CN112062770A - Preparation method of fused ring dihydropyridone - Google Patents

Preparation method of fused ring dihydropyridone Download PDF

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CN112062770A
CN112062770A CN202010852231.0A CN202010852231A CN112062770A CN 112062770 A CN112062770 A CN 112062770A CN 202010852231 A CN202010852231 A CN 202010852231A CN 112062770 A CN112062770 A CN 112062770A
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dihydropyridone
fused ring
preparing
reaction
cdcl
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孙嫚嫚
王治明
杨健国
王磊
马永敏
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Taizhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

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Abstract

The invention discloses a preparation method of condensed ring dihydropyridone, which comprises the following steps: (1) carrying out elimination reaction on the dienyl ester adduct 1 and the aromatic amide 2 under the action of alkali and a solvent to obtain an intermediate reaction liquid; (2) and (2) adding a palladium catalyst, an amino acid ligand and a copper salt into the intermediate reaction solution obtained in the step (1), and carrying out C-H functionalization and allylamination reaction under the action of air or oxygen to obtain the fused ring dihydropyridone. The method has high atom utilization rate and low cost, and has important significance in the synthesis field.

Description

Preparation method of fused ring dihydropyridone
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of fused ring dihydropyridone.
Background
The dihydropyridinone compounds with heteroaromatic ring or condensed aromatic ring are commonly present in natural products and drug molecules with biological activity, and are also synthesis precursors of other important active molecules. Compared with the traditional method for constructing the compound framework through multi-step reaction, the transition metal catalyzed [4+2] cycloaddition reaction of the aromatic amide and the olefin containing C-H activation process is more dominant. However, at present such processes are mainly catalyzed by expensive rhodium catalysts. When palladium is used as the catalyst, the presence of a competing beta-H elimination reaction results primarily in an alkenylated product and does not result in a [4+2] cycloaddition product. In order to solve the problem, chemists use conjugated diene to replace common olefin for reaction, successfully realize [4+2] cycloaddition reaction of aromatic amide and olefin under the catalysis of palladium through a stable allyl palladium intermediate, and synthesize some condensed ring dihydropyridone compounds. However, the conjugated dienes used in the current reports are all relatively simple in structure, and the conjugated dienes mainly comprise chain or single-branch chain substituted conjugated dienes, and the conjugated dienes with multi-substitution, especially electron-withdrawing groups as branches are rarely reported. The main reasons include difficult synthesis of the electron-deficient branched conjugated diene, difficult control of Z/E selectivity of the diene, difficult control of Z/E selectivity of carbon-carbon double bonds in the product and more side reactions of the conjugated diene. Since 1, 3-conjugated dienes are also widely present in natural products and pharmaceutically active molecules and are also very important synthons in organic synthesis, development of a mild and efficient synthetic method for conjugated dienes and a method for preparing fused ring dihydropyridone compounds have great application value.
The organophosphine catalyzed reaction of diacrylates is a very important reaction in organic synthesis and is widely used for the synthesis of cyclic and acyclic compounds. Wherein, the nucleophilic addition reaction of the allenoic acid ester is simple to operate and low in cost, and is an efficient method for preparing the substituted olefin. Although various types of nucleophilic addition reactions have been extensively studied, few reports have been made on the use of nucleophilic addition products. In 2018, a subject group finds that a beta '-addition product of alpha-benzyl allenic acid ester developed by a Kwon subject group is easy to generate elimination reaction under an alkaline condition to obtain a 1, 2-disubstituted electron-deficient conjugated diene compound which is difficult to obtain in the traditional method, and the beta' -addition product and an o-iodophenol compound realize palladium-catalyzed cascade reaction to synthesize a series of dihydrobenzofuran and indoline compounds. The method has the advantages of mild conditions, high conversion efficiency, high product stereoselectivity, and multiple active functional groups in the product, and is a synthetic precursor of the conjugated diene with great application value.
Disclosure of Invention
In order to solve the technical problems, the invention provides a preparation method of fused ring dihydropyridone, which has high atom utilization rate and low cost.
