CN109942497A - Polysubstituted pyrimidone compound and preparation method thereof - Google Patents
Polysubstituted pyrimidone compound and preparation method thereof Download PDFInfo
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- -1 Polysubstituted pyrimidone compound Chemical class 0.000 title claims abstract description 73
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 96
- 238000006243 chemical reaction Methods 0.000 claims abstract description 66
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 54
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 48
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims abstract description 22
- 229910052707 ruthenium Inorganic materials 0.000 claims abstract description 22
- 239000007832 Na2SO4 Substances 0.000 claims abstract description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims abstract description 16
- 239000012074 organic phase Substances 0.000 claims abstract description 16
- 229910052938 sodium sulfate Inorganic materials 0.000 claims abstract description 16
- 239000000654 additive Substances 0.000 claims abstract description 14
- 230000000996 additive effect Effects 0.000 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 239000012948 isocyanate Substances 0.000 claims abstract description 8
- 150000002513 isocyanates Chemical class 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 238000003756 stirring Methods 0.000 claims abstract description 6
- 238000010438 heat treatment Methods 0.000 claims abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 claims description 26
- FFFIRKXTFQCCKJ-UHFFFAOYSA-N 2,4,6-trimethylbenzoic acid Chemical compound CC1=CC(C)=C(C(O)=O)C(C)=C1 FFFIRKXTFQCCKJ-UHFFFAOYSA-N 0.000 claims description 15
- 238000006073 displacement reaction Methods 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 15
- 125000003963 dichloro group Chemical group Cl* 0.000 claims description 13
- YTZKOQUCBOVLHL-UHFFFAOYSA-N p-methylisopropylbenzene Natural products CC(C)(C)C1=CC=CC=C1 YTZKOQUCBOVLHL-UHFFFAOYSA-N 0.000 claims description 13
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 10
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- NHOWDZOIZKMVAI-UHFFFAOYSA-N (2-chlorophenyl)(4-chlorophenyl)pyrimidin-5-ylmethanol Chemical compound C=1N=CN=CC=1C(C=1C(=CC=CC=1)Cl)(O)C1=CC=C(Cl)C=C1 NHOWDZOIZKMVAI-UHFFFAOYSA-N 0.000 claims description 4
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Natural products OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 3
- 125000004802 cyanophenyl group Chemical group 0.000 claims description 3
- 150000003303 ruthenium Chemical class 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
- 125000003944 tolyl group Chemical group 0.000 claims description 3
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- 241000790917 Dioxys <bee> Species 0.000 claims description 2
- JIMXXGFJRDUSRO-UHFFFAOYSA-N adamantane-1-carboxylic acid Chemical compound C1C(C2)CC3CC2CC1(C(=O)O)C3 JIMXXGFJRDUSRO-UHFFFAOYSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- CZKMPDNXOGQMFW-UHFFFAOYSA-N chloro(triethyl)germane Chemical compound CC[Ge](Cl)(CC)CC CZKMPDNXOGQMFW-UHFFFAOYSA-N 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- BIXNGBXQRRXPLM-UHFFFAOYSA-K ruthenium(3+);trichloride;hydrate Chemical compound O.Cl[Ru](Cl)Cl BIXNGBXQRRXPLM-UHFFFAOYSA-K 0.000 claims description 2
- 229960004889 salicylic acid Drugs 0.000 claims description 2
- 229910052709 silver Inorganic materials 0.000 claims description 2
- 239000004332 silver Substances 0.000 claims description 2
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 claims description 2
- 229940071536 silver acetate Drugs 0.000 claims description 2
- 229910001494 silver tetrafluoroborate Inorganic materials 0.000 claims description 2
- 125000005504 styryl group Chemical group 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims 2
