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A kind of (e)-3-aryl-1-fluoro-1,3-butadiene phosphonate compound and its synthesis method and application

A technology of butadiene phosphonate and synthesis method, which is applied to compounds of Group 5/15 elements of the periodic table, chemical instruments and methods, organic chemistry, etc., can solve the problem of poor regioselectivity and stereoselectivity and insufficient biological activity Ideal, harsh reaction conditions and other problems, to achieve the effect of high stereoselectivity, high yield and short reaction time

Active Publication Date: 2021-07-09
NANJING NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Although there have been studies on monofluoroalkenyl phosphonate compounds in the prior art, there are also defects such as unsatisfactory biological activity, complex preparation process, poor regioselectivity and stereoselectivity, low yield, and harsh reaction conditions.

Method used

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  • A kind of (e)-3-aryl-1-fluoro-1,3-butadiene phosphonate compound and its synthesis method and application
  • A kind of (e)-3-aryl-1-fluoro-1,3-butadiene phosphonate compound and its synthesis method and application
  • A kind of (e)-3-aryl-1-fluoro-1,3-butadiene phosphonate compound and its synthesis method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Add 4-methyl-1,1-difluoro-2,3-pentadienephosphonic acid diethyl ester (0.4 mmol), Pd(OAc) to a dry reaction tube 2 (5%mol), PPh 3 (15% mol) aryl boronic acid (0.8mmol), KOH (0.8mmol), 4mL Toluene, placed in a 50 ° C oil bath and stirred, TLC monitoring until the end of the reaction, diluted with ethyl acetate and concentrated by filtration, the crude product with petroleum ether- Ethyl acetate was used as the eluent to separate the product by column chromatography. The reaction process is as follows:

[0036]

[0037] The obtained (E)-3-aryl-1-fluoro-1,3-butadiene phosphonate had the following structure and a yield of 94%.

[0038]

[0039] Diethyl(E)-(1-fluoro-4-methyl-3-phenylpenta-1,3-dien-1-yl)phosphonate

[0040] Yellow oil; IR(film):2927,2850,1454,1377,1270,1115,1018,969,766,708,552cm -1 ; 1 H NMR (400MHz, CDCl 3 ):δ7.33-7.29(m,2H),7.26-7.21(m,1H),7.11-7.09(m,2H),6.76(dd,J H-F =40.4Hz,JH-P =8.8Hz, 1H), 4.18-4.04(m, 4H), 1.95(s, 3H), 1.65(s, 3H), 1.31(...

Embodiment 2

[0042] The operation is the same as before, and the reaction process is as follows

[0043]

[0044] The obtained (E)-3-aryl-1-fluoro-1,3-butadiene phosphonate has the following structure and a yield of 90%.

[0045]

[0046] Diethyl(E)-(1-fluoro-3-(4-methoxyphenyl)-4-methylpenta-1,3-dien-1-yl)phosphonate.

[0047] Yellow oil; IR(film):2966,2918,1609,1512,1454,1377,1260,1115,1027,959,795,533cm -1 ; 1 H NMR (400MHz, CDCl 3 ):δ7.02-6.99(m,2H),6.84-6.81(m,2H),6.72(dd,J H-F =40.4Hz,J H-P =8.4Hz, 1H), 4.17-4.03(m, 4H), 3.77(s, 3H), 1.92(s, 3H), 1.65(s, 3H), 1.30(t, J=7.1Hz, 6H); 13 C NMR (100MHz, CDCl 3 ):δ158.1,147.4(dd,J C-F =282.3Hz,J C-P =234.5Hz), 139.6(d, J C-F =3.0Hz), 132.7, 130.0, 127.5 (d, J C-F =13.6Hz), 122.9(d, J C-F =30.0Hz), 113.2, 62.8(d, J C-P =5.4Hz), 55.0, 22.4, 21.8, 16.2 (d, J C-P = 6.2Hz); 19 F NMR (376MHz, CDCl 3 ):δ-125.9(dd,J F-P =99.6Hz,J H-F =40.2Hz,1F); 31 P NMR (162MHz, CDCl 3 ):δ6.64(d,J F-P =100.1Hz,1P).HRMS Calcd for C 17 h...