The invention provides a preparation method of condensed ring dihydropyridone, which comprises the following steps:
(1) carrying out elimination reaction on the dienyl ester adduct 1 and the aromatic amide 2 under the action of alkali and a solvent to obtain an intermediate reaction liquid;
(2) adding a palladium catalyst, an amino acid ligand and a copper salt into the intermediate reaction solution obtained in the step (1), and carrying out C-H functionalization and allylamination reaction under the action of air or oxygen to obtain the fused ring dihydropyridone;
the reaction formula is as follows:
Figure BDA0002645122960000021
wherein R is-COOEt, -COOMe, -COOBn or CN;
Ar1is a substituted or unsubstituted aryl group, and the substituent on the aryl group is C1～C4Alkyl or halogen; preferably a substituted or unsubstituted phenyl group,
Ar2is a substituted or unsubstituted aryl or heteroaryl group, the substituent C on the aryl or heteroaryl group1～C4Alkyl radical, C1～C4Alkoxy or halogen; preferred are substituted or unsubstituted phenyl, thienyl, furyl, indolyl, benzothienyl.
Preferably, Ar is1Is a substituted or unsubstituted phenyl group.
Preferably, Ar is2Substituted or unsubstituted phenyl, thienyl, furyl, indolyl, benzothienyl.
Preferably, in step (1), the base is a diazabicyclo.
Preferably, in step (1), the organic solvent is p-xylene.
Preferably, in the step (1), the reaction temperature is 80-100 ℃ and the reaction time is 10-20 hours.
Preferably, in the step (2), the palladium catalyst is palladium trifluoroacetate;
the ligand is N-acetyl glycine.
Preferably, in the step (2), the copper salt is copper acetate.
Preferably, in the step (2), the reaction temperature is 110-130 ℃ and the reaction time is 20-30 hours.
Preferably, the fused ring dihydropyridone is one of compounds 4aa to 4am, 4ba to 4ma, and 6a to 6o, with specific results for these compounds being set forth in the detailed description.
Compared with the prior art, the invention has the beneficial effects that:
the catalyst adopted by the invention has the advantages of low price, easily obtained substrate, high conversion efficiency, good selectivity of the obtained product, good atom economy of the method, and important application significance in synthesis because the catalyst can be fused ring dihydropyridone or contain a plurality of functional groups.
Detailed Description
Examples 1 to 16
A10 mL Schlenk tube was charged with the bisallyl ester adduct 1a (0.4mmol), a base (the amount is shown in Table 1) and p-xylene 2mL, and the mixture was reacted at 90 ℃ for 12 hours with open stirring, followed by addition of the heteroaromatic amide 2a (0.2mmol), palladium trifluoroacetate (6.6mg,0.02mmol), a ligand (shown in Table 1, 0.012mmol), copper acetate (7.3mg,0.04mmol), and reaction at 120 ℃ for 24 hours with open stirring. The reaction system was cooled to room temperature, the sand core was filtered, ethyl acetate washed, the solvent was concentrated, and the target product 4aa was obtained by passing through a petroleum ether/ethyl acetate column, the conditions and yields are shown in table 1. The reaction formula is as follows:
Figure BDA0002645122960000031
TABLE 1 reaction conditions and yields of examples 1 to 16
Figure BDA0002645122960000032
Figure BDA0002645122960000041
aIntermediate 3 is not isolated;bthe isolation yield.
Examples 17 to 39
A10 mL Schlenk tube was charged with the bisallyl ester adduct 1(0.4mmol), the heteroarylamide 2(0.2mmol), DBU (60.9mg,0.04mmol) and p-xylene 2mL, and the mixture was reacted at 90 ℃ for 12 hours with open stirring, followed by addition of palladium trifluoroacetate (6.6mg,0.02mmol), N-acetylglycine (4.7mg, 0.012mmol), copper acetate (7.3mg,0.04mmol) and reaction at 120 ℃ for 24 hours with open stirring. And cooling the reaction system to room temperature, filtering by using a sand core, washing by using ethyl acetate, concentrating the solvent, and performing column chromatography by using petroleum ether/ethyl acetate (5/1) or 3/1 to obtain target products of 4 ab-4 am and 4 ba-4 ma.
