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Preparation method of 3, 3-difluoro-4-aminopiperidine compound and derivative thereof

A technology of aminopiperidine and compounds, which is applied in the field of drug synthesis, can solve the problems that restrict the mass production of products, and achieve the effects of simplified operation, high yield and reasonable technical scheme

Active Publication Date: 2020-06-05
AQFLUOROTECH +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, method 1 involves reductive amination by introducing benzyl groups and method 2 introduces hydroxime for reduction, both of which are limited to small-scale preparations in the laboratory, and can only achieve the preparation of racemic compounds in the end.
Although method 3 can realize the preparation of optically pure products, the method of column purification and separation is used for separation in the process, which also greatly restricts the mass production of products

Method used

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  • Preparation method of 3, 3-difluoro-4-aminopiperidine compound and derivative thereof
  • Preparation method of 3, 3-difluoro-4-aminopiperidine compound and derivative thereof
  • Preparation method of 3, 3-difluoro-4-aminopiperidine compound and derivative thereof

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Experimental program
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Effect test

Embodiment 1

[0043] Embodiment 1: Preparation (S)-N-tert-butoxycarbonyl-3,3-difluoro-4-trifluoromethylsulfonyloxypiperidine (VI)

[0044]

[0045] Under nitrogen protection, the compound (S)-N-tert-butoxycarbonyl-3,3-difluoro-4-hydroxypiperidine (100g, 0.42mol, 1.00eq) represented by formula (V) was dissolved in 800mL of dichloromethane , Pyridine (100.0g, 1.26mol, 3.00eq) was added, the mixed solvent was cooled to minus 40°C, and trifluoromethanesulfonic anhydride (177.7g, 0.63mol, 1.50eq) was slowly added. The obtained light yellow clear liquid was slowly returned to room temperature, and the stirring was continued at room temperature for 2 hours, and then the reaction was monitored for completion. The reaction solution was quenched by adding 600 mL of water, and the layers were separated. The separated organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure to obtain 155.0 g of a light y...

Embodiment 2

[0048] Embodiment 2: Preparation (S)-N-benzyl-3,3-difluoro-4-trifluoromethylsulfonyloxypiperidine (VIII)

[0049]

[0050] Under nitrogen protection, the compound (R)-N-benzyl-3,3-difluoro-4-hydroxypiperidine (100g, 0.44mol, 1.00eq) represented by the formula (VII) was dissolved in 800mL of dichloromethane, added Pyridine (104.4g, 1.32mol, 3.00eq), the mixed solvent was cooled to minus 40°C, and trifluoromethanesulfonic anhydride (186.1g, 0.66mol, 1.50eq) was added slowly. The obtained pale yellow clear liquid was slowly returned to room temperature, and the stirring was continued at room temperature for 1.5 hours, and then the reaction was monitored for completion. The reaction solution was quenched by adding 600 mL of water, and the layers were separated. The separated organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure to obtain 159.2 g of a light yellow solid, and the c...

Embodiment 3

[0055] Embodiment 3: Preparation (R)-N-tert-butoxycarbonyl-3,3-difluoro-4-azidopiperidine (IX)

[0056]

[0057] Compound N-tert-butoxycarbonyl-3,3-difluoro-4-trifluoromethylsulfonyloxypiperidine (20g, 54.2mmol, 1.00eq) represented by formula (VI) was dissolved in anhydrous DMF (150mL) In, add sodium azide (5.28g, 81.2mmol, 1.5eq) and stir well. The resulting mixture was warmed to 40°C and stirred for 12 hours. After detecting the completion of the reaction, the reaction was lowered to room temperature, and 200 mL of saturated sodium chloride and 200 mL of ethyl acetate were added to separate the liquid. The aqueous phase was extracted once with ethyl acetate, and the organic phase was combined and washed with saturated brine (200 mL X2). Anhydrous sodium sulfate After drying, filtration and concentration, the crude product was obtained which could be directly used in the next reaction (light yellow oil, 12.78 g, 48.8 mmol, purity 95%, yield 90%).

[0058] Compound shown ...

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Abstract

The invention relates to a preparation method of a 3, 3-difluoro-4-aminopiperidine compound shown as a formula (I) and a derivative thereof, and the compound has the following structure: wherein R ishydrogen, C1-C9 alkyl, aryl, benzyl, CF3CO, R2CO or R3OCO; wherein R1 is C1-C9 alkyl, aryl or benzyl, R2 is C1-C9 alkyl, aryl or benzyl, and R3 is C1-C9 alkyl, aryl or benzyl; the preparation method of the compound and the derivative thereof comprises the following steps: starting from a 3, 3-difluoro-4-hydroxypiperidine structure, introducing a sulfonyloxy leaving group, and carrying out azido (N3) group substitution and azido reduction. According to the preparation method, optically pure 3, 3-difluoro-4-hydroxypiperidine and derivatives thereof are used as starting materials, and the optically pure 3, 3-difluoro-4-aminopiperidine and derivatives thereof with reversed configurations are finally obtained through the conversion.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of 3,3-difluoro-4-aminopiperidine compounds and derivatives thereof. Background technique [0002] The piperidine structure is a very important intermediate in the development of new drugs, and many drugs contain this type of structure. The introduction of fluorine atoms and fluorine-containing groups into piperidine molecules is a new direction for the development of new drugs. It is generally believed that the introduction of fluorine atoms into drugs can improve the metabolic stability and fat solubility of drugs, adjust the acidity and alkalinity of functional groups, and improve the degree of binding between drug molecules and targets. The introduction of fluorine atoms into organic molecules can bring dramatic changes to the molecular activity and its pharmacological properties, and thus has obvious advantages in the development of new drugs. Synthetic f...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/46C07D211/58
CPCC07B2200/07C07D211/46C07D211/58
Inventor 王忠于峰吴香梅晏飞军卢艺苏醒楼斌达卢寿福
Owner AQFLUOROTECH
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