Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
It is noted that the terms first, second and the like in the description and in the claims of the present invention are used for distinguishing between similar elements and not necessarily for describing a particular sequential or chronological order. It is to be understood that the data so used is interchangeable under appropriate circumstances such that the embodiments of the invention described herein are capable of operation in sequences other than those illustrated or described herein. Furthermore, the terms "comprises," "comprising," and "having," and any variations thereof, are intended to cover a non-exclusive inclusion, such that a process, method, system, article, or apparatus that comprises a list of steps or elements is not necessarily limited to those steps or elements expressly listed, but may include other steps or elements not expressly listed or inherent to such process, method, article, or apparatus.
1. The invention is described in further detail below:
the invention discloses a synthesis method of a 2-aminoquinolone compound, which is characterized in that a 2-aminoquinolone compound is generated by a Wittig/rearrangement/6 pi electrical cyclization/isomerization tandem reaction of phosphorus ylide and isocyanate under a heating condition.
The synthetic method of the 2-aminoquinolone compound comprises a first method and a second method:
1) the method comprises the following steps: the same kind of isocyanate reacts with phosphorus ylide, and the reaction formula is as follows:
in the above reaction formula, R1,R2The group is alkyl, alkenyl, alkynyl, aryl or heterocyclic aryl;
the method comprises the following steps: under the protection of nitrogen, adding isocyanate into an organic solvent of phosphorus ylide, and stirring for 36 hours under a heating condition; after the reaction is finished, cooling to room temperature; rotary evaporating, concentrating and column chromatography to obtain 2-amino quinolone compounds.
In the first method, the reaction charge ratio of the phosphorus ylide I and the isocyanate A is 1mol (2.0-2.4) mol; the adopted solvent is 1, 2-dichloroethane; the reaction feed ratio of the phosphorus ylide I to the 1, 2-dichloroethane is (0.45-0.55) mmol:3 mL; the heating temperature is 80-120 ℃.
2) The second method comprises the following steps: reacting different isocyanates with phosphorus ylide, wherein the reaction formula is as follows:
in the above reaction formula, R1,R2,R3The group is alkyl, alkenyl, alkynyl, aryl or heterocyclic aryl;
the method comprises the following steps: (1) adding isocyanate B into an organic solvent of phosphorus ylide I under the protection of nitrogen, and stirring for 1h at room temperature; after the reaction is finished, performing rotary evaporation concentration and column chromatography to obtain an amido substituted phosphorus ylide intermediate II; (2) under the protection of nitrogen, adding another aryl isocyanate C into the organic solvent of the amido-substituted phosphorus ylide II, and stirring for 36 hours under the heating condition; after the reaction is finished, cooling to room temperature, carrying out rotary evaporation concentration and column chromatography to obtain the 2-aminoquinolone compound.
In the second method, the reaction charge ratio of the phosphorus ylide I, the isocyanate B and the aryl isocyanate C is 1mol (1.0-1.2) mol; the adopted solvent is 1, 2-dichloroethane; the reaction charge ratio of the phosphorus ylide I and the 1, 2-dichloroethane is as follows: (0.45-0.55) mmol:3 mL; the heating temperature is 80-120 ℃.
The synthesis method of the 2-aminoquinolone compound disclosed by the invention is simple to operate, raw materials are simple and easy to obtain, and products are easy to separate and purify; the invention overcomes the defects of the synthesis reaction in the prior art and has the following advantages: (1) the raw materials are simple and easy to obtain; (2) the operation is simple; (3) no metal and no catalyst are involved; (4) the product is easy to separate and purify.
2. The specific embodiment is as follows:
example 1
Under the protection of nitrogen, adding 4-methylphenyl isocyanate (0.5mmol) into 1, 2-dichloroethane (3mL) of ethoxycarbonyl methylene triphenylphosphine (0.5mmol), stirring at 100 ℃ for 36-48 h, and cooling to room temperature after the reaction is finished; and (4) performing rotary evaporation concentration and column chromatography to obtain 124mg of a product, wherein the yield is 74%, the product is a yellow solid, and the melting point is 222-224 ℃.
