CN111057002B - Synthetic method of 2-aminoquinolone compound - Google Patents
Synthetic method of 2-aminoquinolone compound Download PDFInfo
- Publication number
- CN111057002B CN111057002B CN201911342621.7A CN201911342621A CN111057002B CN 111057002 B CN111057002 B CN 111057002B CN 201911342621 A CN201911342621 A CN 201911342621A CN 111057002 B CN111057002 B CN 111057002B
- Authority
- CN
- China
- Prior art keywords
- isocyanate
- phosphorus ylide
- aminoquinolone
- reaction
- follows
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a synthesis method of a 2-aminoquinolone compound, which is characterized in that a vinylogous/rearrangement/6 pi electrical cyclization/isomerization tandem reaction is carried out on phosphorus ylide and isocyanate under a heating condition, so that the 2-aminoquinolone compound is obtained. In the synthesis method disclosed by the invention, one isocyanate compound can be selected to react with the phosphorus ylide to synthesize the 2-aminoquinolone compound, and different isocyanates can be selected to react with the phosphorus ylide step by step to synthesize the 2-aminoquinolone compound. The synthetic method disclosed by the invention is simple to operate, the raw materials are easy to obtain, the reaction conditions are mild, no catalyst is needed, the product is easy to separate and purify, the technical difficulties of complicated steps and complex raw materials of the synthetic method in the prior art are solved, the synthetic method is a breakthrough in the prior synthetic technology, and the synthetic method has high application value.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a synthetic method of a 2-aminoquinolone compound.
Background
The quinolone compound has broad-spectrum antibacterial activity, and is widely used in clinical treatment as an antibacterial medicament, including treatment of urogenital tract infection, intestinal tract infection, respiratory tract infection, skeletal system infection, skin and soft tissue infection and the like. According to the invention and the difference of antibacterial property, the quinolone medicaments are divided into first, second, third and fourth generations, the fourth generation quinolone medicaments have the largest antibacterial spectrum at present, wherein typical medicaments comprise moxifloxacin, gatifloxacin, clinafloxacin and the like.
Because the quinolone compounds are widely applied clinically, the development of a high-efficiency synthesis method of the quinolone compounds is of great significance. The 2-aminoquinolone compound has remarkable IMPDH inhibition activity (WO2003035066A1,2003), but the synthesis method is relatively short, and the synthesis method of the 2-aminoquinolone reported in the past has the limitations of long steps, complex raw materials, troublesome operation, requirement of high-temperature conditions or catalysts and the like (chemistry select 2018,3, 1176; Angew. chem., int.Ed.2017,56,1805; J.org.chem.1999,64,3608; J.chem.Soc., Perkin Trans.11998, 2583).
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide a synthetic method of a 2-aminoquinolone compound, which has the advantages of simple operation, no need of a catalyst and easily obtained raw materials, and thus has good application prospect in the field of synthetic methods of 2-aminoquinolone.
In order to achieve the purpose, the invention adopts the following technical scheme to realize the purpose:
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 electrocyclic/isomeric tandem reaction of phosphorus ylide and isocyanate under a heating condition. In particular to two synthesis methods, comprising:
the method comprises the following steps:
the method for synthesizing the 2-aminoquinolone compound by reacting phosphorus ylide with isocyanate comprises the following steps:
under the atmosphere of nitrogen or inert gas, adding isocyanate and phosphorus ylide into an organic solvent, and stirring and reacting for 36-48 h under the heating condition; after the reaction is finished, sequentially cooling, carrying out rotary evaporation concentration and column chromatography treatment on the product mixed system to obtain a 2-aminoquinolone compound;
wherein the structural formula of the phosphorus ylide is as follows:
the structural formula of the isocyanate is as follows:
the structural formula of the 2-aminoquinolone compound is as follows:
R1,R2the group is alkyl, alkenyl, alkynyl, aryl or heterocyclic aryl.
Preferably, in the first method, the molar ratio of the reaction charge of the phosphorus ylide to the isocyanate is 1 (2.0-2.4).
The second method comprises the following steps:
the method for synthesizing the 2-aminoquinolone compound comprises the following steps of reacting phosphorus ylide with two different isocyanates step by step to synthesize the 2-aminoquinolone compound:
(1) adding isocyanate and phosphorus ylide into an organic solvent in nitrogen or inert atmosphere, and stirring for 1-3 h at room temperature; after the reaction is finished, firstly, carrying out rotary evaporation and concentration on a product mixed system, and then carrying out column chromatography on a concentrate to obtain an amido-substituted phosphorus ylide intermediate;
(2) under the atmosphere of nitrogen or inert gas, adding another aryl isocyanate and the amido-substituted phosphorus ylide intermediate into an organic solvent, and stirring for 36-48 h under the heating condition; after the reaction is finished, sequentially cooling, rotary distilling and concentrating and carrying out column chromatography treatment on the product mixed system to obtain a 2-aminoquinolone compound;
wherein the structural formula of the phosphorus ylide is as follows:
the structural formula of the isocyanate is as follows:
R2-NCO；
the structural formula of the amido-substituted phosphorus ylide intermediate is as follows:
the structural formula of the aryl isocyanate is as follows:
the structural formula of the 2-aminoquinolone compound is as follows:
R1,R2,R3the group is alkyl, alkenyl, alkynyl, aryl or heterocyclic aryl.
