A kind of preparation method of 2-(4-phenoxyphenyl)-6-(n-substituted oxycarbonyl piperidine-4-) base nicotinamide

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 ...

Examples

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%.

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 ...

Examples

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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