3,3-difluoro-1,2,3,6-tetrahydropiperidine derivative and preparation method thereof

A technology of tetrahydropiperidine and derivatives, which is applied in the field of 3,3-difluoro-1,2,3,6-tetrahydropiperidine derivatives and their preparation, and can solve the problems of no reported difluoro structure and the like , to achieve the effect of high yield, convenient industrial production operation, and controllable environmental impact

Pending Publication Date: 2020-06-05
SHANGHAI AQ BIOPHARMA CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, among the existing structures, the difluoro structure on the unsubstituted unsaturated piperidine ring has not been reported

Method used

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  • 3,3-difluoro-1,2,3,6-tetrahydropiperidine derivative and preparation method thereof
  • 3,3-difluoro-1,2,3,6-tetrahydropiperidine derivative and preparation method thereof
  • 3,3-difluoro-1,2,3,6-tetrahydropiperidine derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1: Preparation of N-tert-butoxycarbonyl-3,3-difluoro-4-trifluoromethylsulfonyloxypiperidine (V)

[0045]

[0046] Under nitrogen protection, the compound N-tert-butylcarbonyl-3,3-difluoro-4-hydroxypiperidine (100 g, 0.42 mol, 1.00 eq) represented by formula (IV) was dissolved in 800 mL of dichloromethane, and pyridine ( 100.0g, 1.26mol, 3.00eq), the mixed solvent was cooled to minus 40°C, and trifluoromethanesulfonic anhydride (177.7g, 0.63mol, 1.50eq) was slowly added. The obtained pale yellow clear liquid was slowly returned to room temperature, and the reaction was monitored for completion after continuous stirring at room temperature for 2 hours. The reaction solution was quenched by adding 600 mL of water, and the layers were separated. The separated organic phase was washed with a saturated laboratory once, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain 155.0 g of a light yellow solid. The...

Embodiment 2

[0049] Example 2: Preparation of N-benzyl-3,3-difluoro-4-trifluoromethylsulfonyloxypiperidine (VII)

[0050]

[0051] Under nitrogen protection, the compound N-benzyl-3,3-difluoro-4-hydroxypiperidine (100 g, 0.44 mol, 1.00 eq) represented by formula (VII) was dissolved in 800 mL of dichloromethane, and pyridine (104.4 g) was added. , 1.32mol, 3.00eq), the mixed solvent was cooled to minus 40°C, and trifluoromethanesulfonic anhydride (186.1g, 0.66mol, 1.50eq) was slowly added. The obtained pale yellow clear liquid was slowly returned to room temperature, and the reaction was monitored for completion after continuous stirring at room temperature for 1.5 hours. The reaction solution was quenched by adding 600 mL of water, and the layers were separated. The separated organic phase was washed with a saturated laboratory once, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain 159.2 g of a light yellow solid. The crude ...

Embodiment 3

[0054] Example 3: Preparation of N-methyl-3,3-difluoro-1,2,3,6-tetrahydropiperidine (X)

[0055]

[0056] Under nitrogen protection, the compound N-methyl-3,3-difluoro-4-hydroxypiperidine (10 g, 66.2 mmol, 1.00 eq) represented by formula (X) was dissolved in 100 mL of dichloromethane, and pyridine (28.0 g) was added. , 198.6mmol, 3.00eq), the mixed solvent was cooled to minus 40°C, and trifluoromethanesulfonic anhydride (186.1g, 99.3mmol, 1.50eq) was slowly added. The obtained pale yellow clear liquid was slowly returned to room temperature, and the reaction was monitored for completion after continuous stirring at room temperature for 1.5 hours. The reaction solution was quenched by adding 100 mL of water, and the layers were separated. The separated organic phase was washed with a saturated laboratory once, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a light yellow oil. %yield): 1 H NMR (400MHz, CDCl 3...

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Abstract

The invention discloses a 3,3-difluoro-1,2,3,6-tetrahydropiperidine derivative, which is characterized in that the structure of the 3,3-difluoro-1,2,3,6-tetrahydropiperidine derivative is shown as a formula I, and R is any one of hydrogen, C1-C9 alkyl group, aryl group, benzyl group, CF3CO, R2CO or R3OCO; R2 is any one of hydrogen, a C1-C9 alkyl group, an aryl group or a benzyl group; R3 is any one of C1-C9 alkyl group, aryl group or benzyl group; and each group is optionally not substituted or substituted by one or more substituent groups consisting of any one or more of alkyl group, haloalkyl group, hydroxyalkyl group, halogen, alkoxy group or hydroxyl group. The invention also discloses a preparation method thereof. The invention discloses the method for synthesizing the difluoro-substituted unsaturated piperidine structure for the first time, and the method is simple in process, easy for industrial operation and low in cost.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to a 3,3-difluoro-1,2,3,6-tetrahydropiperidine derivative and a preparation method thereof. Background technique [0002] In the field of medicinal chemistry research, the method of introducing fluorine atoms is commonly used to improve the metabolic stability and lipid solubility of drugs, adjust the acidity and alkalinity of functional groups, and improve the binding degree of drug molecules to targets. Due to the uniqueness of fluorine atoms, the introduction of fluorine atoms into organic molecules can bring dramatic changes in molecular activity and pharmacological properties, especially in the development of safe and selective drug molecules. Thus attracting more and more pharmacologists and pharmaceutical companies to join the ranks of fluorine-containing drug research and development (E.P.Gillis, K.J.Eastman, M.D.Hill, D.J.Donnelly, N.A.Meanwell, J.Med.Chem., 2015, 58, 8315; J. Wang...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/46C07D211/72
CPCC07D211/46C07D211/72
Inventor 吴香梅于峰晏飞军刘井洲卢艺苏醒卢寿福
Owner SHANGHAI AQ BIOPHARMA CO LTD
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