CN110272392B - 过渡金属催化的c-h偶联高效制备2-(4(3h)-喹唑啉酮)芳基乙酸烷基酯衍生物 - Google Patents
过渡金属催化的c-h偶联高效制备2-(4(3h)-喹唑啉酮)芳基乙酸烷基酯衍生物 Download PDFInfo
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- -1 aryl alkyl acetate derivative Chemical class 0.000 title claims abstract description 23
- QMNUDYFKZYBWQX-UHFFFAOYSA-N 1H-quinazolin-4-one Chemical compound C1=CC=C2C(=O)N=CNC2=C1 QMNUDYFKZYBWQX-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 229910052723 transition metal Inorganic materials 0.000 title claims abstract description 9
- 150000003624 transition metals Chemical class 0.000 title claims abstract description 9
- 238000005859 coupling reaction Methods 0.000 title claims abstract description 6
- 238000010168 coupling process Methods 0.000 title claims description 3
- 230000008878 coupling Effects 0.000 title claims 2
- 239000002253 acid Substances 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 6
- 230000002152 alkylating effect Effects 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 16
- HSYLTRBDKXZSGS-UHFFFAOYSA-N silver;bis(trifluoromethylsulfonyl)azanide Chemical group [Ag+].FC(F)(F)S(=O)(=O)[N-]S(=O)(=O)C(F)(F)F HSYLTRBDKXZSGS-UHFFFAOYSA-N 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 239000000654 additive Substances 0.000 claims description 6
- 230000000996 additive effect Effects 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- YRCVEMYVKSXPLM-UHFFFAOYSA-N 5-diazonio-2,2-dimethyl-6-oxo-1,3-dioxin-4-olate Chemical compound CC1(C)OC([O-])=C([N+]#N)C(=O)O1 YRCVEMYVKSXPLM-UHFFFAOYSA-N 0.000 claims description 2
- QVLTVILSYOWFRM-UHFFFAOYSA-L CC1=C(C)C(C)([Rh](Cl)Cl)C(C)=C1C Chemical class CC1=C(C)C(C)([Rh](Cl)Cl)C(C)=C1C QVLTVILSYOWFRM-UHFFFAOYSA-L 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 125000003172 aldehyde group Chemical group 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- MMAGMBCAIFVRGJ-UHFFFAOYSA-J iridium(3+);1,2,3,4,5-pentamethylcyclopenta-1,3-diene;tetrachloride Chemical group Cl[Ir+]Cl.Cl[Ir+]Cl.CC=1C(C)=C(C)[C-](C)C=1C.CC=1C(C)=C(C)[C-](C)C=1C MMAGMBCAIFVRGJ-UHFFFAOYSA-J 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
- 238000010898 silica gel chromatography Methods 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims 1
- 238000004821 distillation Methods 0.000 claims 1
- 238000010189 synthetic method Methods 0.000 claims 1