- ZWLPBLYKEWSWPD-UHFFFAOYSA-N o-toluic acid Chemical compound CC1=CC=CC=C1C(O)=O ZWLPBLYKEWSWPD-UHFFFAOYSA-N 0.000 claims 2
- 239000005711 Benzoic acid Substances 0.000 claims 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 235000010233 benzoic acid Nutrition 0.000 claims 1
- REHHBTUVMSHZNT-UHFFFAOYSA-N bromocyclohexatriene Chemical group BrC1=CC=C=C[CH]1 REHHBTUVMSHZNT-UHFFFAOYSA-N 0.000 claims 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims 1
- 239000000741 silica gel Substances 0.000 claims 1
- 229910002027 silica gel Inorganic materials 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 21
- 230000015572 biosynthetic process Effects 0.000 abstract description 20
- 239000000758 substrate Substances 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000001816 cooling Methods 0.000 abstract 1
- 125000005610 enamide group Chemical group 0.000 abstract 1
- 238000010791 quenching Methods 0.000 abstract 1
- 230000000171 quenching effect Effects 0.000 abstract 1
- 239000000047 product Substances 0.000 description 29
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 26
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 15
- 229910052739 hydrogen Inorganic materials 0.000 description 15
- 239000001257 hydrogen Substances 0.000 description 15
- 238000010898 silica gel chromatography Methods 0.000 description 14
- 238000001228 spectrum Methods 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- DVKJHBMWWAPEIU-UHFFFAOYSA-N toluene 2,4-diisocyanate Chemical compound CC1=CC=C(N=C=O)C=C1N=C=O DVKJHBMWWAPEIU-UHFFFAOYSA-N 0.000 description 9
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 5
- IXRNQIKIVWWFBH-UHFFFAOYSA-N n-(1-phenylethenyl)acetamide Chemical compound CC(=O)NC(=C)C1=CC=CC=C1 IXRNQIKIVWWFBH-UHFFFAOYSA-N 0.000 description 5
- YCIPQJTZJGUXND-UHFFFAOYSA-N Aglaia odorata Alkaloid Natural products C1=CC(OC)=CC=C1C1(C(C=2C(=O)N3CCCC3=NC=22)C=3C=CC=CC=3)C2(O)C2=C(OC)C=C(OC)C=C2O1 YCIPQJTZJGUXND-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- DHCWLIOIJZJFJE-UHFFFAOYSA-L dichlororuthenium Chemical class Cl[Ru]Cl DHCWLIOIJZJFJE-UHFFFAOYSA-L 0.000 description 2
- 238000006471 dimerization reaction Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000007115 1,4-cycloaddition reaction Methods 0.000 description 1
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 description 1
- 239000004912 1,5-cyclooctadiene Substances 0.000 description 1
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 238000010499 C–H functionalization reaction Methods 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- BKRRFMWOARICES-UHFFFAOYSA-N N-[1-(2-fluorophenyl)ethenyl]acetamide Chemical compound CC(=O)NC(=C)C1=CC=CC=C1F BKRRFMWOARICES-UHFFFAOYSA-N 0.000 description 1
- QPJAPPPFYPZKDR-UHFFFAOYSA-N N=C=O.BrC1=CC=CC=C1 Chemical class N=C=O.BrC1=CC=CC=C1 QPJAPPPFYPZKDR-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 1
- 229960003459 allopurinol Drugs 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- QPQDOIAJMPGRCZ-UHFFFAOYSA-N anisole;isocyanic acid Chemical class N=C=O.COC1=CC=CC=C1 QPQDOIAJMPGRCZ-UHFFFAOYSA-N 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 230000001857 anti-mycotic effect Effects 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 238000006210 cyclodehydration reaction Methods 0.000 description 1
- WUDNUHPRLBTKOJ-UHFFFAOYSA-N ethyl isocyanate Chemical compound CCN=C=O WUDNUHPRLBTKOJ-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000007172 homogeneous catalysis Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 150000002561 ketenes Chemical class 0.000 description 1
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 239000008164 mustard oil Substances 0.000 description 1
- YPIDOFMLPMJTJX-UHFFFAOYSA-N n-(1-phenylethenyl)propanamide Chemical compound CCC(=O)NC(=C)C1=CC=CC=C1 YPIDOFMLPMJTJX-UHFFFAOYSA-N 0.000 description 1
