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A kind of preparation method of 2-(4-phenoxyphenyl)-6-(piperidin-4-) base nicotinamide

A technology of phenoxyphenyl, nicotinamide, which is applied in the field of medicine and chemical industry, and can solve problems such as undiscovered

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

AI Technical Summary

Problems solved by technology

[0005] At present, there is no relevant report on the preparation technology of 2-(4-phenoxyphenyl)-6-(piperidin-4-)yl nicotinamide in the prior art. Therefore, a 2-(4-phenyl A low-cost green preparation process of oxyphenyl)-6-(piperidin-4-)ylnicotinamide is of great significance for the production of obrutinib

Method used

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  • A kind of preparation method of 2-(4-phenoxyphenyl)-6-(piperidin-4-) base nicotinamide
  • A kind of preparation method of 2-(4-phenoxyphenyl)-6-(piperidin-4-) base nicotinamide
  • A kind of preparation method of 2-(4-phenoxyphenyl)-6-(piperidin-4-) base nicotinamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Example 1: Preparation of 2-(4-phenoxyphenyl)-6-(piperidin-4-)ylnicotinamide (I)

[0052] To a 1000 ml four-necked flask equipped with a stirring and thermometer, add 100 g of water, 200 g of methanol, 29.8 g (0.2 mol) of 3,3-dimethoxy-1-nitropropane, 26 g (0.26 mol) of 40 % sodium hydroxide, cooled, keeping the temperature at 0-5 ℃, dropwise added a solution of 41.5 g (0.22 mol) N-benzylpiperidin-4-one and 100 g methanol, the dropwise addition was completed in about 1 hour, after that, 10 The reaction was stirred at -15°C for 3 hours. 25 g of ammonium chloride, 51.5 g (0.202 mol) of 3-(4-phenoxyphenyl)-3-oxo-propionamide were added, and the reaction was stirred at 40-45° C. for 4 hours. The obtained reaction solution was transferred to a 1000 ml stainless steel autoclave, 0.8 g of 5% palladium carbon and 0.15 g of triphenylphosphine were added, and after nitrogen replacement 3 times, the pressure was filled with hydrogen to 0.4-0.5 MPa, and 30-35 ℃ of catalytic hydrog...

Embodiment 2

[0056] Example 2: Preparation of 2-(4-phenoxyphenyl)-6-(piperidin-4-)ylnicotinamide (I)

[0057] To a 1000 ml four-necked flask equipped with a stirring thermometer, add 100 g of water, 200 g of methanol, 35.4 g (0.2 mol) of 3,3-diethoxy-1-nitropropane, 16.8 g (0.3 mol) of hydrogen Potassium oxide, cooled, keeping the temperature at 0-5 ℃, dropwise added a solution of 41.5 g (0.22 mol) N-benzylpiperidin-4-one and 80 g methanol, the dropwise addition was completed in about 1.0 hours, after that, 10-15 The reaction was stirred for 3 hours. 30 g of ammonium chloride, 51.5 g (0.202 mole) of 3-(4-phenoxyphenyl)-3-oxo-propionamide were added, and the reaction was stirred at 40-45° C. for 4 hours. The obtained reaction solution was transferred to a 1000-milliliter stainless steel autoclave, 0.8 g of 5% palladium carbon and 0.15 g of triphenylphosphine were added, and after nitrogen replacement for 3 times, the pressure was filled with hydrogen to 0.4-0.5 MPa, and catalytic hydrogena...

Embodiment 3

[0058] Example 3: Preparation of 2-(4-phenoxyphenyl)-6-(piperidin-4-)ylnicotinamide (I)

[0059] To a 1000 ml four-necked flask equipped with a stirring thermometer, add 100 g of water, 200 g of methanol, 35.4 g (0.2 mol) of 3,3-diethoxy-1-nitropropane, 16.8 g (0.3 mol) of hydrogen Potassium oxide, cooled, keeping the temperature at 0-5 °C, dropwise added a solution of 48.2 g (0.22 mol) N-(4-p-methoxybenzyl)piperidin-4-one and 100 g methanol, about 1.0 hours dropwise After the addition was complete, the reaction was stirred at 15-20°C for 3 hours. 30 g of ammonium chloride and 51.5 g (0.202 mole) of 3-(4-phenoxyphenyl)-3-oxo-propionamide were added, and the reaction was stirred at 40-45° C. for 4 hours. The obtained reaction solution was transferred to a 1000-milliliter stainless steel autoclave, 0.8 g of 5% palladium carbon and 0.15 g of 4-dimethylaminopyridine were added, and after 3 times of nitrogen replacement, the pressure was filled with hydrogen to 0.4-0.5 MPa, and ca...

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Abstract

The invention provides a preparation method of 2-(4-phenoxyphenyl)-6-(piperidine-4-) nicotinamide, which utilizes 3,3-dialkoxy-1-nitropropane and N-P substituent piperidin-4-ketone obtains N-P substituent-4-hydroxy-4-(1-nitro-3,3-dialkoxy) through the first condensation reaction under the action of alkali propyl piperidine, then add ammonium salt and 3-(4-phenoxyphenyl)-3-oxo-propionamide to its reaction solution, obtain 2-(4-phenoxy through the second condensation reaction Benzoyl)-5-nitro-5-(N-P substituent-4-hydroxy-4-yl) piperidinyl n-pent-2-enamide, then under the effect of catalyst and hydrogen, under temperature-programmed conditions , obtain 2-(4-phenoxyphenyl)-6-(piperidine-4-) base nicotinamide through reduction-cyclization reaction and isomerization reaction. 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-(piperidin-4-)ylnicotinamide, and belongs to the technical field of medicine and chemical industry. Background technique [0002] 2-(4-phenoxyphenyl)-6-(piperidin-4-) nicotinamide (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 is significantly better than that of ibrutinib and zanu...

Claims

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Application Information

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