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical class C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 abstract description 3
- 229930014626 natural product Natural products 0.000 abstract description 2
- 230000000144 pharmacologic effect Effects 0.000 abstract description 2
- 229940000406 drug candidate Drugs 0.000 abstract 1
- 230000004048 modification Effects 0.000 abstract 1
- 238000012986 modification Methods 0.000 abstract 1
- 239000002547 new drug Substances 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 239000012043 crude product Substances 0.000 description 16
- 239000000047 product Substances 0.000 description 14
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
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- 238000001816 cooling Methods 0.000 description 8
- 239000003480 eluent Substances 0.000 description 8
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- 230000008018 melting Effects 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- INWHPBGNSUYRME-UHFFFAOYSA-N 2-(3-bromophenyl)-1h-quinazolin-4-one Chemical compound BrC1=CC=CC(C=2NC(=O)C3=CC=CC=C3N=2)=C1 INWHPBGNSUYRME-UHFFFAOYSA-N 0.000 description 3
- VDULOAUXSMYUMG-UHFFFAOYSA-N 2-phenyl-1h-quinazolin-4-one Chemical class N=1C2=CC=CC=C2C(O)=NC=1C1=CC=CC=C1 VDULOAUXSMYUMG-UHFFFAOYSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 229910052741 iridium Inorganic materials 0.000 description 3
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 3
- 229910052703 rhodium Inorganic materials 0.000 description 3
- 239000010948 rhodium Substances 0.000 description 3
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- CZKMPDNXOGQMFW-UHFFFAOYSA-N chloro(triethyl)germane Chemical compound CC[Ge](Cl)(CC)CC CZKMPDNXOGQMFW-UHFFFAOYSA-N 0.000 description 2
- SONJTKJMTWTJCT-UHFFFAOYSA-K rhodium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Rh+3] SONJTKJMTWTJCT-UHFFFAOYSA-K 0.000 description 2
- 229910052707 ruthenium Inorganic materials 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- POYBJJLKGYXKJH-PHFPKPIQSA-N (1z,5z)-cycloocta-1,5-diene;2-methanidylprop-1-ene;ruthenium(2+) Chemical compound [Ru+2].CC([CH2-])=C.CC([CH2-])=C.C\1C\C=C/CC\C=C/1 POYBJJLKGYXKJH-PHFPKPIQSA-N 0.000 description 1
