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Synthesis method of alpha, alpha-difluoro-gamma-hydroxyacetamide derivative

A technology of glycolamide and bromodifluoroacetanilide, which is applied in the field of synthesis of α,α-difluoro-γ-hydroxyacetamide derivatives, can solve the problem of single substrate and achieve good substrate applicability and reaction The effect of good selectivity and good application prospects

Active Publication Date: 2021-03-30
ZHEJIANG UNIV OF TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Existing literatures have reported methods for synthesizing difluoroalkyl alcohols partially through olefin difunctionalization (for example: (a) J.Org.Chem.2016, 81, 7001-7007; (b) Chem.Eur.J. 2016, 22, 1262-1265; (c) ChemSusChem.2019, 12, 3060-3063), but existing research mainly focuses on introducing difluoro groups into active olefin molecules such as styrene, and the substrate is relatively single

Method used

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  • Synthesis method of alpha, alpha-difluoro-gamma-hydroxyacetamide derivative
  • Synthesis method of alpha, alpha-difluoro-gamma-hydroxyacetamide derivative

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Embodiment 1

[0023] Add 2-bromo-2,2-difluoro-N-phenylacetamide (0.2mmol, 50mg), Rhodamine 6G (0.0025mmol, 1mg) and PMDETA (0.4mmol, 69mg) into a 5mL single-port reaction flask, add olefin Propylbenzene (2 mL) was used as a solvent and a reaction raw material, and reacted for 20 h under 3w white light irradiation at a temperature of 25° C. under an air atmosphere. After the reaction was completed, the reaction system was washed with water and extracted with dichloromethane, and separated into an organic layer and an aqueous layer. After the organic layer was dried with anhydrous sodium sulfate, the solvent was evaporated and concentrated under reduced pressure to obtain a colorless oil. The colorless oil was separated by column chromatography, using a mixture of petroleum ether and ethyl acetate with a volume ratio of 10:1 as the eluent, collecting the eluate containing the target compound, distilling off the solvent and drying to obtain 50 mg of white crystal 2, 2-Difluoro-4-hydroxy-N, 5-d...

Embodiment 2

[0026] The experimental process of Example 2 is the same as that of Example 1, except that "the organic base (PMDETA) in the system is replaced by DIPEA (0.4mmol, 51.6mg)", and other operations are the same as in Example 1, finally obtaining 25mg of white solid 2,2-difluoro-4-hydroxy-N,5-diphenylpentanamide, yield 40%.

Embodiment 3

[0028] The experimental process of embodiment 3 is the same as that of embodiment 1, and the only difference is that "the amount of photocatalyst (Rhodamine 6G) is changed to 0.02mmol". Other operations are the same as in embodiment 1, and finally 34mg of white solid 2,2-difluoro- 4-Hydroxy-N,5-diphenylpentanamide, yield 57%.

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Abstract

The invention discloses a synthesis method of an alpha, alpha difluoro gamma hydroxyacetamide derivative, which comprises the following steps: dissolving a bromo difluoro acetanilide compound shown ina formula (II), a photocatalyst and an organic alkali in an olefin derivative shown in a formula (I), reacting at room temperature for 5-24 hours under the irradiation of visible light, and after thereaction is finished, filtering to obtain the alpha, alpha difluoro gamma hydroxyacetamide derivative. A reaction system is subjected to post-treatment to obtain the alpha, alpha difluoro gamma hydroxyacetamide derivative shown in the formula (III), and the reaction formula is shown in the specification, in the formula (I) and the formula (III), a substituent group R1 is C2-C11 linear alkyl, arylor substituted aryl; in the formula (II) and the formula (III), the substituent R2 is H, methyl, methoxy, fluorine, chlorine, bromine or aromatic heterocycle. According to the invention, light is used as a reaction energy source to realize hydroxylation of olefin acetamide, so that the reaction is safer and greener, the cost is lower, the substrate application range of the reaction is expanded, and a simpler and more convenient method for preparing the alpha, alpha-difluoro gamma-hydroxyacetamide compound is provided.

Description

technical field [0001] The invention relates to a synthesis method of α,α-difluoro-γ-hydroxyacetamide derivatives. Background technique [0002] The introduction of fluorine atoms into the drug structure will change the lipophilicity, metabolic stability, bioavailability and other properties of the compound, which is a common method for new drug design. Difluoroalkyl alcohol compounds have been widely used in the synthesis of active molecules such as nucleotide analogs and enzyme inhibitors (for example: (a) Xu, Y.; Prestwich, G.D.Org.Lett.2002,4,4021. (b) Matulic-Adamic J.; Haeberli, P.; Usman, N. J. Org. Chem. 1995, 60, 2563. (c) Ladame, S.; Willson, M.; .Org.Chem.2002, 2640.(d) Butt, A.H.; Percy, J.M.; Spencer, N.S.Chem.Commun.2000, 1691.(e) Lopin, C.; , S.R.J. Am. Chem. Soc. 2002, 124, 14668.). In addition, studies have shown that difluoroketones have weak nucleophilicity, and medicinal chemists have used this property to design a series of protease inhibitors, which ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/12C07C235/38
CPCC07C231/12C07C235/38Y02B20/00
Inventor 朱蕊孙彬金灿
Owner ZHEJIANG UNIV OF TECH
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