Synthesis method of aryl deuterated difluoromethyl compound

A synthesis method and difluoromethyl technology, which are applied in the field of synthesis of aryl deuterated difluoromethyl compounds, can solve the problems of few types of aryl deuterated difluoromethyl compounds, poor substrate adaptability, etc., and achieve applicable Effects with a wide range, easy operation, and simple steps

Active Publication Date: 2022-02-11
NANXIN PHARM TECH RES INST CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In summary, the current methods for synthesizing aryl deuterated difluoromethyl compounds generally require expensive reagents, and the substrate adaptability is poor, resulting in fewer types of aryl deuterated difluoromethyl compounds

Method used

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  • Synthesis method of aryl deuterated difluoromethyl compound
  • Synthesis method of aryl deuterated difluoromethyl compound
  • Synthesis method of aryl deuterated difluoromethyl compound

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preparation example Construction

[0037] The invention provides a kind of synthetic method of aryl deuterated difluoromethyl compound, comprising the following steps:

[0038] An aryl trifluoromethyl compound, an electrolyte, an activator, heavy water and a solvent are mixed for an electrolysis reaction to obtain an aryl deuterated difluoromethyl compound.

[0039] In the present invention, the general structural formula of the aryl trifluoromethyl compound is shown in formula I:

[0040] Ar-CF 3 Formula I;

[0041] In formula I: Ar represents phenyl, substituted phenyl, heteroaryl or heteroaryl; the substituents in the substituted phenyl include alkoxy, aryloxy, halogen, borate ester, silyl, Thioether group, NH 2 -, amino, acylamino, furyl, phenyl, substituted phenyl or amido; the alkyl in the alkoxy is preferably an alkanyl or cycloalkyl, and the number of carbon atoms in the alkoxy is preferably is 1 to 12, more preferably 3 to 10; the aryloxy group is preferably phenoxy, substituted phenoxy, naphthylo...

Embodiment 1

[0070] The raw material that adopts is compound 1a, and product is compound 2a, and reaction formula is as follows:

[0071]

[0072] Add compound 1a (0.2mmol), tetrabutylammonium bromide (0.2mmol), lithium tert-butoxide (0.2mmol) in two heart-shaped flasks, place between two pieces of graphite felt (1 × 1 × 0.5cm) A polytetrafluoroethylene film to ensure that the distance between the poles is not less than 0.2mm. Put two pieces of graphite felt into two heart-shaped bottles, connect a platinum wire to one piece of graphite felt, connect the positive pole of the power supply as an anode, and connect a piece of graphite felt to the anode. Insert a silver wire to connect the negative pole of the power supply as the cathode. After replacing the atmosphere in the reaction bottle with argon, add 5mL of N,N-dimethylformamide and heavy water (10mmol), and apply a voltage of 3.6V on the cathode and anode, that is, the voltage between the platinum wire and the silver wire is +3.6V, ...

Embodiment 2～37

[0077] Other conditions are the same as in Example 1, only the raw material compound 1a is replaced, the reaction voltage is adjusted, the reaction is monitored by gas chromatography to the end, and the reaction time is recorded; the raw material used in each embodiment is the -CDF in the product 2 Replace with -CF 3 After the compound, the specific structure is no longer listed one by one; in addition, the amount of 2n, 2ai, 2aj, 2an, 2at group reaction substrate is 0.1mmol, the amount of tetrabutylammonium bromide, lithium tert-butoxide and heavy water It is also halved on the basis of Example 1; the reaction temperature of Group 2an is 15° C., and the conditions not listed are all consistent with Example 1.

[0078]Product structure, reaction conditions and productive rate, deuterium substitution rate in the embodiment are shown in Table 1:

[0079] The product structure, reaction conditions, productive rate and deuterated rate of table 1 embodiment 2~37

[0080]

[00...

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Abstract

The invention relates to the technical field of organic synthesis, and provides a synthesis method of an aryl deuterated difluoromethyl compound. The aryl deuterated difluoromethyl compound is synthesized by taking an aryl trifluoromethyl compound as a raw material and heavy water as a deuterium source, activating a C-F bond in the aryl trifluoromethyl compound through an electrolytic reaction and introducing a deuterium atom. The deuterium water is used as the only deuterium source, other deuterated reagents are not needed, any transition metal is not used, and the method is suitable for synthesizing drugs sensitive to heavy metal residues. An electrochemical method is used for preparation, an additional reducing agent is not needed, the whole preparation process is simple in step and easy to operate, the product yield is high, and the deuteration rate is high. The method provided by the invention is wide in functional group application range, can synthesize various aryl deuterated difluoromethyl compounds with different functional groups, is suitable for later modification of drugs, and is beneficial to grafting to modification of existing drugs.

Description

technical field [0001] The technical field of organic synthesis of the present invention relates in particular to a method for synthesizing aryl deuterated difluoromethyl compounds. Background technique [0002] Deuterated difluoromethyl is a functional group that combines the structural characteristics of trifluoromethyl and trideuteromethyl. This functional group has unique properties in regulating metabolic stability and hydrogen bond network. At present, difluoromethyl free have been used in medicinal chemistry. [0003] In the existing technology, the synthesis of deuterated difluoromethyl compounds mainly focuses on the deuterated difluoromethyl functional groups substituted by alkyl groups, as reported by the Colby research group in 2017 using D 2 O was used as a deuterium source to protonate hydrated 1,3-diketone to obtain deuterated trifluoromethyl groups at the α-position of the carbonyl, and the reaction was shown in formula 1 (Sowaileh, M.F.; Han, C.; Hazlitt, R...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C25B3/11C25B3/25
CPCC25B3/11C25B3/25
Inventor 程旭盛杰
Owner NANXIN PHARM TECH RES INST CO LTD
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