The chemical reaction formula is as follows:
Figure BDA0002645122960000042
the structures of the target products 4 ab-4 am are as follows:
Figure BDA0002645122960000051
the structures and yields of the target products 4 ba-4 ma are as follows:
Figure BDA0002645122960000052
examples 40 to 54
A10 mL Schlenk tube was charged with the bisalkenyl ester adduct 1a (0.6mmol), benzamide 5 (0.2mmol), DBU (91.3mg,0.06mmol), and p-xylene (2 mL), and the mixture was reacted at 90 ℃ for 12 hours with open stirring, followed by the addition of palladium trifluoroacetate (6.6mg,0.02mmol), N-acetylglycine (4.7mg, 0.012mmol), copper acetate (7.3mg,0.04mmol), and the reaction was reacted at 120 ℃ for 24 hours with open stirring. And cooling the reaction system to room temperature, filtering by using a sand core, washing by using ethyl acetate, concentrating the solvent, and carrying out column chromatography by using petroleum ether/ethyl acetate (5/1) or 3/1 to obtain target products 6 a-6 o.
The chemical reaction formula is as follows:
Figure BDA0002645122960000053
the structures and yields of compounds 6 a-6 o are as follows:
Figure BDA0002645122960000061
wherein 6i and 6i ', 6j and 6j ', 6k and 6k ' are cis-trans isomeric mixtures.
The characterization data for the products of examples 1-54 are as follows:
compound 4aa
Figure BDA0002645122960000062
1H NMR(400MHz,CDCl3)8.36(d,J＝8.6Hz,2H),8.23(d,J＝8.6 Hz,2H),7.61(d,J＝7.9Hz,1H),7.54(d,J＝8.3Hz,1H),7.49(t,J＝7.7Hz, 1H),7.34(t,J＝7.5Hz,1H),7.31–7.25(m,3H),7.09–7.06(m,2H),6.73(s, 1H),5.99(d,J＝7.1Hz,1H),3.76(dd,J＝17.4,7.2Hz,1H),3.66–3.58(m, 1H),3.57–3.49(m,1H),3.46(d,J＝17.5Hz,1H),0.69(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)167.7,156.8,155.9,150.5,143.9,141.4,134.9, 133.5,131.3,130.9,129.3,128.7,128.1,126.0,125.2,124.4,123.5,121.7, 112.9,61.6,60.9,26.2,13.1；HRMS(ESI-TOF)m/z calcd for[M+ Na]+(C28H22N2O8SNa)569.0995,found 569.0998.
Compound 4ab
Figure BDA0002645122960000071
1H NMR(400MHz,CDCl3)8.36(d,J＝8.9Hz,2H),8.23(d,J＝8.9 Hz,2H),7.43(d,J＝9.1Hz,1H),7.31–7.28(m,3H),7.12–7.04(m,3H), 6.96(d,J＝2.6Hz,1H),6.72(s,1H),5.97(d,J＝7.2Hz,1H),3.84(s,3H), 3.73(dd,J＝17.3,7.3Hz,1H),3.69–3.54(m,2H),3.43(d,J＝17.4Hz,1H), 0.73(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)167.7,157.0,155.8, 152.0,150.5,144.0,142.0,134.9,133.5,131.2,131.0,129.3,128.6,128.1, 125.9,125.6,123.5,119.3,113.6,102.3,61.6,60.8,55.9,26.2,13.2；HRMS (ESI-TOF)m/z calcd for[M+Na]+(C29H24N2O9SNa)599.1100,found 599.1098.
Compound 4ae
Figure BDA0002645122960000072
1H NMR(400MHz,CDCl3)8.35(d,J＝8.9Hz,2H),8.25(d,J＝8.9 Hz,2H),7.86(d,J＝7.9Hz,1H),7.78(d,J＝7.3Hz,1H),7.50(t,J＝7.6Hz, 1H),7.45(t,J＝7.2Hz,1H),7.31–7.27(m,3H),7.12–7.09(m,2H),6.76(s, 1H),6.00(d,J＝6.9Hz,1H),3.74(dd,J＝17.3,7.0Hz,1H),3.67–3.52(m, 2H),3.46–3.38(m,1H),0.62(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3) 167.7,159.5,150.5,144.0,143.1,139.9,136.8,134.7,133.5,131.3,131.1, 129.3,129.2,128.7,128.4,128.1,125.4,123.7,123.5,123.4,61.6,60.6,28.9, 13.0；HRMS(ESI-TOF)m/z calcd for[M+Na]+(C28H22N2O7S2Na)585.0766, found 585.0770.
