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Preparation method of 2-(4-phenoxyphenyl)-6-(piperidine-4-) yl 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: 2021-10-29
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[0052] Add 100 grams of water, 200 grams of methanol, 29.8 grams (0.2 moles) of 3,3-dimethoxyl-1-nitropropane, 26 grams (0.26 moles) of 40 % sodium hydroxide, cooling, keeping the temperature at 0-5°C, adding dropwise a solution of 41.5 grams (0.22 moles) of N-benzylpiperidin-4-one and 100 grams of methanol, and the addition was completed in about 1 hour. After that, The reaction was stirred at 10-15°C for 3 hours. Add 25 grams of ammonium chloride, 51.5 grams (0.202 moles) of 3-(4-phenoxyphenyl)-3-oxo-propionamide, and stir at 40-45°C for 4 hours. Transfer the resulting reaction solution to a 1000 ml stainless steel pressure vessel, add 0.8 g of 5% palladium carbon, 0.15 g of triphenylphosphine, replace nitrogen for 3 times, fill the hydrogen pressure to 0.4-0.5 MPa, and perform catalytic hydrogenation at 30-35°C Reaction for 5 hours, after the reduction-cyclization reaction, isomeriza...

Embodiment 2

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

[0057] Add 100 grams of water, 200 grams of methanol, 35.4 grams (0.2 moles) of 3,3-diethoxy-1-nitropropane, 16.8 grams (0.3 moles) of hydrogen into a 1000 milliliter four-necked flask equipped with a stirring and thermometer. Potassium oxide, cooling, keeping the temperature at 0-5°C, adding dropwise a solution of 41.5 grams (0.22 moles) of N-benzylpiperidin-4-one and 80 grams of methanol, and the addition was completed in about 1.0 hours. After that, 10-15 The reaction was stirred at °C for 3 hours. Add 30 grams of ammonium chloride, 51.5 grams (0.202 moles) of 3-(4-phenoxyphenyl)-3-oxo-propionamide, and stir at 40-45°C for 4 hours. Transfer the resulting reaction liquid to a 1000 ml stainless steel pressure vessel, add 0.8 g of 5% palladium carbon, 0.15 g of triphenylphosphine, replace nitrogen three times, fill the hydrogen pressure to 0.4-0.5 MPa, and carry out catalytic hydrogenati...

Embodiment 3

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

[0059] Add 100 grams of water, 200 grams of methanol, 35.4 grams (0.2 moles) of 3,3-diethoxy-1-nitropropane, 16.8 grams (0.3 moles) of hydrogen into a 1000 milliliter four-necked flask equipped with a stirring and thermometer. Potassium oxide, cooling, keeping the temperature at 0-5 ° C, dropwise adding a solution of 48.2 grams (0.22 moles) of N-(4-p-methoxybenzyl) piperidin-4-one and 100 grams of methanol, about 1.0 hours After the addition was complete, the reaction was stirred at 15-20°C for 3 hours thereafter. Add 30 grams of ammonium chloride, 51.5 grams (0.202 moles) of 3-(4-phenoxyphenyl)-3-oxo-propionamide, and stir at 40-45°C for 4 hours. Transfer the resulting reaction liquid to a 1000 ml stainless steel pressure vessel, add 0.8 g of 5% palladium carbon, 0.15 g of 4-dimethylaminopyridine, replace nitrogen three times, fill the hydrogen pressure to 0.4-0.5 MPa, and catalyze at 3...

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Abstract

The invention provides a preparation method of 2-(4-phenoxyphenyl)-6-(piperidine-4-)-yl nicotinamide, which comprises the following steps: carrying out primary condensation reaction on 3, 3-dialkoxy-1-nitropropane and N-P substituent piperidine-4-ketone under the action of alkali to obtain N-P substituent 4-hydroxy-4-(1-nitro-3, 3-dialkoxy) propyl piperidine, adding ammonium salt and 3-(4-phenoxy phenyl)-3-oxo-propanamide into reaction liquid, performing a second condensation reaction to obtain 2-(4-phenoxy benzoyl)-5-nitro-5-(N-P substituent-4-hydroxy-4-yl) piperidinyl n-pentyl-2-acrylamide, and under the action of a catalyst and hydrogen, under the temperature programming condition, carrying out a reduction-cyclization reaction and an isomerization reaction to obtain the 2-(4-phenoxyphenyl)-6-(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-(piperidin-4-)ylnicotinamide, which belongs to the technical field of medicine and chemical industry. Background technique [0002] 2-(4-phenoxyphenyl)-6-(piperidin-4-)ylnicotinamide (I) is an important pyridine derivative, which can be used in the preparation of 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 than that of ibrutinib and zanubrutinib. T...

Claims

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Application Information

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Patent Type & Authority Applications(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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