1H NMR(400MHz,DMSO-d6)δ10.69(br s,1H),10.60(br s,1H),7.80(s,1H),7.42(d,J=8.3Hz,1H),7.33(d,J=7.5Hz,1H),7.28(m,4H),4.21(q,J=7.0Hz,2H),2.35(s,3H),2.34(s,3H),1.26(t,J=7.1Hz,3H).
13C NMR(100MHz,DMSO-d6)δ173.6,169.6,153.3,135.2,135.1,134.3,132.7,132.0,130.3,124.9,124.2,123.9,117.4,93.3,59.6,20.6,20.6,14.3.
IRνmax(neat):2956,1632,1578,1514,1434,1365,1281,1200,1148,1096,1018,807,742,665,556,541,520,489cm-1.
HRMS(ESI)calcd for C20H21N2O3[M+H]+:337.1547,found:337.1540.
Example 2
The procedure is as described in example 1, except that the substrates used are: 4-phenoxyphenyl isocyanate (0.5mmol), ethoxycarbonylmethylenetriphenylphosphine (0.5mmol) and 1, 2-dichloroethane (3mL) to give 118mg of product in 48% yield as a yellow solid with a melting point of 157-159 ℃.
1H NMR(400MHz,DMSO-d6)δ10.82(br s,1H),10.59(br s,1H),7.58(d,J=8.9Hz,1H),7.43(ddd,J=16.3,7.1,2.7Hz,7H),7.31(dd,J=8.9,2.8Hz,1H),7.18(t,J=7.4Hz,2H),7.11–7.03(m,6H),4.20(q,J=7.0Hz,2H),1.25(t,J=7.1Hz,4H).
13C NMR(100MHz,DMSO-d6)δ172.9,169.4,156.6,156.6,154.7,153.4,152.7,133.3,132.2,130.1,130.1,126.5,125.2,123.7,123.6,123.5,119.8,119.6,118.8,118.7,112.9,93.1,59.7,14.3.
IRνmax(neat):2977,1632,1582,1524,1503,1485,1368,1303,1280,1217,1161,1095,1051,872,844,807,768,742,706,688,566,523,506,428cm-1.
HRMS(ESI)calcd for C30H25N2O5[M+H]+:493.1758,found:493.1762.
Example 3
The procedure is as described in example 1, except that the substrates used are: 4-trifluoromethylphenyl isocyanate (0.5mmol), ethoxycarbonylmethylenetriphenylphosphine (0.5mmol) and 1, 2-dichloroethane (3mL) to give 144mg of product in 65% yield as a yellow solid with a melting point of 124-126 ℃.
1H NMR(400MHz,CDCl3)δ12.79(br s,1H),9.54(br s,1H),8.36(s,1H),7.92(d,J=8.5Hz,2H),7.76(dd,J=8.8,2.1Hz,1H),7.62(dd,J=18.9,8.7Hz,3H),4.59(q,J=7.1Hz,2H),1.58(t,J=7.1Hz,3H).
13C NMR(100MHz,CDCl3)δ169.8,169.3,152.6,142.6,129.0(q,J=10Hz),128.2 127.1,126.1(q,J=12Hz),124.2(q,J=289Hz),125.1,124.8,122.9,122.8,121.9(q,J=13Hz),116.9,93.6,63.5,14.1.
IRνmax(neat):3392,1660,1635,1597,1547,1443,1415,1316,1257,1150,1110,1064,1011,950,908,870,850,834,730,609,525,414cm-1.
HRMS(ESI)calcd for C20H15F6N2O3[M+H]+:445.0982,found:445.0974.
Example 4
The procedure is as described in example 1, except that the substrates used are: 4-trifluoromethoxyphenyl isocyanate (0.5mmol), ethoxycarbonyl methylene triphenylphosphine (0.5mmol) and 1, 2-dichloroethane (3mL) to obtain 125mg of the product, the yield is 52%, the product is a yellow solid, and the melting point is 167-169 ℃.