Compound 4ag
Figure BDA0002645122960000081
1H NMR(400MHz,CDCl3)8.34(d,J＝9.0Hz,2H),8.27(d,J＝9.0 Hz,2H),7.56(d,J＝1.9Hz,1H),7.33(dd,J＝8.9,2.0Hz,1H),7.32–7.24(m, 4H),7.12–7.06(m,2H),6.76(s,1H),5.95(d,J＝6.8Hz,1H),3.95(s,3H), 3.71(dd,J＝16.8,6.9Hz,1H),3.59–3.51(m,1H),3.44(d,J＝16.9Hz,1H), 3.36–3.28(m,1H),0.65(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3) 168.0,158.5,150.4,144.5,138.6,134.5,133.8,131.5,130.9,129.1,128.6, 128.0,127.2,126.8,125.0,124.5,123.6,120.2,118.9,111.6,61.2,61.0,31.7, 26.5,13.1；HRMS(ESI-TOF)m/z calcd for[M+ Na]+(C29H24ClN3O7SNa)616.0921,found 616.0928.
Compound 4ah
Figure BDA0002645122960000082
1H NMR(400MHz,CDCl3)8.36(d,J＝9.0Hz,2H),8.22(d,J＝8.9 Hz,2H),8.00(d,J＝7.5Hz,1H),7.35–7.18(m,6H),7.13–7.04(m,2H),6.74 (s,1H),5.95(d,J＝7.0Hz,1H),3.69(s,3H),3.67(dd,J＝15.6,7.2Hz,1H), 3.61–3.53(m,1H),3.43(d,J＝17.2Hz,1H),3.39–3.32(m 1H),0.73(t,J＝ 7.2Hz,3H)；13C NMR(100MHz,CDCl3)167.9,160.6,150.2,145.3,144.1, 138.0,134.4,133.6,131.4,130.9,129.2,128.6,128.1,124.9,123.5,123.4, 122.9,120.7,109.8,104.1,61.6,59.3,30.1,27.2,13.2；HRMS(ESI-TOF)m/z calcd for[M+Na]+(C29H25N3O7SNa)582.1311,found 582.1310.
Compound 4aj
Figure BDA0002645122960000091
1H NMR(400MHz,CDCl3)8.33(d,J＝8.9Hz,2H),8.22(d,J＝8.9 Hz,2H),7.59(d,J＝1.7Hz,1H),7.32–7.28(m,3H),7.08–7.06(m,2H),6.62 (s,1H),6.42(d,J＝1.7Hz,1H),5.86(d,J＝7.1Hz,1H),3.90–3.71(m,2H), 3.58(dd,J＝17.3,7.2Hz,1H),3.20(d,J＝17.3Hz,1H),0.90(t,J＝7.1Hz, 3H)；13C NMR(100MHz,CDCl3)167.6,154.7,150.5,149.1,144.1,140.9, 134.9,133.6,131.2,131.2,131.0,129.2,128.6,128.1,123.4,111.3,61.6,60.7, 27.4,13.4；HRMS(ESI-TOF)m/z calcd for[M+ Na]+(C24H20N2O8SNa)519.0838,found 519.0844.
Compound 4ak
Figure BDA0002645122960000092
1H NMR(400MHz,CDCl3)8.32(d,J＝8.7Hz,2H),8.23(d,J＝9.0 Hz,2H),7.62(d,J＝4.9Hz,1H),7.31–7.29(m,3H),7.09–7.07(m,2H), 6.93(d,J＝4.9Hz,1H),6.66(s,1H),5.89(d,J＝7.0Hz,1H),3.76–3.68(m, 2H),3.62(dd,J＝17.1,7.1Hz,1H),3.38(d,J＝17.1Hz,1H),0.88(t,J＝7.2 Hz,3H)；13C NMR(100MHz,CDCl3)167.6,158.8,150.5,144.5,144.2, 135.4,134.8,133.7,131.2,131.2,129.2,129.2,128.6,128.1,127.5,123.4, 61.5,60.4,30.5,13.4；HRMS(ESI-TOF)m/z calcd for[M+ Na]+(C24H20N2O7S2Na)535.0610,found 535.0616.
Compound 4al
Figure BDA0002645122960000101
1H NMR(400MHz,CDCl3)8.31(d,J＝9.0Hz,2H),8.24(d,J＝8.9 Hz,2H),7.32–7.26(m,3H),7.13–7.04(m,2H),6.74(d,J＝2.4Hz,1H),6.62 (s,1H),5.94(d,J＝2.4Hz,1H),5.84(d,J＝6.8Hz,1H),3.82–3.77(m,5H), 3.52(dd,J＝16.8,6.9Hz,1H),3.15(d,J＝16.7Hz,1H),0.94(t,J＝7.2Hz, 3H)；13C NMR(100MHz,CDCl3)167.9,157.4,150.2,145.2,134.2,134.1, 132.0,131.7,130.7,128.8,128.8,128.5,128.1,123.5,119.4,106.8,61.2,60.9, 36.3,28.3,13.5；HRMS(ESI-TOF)m/z calcd for[M+ Na]+(C25H23N3O7SNa)532.1154,found 532.1158.
Compound 4am
Figure BDA0002645122960000102
1H NMR(400MHz,CDCl3)8.33–8.26(m,4H),7.35–7.29(m,4H), 7.12–7.04(m,2H),6.67(s,1H),5.86(d,J＝6.9Hz,1H),4.06(s,3H), 3.77–3.64(m,2H),3.53(dd,J＝16.5,6.9Hz,1H),3.21(dd,J＝16.6,1.3Hz, 1H),0.90(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)167.9,156.6, 150.6,144.1,135.4,134.8,133.7,131.2,131.0,129.2,129.2,128.6,128.0,123.6,121.4,61.7,61.5,39.1,26.2,13.4；HRMS(ESI-TOF)m/z calcd for[M +Na]+(C24H22N4O7SNa)533.1107,found 533.1109.
Compound 4ba
Figure BDA0002645122960000111
1H NMR(400MHz,CDCl3)8.35(d,J＝8.9Hz,2H),8.22(d,J＝8.9 Hz,2H),7.61(d,J＝7.7Hz,1H),7.54(d,J＝8.4Hz,1H),7.49(t,J＝7.7Hz, 1H),7.34(t,J＝7.4Hz,1H),7.09(d,J＝8.0Hz,2H),6.97(d,J＝8.1Hz,2H), 6.68(s,1H),5.96(d,J＝7.1Hz,1H),3.76(dd,J＝17.4,7.3Hz,1H), 3.67–3.56(m,1H),3.56–3.48(m,1H),3.45(d,J＝17.0Hz,1H),2.32(s,3H), 0.70(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)167.9,156.8,155.9, 150.5,143.9,141.4,139.6,134.8,131.3,130.5,129.7,129.4,129.2,128.1, 126.0,125.2,124.4,123.5,121.7,112.9,61.5,61.1,26.2,21.3,13.1；HRMS (ESI-TOF)m/z calcd for[M+Na]+(C29H24N2O8SNa)583.1151,found 583.1152.
Compound 4ca
Figure BDA0002645122960000112
1H NMR(400MHz,CDCl3)8.40–8.32(m,2H),8.28–8.20(m,2H), 7.60(d,J＝7.9Hz,1H),7.55(d,J＝8.4Hz,1H),7.5(t,J＝7.2Hz,1H),7.34 (t,J＝7.5Hz,1H),7.32–7.27(m,2H),7.05–6.95(m,2H),6.65(s,1H),5.96(d, J＝7.1Hz,1H),3.76(dd,J＝17.3,7.2Hz,1H),3.68–3.52(m,2H),3.45(dd,J ＝17.4,1.0Hz,1H),1.28(s,9H),0.72(t,J＝7.1Hz,3H)；13C NMR(100 MHz,CDCl3)167.9,156.8,155.9,152.8,150.5,143.9,141.4,134.8,131.3, 130.4,129.7,129.2,128.0,126.0,125.6,125.2,124.4,123.5,121.6,112.9, 61.5,61.0,34.8,31.1,26.3,13.1；HRMS(ESI-TOF)m/z calcd for[M+ Na]+(C32H30N2O8SNa)625.1621,found 625.1620.