- WSMPLUKWVPUMKQ-UHFFFAOYSA-N n-[1-(4-methylphenyl)ethenyl]acetamide Chemical compound CC(=O)NC(=C)C1=CC=C(C)C=C1 WSMPLUKWVPUMKQ-UHFFFAOYSA-N 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 150000002932 p-cymene derivatives Chemical class 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- FNKQXYHWGSIFBK-RPDRRWSUSA-N sapropterin Chemical compound N1=C(N)NC(=O)C2=C1NC[C@H]([C@@H](O)[C@@H](O)C)N2 FNKQXYHWGSIFBK-RPDRRWSUSA-N 0.000 description 1
- 229960004617 sapropterin Drugs 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- XBJWOGLKABXFJE-YFKPBYRVSA-N telmesteine Chemical compound CCOC(=O)N1CSC[C@H]1C(O)=O XBJWOGLKABXFJE-YFKPBYRVSA-N 0.000 description 1
- 229960002384 telmesteine Drugs 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a polysubstituted pyrimidone compound, which has a structure shown as the following formula:the preparation method comprises the following steps of respectively adding substituted enamide, isocyanate, a ruthenium catalyst, an additive I and an additive II into a Schlenk reaction tube under the protection of nitrogen; replacing the reaction tube with nitrogen for 3 times, adding 2mL of solvent into the reaction tube by using an injector under the protection of nitrogen, and heating and stirring; after the reaction of the reaction solution is finished, cooling the reaction solution to room temperature, quenching the reaction solution by using 10mL of saturated sodium bicarbonate solution, and extracting the reaction solution for 3 times by using 10mL of dichloromethane; the organic phases were combined and washed with anhydrous Na2SO4The new synthetic route of the pyrimidone compound provided by the invention has the advantages of high efficiency, atom economy, mild reaction conditions, wide substrate application range and the like, and has potential application prospect in the field of drug synthesis.
Description
Technical field
The present invention relates to organic chemical synthesis technical field, specially a kind of polysubstituted pyrimidine ketone compound and its preparation side
Method.
Background technique
Pyrimidone is a kind of highly important nitrogen-containing heterocycle compound, is widely present in biologically active drug molecule
In functional material.As the basic structural unit of base in hereditary material DNA and RNA, pyrimidone is in biological medicine and pesticide
Synthesis also plays indispensable role in field.For example, Muconorm (antihistamine), (cognition assists sapropterin
Medicine), Allopurinol (treatment goat) and Lamivudine (antiviral agent) be using pyrimidone as precursor structure, in addition, this kind ofization
Close object also have anti-cancer (ACS Med.Chem.Lett.2018,9,238-243.), blood pressure lowering (J.Med.Chem.1995,
38,4806-4820), important bioactivity such as antimycotic (Bioorg.Med.Chem.Lett.2003,13,1713-1716).
The method of synthesis pyrimidinone compound includes: (1) A.Pinner anti-using β-carbonyl ester and amidine generation condensation at present
It answers, but reaction time consumption is long, conversion ratio is lower, and substrate spectrum is relatively narrow；(2) M.P.Mahajan utilizes 1,3- diaza -1,3- fourth two
[4+2] cycloaddition reaction occurs for alkene and ketenes, but raw material is not easy to prepare, and reacts and generate a large amount of wastes；(3) with β-carbonyl ester
Or beta-amino ester is raw material, constructs pyrimidone skeleton, this method complex steps by multistep reaction, and reaction selectivity is lower.
Therefore, it is polysubstituted still to lack a kind of efficient, Atom economy, mild condition, wide application range of substrates method synthesis for this field
Pyrimidinone compound.
Summary of the invention
The purpose of the present invention is to provide a kind of polysubstituted pyrimidine ketone compounds and preparation method thereof to solve above-mentioned background
The problem of being proposed in technology.
