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A kind of preparation method of 2-(4-phenoxyphenyl)-6-(n-substituted oxycarbonyl piperidine-4-) base 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, easy operation of technological process, and cheap and readily available raw materials

Active Publication Date: 2022-07-01
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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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  • A kind of preparation method of 2-(4-phenoxyphenyl)-6-(n-substituted oxycarbonyl piperidine-4-) base nicotinamide
  • A kind of preparation method of 2-(4-phenoxyphenyl)-6-(n-substituted oxycarbonyl piperidine-4-) base nicotinamide
  • A kind of preparation method of 2-(4-phenoxyphenyl)-6-(n-substituted oxycarbonyl piperidine-4-) base 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] To a 500-mL four-necked flask equipped with a stirrer, a thermometer, a water separator and a reflux condenser, add 250 g of cyclohexane, 20.6 g (0.2 mol) of 3-nitropropanal, 51.0 g (0.2 mol) of 3-( 4-phenoxyphenyl)-3-oxopropionamide, 0.6 g of p-toluenesulfonic acid, reflux with water at 80-82°C for 3 hours with stirring, until the water is completely carried. The solvent was recovered by distillation under reduced pressure at 40°C, 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 n-Pent-2-enamide (IV), yield 92.6%, liquid phase purity 99.9%.

Embodiment 2

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

[0061] To a 500 ml four-necked flask equipped with stirring, a thermometer and a reflux condenser, add 250 g of ethanol, 20.6 g (0.2 mol) of 3-nitropropionaldehyde, 51.0 g (0.2 mol) of 3-(4-phenoxybenzene) yl)-3-oxopropionamide, 0.5 g of 98% sulfuric acid, and the reaction was stirred at 60-65 °C for 3 hours. Cool to 10-15°C, filter and dry to obtain 61.5 g 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] To a 500-mL four-necked flask equipped with a stirrer, a thermometer, a water separator and a reflux condenser, add 250 g of 2-methyltetrahydrofuran, 20.6 g (0.2 mol) of 3-nitropropanal, 51.0 g (0.2 mol) of 3 -(4-phenoxyphenyl)-3-oxopropionamide, 0.6 g of p-toluenesulfonic acid, reflux with water for 3 hours under stirring at 75-80° C. until the water is completely carried. The solvent was recovered by distillation under reduced pressure at 40°C, 200 g of 90% methanol aqueous solution was added to the residue, recrystallized by heating, filtered and dried to obtain 62.1 g of 2-(4-phenoxybenzoyl)-5-nitro n-Pent-2-enamide (IV), yield 91.3%, liquid phase purity 99.7%.

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Abstract

The invention provides a preparation method of 2-(4-phenoxyphenyl)-6-(N-substituted oxycarbonyl piperidine-4-) base nicotinamide, the method utilizes 3-nitropropionaldehyde and 3-nitropropionaldehyde -(4-phenoxyphenyl)-3-oxo-propionamide obtains 2-(4-phenoxybenzoyl)-5-nitro-n-pentane through the first condensation reaction under the action of an acid catalyst -2-enamide, then under the action of alkali and N-substituted oxycarbonyl piperidine-4-ketone through the second condensation reaction to obtain 2-(4-phenoxybenzoyl)-5-nitro- The reaction of 5-(N-substituted oxycarbonyl-4-hydroxy-4-yl) piperidinyl n-pent-2-enamide, adding ammonium salt, catalyst, under temperature-programmed conditions, through reduction-cyclization reaction and Isomerization reaction to obtain 2-(4-phenoxyphenyl)-6-(N-substituted oxycarbonyl piperidine-4-) base nicotinamide. The raw materials used in the invention are cheap and easy to obtain, the technological process is easy to operate, the target product has low cost, high yield and high purity, and is suitable 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, and 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 that can be used to prepare Orelabrutinib ). Orelabrutinib, CAS No. [1655504-04-3], is a specific and selective BTK inhibitor developed by China Nuocheng Jianhua, China National Medical Products Administration (NMPA) has accepted Orelabrutinib (ICP-022) New drug listing for the treatment of relapsed / refractory chronic lymphocytic leukemia (CLL) and the treatment of relapsed or refractory chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), application for the treatment of tumors and For autoimmune diseases, the overall efficacy of orelabrutinib is better than that of ibrutinib, and the safety factor ...

Claims

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Application Information

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