1H NMR(400MHz,DMSO-d6)δ11.30(br s,1H),10.46(s,1H),7.86(s,1H),7.63(d,J=9.0Hz,1H),7.56(dd,J=15.8,6.3Hz,3H),7.42(d,J=8.6Hz,2H),4.22(q,J=7.1Hz,2H),1.26(t,J=7.1Hz,3H).
13C NMR(100MHz,DMSO-d6)δ13C NMR 168.6,152.8,145.3(q,J=14Hz),143.9,136.9,125.2,125.0(q,J=10Hz),122.7(q,J=259Hz),122.36,117.6(q,J=258Hz),116.5,99.5,95.1,60.1,14.16.
IRνmax(neat):2968,1656,1583,1508,1449,1352,1239,1191,1160,1016,919,832,800,665,597,571,541,474cm-1.
HRMS(ESI)calcd for C20H15F6N2O5[M+H]+:447.0880,found:447.0873.
Example 5
The procedure is as described in example 1, except that the substrates used are: 2-methylphenyl isocyanate (0.5mmol), ethoxycarbonylmethylenetriphenylphosphine (0.5mmol) and 1, 2-dichloroethane (3mL) to give 113mg of product in 67% yield as a yellow solid with a melting point of 84-86 ℃.
1H NMR(400MHz,CDCl3)keto:δ11.26(br s,1H),8.19(d,J=7.9Hz,1H),7.61(br s,1H),7.44(d,J=6.2Hz,1H),7.40–7.38(m,3H),7.30–7.26(m,1H),7.16–7.11(m,1H),4.45(q,J=7.1Hz,2H),2.35(s,3H),2.03(s,3H),1.49(t,J=7.1Hz,3H);enol:δ12.83(br s,1H),9.06(br s,1H),8.70(d,J=8.0Hz,1H),7.98–7.96(m,1H),7.49(d,J=7.0Hz,1H),7.26–7.21(m,2H),7.01(td,J=7.4,1.0Hz,2H),4.64(q,J=7.2Hz,2H),2.57(s,3H),2.38(s,3H),1.54(t,J=7.2Hz,3H).
13C NMR(100MHz,CDCl3)keto:δ175.4,170.7,154.2,135.7,134.2,132.8,132.3,128.5,127.8,126.5,125.2,124.35,123.1,122.0,91.9,60.5,17.8,15.3,14.4;enol:δ170.2,169.9,150.8,148.2,138.6,134.4,133.3,133.1,130.0,127.5,126.1,122.5,121.8,121.2,116.0,92.5,62.8,18.5,18.0,14.5.
IRνmax(neat):3421,1622,1577,1544,1467,1393,1373,1306,1237,1178,1156,1071,1027,870,780,752,569,541,454cm-1.
HRMS(ESI)calcd for C20H21N2O3[M+H]+:337.1547,found:337.1536.
Example 6
The procedure is as described in example 1, except that the substrates used are: 2, 3-dimethylphenyl isocyanate (0.5mmol), ethoxycarbonylmethylenetriphenylphosphine (0.5mmol) and 1, 2-dichloroethane (3mL) to give 131mg of product in 72% yield as a yellow solid with a melting point of 116-118 ℃.
1H NMR(400MHz,CDCl3)δ11.21(br s,1H),8.08(d,J=7.9Hz,1H),7.67(br s,1H),7.28–7.24(m,3H),7.03(d,J=8.2Hz,1H),4.44(q,J=7.0Hz,2H),2.38(s,3H),2.30(s,3H),2.24(s,3H),1.87(s,3H),1.49(t,J=7.0Hz,3H).
13C NMR(100MHz,CDCl3)δ175.5,170.7,154.4,140.3,139.8,134.3,134.1,132.9,130.0,127.0,125.4,124.3,122.4,119.9,91.3,60.4,20.5,14.4,14.1,11.3.
IRνmax(neat):3416,2921,1621,1600,1581,1536,1462,1369,1297,1239,1218,1183,1165,1092,1019,882,866,794,777,714,593,573,538,455cm-1.
