Preparation method of glyoxylamide compound

Abstract

The invention provides a preparation method of a glyoxylamide compound. The method comprises the step of allowing an arylalkynyl compound and amine to react in an organic solvent in the presence of an oxidant, a catalyst and a ligand to obtain the glyoxylamide compound. The method realizes high-yield synthesis of the glyoxylamide compound, and has good application prospects and industrial production potential.

Description

technical field

[0001] The invention relates to a preparation method of a biologically active intermediate compound, more particularly to a preparation method of a drug intermediate glyoxylamide compound, belonging to the technical field of medicine and organic chemical synthesis. Background technique

[0002] Glyoxylamide compounds are important structural components and important synthetic intermediates of many active biomolecules, and can be easily synthesized to obtain other active compounds, especially heterocyclic compounds, which themselves also exhibit significant biological activity, such as in application in antineoplastic drugs.

[0003] The preparation method of glyoxylamide compound has been paid more and more attention by scientists, and people have carried out a lot of research on it, and achieved certain results. So far, the preparation methods of glyoxylamide compounds have been reported in the prior art, but there are still some defects in these existing m...

Examples

Embodiment 1

[0034]

[0035] Add 20ml dimethyl sulfoxide and 1mmol compound of formula (I-1), 1.5mmol tert-butylamine, 0.1mmol rhodium triphenylphosphinecarbonyl acetylacetonate, 0.1mmol ligand L1, 2mmol bis(trifluoroacetic acid) in the reactor Iodobenzene and 1 mmol triethylamine were reacted with stirring at 60°C for 8 hours. After the reaction was completed, the reaction mixture was concentrated and evaporated to dryness, the residue was dissolved in chloroform, washed with water, and the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to remove the solvent, and the resulting residue was separated by silica gel column chromatography. , the above-mentioned compound of formula (II-1) was obtained with a yield of 96.2%. 1H NMR (CDCl 3 ,400MHz): δ9.58(s,1H,Ar-H); 8.12(d,8Hz,1H,Ar-H); 7.03(br s,2H,NH2); 6.79(br s,1H,CONH); 6.70 (d, 8Hz, 1H, Ar-H); 1.40 (s, 9H, C(CH3)3).

Embodiment 2

[0037]

[0038] Add 20ml dimethyl sulfoxide and 1mmol compound of formula (I-2), 1.5mmol tert-butylamine, 0.15mmol rhodium triphenylphosphinecarbonyl acetylacetonate, 0.2mmol ligand L1, 3mmol bis(trifluoroacetic acid) in the reactor Iodobenzene and 1.5 mmol triethylamine were stirred and reacted at 50°C for 8 hours. After the reaction was completed, the reaction mixture was concentrated and evaporated to dryness, the residue was dissolved in chloroform, washed with water, and the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to remove the solvent, and the resulting residue was separated by silica gel column chromatography. , the compound of formula (II-2) was obtained with a yield of 95.3%. 1 H NMR (CDCl 3 ,400MHz): δ8.44(s,1H,Ar-H); 7.18(d,8Hz,1H,Ar-H); 6.71(br s,1H,CONH); 6.59(d,8Hz,1H,Ar- H); 6.23 (brs,2H,NH 2 ); 1.42(s,9H,C(CH 3 ) 3 ).

Embodiment 3

[0040]

[0041]In the reactor, add 20ml dimethyl sulfoxide and 1mmol compound of formula (I-3), 1.5mmol tert-butylamine, 0.1mmol rhodium triphenylphosphinecarbonyl acetylacetonate, 0.1mmol ligand L2, 2mmol bis(trifluoroacetic acid) Iodobenzene and 1.5 mmol triethylamine were stirred and reacted at 60°C for 8 hours. After the reaction was completed, the reaction mixture was concentrated and evaporated to dryness, the residue was dissolved in chloroform, washed with water, organically dried over anhydrous sodium sulfate, filtered and evaporated to remove the solvent, and the resulting residue was separated by silica gel column chromatography , the compound of formula (II-3) was obtained with a yield of 93.8%. 1 H NMR (CDCl 3 ,400MHz):δ8.14(s,1H,Ar-H); 7.12(d,8Hz,1H,Ar-H); 6.61(br s,1H,CONH); 6.56(d,8Hz,1H,Ar- H); 6.08 (brs,2H,NH 2 ); 2.19(s,3H,CH 3 ); 1.41(s,9H,C(CH 3 ) 3 ).