Preferably, in the second method, the reaction molar ratio of the phosphorus ylide to the isocyanate to the aryl isocyanate is 1 (1.0-1.2) to 1.0-1.2.
Preferably, in the first method and the second method, the reaction charge ratio of the phosphorus ylide to the organic solvent is (0.45-0.55) mmol:3 mL.
Further preferably, the charge ratio of the phosphorus ylide to the organic solvent is 0.50mmol:3 mL.
Preferably, in the first and second methods, the organic solvent used for the reaction comprises 1, 2-dichloroethane, acetonitrile, toluene, benzene, dimethyl sulfoxide, 1, 4-dioxane and tetrahydrofuran.
Further preferably, the organic solvent used for the reaction is 1, 2-dichloroethane.
Preferably, in the first method and the second method, the heating condition is 80-120 ℃.
Compared with the prior art, the invention has the following beneficial effects:
the invention discloses a synthesis method of a 2-aminoquinolone compound, which is characterized in that the 2-aminoquinolone compound is efficiently synthesized by a vinylogous/rearrangement/6 pi electrocyclic/isomeric tandem reaction of phosphorus ylide and isocyanate under a heating condition. In the synthesis method, the used reaction raw materials of phosphorus ylide and isocyanate are obtained in the mean square manner, so that the problem of complex raw material sources in the prior art is solved; the target product is obtained by the reactant through a Wittig/rearrangement/6 pi electrocyclic/isomeric series reaction under the heating condition, the series reaction condition is consistent and does not need to be adjusted, and other components such as a catalyst and the like do not need to be added in the reaction system, so that on one hand, impurities such as metal and the like cannot be introduced into the system, on the other hand, the separation and purification processes of the product are simple, and the method is a synthetic method with simple operation and mild reaction condition.
Furthermore, in the synthesis method provided by the invention, one isocyanate compound can be selected to react with the phosphorus ylide to synthesize the 2-aminoquinolone compound, and two different isocyanates can be selected to react with the phosphorus ylide step by step to synthesize the 2-aminoquinolone compound, so that the synthesis method has good practical application value.
Furthermore, in the synthesis method provided by the invention, the reaction is carried out at 80-120 ℃, so that the high conversion rate of the 2-aminoquinolone compound can be ensured, and the convenience and safety in operation can be ensured.
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.
Claims (6)
1. A synthetic method of 2-aminoquinolone compounds is characterized in that the 2-aminoquinolone compounds are generated through a Wittig/rearrangement/6 pi electrical cyclization/isomerization tandem reaction of phosphorus ylide and isocyanate under the heating condition, and the method comprises the following steps:
under an inert atmosphere, adding isocyanate and phosphorus ylide into an organic solvent, and stirring and reacting for 36-48 h under a heating condition; after the reaction is finished, sequentially cooling, carrying out rotary evaporation concentration and column chromatography treatment on the product mixed system to obtain a 2-aminoquinolone compound;
wherein the structural formula of the phosphorus ylide is as follows:
the structural formula of the isocyanate is as follows:
the structural formula of the 2-aminoquinolone compound is as follows:
R1,R2the group is alkyl, alkenyl, alkynyl, aryl or heterocyclic aryl;
the molar ratio of the phosphorus ylide to isocyanate in the reaction is 1 (2.0-2.4).
2. A synthetic method of 2-aminoquinolone compounds is characterized in that the 2-aminoquinolone compounds are synthesized by stepwise reaction of phosphorus ylide and two different isocyanates, and the method comprises the following steps:
(1) adding isocyanate and phosphorus ylide into an organic solvent under an inert atmosphere, and stirring for 1-3 h at room temperature; after the reaction is finished, firstly, carrying out rotary evaporation and concentration on a product mixed system, and then carrying out column chromatography on a concentrate to obtain an amido-substituted phosphorus ylide intermediate;
(2) under an inert atmosphere, adding another aryl isocyanate and the amido-substituted phosphorus ylide intermediate into an organic solvent, and stirring for 36-48 h under a heating condition; after the reaction is finished, sequentially cooling, rotary distilling and concentrating and carrying out column chromatography treatment on the product mixed system to obtain a 2-aminoquinolone compound;
wherein the structural formula of the phosphorus ylide is as follows:
the structural formula of the isocyanate is as follows:
R2-NCO；
the structural formula of the amido-substituted phosphorus ylide intermediate is as follows:
the structural formula of the aryl isocyanate is as follows:
the structural formula of the 2-aminoquinolone compound is as follows:
R1,R2,R3the group is alkyl, alkenyl, alkynyl, aryl or heterocyclic aryl;
the reaction molar ratio of the phosphorus ylide to the isocyanate to the aryl isocyanate is 1 (1.0-1.2) to 1.0-1.2.
