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Synthesis method of 4,4-difluoropiperidine-1-formyl chloride

A technique for the synthesis of difluoropiperidine and its synthesis method, which is applied in the field of synthesis of 4,4-difluoropiperidine-1-formyl chloride, and can solve the problems of unstable raw materials and products, hazards to humans and the environment, and low reaction yields , to achieve the effects of simple post-treatment, high total yield and simple reaction

Inactive Publication Date: 2019-10-25
苏州汉德创宏生化科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In the above method, tert-butoxycarbonylpiperidone is unstable in raw materials and products during deoxyfluorination and aftertreatment, and the by-product of de-tert-butoxycarbonyl is generated, which causes difficulties for aftertreatment and low reaction yield; acid A large amount of acid will be used in the deprotection process, which will cause great pressure on the environment. In the last step, highly toxic carbonyl chloride will be used, which will cause great harm to people and the environment.

Method used

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  • Synthesis method of 4,4-difluoropiperidine-1-formyl chloride
  • Synthesis method of 4,4-difluoropiperidine-1-formyl chloride
  • Synthesis method of 4,4-difluoropiperidine-1-formyl chloride

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Embodiment 1

[0025] A kind of synthetic method of 4,4-difluoropiperidine-1-formyl chloride, prepare through the following steps:

[0026] Step 1: Add benzylpiperidone (100.0g, 528.4mmol) and dichloromethane (1.0 L) into a three-neck flask at room temperature, then add DAST (85.2g, 528.4mmol) dropwise at 0±5°C ). After the addition, the temperature was raised to room temperature and reacted at room temperature for 10-20 hours; after the reaction was completed, quenched with water (500 mL), added concentrated hydrochloric acid (50 mL), separated the aqueous phase, and washed the organic phase with water (500 mL); combined the aqueous phases, Basified with sodium carbonate, then extracted with dichloromethane (500mL×2), the obtained organic phase was dried over anhydrous magnesium sulfate, concentrated and purified to obtain the target product compound II 1-benzyl-4,4-difluoropiperidine 97.1g (87.0% yield, 98% purity).

[0027] The second step: at room temperature, the 1-benzyl-4,4-difluoro...

Embodiment 2

[0033] A kind of synthetic method of 4,4-difluoropiperidine-1-formyl chloride, prepare through the following steps:

[0034] Step 1: Add benzylpiperidone (100.0g, 528.4mmol) and dichloromethane (1.0 L) into a three-neck flask at room temperature, then add DAST (127.8g, 792.6mmol) dropwise at 0±5°C ), after the addition, the temperature was raised to room temperature and reacted at room temperature for 10-20 hours. After the reaction was completed, quenched with water (500 mL), added concentrated hydrochloric acid (50 mL), separated the aqueous phase, washed the organic phase with water (500 mL), combined with water Phase was basified with sodium carbonate, and then extracted with dichloromethane (500mL×2). The obtained organic phase was dried over anhydrous magnesium sulfate, concentrated and purified to obtain 98.2g of the target product (yield 88.0%, purity 98%).

[0035] The second step: at room temperature, the 1-benzyl-4,4-difluoropiperidine (98.0g, 463.9mmol) prepared in...

Embodiment 3

[0039] A kind of synthetic method of 4,4-difluoropiperidine-1-formyl chloride, prepare through the following steps:

[0040] Step 1: Add benzylpiperidone (100.0g, 528.4mmol) and N,N-dimethylformamide (1.0 L) into a three-necked flask at room temperature, then add DAST dropwise at 0±5°C (255.5g, 1585.2mmol), after the addition, the temperature was raised to room temperature and reacted at room temperature for 10-20 hours; after the reaction was completed, quenched with water (500mL), added concentrated hydrochloric acid (50mL), separated the aqueous phase, and washed the organic phase with water (500mL), the combined aqueous phase was alkalized with sodium carbonate, then extracted with dichloromethane (500mL×2), the obtained organic phase was dried over anhydrous magnesium sulfate, concentrated and purified to obtain 96.0g of the target product (yield 86.0%, purity 98%).

[0041]The second step: at room temperature, the 1-benzyl-4,4-difluoropiperidine (98.0g, 463.9mmol) obtai...

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Abstract

The invention discloses a synthesis method of 4,4-difluoropiperidine-1-formyl chloride. The synthesis method comprises the following steps that first, a compound I, namely benzylpiperidin-4-one, and afluorine reagent are deoxidized and fluorated in a first reaction solvent to obtain a compound II, namely 1-benzyl-4,4-difluoropiperidine; second, the compound II is subjected to benzyl removing in asecond reaction solvent under existence of a catalyst to obtain a compound III, namely 4,4-difluoropiperidine; and third, the compound III reacts with trichloromethyl carbonate in a third reaction solvent under the alkali effect to obtain a compound IV, namely the 4,4-difluoropiperidine-1-formyl chloride. According to the synthesis method of the 4,4-difluoropiperidine-1-formyl chloride, the benzylpiperidin-4-one with the low cost is taken as a raw material, a target product is obtained through deoxidization, fluorination, removing of amino-protecting groups and chlorine formylation, the raw material is low in cost and easy to obtain, atom economy is good, the total yield is high, reaction is easy, aftertreatment is easy and convenient, operability is high, and the 4,4-difluoropiperidine-1-formyl chloride is quite suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical fields of medicine and chemical industry, and in particular relates to a synthesis method of 4,4-difluoropiperidine-1-formyl chloride. Background technique [0002] 4,4-Difluoropiperidine-1-carbonyl chloride is an important structural unit in the field of medicine and chemical industry, widely exists in many pharmaceutical and chemical intermediates, and can be further reacted with alcohols and amines to prepare fluorine-containing compounds Esters, amides. At present, there are few synthetic methods for the compound 4,4-difluoropiperidine-1-carbonyl chloride, basically all of which use tert-butoxycarbonylpiperidone as the starting material, undergo deoxyfluorination, acid deprotection, and then use carbonyl chloride A chloroformylation reaction was carried out. In the above method, tert-butoxycarbonylpiperidone is unstable in raw materials and products during deoxyfluorination and aftertreatment, and the by-pro...

Claims

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Application Information

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IPC IPC(8): C07D211/38
CPCC07D211/38Y02P20/55
Inventor 茅仲平马东旭汪家喜
Owner 苏州汉德创宏生化科技有限公司
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