Embodiment 3

[0049] The operation is the same as before, and the reaction process is as follows

[0050]

[0051] The obtained (E)-3-aryl-1-fluoro-1,3-butadiene phosphonate has the following formula, and the yield is 84%.

[0052]

[0053] Diethyl(E)-(1-fluoro-3-(4-fluorophenyl)-4-methylpenta-1,3-dien-1-yl)phosphonate.

[0054] Yellow oil; IR(film):2956,2908,1609,1512,1444,1388,1270,1105,1037,814,708,582,552 cm -1 ; 1 H NMR (400MHz, CDCl 3 ):δ7.07-7.03(m,2H),7.01-6.95(m,2H),6.73(dd,J H-F =40.2Hz,J H-P =8.6Hz, 1H), 4.18-4.04(m, 4H), 1.94(s, 3H), 1.63(s, 3H), 1.31(t, J=7.0Hz, 6H); 13 C NMR (100MHz, CDCl 3 ):δ161.5(d,J C-F =243.7Hz), 147.7(dd, J C-F =283.0Hz,J C-P =235.2Hz), 140.4(d, J C-F =3.1Hz), 136.3, 130.5(dd, J C-F =7.9,1.4Hz),127.2(d,J C-F =13.8Hz), 122.3(d, J C-F =30.2Hz), 114.8(d, J C-F =21.2Hz), 62.9(d, J C-P =5.5Hz), 22.4, 21.6, 16.1 (d, J C-F = 6.1Hz); 19 F NMR (376MHz, CDCl 3 ):δ-116.1--116.0(m,1F),-125.5(dd,J F-P =99.3Hz,J H-F =40.2Hz,1F); 31 P NMR (16...

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Abstract

The invention discloses an E-3-aryl-1-fluoro-1,3-butadiene phosphonate compound, and a method for synthesizing coupling defluorination with high regio and high stereoselectivity catalyzed by metal palladium , and the application of the E-3-aryl-1-fluoro-1,3-butadiene phosphonate compound as an enzyme inhibitor and in the preparation of antitumor drugs. The structure of the compound is shown in the following formula (1): wherein: substituent R 1 , R 2 is an alkyl group, or R 1 R 2 linked to form C 3 -C 6 Cycloalkyl, R 3 selected from substituted or unsubstituted aryl groups. The method of the invention is simple and convenient, has mild conditions, good substrate applicability, excellent yield, the yield of the target object can reach 80%-94%, high regioselectivity, and the coupling reaction is selectively at the 2,3-position of allene Occur on the double bond, and defluorination reaction occurs at the same time, and the monofluoroalkenyl phosphonate of E-configuration is synthesized with high stereoselectivity.

Description

technical field [0001] The invention relates to an (E)-3-aryl-1-fluoro-1,3-butadiene phosphonate compound and a synthesis method and application thereof, belonging to the technical field of fluorine-containing phosphonate compounds. Background technique [0002] Due to the unique properties of fluorine atoms, the synthesis of potentially biologically active fluorine-containing organic compounds has attracted much attention from chemists and pharmacologists. The monofluoroalkenyl structure acts as the bioisostere of the amide bond (Scheme 1), because it is not easily recognized and hydrolyzed by enzymes in the body, and the C=C double bond in the molecule has different Z or E configurations, it is used as a polypeptide mimic When it is used, the peptide mimics can have different spatial structures, so that their biological activities can be better explored and have better simulation effects. At present, alkenyl fluorine compounds have been widely used in the research of vari...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/40A61P35/00
CPCA61P35/00C07F9/4056
Inventor 林云穆甜甜贾如月王丹丹姜文丽
Owner NANJING NORMAL UNIVERSITY
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