3. The method for synthesizing a 2-aminoquinolone compound according to claim 1 or 2, wherein the reaction charge ratio of the phosphorus ylide to the organic solvent is (0.45-0.55) mmol:3 mL.
4. The method of claim 3, wherein the charge ratio of the phosphorus ylide to the organic solvent is 0.50mmol:3 mL.
5. The method for synthesizing a 2-aminoquinolone compound according to claim 1 or 2, wherein the organic solvent used in the reaction is 1, 2-dichloroethane.
6. The method for synthesizing a 2-aminoquinolone compound according to claim 1 or 2, wherein the heating is carried out at a temperature of 80 to 120 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911342621.7A CN111057002B (en) | 2019-12-23 | 2019-12-23 | Synthetic method of 2-aminoquinolone compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911342621.7A CN111057002B (en) | 2019-12-23 | 2019-12-23 | Synthetic method of 2-aminoquinolone compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111057002A CN111057002A (en) | 2020-04-24 |
| CN111057002B true CN111057002B (en) | 2021-08-13 |
Family
ID=70302658
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911342621.7A Active CN111057002B (en) | 2019-12-23 | 2019-12-23 | Synthetic method of 2-aminoquinolone compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111057002B (en) |
-
2019
- 2019-12-23 CN CN201911342621.7A patent/CN111057002B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN111057002A (en) | 2020-04-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| HRP970425A2 (en) | Substituted pyridines and biphenyls | |
| CN108976170B (en) | 5-trifluoromethyl-4H-imidazoline-4-ketone derivative and synthetic method thereof | |
| EP4186915A1 (en) | Method for synthesizing c-nucleoside compound | |
| CN115572300A (en) | Synthesis method of sulfonamide substituted polycyclic quinazolinone compound | |
| CN111057002B (en) | Synthetic method of 2-aminoquinolone compound | |
| CN110204533B (en) | Preparation method of 4- (isochromen-1-yl) isoquinoline derivative | |
| CN104557957B (en) | Synthetic method of spiro-oxoindole ethylene oxide derivative | |
| CN109761918B (en) | N1- (2,2, 2-trifluoro-1-aryl ethyl) -triazole derivative and synthesis method thereof | |
| CN108558785B (en) | 5-aryl-2-arylseleno-1, 3-oxazole compound and preparation method thereof | |
| Zhang et al. | Copper (I)‐Catalyzed Intramolecular N‐N Coupling of Cyclopropyl O‐Acyl Ketoximes: Synthesis of Spiro‐fused Pyrazolin‐5‐ones | |
| CN109400611B (en) | Synthesis method of 1-vinyl-4, 5-dihydropyrrole [1,2-a ] quinoxaline compound | |
| CN112645896B (en) | Method for synthesizing 4-aryl isoxazole derivative | |
| CN110028448B (en) | Preparation method of 3-hydroxy-2,3-dihydroisoquinoline-1, 4-diketone compound | |
| Gronowitz et al. | On the Synthesis of Isomeric Dithiophene Analogues of Phenathridine-N-oxides | |
| Mulhern et al. | A practical ortholithiation-based synthesis of 2-chloro-6-methylaniline | |
| WO2005005456A2 (en) | Peptide deformylase inhibitors | |
| CN103848830A (en) | Simple method for synthesizing imidazo (1,2-a) pyridine derivatives | |
| Dickman et al. | Synthesis of A-79175: a second generation 5-lipoxygenase inhibitor | |
| CN112125843B (en) | Preparation method of 3-hydroxymethyl-4-phenyl-3, 4-dihydroquinolinone compound | |
| CN110423224B (en) | Synthesis method of 2-aminopyrimidine type antiplatelet compound | |
| CN101555225B (en) | Method for preparing poly-substituted quinoline compound | |
| CN112745275B (en) | Synthetic method of 1,3, 4-oxadiazole heterocyclic compound | |
| CN110452213B (en) | Synthetic method of piperine | |
| CN111196786B (en) | Trifluoromethanesulfonyl substituted isoxazole compound and synthesis method thereof | |
| Tishchenko et al. | Synthesis of Carbamoyl Azides and 1-Substituted Tetrazol-5-ones from Isocyanates and NaN3 in the Presence of ZnCl2 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |