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Preparation method of alpha, alpha-diphenyl-4-piperidine methanol

A technology of piperidine methanol and benzyl alcohol, applied in the field of alpha, can solve the problems of unsafe storage and use in industrial production, increased production cost, toxic methyl iodide, etc., and achieves avoiding the problem of three wastes, low production cost, storage and use safe effect

Active Publication Date: 2021-04-30
南京方生和医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The method is cumbersome to operate, not only uses expensive Grignard reagents, but also uses highly toxic and easily decomposed methyl iodide, which is unsafe for industrial production and storage. In addition, it is difficult to demethylate after N-methylation protection, and it is necessary to add additional process steps, making the production cost higher

Method used

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  • Preparation method of alpha, alpha-diphenyl-4-piperidine methanol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] 1) α, the synthesis of α-diphenyl-4-pyridinemethanol:

[0030] Put 52g (0.5mol) of 4-cyanopyridine, 136.5g (0.75mol) of benzophenone, and 1L of xylene into a 2L four-necked bottle equipped with a nitrogen protection device, and add 25g (1.1mol) of metal sodium particles under nitrogen protection. ), then start heating, reflux reaction for 2 to 3 hours, after the reaction, cool down the system, then add 0.8L of ice water dropwise, a yellow solid precipitates during the dropwise addition, filter, wash the filter cake with clear water, and then reconstitute it with 0.8L of methanol Crystallized to obtain a white solid with a yield of 94%.

[0031] 2) Synthesis of N-benzyl-α, α-diphenyl-4-pyridinemethanol chloride:

[0032] Add 118g (0.45mol) of α,α-diphenyl-4-pyridinemethanol, 63.3g (0.50mol) of benzyl chloride, and 1L of acetonitrile into a 2L four-neck flask, then start heating, reflux for 2-3 hours, and the reaction ends Afterwards, the system was cooled down, filtere...

Embodiment 2

[0038] 1) α, the synthesis of α-diphenyl-4-pyridinemethanol:

[0039] Put 52g (0.5mol) of 4-cyanopyridine, 91g (0.5mol) of benzophenone, and 1L of xylene into a 2L four-necked bottle equipped with a nitrogen protection device, and add 17.3g (0.75mol) of metal sodium particles under nitrogen protection. ), then start heating, reflux reaction for 2 to 3 hours, after the reaction, cool down the system, then add 0.8L of ice water dropwise, a yellow solid precipitates during the dropwise addition, filter, wash the filter cake with clear water, and then reconstitute it with 0.8L of methanol Crystallized to obtain a white solid with a yield of 92%.

[0040] 2) Synthesis of N-benzyl-α, α-diphenyl-4-pyridinemethanol bromide:

[0041] Add 118g (0.45mol) of α,α-diphenyl-4-pyridinemethanol, 77g (0.45mol) of benzyl bromide, and 1L of acetonitrile into a 2L four-neck flask, then start heating, and reflux for 2 to 3 hours. The system was cooled down, filtered, and the filter cake and 0.6 L...

Embodiment 3

[0047] 1) α, the synthesis of α-diphenyl-4-pyridinemethanol:

[0048] Put 52g (0.5mol) of 4-cyanopyridine, 182g (1mol) of benzophenone, and 1L of xylene into a 2L four-necked bottle equipped with a nitrogen protection device, and add 8.7g (1.25mol) of lithium metal under nitrogen protection. Then start heating, reflux reaction for 2 to 3 hours, after the reaction, cool down the system, then add 0.8L of ice water dropwise, during the dropwise addition, a yellow solid precipitates, filter, wash the filter cake with water, and then recrystallize with 0.8L of methanol, A white solid was obtained with a yield of 96%.

[0049] 2) Synthesis of N-benzyl-α, α-diphenyl-4-pyridinemethanol chloride:

[0050] Add 118g (0.45mol) of α,α-diphenyl-4-pyridinemethanol, 68.4g (0.54mol) of benzyl chloride, and 1L of acetonitrile into a 2L four-neck flask, then start heating, reflux for 2-3 hours, and the reaction ends Afterwards, the system was cooled down, filtered, and the filter cake and 0.6L...

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Abstract

The invention discloses a preparation method of alpha, alpha-diphenyl-4-piperidine methanol, which comprises the following steps of by using benzophenone and 4-cyanopyridine as raw materials, carrying out free radical coupling reaction under the action of alkali metal to obtain alpha, alpha-diphenyl-4-piperidine methanol, reacting the obtained alpha, alpha-diphenyl-4-pyridine methanol with a benzylation reagent to generate N-benzyl-alpha, alpha-diphenyl-4-pyridine methanol, carrying out hydroboration reduction on the N-benzyl-alpha, alpha-diphenyl-4-pyridine methanol to obtain (1-benzyl-1, 2, 3, 6-tetrahydropyridine-4-yl)benzhydrol, ane enabling (1-benzyl-1, 2, 3, 6-tetrahydropyridine-4-yl)benzhydrol to be subjected to catalytic hydrogenation and debenzylation protection to obtain alpha, alpha-diphenyl-4-piperidine methanol. The method has the advantages of cheap and accessible raw materials, high reaction yield and high controllability, and is suitable for industrial production requirements.

Description

technical field [0001] The invention relates to a preparation method of diphenyl-4-piperidinemethanol, in particular to a preparation method of α,α-diphenyl-4-piperidinemethanol. Background technique [0002] Fexofenadine is a new generation of receptor antagonist without sedation and drowsiness. It was developed by Hermero (HMR) in Germany and was first listed in the United States after being approved by the FDA in 1996. , whose trade name is Allegra, is mainly used clinically for the treatment of seasonal allergic rhinitis and chronic idiopathic urticaria. α, α-diphenyl-4-piperidinemethanol is the key intermediate for the synthesis of fexofenadine, the main preparation methods are: [0003] (1) Patent CN104003929 reports the route of obtaining the target product by using 4-piperidinecarboxylic acid as raw material, N-acetylation, Friedel-Crafts acylation, addition with Grignard reagent phenylmagnesium halide, and then hydrolysis to deacetylate protection. This route raw ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/22
CPCC07D211/22Y02P20/55
Inventor 周步高魏洋飞
Owner 南京方生和医药科技有限公司
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