- GWSNVTCOTFANCA-UHFFFAOYSA-N (4,6-dioxo-1,3,2-dioxazinan-2-ium-2-ylidene)azanide Chemical class [N-]=[N+]1OC(=O)CC(=O)O1 GWSNVTCOTFANCA-UHFFFAOYSA-N 0.000 description 1
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 description 1
- UCXDWSTYBSBFFB-UHFFFAOYSA-L 1-methyl-4-propan-2-ylbenzene;ruthenium(2+);dichloride Chemical class Cl[Ru]Cl.CC(C)C1=CC=C(C)C=C1 UCXDWSTYBSBFFB-UHFFFAOYSA-L 0.000 description 1
- DWMWFLPOXYGDND-UHFFFAOYSA-N 2-(2-methoxyphenyl)-1h-quinazolin-4-one Chemical compound COC1=CC=CC=C1C1=NC(=O)C2=CC=CC=C2N1 DWMWFLPOXYGDND-UHFFFAOYSA-N 0.000 description 1
- AKHUKZJZNGHOJU-UHFFFAOYSA-N 2-(4-chlorophenyl)-1h-quinazolin-4-one Chemical compound C1=CC(Cl)=CC=C1C1=NC(=O)C2=CC=CC=C2N1 AKHUKZJZNGHOJU-UHFFFAOYSA-N 0.000 description 1
- RYKLZUPYJFFNRR-UHFFFAOYSA-N 3-hydroxypiperidin-2-one Chemical compound OC1CCCNC1=O RYKLZUPYJFFNRR-UHFFFAOYSA-N 0.000 description 1
- SAXQOYZKDFVDTH-UHFFFAOYSA-N CC1=C(C(=C(C1(C)[Rh])C)C)C Chemical compound CC1=C(C(=C(C1(C)[Rh])C)C)C SAXQOYZKDFVDTH-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 238000004252 FT/ICR mass spectrometry Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910021638 Iridium(III) chloride Inorganic materials 0.000 description 1
- 229910021604 Rhodium(III) chloride Inorganic materials 0.000 description 1
- NWBUFJZQWAXFGH-UHFFFAOYSA-K [Ir](Cl)(Cl)Cl.C1=CCCC=CCC1.C1=CCCC=CCC1 Chemical compound [Ir](Cl)(Cl)Cl.C1=CCCC=CCC1.C1=CCCC=CCC1 NWBUFJZQWAXFGH-UHFFFAOYSA-K 0.000 description 1
- KTYAQHYBYRVCGD-UHFFFAOYSA-N [Ir].COC1=CC=CCCCC1 Chemical class [Ir].COC1=CC=CCCCC1 KTYAQHYBYRVCGD-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000006757 chemical reactions by type Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 150000008049 diazo compounds Chemical class 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 230000006203 ethylation Effects 0.000 description 1
- 238000006200 ethylation reaction Methods 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- RPNNPZHFJPXFQS-UHFFFAOYSA-N methane;rhodium Chemical compound C.[Rh] RPNNPZHFJPXFQS-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- SVOOVMQUISJERI-UHFFFAOYSA-K rhodium(3+);triacetate Chemical compound [Rh+3].CC([O-])=O.CC([O-])=O.CC([O-])=O SVOOVMQUISJERI-UHFFFAOYSA-K 0.000 description 1
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 1