Compound 4ja
Figure BDA0002645122960000121
1H NMR(400MHz,CDCl3)8.39(d,J＝8.9Hz,2H),8.23(d,J＝8.8 Hz,2H),7.83–7.69(m,3H),7.62(d,J＝7.9Hz,1H),7.59–7.43(m,5H),7.34 (t,J＝7.5Hz,1H),7.16(d,J＝8.5Hz,1H),6.88(s,1H),6.03(d,J＝7.0Hz, 1H),3.78(dd,J＝17.4,7.3Hz,1H),3.70–3.61(m,1H),3.61–3.54(m,1H), 3.51(d,J＝17.5Hz,1H),0.69(t,J＝7.2Hz,3H)；13C NMR(100MHz, CDCl3)167.9,156.9,155.9,150.6,143.9,141.4,135.0,133.3,133.0,131.3, 131.0,131.0,129.3,128.5,128.4,128.2,127.7,127.2,126.8,126.0,125.2, 124.8,124.4,123.5,121.7,112.9,61.6,61.0,26.3,13.2；HRMS(ESI-TOF)m/zcalcd for[M+Na]+(C32H24N2O8SNa)619.1151,found 619.1155.
Compound 4la
Figure BDA0002645122960000122
1H NMR(400MHz,CDCl3)8.27(d,J＝8.9Hz,2H),8.05(d,J＝9.0 Hz,2H),7.59–7.56(m,2H),7.52(t,J＝7.7Hz,1H),7.35(t,J＝7.6Hz,1H), 7.29–7.16(m,6H),7.01(d,J＝7.3Hz,2H),6.81(d,J＝7.0Hz,2H),6.75(s, 1H),5.97(d,J＝7.1Hz,1H),4.52–4.44(m,2H),3.76(dd,J＝17.4,7.3Hz, 1H),3.45(d,J＝17.2Hz,1H)；13C NMR(100MHz,CDCl3)167.4,156.9, 155.8,150.3,143.7,141.4,135.2,133.6,133.3,131.1,130.7,129.3,129.0, 128.7,128.4,128.1,126.1,125.2,124.4,123.3,121.7,112.9,67.5,61.0,26.1； HRMS(ESI-TOF)m/z calcd for[M+Na]+(C33H24N2O8SNa)631.1151,found 631.1151.
Compound 4ma
Figure BDA0002645122960000131
1H NMR(400MHz,CDCl3)8.36–8.29(m,4H),7.64(d,J＝7.9Hz, 1H),7.60–7.56(m,3H),7.53(t,J＝7.8Hz,1H),7.46–7.35(m,4H),7.09(s, 1H),5.97(d,J＝6.9Hz,1H),3.77(dd,J＝17.7,6.9Hz,1H),3.58(d,J＝16.8 Hz,1H)；13C NMR(100MHz,CDCl3)157.2,155.3,150.8,146.1,143.7, 141.2,131.8,131.5,130.9,129.7,129.3,129.2,125.6,124.9,124.6,124.0, 121.6,116.3,113.1,108.6,59.3,26.4；HRMS(ESI-TOF)m/z calcd for[M+ Na]+(C26H17N3O6SNa)522.0736,found 522.0742.
Compound 6a
Figure BDA0002645122960000132
1H NMR(400MHz,CDCl3)8.34(d,J＝9.1Hz,2H),8.28(d,J＝9.0 Hz,2H),7.96(d,J＝7.9Hz,1H),7.50(t,J＝7.6Hz,1H),7.33(t,J＝7.6Hz, 1H),7.29–7.24(m,3H),7.21(d,J＝7.6Hz,1H),7.10–7.01(m,2H),6.64(s, 1H),5.86(d,J＝6.3Hz,1H),3.75(dd,J＝16.6,6.7Hz,1H),3.65(q,J＝7.1 Hz,2H),3.32(dd,J＝16.6,1.7Hz,1H),0.87(t,J＝7.2Hz,3H)；13C NMR (100MHz,CDCl3)167.6,163.0,150.5,144.2,136.0,135.3,134.3,133.9, 131.14,131.13,129.0,128.6,128.5,128.4,128.1,127.9,127.2,123.5,61.3, 58.4,33.7,13.4；HRMS(ESI-TOF)m/z calcd for[M+ Na]+(C26H22N2O7SNa)529.1045,found 529.1047.