HRMS(ESI)calcd for C22H25N2O3[M+H]+:365.1859,found:365.1851.
Example 7
The procedure is as described in example 1, except that the substrates used are: 3, 5-bis (trifluoromethyl) phenyl isocyanate (0.5mmol), ethoxycarbonyl methylene triphenylphosphine (0.5mmol) and 1, 2-dichloroethane (3mL) to give 175mg of product, 60% yield, yellow solid product, melting point 79-81 ℃.
1H NMR(400MHz,CDCl3)δ13.48(br s,1H),9.71(br s,1H),8.30(s,2H),8.03(s,1H),7.90(s,1H),7.61(s,1H),4.73(q,J=7.1Hz,2H),1.64(t,J=7.1Hz,3H).
13C NMR(100MHz,CDCl3)δ169.3,168.9,152.2,150.1,140.5,133.6,133.3,132.1(q,J=99Hz),129.2(d,J=3Hz),128.6,128.2,124.6,121.9,120.49(d,J=4Hz),116.5(septet,J=22Hz),115.3,94.9,64.3,14.2.
IRνmax(neat):3392,1663,1590,1562,1473,1377,1272,1272,1121,998,947,882,850,773,725,701,681,613,539,452cm-1.
HRMS(ESI)calcd for C22H13F12N2O3[M+H]+:581.0729,found:581.0729.
Example 8
The procedure is as described in example 1, except that the substrates used are: naphthyl isocyanate (0.5mmol), carbethoxymethylene triphenylphosphine (0.5mmol) and 1, 2-dichloroethane (3mL) to give 113mg of product in 78% yield as a yellow solid with a melting point of 105-107 ℃.
1H NMR(400MHz,CDCl3)δ12.65(br s,1H),9.73(br s,1H),8.80(d,J=8.2Hz,1H),8.64(d,J=7.4Hz,1H),8.09–8.07(m,1H),7.99(d,J=8.9Hz,1H),7.92–7.90(m,1H),7.77(d,J=7.8Hz,1H),7.69(d,J=8.1Hz,1H),7.63–7.57(m,2H),7.53–7.47(m,4H),4.61(q,J=7.2Hz,2H),1.54(t,J=7.2Hz,3H).
13C NMR(100MHz,CDCl3)δ170.1,168.8,152.7,148.5,135.8,135.1,134.3,130.0,128.8,128.7,127.5,126.2,125.8,125.7,125.7,125.6,123.6,122.9,121.2,119.8,119.5,112.1,92.9,63.0,14.4.
IRνmax(neat):3428,2975,1618,1577,1540,1503,1446,1404,1369,1301,1273,1245,1162,1092,1021,881,865,832,816,798,780,762,694,653,629,567,534,487,451cm-1.
HRMS(ESI)calcd for C26H21N2O3[M+H]+:409.1546,found:409.1538.
Example 9
(1) Under the protection of nitrogen, adding 4-methyl isocyanate (0.5mmol) into a1, 2-dichloroethane solution (3mL) of ethoxycarbonyl methylene triphenylphosphine (0.5mmol), stirring at room temperature for 1-3 h, after the reaction is finished, performing rotary evaporation concentration, and performing column chromatography to obtain an intermediate. (2) Under the protection of nitrogen, adding benzyl isocyanate (0.5mmol) into 1, 2-dichloroethane (3mL) of an intermediate, stirring at 100 ℃ for 36-48 h, cooling to room temperature after the reaction is finished, performing rotary evaporation concentration, and performing column chromatography to obtain 138mg of a product, wherein the yield is 64%, the product is a yellow solid, and the melting point is 209-211 ℃.
1H NMR(400MHz,DMSO-d6)δ10.46(br s,1H),9.77(br s,1H),7.78(d,J=1.0Hz,1H),7.47(d,J=8.3Hz,1H),7.41(d,J=4.4Hz,4H),7.37–7.31(m,2H),4.72(d,J=5.6Hz,2H),4.16(q,J=7.0Hz,2H),2.34(s,3H),1.23(t,J=7.1Hz,3H).