- VIHDTGHDWPVSMM-UHFFFAOYSA-N ruthenium;triphenylphosphane Chemical compound [Ru].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 VIHDTGHDWPVSMM-UHFFFAOYSA-N 0.000 description 1
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 description 1
- 229940071536 silver acetate Drugs 0.000 description 1
- 229910001958 silver carbonate Inorganic materials 0.000 description 1
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 229910000367 silver sulfate Inorganic materials 0.000 description 1
- YPNVIBVEFVRZPJ-UHFFFAOYSA-L silver sulfate Chemical compound [Ag+].[Ag+].[O-]S([O-])(=O)=O YPNVIBVEFVRZPJ-UHFFFAOYSA-L 0.000 description 1
- 229910001494 silver tetrafluoroborate Inorganic materials 0.000 description 1
- JUDUFOKGIZUSFP-UHFFFAOYSA-M silver;4-methylbenzenesulfonate Chemical compound [Ag+].CC1=CC=C(S([O-])(=O)=O)C=C1 JUDUFOKGIZUSFP-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- DANYXEHCMQHDNX-UHFFFAOYSA-K trichloroiridium Chemical compound Cl[Ir](Cl)Cl DANYXEHCMQHDNX-UHFFFAOYSA-K 0.000 description 1
- FEQPHYCEZKWPNE-UHFFFAOYSA-K trichlororhodium;triphenylphosphane Chemical compound Cl[Rh](Cl)Cl.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 FEQPHYCEZKWPNE-UHFFFAOYSA-K 0.000 description 1
- CMTKJYPJPSONIT-UHFFFAOYSA-K trichlororuthenium;triphenylphosphane Chemical compound Cl[Ru](Cl)Cl.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 CMTKJYPJPSONIT-UHFFFAOYSA-K 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
- C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
喹唑啉酮类化合物具有广泛的药理活性。本发明涉及一种以5‑重氮米氏酸作为烷基化试剂，通过过渡金属催化的C‑H偶联反应高效制备2‑(4(3H)‑喹唑啉酮)芳基乙酸烷基酯衍生物的方法。本发明能高效快速地获得2‑芳基喹唑啉酮衍生物分子库，可以对天然化合物进行后期修饰，从而合成新的药物候选分子。
Description
技术领域
本发明涉及一种以5-重氮米氏酸作为烷基化试剂，通过过渡金属催化的C-H偶联反应高效制备2-(4(3H)-喹唑啉酮)芳基乙酸烷基酯衍生物的方法。
背景技术
喹唑啉酮类化合物广泛分布于天然产物和生物活性分子中，因其具有抗癌、抗炎、抗菌、抗疟、抗糖尿病、降压等多种药理活性而受到了来自医药化学领域的高度重视[参见：(a) G. H. Zhang, W. B. Xue, Y. F. An, J. M. Yuan, J. K. Qin, C. X. Pan, G. F.Su, Eur. J. Med. Chem., 2015, 95, 377-387; (b) K. Ozaki, Y. Yamada, T, Oine,T. Ishizuka, Y. Iwasawa, J. Med. Chem., 1985, 28, 568-576; (c) K. Ozaki, Y.Yamada, T, Oine, T. Ishizuka, Y. Iwasawa, J. Med. Chem., 1985, 28, 568-576;(d) R. Gali, J. Banothu, M. Porika, R. Velpula, S. Hnamte, R. Bavantula, S.Abbagani, S. Busi, Bioorg. Med. Chem. Lett., 2014, 24, 4239-4242.]。