Compound 6b
Figure BDA0002645122960000141
1H NMR(400MHz,CDCl3)8.34(d,J＝9.0Hz,2H),8.27(d,J＝8.9 Hz,2H),7.84(d,J＝8.0Hz,1H),7.31–7.23(m,3H),7.12(d,J＝8.0Hz,1H), 7.09–7.02(m,2H),7.00(s,1H),6.60(s,1H),5.85(d,J＝6.4Hz,1H),3.73- 3.66(m,3H),3.26(d,J＝16.6Hz,1H),2.35(s,3H),0.90(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)157.6,163.0,150.5,145.5,144.3,136.1,135.1, 134.0,131.2,131.1,128.9,128.9,128.8,128.7,128.5,128.1,124.6,123.5, 61.4,58.3,33.7,21.7,13.4；HRMS(ESI-TOF)m/z calcd for[M+ Na]+(C27H24N2O7SNa)543.1202,found 543.1209.
Compound 6e
Figure BDA0002645122960000142
1H NMR(400MHz,CDCl3)8.34(d,J＝9.0Hz,2H),8.27(d,J＝8.9 Hz,2H),7.91(d,J＝8.8Hz,1H),7.31–7.23(m,3H),7.06–7.03(m,2H),6.82 (dd,J＝8.8,2.4Hz,1H),6.65(d,J＝1.9Hz,1H),6.59(s,1H),5.85(d,J＝6.4 Hz,1H),3.82(s,3H),3.80–3.66(m,3H),3.26(d,J＝16.6Hz,1H),0.91(t,J ＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)167.6,164.4,162.7,150.5, 144.4,138.5,135.2,134.0,131.2,131.1,131.0,128.9,128.5,128.1,123.5, 119.7,113.9,112.9,61.4,58.2,55.6,34.0,13.4；HRMS(ESI-TOF)m/z calcd for[M+Na]+(C27H24N2O8SNa)559.1151,found 559.1159.
Compound 6i
Figure BDA0002645122960000151
1H NMR(400MHz,CDCl3)8.34–8.27(m,4H),7.90(d,J＝8.4Hz, 1H),7.34–7.27(m,4H),7.22(s,1H),7.07–7.04(m,2H),6.61(s,1H),5.86(d, J＝6.3Hz,1H),3.78–3.65(m,3H),3.30(d,J＝16.8Hz,1H),0.91(t,J＝7.1 Hz,3H)；13C NMR(100MHz,CDCl3)167.6,162.2,150.6,143.9,140.7, 137.8,135.5,133.8,131.2,130.8,130.2,129.1,128.5,128.4,128.3,128.1, 125.7,123.6,61.5,58.2,33.6,13.4；HRMS(ESI-TOF)m/z calcd for[M+ Na]+(C26H21ClN2O7SNa)563.0656,found 563.0662.
Compound 6i'
Figure BDA0002645122960000152
1H NMR(400MHz,CDCl3)8.33(d,J＝8.9Hz,2H),8.24(d,J＝8.9 Hz,2H),7.92(d,J＝8.4Hz,1H),7.79(s,1H),7.55–7.51(m,2H),7.48–7.45 (m,3H),7.29(d,J＝8.4Hz,1H),7.16(s,1H),6.21(d,J＝7.7Hz,1H),3.76 (dd,J＝16.5,8.0Hz,1H),3.72–3.65(m,1H),3.63–3.55(m,1H),3.05(d,J＝ 16.7Hz,1H),0.86(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)165.9, 162.8,150.5,144.2,143.3,139.7,137.3,133.9,131.2,130.9,129.7,129.4, 129.1,128.4,128.0,127.5,127.2,123.5,61.2,51.9,34.7,13.7；HRMS (ESI-TOF)m/z calcd for[M+Na]+(C26H21ClN2O7SNa)563.0656,found 563.0658.