13C NMR(100MHz,DMSO-d6)δ173.2,169.9,155.4,137.3,135.2,132.7,131.8,128.8,128.2,127.6,127.4,127.2,125.2,123.6,116.7,90.9,59.2,45.0,20.6,14.4.
IRνmax(neat):2979,1642,1606,1576,1531,1494,1423,1328,1306,1280,1224,1140,1109,1077,1051,1027,957,912,821,807,767,718,673,641,581,561,537,484,455,429cm-1.
HRMS(ESI)calcd for C20H21N2O3[M+H]+:337.1546,found:337.1552.
Example 10
The procedure is as described in example 9, except that the substrates used are: p-methyl phenyl isocyanate (0.5mmol), carbethoxymethylene triphenylphosphine (0.5mmol), p-methylbenzyl isocyanate and 1, 2-dichloroethane (3mL) to give 146mg of product in 83% yield as a yellow solid with a melting point of 214-216 ℃.
1H NMR(400MHz,DMSO-d6)δ10.40(br s,1H),9.70(t,J=5.2Hz,1H),7.77(s,1H),7.47(d,J=8.3Hz,1H),7.35(dd,J=8.2,1.4 1H),7.30(d,J=7.9Hz,2H),7.21(d,J=7.8Hz,2H),4.65(d,J=5.3Hz,2H),4.15(q,J=7.1Hz,2H),2.34(s,3H),2.30(s,3H),1.23(t,J=7.1Hz,3H).
13C NMR(100MHz,DMSO-d6)173.2,169.9,155.3,136.9,135.2,134.1,132.7,131.8,129.4,127.5,125.2,123.6,116.7,90.9,59.2,44.9,20.7,20.6,14.40.
IRνmax(neat):2986,1648,1596,1571,1526,1444,1380,1282,1220,1169,1131,1102,1045,1009,821,809,768,746,709,674,556,543,480,435cm-1.
HRMS(ESI)calcd for C21H23N2O3[M+H]+:351.1703,found:351.1700.
Example 11
The procedure is as described in example 9, except that the substrates used are: p-methyl phenyl isocyanate (0.5mmol), ethoxycarbonyl methylene triphenylphosphine (0.5mmol), p-tert-butylbenzyl isocyanate and 1, 2-dichloroethane (3mL) to give 165mg of product in 84% yield as a yellow solid with a melting point of 197-199 deg.C.
1H NMR(400MHz,DMSO-d6)δ10.47(br s,1H),9.75(br s,1H),7.79(s,1H),7.50(d,J=8.2Hz,1H),7.42(d,J=7.8Hz,2H),7.34(t,J=7.4Hz,3H),4.67(d,J=4.9Hz,2H),4.16(q,J=6.8Hz,2H),2.34(s,3H),1.27(s,9H),1.23(t,J=7.1Hz,3H).
13C NMR(100MHz,DMSO-d6)δ173.2,169.9,155.4,150.1,135.2,134.1,132.6,131.8,127.2,125.6,125.2,123.6,116.7,90.8,59.1,44.8,34.2,31.1,20.6,14.4.IRνmax(neat):2960,1624,1582,1513,1436,1366,1300,1166,1095,806,777,746,690,554,518,486cm-1.
HRMS(ESI)calcd for C24H29N2O3[M+H]+:393.2172,found:393.2167.
Example 12
The procedure is as described in example 9, except that the substrates used are: p-methyl phenyl isocyanate (0.5mmol), ethoxycarbonyl methylene triphenylphosphine (0.5mmol), p-fluorobenzyl isocyanate and 1, 2-dichloroethane (3mL) to obtain 100mg of a product, wherein the yield is 56%, the product is a yellow solid, and the melting point is 195-197 ℃.