近年来，随着过渡金属催化的C-H键活化研究的飞速发展，为达到快速构建多取代喹唑啉酮化合物的目的，合成化学家们开发了以喹唑啉-4(3H)-酮作为导向基团的C-H键官能团化方法[参见：(a) B. Reddy, G. Narasimhulu, N. Umadevi, J. Yadav, Synlett2012, 23, 1364-1370;(b) J. B. Lee, M. E. Kang, J. Kim, C. Y. Lee, J. M. Kee, K. Myung, J. U.Park, S. Y. Hong,Chem. Commun., 2017, 53, 10394-10397; (c) M. Dabiri, N.Farajinia Lehi, S. Kazemi Movahed, H. R. Khavasi,Org. Bio. Chem., 2017, 15,6264-6268; (d)M. Lou, Z. Deng, X. Mao, Y. Fu, Q. Yang, Y. Peng, Org. Bio. Chem., 2018, 16, 1851-1859; (e) A. B. Viveki, S. B. Mhaske, J. Org. Chem., 2018, 83, 8906-8913.]。但目前的反应类型相对单一，结合喹唑啉酮类化合物的应用前景，因此，十分有必要发展更多的C-H键活化方法。
另一方面，重氮类化合物，特别是α-重氮丙二酸酯衍生物在过渡金属的作用下释放氮气后生成的金属卡宾体能参与C-H键活化反应。作为α-羰基重氮化合物的典型代表，市售的5-重氮米氏酸具有反应活性高，使用安全方便等特点，是常用的C-H键烷基化反应试剂[参见：(a) P. Patel, G. Borah,Chem. Commun., 2016, 53, 443-446; (b) R. S.Phatake, P. Patel, C. V. Ramana, Org. Lett., 2016, 18, 2828-2831; (c) S.Sharma, S. H. Han, S. Han, W. Ji, J. Oh, S. Y. Lee, J. S. Oh, Y. H. Jung, I.S. Kim, Org. Lett., 2015, 17, 2852-2855; (d)J. Shi, Y. Yan, Q. Li, H. E. Xu,W. Yi,Chem. Commun., 2014, 50, 6483-6486.]。但目前未见其与2-芳基喹唑啉酮类化合物的偶联反应。
发明内容
本发明涉以5-重氮米氏酸作为烷基化试剂，以醇类作为溶剂，通过过渡金属催化的C-H偶联反应高效制备2-(4(3H)-喹唑啉酮)芳基乙酸烷基酯衍生物。
本发明的技术路线以2-苯基-4(3H)-喹唑啉酮类化合物为底物，以5-重氮米氏酸作为烷基化试剂。其化学反应式如下所示：
A环为苯基、α-萘基、β-萘基、噻吩基、呋喃基、吡啶基、吡咯基、吲哚基、二氢吲哚基；R1为氢、卤素、烷基、苯基、烷氧基、羰基、醛基、羧基、烷酰氧基、氰基、酰胺基中的一种或一种以上；R2为甲基、乙基、正丙基、正丁基；R3为氢或者CH2CO2R2。
制备步骤如下：
（1）向洁净的封管中依次加入2-苯基-4(3H)-喹唑啉酮类化合物、5-重氮米氏酸、催化剂、添加剂和醇类溶剂，于80-100 oC搅拌18-24小时；
（2）反应完全后，直接减压浓缩除去溶剂，残留物采用硅胶柱层析分离纯化，即得产品。
步骤（1）中的催化剂为铑碳、三氯化铑、醋酸铑、乙酰丙酮三苯基膦羰基铑、双环辛烯氯化铑二聚体、二氯（五甲基环戊二烯）合铑（III）二聚体、二(六氟锑酸)三乙腈(五甲基环戊二烯基)铑(III)、三苯基膦氯化铑、三氯化钌、三苯基膦氯化钌、二氯二羰基双三苯基膦钌、双（2-甲基烯丙基）（1,5-环辛二烯）钌（II）、对伞花烃二氯化钌二聚体、三氯化铱、二氯（五甲基环戊二烯）合铱（III）二聚体、双（1,5-环辛二烯）氯化铱（I）二聚体、甲氧基（环辛二烯）合铱二聚体中的一种或一种以上。
步骤（1）中的添加剂为硝酸银、乙酸银、碳酸银、硫酸银、甲烷磺酸银、三氟甲烷磺酸银、对甲苯磺酸银、双三氟甲烷磺酰亚胺银、三氟甲烷磺酸银、六氟锑酸银、四氟硼酸银、六氟磷酸银中的一种或一种以上。
步骤（1）中2-芳基-4(3H)-喹唑啉酮化合物：5-重氮米氏酸：催化剂：添加剂的摩尔比为1：（1.5~3.0）：（0.01~0.02）：（0.1~0.2）。
采用核磁共振氢谱（1H NMR）、碳谱（13C NMR）以及高分辨质谱对产品的结构进行了确证，证明其为2-(2-烷基苯基)-4(3H)-喹唑啉酮衍生物。其中，核磁共振图谱采用VarianUNITY INOVA400高分辨率超导核磁共振仪测定，以四甲基硅烷（TMS）为内标（δ 0ppm），氘代二甲基亚砜（DMSO-d 6）为溶剂；高分辨质谱采用Bruker Apex IV FTMS质谱仪测定。
相比于传统的反应条件，本发明具有以下特点：
1. 铑、钌和铱三种过渡金属复合物均能催化该反应。其中，使用铑或钌催化体系主要得到了单烷基化取代产物，而使用铱催化体系则选择性生成了双烷基化取代产物；
2. 催化剂使用量极低；
3. 以醇类作为反应溶剂，价格低廉，无毒无污染；
4. 反应步骤简单，可一步制得邻位烷氧羰乙基化取代产物。
具体实施方法
下面结合具体实施方法对本发明作进一步描述，有助于对本发明的理解。但并不能以此来限制本发明的权利范围，而本发明的权利范围应以权利要求书阐述的为准。
实施实例1：2-(4(3H)-喹唑啉酮基)苯乙酸甲酯的合成