Compound 6l
Figure BDA0002645122960000161
1H NMR(400MHz,CDCl3)8.56(s,1H),8.38(d,J＝9.0Hz,2H),8.30 (d,J＝9.0Hz,2H),7.88(d,J＝8.2Hz,1H),7.77(d,J＝8.2Hz,1H),7.63(s, 1H),7.57(t,J＝7.5Hz,1H),7.48(t,J＝7.2Hz,1H),7.27–7.16(m,3H), 7.02–6.94(m,2H),6.59(s,1H),5.95(d,J＝5.8Hz,1H),3.85(dd,J＝16.2, 6.3Hz,1H),3.72–3.59(m,2H),3.51(d,J＝16.2Hz,1H),0.84(t,J＝7.1Hz, 3H)；13C NMR(100MHz,CDCl3)167.6,163.4,150.6,144.2,136.0,135.4, 134.0,132.0,131.2,131.2,130.8,130.8,129.6,129.3,128.9,128.4,128.1, 127.3,127.1,126.8,125.1,123.6,61.3,58.3,34.1,13.3；HRMS(ESI-TOF) m/z calcd for[M+Na]+(C30H24N2O7SNa)579.1202,found 579.1199.
Compound 6n
Figure BDA0002645122960000162
1H NMR(400MHz,CDCl3)8.14(d,J＝7.9Hz,1H),7.53(t,J＝7.5Hz, 1H),7.39(t,J＝7.6Hz,1H),7.31–7.21(m,4H),7.17-7.14(m,2H),6.74(s, 1H),5.63(d,J＝6.5Hz,1H),3.77–3.55(m,3H),3.50(s,3H),3.27(d,J＝ 16.6Hz,1H),0.96(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)168.1, 163.9,136.3,134.8,134.2,134.0,131.3,128.7,128.7,128.4,128.2,128.2, 127.8,127.5,61.4,58.1,42.3,33.5,13.4；HRMS(ESI-TOF)m/z calcd for[M +Na]+(C21H21NO5SNa)422.1038,found 422.1046。

Claims (10)

1. A method for preparing a fused ring dihydropyridone, comprising:
(1) carrying out elimination reaction on the dienyl ester adduct 1 and the aromatic amide 2 under the action of alkali and a solvent to obtain an intermediate reaction liquid;
(2) adding a palladium catalyst, an amino acid ligand and a copper salt into the intermediate reaction solution obtained in the step (1), and carrying out C-H functionalization and allylamination reaction under the action of air or oxygen to obtain the fused ring dihydropyridone;
the reaction formula is as follows:
Figure FDA0002645122950000011
wherein R is-COOEt, -COOMe, -COOBn or CN;
Ar1is a substituted or unsubstituted aryl group, and the substituent on the aryl group is C1～C4Alkyl or halogen;
Ar2is a substituted or unsubstituted aryl or heteroaryl group, the substituent C on the aryl or heteroaryl group1～C4Alkyl radical, C1～C4Alkoxy or halogen.
2. A process for preparing a fused ring dihydropyridone according to claim 1 characterized in that Ar is1Is a substituted or unsubstituted phenyl group.
3. A process for preparing a fused ring dihydropyridone according to claim 1 characterized in that Ar is2Substituted or unsubstituted phenyl, thienyl, furyl, indolyl, benzothienyl.
4. A process for the preparation of a fused ring dihydropyridone as claimed in claim 1, characterised in that in step (1) the base is a nitrogen bis heterocyclic diazabicyclo ring.
5. A process for preparing a fused ring dihydropyridone according to claim 1 characterized in that in step (1) the organic solvent is p-xylene.
6. The method for preparing a fused ring dihydropyridone according to claim 1, characterized in that in step (1), the reaction temperature is 80 to 100 ℃ and the reaction time is 10 to 20 hours.
7. A process for preparing a fused ring dihydropyridone according to claim 1 wherein in step (2), the palladium catalyst is palladium trifluoroacetate;
the ligand is N-acetyl glycine.
8. A process for preparing a fused ring dihydropyridone according to claim 1, characterized in that in step (2), the copper salt is copper acetate.
9. The method for preparing a fused ring dihydropyridone according to claim 1, characterized in that in step (2), the reaction temperature is 110 to 130 ℃ and the reaction time is 20 to 30 hours.
10. A method of preparing a fused ring dihydropyridone according to claim 1 characterized in that the fused ring dihydropyridone is one of the compounds 4aa to 4am, 4ba to 4ma and 6a to 6 o.
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CA2508951A1 (en) * 2002-12-20 2004-07-08 F. Hoffmann-La Roche Ag Pyridino[2,3-d]pyrimidine derivatives as selective kdr and fgfr inhibitors
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