developed by China InnoCare, and the National Medical Products Administration (NMPA) of China has accepted Obrutinib (ICP-022) New drug for the treatment of relapsed / refractory chronic lymphocytic leukemia (CLL) and relapsed or refractory chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), application for the treatment of tumors and For autoimmune diseases, the overall curative effect of obrutinib is better than that of ibrutinib, and the safety factor is significantly better...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 吕强三戚聿新王保林常清泉
Owner XINFA PHARMA