向洁净的封管中依次加入2-苯基-4(3H)-喹唑啉酮（44.4 mg，0.2 mmol）、5-重氮米氏酸（54.4 mg，0.32 mmol）、[Cp*RhCl2]2（1.2 mg，1 mol%）、AgNTf2（7.8 mg，0.02 mmol）和2 mL MeOH，于80 oC反应18 h后冷却至室温。
反应液经减压浓缩后得到粗产品。粗产品进行柱层析（洗脱剂为石油醚/丙酮=20/1，v/v）即得产物47.8 mg，白色固体，收率81%。熔点165-166 oC；1H NMR (400 MHz,DMSO-d 6) δ 12.49 (s, 1H), 8.15 (d, J = 8.0, 1H), 7.83 (t, J = 8.0 Hz, 1H),7.66 (d, J = 8.0 Hz, 2H), 7.54-7.50 (m, 2H), 7.45 (t, J = 8.0 Hz, 2H), 3.97(s, 2H), 3.45 (s, 3H)；13C NMR (150 MHz, DMSO-d 6) δ 171.3, 161.7, 153.3, 148.6,137.1, 134.4, 134.2, 130.9, 129.7, 128.9, 127.3, 126.6, 126.1, 125.7, 121.1,51.9, 38.6；HRMS (ESI)：计算值C17H15N2O3 [M+H]+: 295.1083，实测值295.1082。
实施实例2：2-(4(3H)-喹唑啉酮基)-5-氯苯乙酸甲酯的合成
向洁净的封管中依次加入2-(4-氯苯基)-4(3H)-喹唑啉酮（51.3 mg，0.2 mmol）、5-重氮米氏酸（54.4 mg，0.32 mmol）、[Cp*RhCl2]2（1.2 mg，1 mol%）、AgNTf2（7.8 mg，0.02mmol）和2 mL MeOH，于80 oC反应18 h后冷却至室温。
反应液经减压浓缩后得到粗产品。粗产品进行柱层析（洗脱剂为石油醚/丙酮=20/1，v/v）即得产物59.8 mg，白色固体，收率91%。熔点193-194 oC；1H NMR (400 MHz,DMSO-d 6) δ 12.56 (s, 1H), 8.15 (dd, J = 8.0, 1.2 Hz, 1H), 7.84 (ddd, J = 8.4,7.2, 1.6 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.60-7.57 (m, 2H), 7.56-7.51 (m,2H), 3.99 (s, 2H), 3.48 (s, 3H)；13C NMR (100 MHz, DMSO-d 6) δ 171.4, 162.5,153.0, 148.6, 136.8, 135.1, 135.0, 132.7, 132.2, 131.78, 127.7, 127.5, 127.3,126.2, 121.4, 52.0, 39.1；HRMS (ESI)：计算值C17H14ClN2O3 [M+H]+ 329.0693，测定值329.0693。
实施实例3：2-(4(3H)-喹唑啉酮基)-4-溴苯乙酸甲酯的合成
向洁净的封管中依次加入2-(3-溴苯基)-4(3H)-喹唑啉酮（60.2 mg，0.2 mmol）、5-重氮米氏酸（54.4 mg，0.32 mmol）、[Cp*RhCl2]2（1.2 mg，1 mol%）、AgNTf2（7.8 mg，0.02mmol）和2 mL MeOH，于80 oC反应18 h后冷却至室温。
反应液经减压浓缩后得到粗产品。粗产品进行柱层析（洗脱剂为石油醚/丙酮=20/1，v/v）即得产物38.1 mg，白色固体，收率51%。熔点157-159oC；1H NMR (400 MHz, DMSO-d 6) δ 12.42 (s, 1H), 8.15 (dd, J = 8.0, 1.2 Hz, 1H), 7.83 (ddd, J = 8.4, 7.2,1.6 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.55-7.49 (m, 2H), 7.31 (d, J = 0.8Hz, 2H), 3.93 (s, 2H), 2.37 (s, 3H)；13C NMR (100 MHz, DMSO-d 6) δ 172.0, 162.5,154.1, 148.8, 136.9, 134.9, 133.7, 132.4, 131.3, 131.2, 130.6, 127.7 127.1,126.2, 121.2, 51.8, 39.1；HRMS (ESI)：计算值C17H14BrN2O3 [M+H]+ 373.0188，测定值373.0188。
实施实例4：2-(4(3H)-喹唑啉酮基)-3-(甲氧基)苯乙酸甲酯的合成
向洁净的封管中依次加入2-(2-甲氧基苯基)-4(3H)-喹唑啉酮（50.5 mg，0.2mmol）、5-重氮米氏酸（54.4 mg，0.32 mmol）、[Cp*RhCl2]2（1.2 mg，1 mol%）、AgNTf2（7.8mg，0.02 mmol）和2 mL MeOH，于80 oC反应18 h后冷却至室温。