technical field

[0001] The invention relates to a preparation method of a biologically active intermediate compound, more particularly to a preparation method of a drug intermediate glyoxylamide compound, belonging to the technical field of medicine and organic chemical synthesis. Background technique

[0002] Glyoxylamide compounds are important structural components and important synthetic intermediates of many active biomolecules, and can be easily synthesized to obtain other active compounds, especially heterocyclic compounds, which themselves also exhibit significant biological activity, such as in application in antineoplastic drugs.

[0003] The preparation method of glyoxylamide compound has been paid more and more attention by scientists, and people have carried out a lot of research on it, and achieved certain results. So far, the preparation methods of glyoxylamide compounds have been reported in the prior art, but there are still some defects in these existing m...

Examples

Embodiment 1

[0034]

[0035] Add 20ml dimethyl sulfoxide and 1mmol compound of formula (I-1), 1.5mmol tert-butylamine, 0.1mmol rhodium triphenylphosphinecarbonyl acetylacetonate, 0.1mmol ligand L1, 2mmol bis(trifluoroacetic acid) in the reactor Iodobenzene and 1 mmol triethylamine were reacted with stirring at 60°C for 8 hours. After the reaction was completed, the reaction mixture was concentrated and evaporated to dryness, the residue was dissolved in chloroform, washed with water, and the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to remove the solvent, and the resulting residue was separated by silica gel column chromatography. , the above-mentioned compound of formula (II-1) was obtained with a yield of 96.2%. 1H NMR (CDCl 3 ,400MHz): δ9.58(s,1H,Ar-H); 8.12(d,8Hz,1H,Ar-H); 7.03(br s,2H,NH2); 6.79(br s,1H,CONH); 6.70 (d, 8Hz, 1H, Ar-H); 1.40 (s, 9H, C(CH3)3).

Embodiment 2

[0037]

[0038] Add 20ml dimethyl sulfoxide and 1mmol compound of formula (I-2), 1.5mmol tert-butylamine, 0.15mmol rhodium triphenylphosphinecarbonyl acetylacetonate, 0.2mmol ligand L1, 3mmol bis(trifluoroacetic acid) in the reactor Iodobenzene and 1.5 mmol triethylamine were stirred and reacted at 50°C for 8 hours. After the reaction was completed, the reaction mixture was concentrated and evaporated to dryness, the residue was dissolved in chloroform, washed with water, and the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to remove the solvent, and the resulting residue was separated by silica gel column chromatography. , the compound of formula (II-2) was obtained with a yield of 95.3%. 1 H NMR (CDCl 3 ,400MHz): δ8.44(s,1H,Ar-H); 7.18(d,8Hz,1H,Ar-H); 6.71(br s,1H,CONH); 6.59(d,8Hz,1H,Ar- H); 6.23 (brs,2H,NH 2 ); 1.42(s,9H,C(CH 3 ) 3 ).

Embodiment 3

[0040]

[0041]In the reactor, add 20ml dimethyl sulfoxide and 1mmol compound of formula (I-3), 1.5mmol tert-butylamine, 0.1mmol rhodium triphenylphosphinecarbonyl acetylacetonate, 0.1mmol ligand L2, 2mmol bis(trifluoroacetic acid) Iodobenzene and 1.5 mmol triethylamine were stirred and reacted at 60°C for 8 hours. After the reaction was completed, the reaction mixture was concentrated and evaporated to dryness, the residue was dissolved in chloroform, washed with water, organically dried over anhydrous sodium sulfate, filtered and evaporated to remove the solvent, and the resulting residue was separated by silica gel column chromatography , the compound of formula (II-3) was obtained with a yield of 93.8%. 1 H NMR (CDCl 3 ,400MHz):δ8.14(s,1H,Ar-H); 7.12(d,8Hz,1H,Ar-H); 6.61(br s,1H,CONH); 6.56(d,8Hz,1H,Ar- H); 6.08 (brs,2H,NH 2 ); 2.19(s,3H,CH 3 ); 1.41(s,9H,C(CH 3 ) 3 ).

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