1H NMR(400MHz,DMSO-d6)δ10.46(br s,1H),9.74(br s,1H),7.77(s,1H),7.46(dd,J=11.1,5.1Hz,3H),7.35(dd,J=8.3,1.4Hz,1H),7.23(t,J=8.8Hz,2H),4.70(d,J=5.5Hz,2H),4.16(q,J=7.0Hz,2H),2.34(s,3H),1.23(t,J=7.1Hz,3H).
13C NMR(100MHz,DMSO-d6)δ173.2,169.9,161.6(d,J=242Hz),155.3,135.2,133.6,132.7,131.9,129.6(d,J=8Hz),125.1,123.7,116.7,115.6(d,J=21Hz),91.0,59.2,44.2,20.6,14.4.
IRνmax(neat):2976,1642,1601,1582,1538,1508,1425,1328,1305,1281,1226,1138,1111,1094,1053,1027,956,902,830,802,768,735,674,643,567,540,498,454cm-1.
HRMS(ESI)calcd for C20H20FN2O3[M+H]+:335.1452,found:335.1447.
Example 13
The procedure is as described in example 9, except that the substrates used are: p-methyl phenyl isocyanate (0.5mmol), ethoxycarbonyl methylene triphenylphosphine (0.5mmol), p-trifluoromethyl benzyl isocyanate and 1, 2-dichloroethane (3mL) to obtain 102mg of a product, the yield is 50%, the product is a yellow solid, and the melting point is 194-196 ℃.
1H NMR(400MHz,DMSO-d6)δ10.47(br s,1H),9.84(t,J=6.0Hz,1H),7.76(d,J=8.0Hz,3H),7.59(d,J=8.1Hz,2H),7.44(d,J=8.3Hz,1H),7.34(dd,J=8.3,1.4Hz,1H),4.86(d,J=5.9Hz,2H),4.18(q,J=7.1Hz,2H),2.33(s,3H),1.24(t,J=7.1Hz,3H).
13C NMR(100MHz,DMSO-d6)δ173.2,169.9,155.4,142.6,135.2,132.3(d,J=78Hz),127.3(q,J=259Hz),125.6(q,J=8Hz),125.1,123.7,122.9,116.7,91.2,59.2,44.3,20.6,14.4.
IRνmax(neat):2957,1649,1602,1569,1525,1428,1369,1322,1281,1223,1162,1125,1105,1066,1017,954,902,820,808,716,676,638,591,566,543,518,470,439cm-1.
HRMS(ESI)calcd for C21H20F3N2O3[M+H]+:405.1420,found:405.1420.
Example 14
The procedure is as described in example 9, except that the substrates used are: 4-methylbenzene isocyanate (0.5mmol), ethoxycarbonyl methylene triphenylphosphine (0.5mmol), 2-methylbenzyl isocyanate and 1, 2-dichloroethane (3mL) to give 124mg of product in 71% yield as a yellow solid with a melting point of 179-181 ℃.
1H NMR(400MHz,DMSO-d6)δ10.45(br s,1H),9.65(br s,1H),7.78(s,1H),7.48(d,J=8.3Hz,1H),7.37(d,J=8.1Hz,1H),7.32(d,J=6.7Hz,1H),7.24(dd,J=12.2,4.2Hz,3H),4.68(d,J=5.1Hz,2H),4.15(q,J=7.1Hz,2H),3.35(s,3H),2.34(s,3H),1.22(t,J=7.0Hz,3H).
13C NMR(100MHz,DMSO-d6)δ173.1,170.0,155.5,136.1,135.2,135.1,132.7,131.8,130.5,127.8,127.5,126.3,125.2,123.7,116.7,90.8,59.2,43.5,20.6,18.6,14.3.
IRνmax(neat):2974,1651,1600,1571,1528,1443,1424,1331,1280,1222,1171,1136,1096,1051,954,824,810,770,745,730,673,558,542,469,427cm-1.
HRMS(ESI)calcd for C21H23N2O3[M+H]+:351.1703,found:351.1700.
The above-mentioned contents are only for illustrating the technical idea of the present invention, and the protection scope of the present invention is not limited thereby, and any modification made on the basis of the technical idea of the present invention falls within the protection scope of the claims of the present invention.