反应液经减压浓缩后得到粗产品。粗产品进行柱层析（洗脱剂为石油醚/丙酮=20/1，v/v）即得目标产物56.4 mg，白色固体，收率87%。熔点170-171 oC；1H NMR (600 MHz,DMSO-d 6) δ 12.32 (s, 1H), 8.15 (d, J = 7.6 Hz, 1H), 7.82 (t, J = 7.6 Hz, 1H),7.60 (d, J = 8.0 Hz, 1H), 7.54 (t, J = 7.6Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H),7.10 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 7.6 Hz, 1H), 3.77 (s, 3H), 3.67 (s,2H), 3.42 (s, 3H); 13C NMR (100 MHz, DMSO-d 6) δ 171.2, 162,0, 157.7, 152.0,149.1, 135.0, 134.8, 131.2, 127.7, 127.2, 126.2, 124.0, 123.5, 121.7, 110.8,56.2, 52.0, 38.7; HRMS (ESI)：计算值C18H17N2O4 [M+H]+ 325.1188，测定值325.1188。
实施实例5：2-(4(3H)-喹唑啉酮基)-1,3-苯二乙酸二甲酯的合成
向洁净的封管中依次加入2-苯基喹唑啉-4(3H)-酮（44.4 mg，0.2 mmol）、5-重氮米氏酸（74.9 mg，0.44 mmol）、[Cp*IrCl2]2（3.2 mg，2 mol%）、AgNTf2（7.8 mg，0.02 mmol）和2 mL MeOH，于80 oC反应24 h后冷却至室温。
反应液经减压浓缩后得到粗产品。粗产品进行柱层析（洗脱剂为石油醚/丙酮=15/1，v/v）即得目标产物65.9 mg，白色固体，收率90%。熔点120-122 oC； 1H NMR (400 MHz,DMSO-d 6) δ 12.41 (s, 1H), 8.16 (d, J = 8.0, 1H), 7.84 (t, J = 8.0 Hz, 1H),7.62 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.47 (d, J = 8.0, 1H),7.37 (d, J = 8.0, 1H), 3.72 (s, 2H), 3.62 (s, 2H), 3.38 (s, 6H)；13C NMR (150MHz, DMSO-d 6) δ 171.5, 153.4, 151.8, 146.8, 136.2, 135.4, 135.3, 130.9, 129.4,128.2, 127.5, 126.6, 121.9, 52.1, 38.3；HRMS (ESI)：计算值C20H19N2O5 [M+H]+367.1294，实测值367.1294。
实施实例6：2-(4(3H)-喹唑啉酮基)-5-氯-1,3-苯二乙酸二甲酯的合成
向洁净的封管中依次加入2-(4-氯苯基)-4(3H)-喹唑啉酮（51.3 mg，0.2 mmol）、5-重氮米氏酸（74.9 mg，0.44 mmol）、[Cp*IrCl2]2（3.2 mg，2 mol%）、AgNTf2（7.8 mg，0.02mmol）和2 mL MeOH，于80 oC反应24 h后冷却至室温。
反应液经减压浓缩后得到粗产品。粗产品进行柱层析（洗脱剂为石油醚/丙酮=15/1，v/v）即得目标产物51.3 mg，白色固体，收率64%。熔点150-152 oC；1H NMR (400 MHz,DMSO-d 6) δ 12.45 (s, 1H), 8.16 (dd, J = 8.0, 1.2 Hz, 1H), 7.84 (ddd, J = 8.4,7.2, 1.6 Hz, 1H), 7.62 (d, J = 7.6Hz, 1H), 7.60-7.54 (m, 1H), 7.51 (s, 2H),3.75 (s, 2H), 3.64 (s, 2H), 3.39 (s, 6H);13C NMR (100 MHz, DMSO-d 6) δ 170.7,161.9, 151.9, 148.8, 136.1, 134.9, 134.2, 134.0, 129.9, 127.9, 127.6, 126.3,121.7, 52.2, 38.5; HRMS (ESI)：计算值C20H18ClN2O5 [M+H]+ 401.0904，测定值401.0905。
实施实例7：2-(4(3H)-喹唑啉酮基)-4-溴-1,3-苯二乙酸二甲酯的合成
向洁净的封管中依次加入2-(3-溴苯基)-4(3H)-喹唑啉酮（60.2 mg，0.2 mmol）、5-重氮米氏酸（74.9 mg，0.44 mmol）、[Cp*IrCl2]2（3.2 mg，2 mol%）、AgNTf2（7.8 mg，0.02mmol）和2 mL MeOH，于80 oC反应24 h后冷却至室温。
反应液经减压浓缩后得到粗产品。粗产品进行柱层析（洗脱剂为石油醚/丙酮=15/1，v/v）即得目标产物43.6 mg，白色固体，收率49%。熔点124-125oC；1H NMR (400 MHz,DMSO-d 6) δ 11.47 (s, 1H), 8.06 (d, J = 6.8 Hz, 1H), 7.89-7.7 (m, 3H), 7.45(d, J = 8.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 3.76 (s, 2H), 3.67 (s, 2H),3.35 (s, 6H)；13C NMR (100 MHz, DMSO-d 6) δ 171.3, 171.0, 162.0, 153.3, 145.0,137.2, 135.7, 134.9, 132.2, 131.7, 131.0, 129.9, 127.8, 127.4, 126.3, 121.6,52.1, 52.0, 39.2, 38.8；HRMS (ESI)：计算值C20H18BrN2O5 [M+H]+ 445.0399，测定值445.0401。
