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Synthesis method for pyridone

A synthetic method and technology of pyridone, applied in the direction of organic chemistry, can solve the problems of harsh reaction conditions, flammable and explosive sodium hydrogen, expensive starting materials, etc., achieve mild and safe reaction conditions, shorten the reaction route, and optimize the synthesis route Effect

Inactive Publication Date: 2014-09-10
河北序能生物技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, there are still some problems and defects as follows in the preparation of Compound I at this stage: 1. The reaction route is long; 2. The reaction repeatability is poor, the system purity is unstable, and the post-processing operation is more loaded down with trivial details; 3. The reagent sodium hydrogen used during cyclization is flammable Explosive, harsh reaction conditions; 4. The starting materials are more expensive and the cost is high

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Embodiment 1: a kind of synthetic method of pyridone, it comprises the following steps

[0026] (1) Add 100 kg tetrahydrofuran into the reaction kettle, start stirring, then add 10 kg p-phenylenediamine and 28 kg triethylamine, cool the system down to 0°C, add 35 kg 5-chlorovaleryl chloride dropwise, drop After the addition was completed, the temperature was controlled at 20°C, and the reaction was carried out for 5 hours; after the reaction was completed, the temperature was lowered to 0°C, and 25 kg of potassium tert-butoxide was added to it in five batches, about 5 kg per batch, after the addition was completed, the temperature was controlled at 28°C, and the reaction was performed for 1 hours; after the reaction was completed, distill under reduced pressure at 40°C, then add the distillation residue to 180 kg ethyl acetate and 150 kg water for extraction, wash the organic phase with salt, then separate the organic phase and dry it with anhydrous sodium sulfate, separ...

Embodiment 2

[0029] Embodiment 2: a kind of synthetic method of pyridone, it comprises the following steps

[0030] (1) Add 120 kg of tetrahydrofuran into the reaction kettle, start stirring, then add 10 kg of p-phenylenediamine and 30 kg of triethylamine, cool the system down to 10°C, add dropwise 38 kg of 5-chlorovaleryl chloride, dropwise After the addition was completed, the temperature was controlled at 25°C for 8 hours; after the reaction was completed, the temperature was lowered to 5°C, and 28 kg of potassium tert-butoxide was added in five batches, adding 5 to 6 kg in each batch. After the addition was completed, the temperature was controlled at 22°C for 3 hours; After completion, distill under reduced pressure at 45-55°C, add 200 kg of ethyl acetate and 180 kg of water to the distillation residue for extraction, wash with salt, separate the organic phase and dry it with anhydrous sodium sulfate, filter, and separate the organic phase at 45 Distill under reduced pressure again at...

Embodiment 3

[0033] Embodiment 3: a kind of synthetic method of pyridone, it comprises the following steps

[0034](1) Add 110 kg of tetrahydrofuran into the reaction kettle, start stirring, then add 10 kg of p-phenylenediamine and 29 kg of triethylamine, cool the system to 4°C, add 36 kg of 5-chlorovaleryl chloride dropwise, drop After the addition, control the temperature at 30°C and react for 10 hours; after the reaction, cool down to 5°C and add 26 kg of potassium tert-butoxide in six batches, adding 4 to 5 kg in each batch. After the addition is complete, control the temperature at 20°C for 5 hours; After the reaction is completed, distill under reduced pressure at 40-50°C, add 190 kg of ethyl acetate and 160 kg of water for extraction of the distillation residue, wash with salt, separate the organic phase and dry it with anhydrous sodium sulfate, filter and dry the organic phase at 40 Distill under reduced pressure again at ~50°C, add the distillation residue to 60 kg ethyl acetate t...

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Abstract

The invention discloses a synthesis method for pyridone, and relates to the technical field of synthesis of a heterocyclic compound containing three heterocyclic rings one of which takes nitrogen and oxygen as the only one heteroatom. The synthesis method comprises the following steps: reacting tetrahydrofuran, ursol, triethylamine and 5-chlorin valeryl chloride which are taken as raw materials, and after the reaction, adding potassium tert-butoxide for reacting again, thereby obtaining a monomer 1 after reaction; reacting the monomer 1 with phosphorus pentachloride in a dichloromethane solvent, thereby obtaining a monomer 2 after reaction; reacting the monomer 2 with morpholine to obtain a final product I. The synthesis method has the advantages that the raw materials are cheap and easily available, and the reaction process is greatly shortened in comparison with that of the prior art, and the synthesis method is mild and safe in reaction conditions, good in reaction reproducibility, low in cost, and high in efficiency, and has simple and easy operations in the reaction.

Description

technical field [0001] The invention relates to the technical field of synthesis of a heterocyclic compound containing three heterocyclic rings and one heterocyclic ring with nitrogen and oxygen as the only heteroatoms. Background technique [0002] The chemical name of compound I is 5,6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-1-piperidinyl)phenyl]-2(1H)-pyridine Ketone, which is a key intermediate often used in the synthesis of apixaban, has the following structural formula: . [0003] Apixaban (Apixaban), trade name Eliquis (Eliquis), chemical name 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidine) -1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, its structural formula is as follows; [0004] . [0005] Apixaban is an oral selective activated factor X inhibitor jointly developed by Pfizer and Bristol-Myers Squibb. It can prevent blood clots, and has the following advantages compared with other similar drugs: It reduces the risk of stroke witho...

Claims

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Application Information

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IPC IPC(8): C07D211/76
CPCC07D211/76
Inventor 张基勇王平张伟张少平刘劲松孙海丽
Owner 河北序能生物技术有限公司
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