实施实例8：3-(4(3H)-喹唑啉酮基)-2,4-噻吩二乙酸二甲酯的合成
向洁净的封管中依次加入2-(3-溴苯基)-4(3H)-喹唑啉酮（45.7 mg，0.2 mmol）、5-重氮米氏酸（74.9 mg，0.44 mmol）、[Cp*IrCl2]2（3.2 mg，2 mol%）、AgNTf2（7.8 mg，0.02mmol）和2 mL MeOH，于80 oC反应24 h后冷却至室温。
反应液经减压浓缩后得到粗产品。粗产品进行柱层析（洗脱剂为石油醚/丙酮=15/1，v/v）即得目标产物59.7 mg，白色固体，收率80%。熔点148-149oC；1H NMR (400 MHz,DMSO-d 6) δ 12.31 (s, 1H), 8.13 (dd, J = 8.0, 1.2 Hz, 1H), 7.82 (ddd, J = 8.4,7.2, 1.6 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.55-7.50 (m, 1H), 7.41 (s, 1H),4.08 (s, 2H), 3.83 (s, 2H), 3.52 (s, 3H), 3.37 (s, 3H)；13C NMR(100 MHz, DMSO-d 6) δ 171.3, 170.6, 162.2, 150.2, 149.1, 137.4, 134.9, 133.9, 133.5, 127.7,127.1, 126.2, 124.0, 121.4, 52.4, 52.0, 34.9, 34.0；HRMS (ESI): 计算值C18H17N2O5S [M+H]+ 373.0858，测定值373.0858。
Claims (3)
1.一种基于过渡金属催化的C-H偶联制备2-(4(3H)-喹唑啉酮)芳基乙酸烷基酯衍生物的合成方法，其特征在于以5-重氮米氏酸作为烷基化试剂，以醇类作为溶剂，制备了2-(4(3H)-喹唑啉酮)芳基乙酸烷基酯，其化学反应式为：
其中：
A环为苯基、α-萘基、β-萘基、噻吩基、呋喃基、吡啶基、吡咯基、吲哚基、二氢吲哚基；
R1为氢、卤素、烷基、苯基、烷氧基、羰基、醛基、羧基、烷酰氧基、氰基、酰胺基中的一种或一种以上；
R2为甲基、乙基、正丙基、正丁基；
R3为氢，催化剂为二氯（五甲基环戊二烯）合铑（III）二聚体；
R3为CH2CO2R2，催化剂为二氯（五甲基环戊二烯基）合铱(III)二聚体；
添加剂为双(三氟甲烷磺酰基)酰亚胺银。
2.根据权利要求1，一种制备合成2-(4(3H)-喹唑啉酮)芳基乙酸烷基酯衍生物的方法，其特征在于采用如下制备步骤：
(1)在洁净的反应器中加入2-芳基-4(3H)-喹唑啉酮化合物、5-重氮米氏酸化合物、催化剂、添加剂和醇类溶剂，于80-100oC搅拌18-24小时；
(2)反应完全后，直接减压蒸馏除去溶剂，残留物采用硅胶柱层析分离纯化，即得产品。
3.根据权利要求2所述的制备方法，其特征在于步骤（1）中2-芳基-4(3H)-喹唑啉酮化合物：5-重氮米氏酸：催化剂：添加剂的摩尔比为1：（1.5~3.0）：（0.01~0.02）：（0.1~0.2）。
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| Iridium(III)-Catalyzed Regioselective Carbenoid Insertion C–H Alkylation by α-Diazotized Meldrum"s Acid;Honggui Lv,等;《Eur. J. Org. Chem》;20161231;5637-5641 * |
| Rh(III)-catalyzed C–H alkylation of 2-arylbenzothiazoles with a-diazo esters;Miji Choi，等;《Tetrahedron Letters》;20151231;第56卷;4678-4682 * |
| Rhodium(III)-Catalyzed Azacycle-Directed Intermolecular Insertion of Arene C−H Bonds into α‑Diazocarbonyl Compounds;Xinzhang Yu，等;《J. Org. Chem.》;20131231;第78卷;5444-5452 * |
| Synthesis of Imidazopyridines via Copper-Catalyzed, Formal Aza-[3 +2] Cycloaddition Reaction of Pyridine Derivatives with α‑Diazo Oxime Ethers;Sangjune Park，等;《J. Org. Chem.》;20171231;第82卷;10209-10218 * |
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