To achieve the above object, the invention provides the following technical scheme: a kind of polysubstituted pyrimidine ketone compound, structure is such as
Shown under formula:
In formula, R1For p-trifluoromethyl phenyl, 1,2- methylene dioxy phenyl group, p-methylphenyl, to cyano benzene
Base, m-methoxyphenyl, p-bromophenyl, o-fluorophenyl, 2- naphthalene, tert-butyl, 2- thienyl, p-fluorophenyl, rubigan, 3,
4- ihydro naphthyl, adamantyl；R2For methyl, ethyl, propyl, isobutyl group, cyclohexyl, styryl；R3For p-methylphenyl, neighbour
Tolyl, normal-butyl, Chloro-O-Phenyl, ethyl, cyclohexyl, rubigan, tolyl, p-methoxyphenyl, benzyl, to fluorobenzene
Base, 1- naphthalene, p-trifluoromethyl phenyl, acetylphenyl, to cyano-phenyl, n-octyl.
The present invention also provides the preparation methods of above-mentioned polysubstituted pyrimidine ketone compound, comprising the following steps:
(1) under nitrogen protection, to the substitution alkene for being separately added into 0.45~0.75mmol in the Schlenk reaction tube of 10mL
Amide, the isocyanates of 0.3mmol, the ruthenium catalyst of 5mol%, the additive one of 20mol% and the additive of 0.45mmol
Two；
(2) with nitrogen displacement reaction tube 3 times, and under nitrogen protection, the molten of 2mL is added into reaction tube with syringe
Agent, and carry out heating and stirring, and be heated to 60~120 DEG C, mixing time is 12~for 24 hours；
(3) when the reaction solution in (2) after reaction, reaction solution is cooled to room temperature, it is molten with 10mL saturated sodium bicarbonate
Liquid is quenched, then is extracted 3 times with 10mL methylene chloride；
(4) merge organic phase, and use anhydrous Na2SO4It dry half an hour, is then filtered and is concentrated, then use silica gel
Column chromatography carries out isolated net product.
Specifically, described to replace acrylamide, isocyanates, ruthenium catalyst, additive one, additive two and organic solvent
Molal volume ratio corresponds to 1.5~2.5mmol:1.0mmol:0.05mmol:0.2mmol:0.45mmol:2mL respectively.
Specifically, the solvent is non-protonic solvent, and solvent is acetonitrile, Isosorbide-5-Nitrae-dioxane, chlorobenzene, tetrahydro furan
It mutters, one of methylene chloride, 1,2- tetrachloroethanes, toluene.
Specifically, the ruthenium catalyst is that ten dicarbapentaborane, three ruthenium, hydrate ruthenium trichloride, acetylacetone,2,4-pentanedione ruthenium, dichloro are bis- (to first
Base isopropyl phenyl) one of ruthenium dimer and (1,5- cyclo-octadiene) ruthenous chloride.
Specifically, the additive one is silver trifluoromethanesulfonate, silver acetate, silver tetrafluoroborate, silver hexafluoroantimonate and double three
One of fluorine methylsulfonimide silver.
Specifically, the additive two is organic acid, such as acetic acid, trifluoroacetic acid, pivalic acid, adamantanecarboxylic acid, benzene first
One of acid, 2,4,6- trimethylbenzoic acid, 2,6- mesitylenic acid and salicylic acid.
Compared with prior art, the beneficial effects of the present invention are:
(1) present invention is selected using ruthenium catalyst homogeneous catalysis acrylamide by site under relatively mild reaction condition
Property carbon-hydrogen bond activation, concatenated amine acylation/cyclization occurs with isocyanates, quickly and easily building contains multiple substituent groups
Pyrimidone skeleton, reactive chemistry formula is as follows:
(2) by (1) it is found that participating in reaction process without oxidant, and reaction condition is mild, from raw material and product
From the point of view of structure, harmless water is only generated as byproduct, there is good Atom economy.
(3) in the preparation, raw material used includes that acrylamide and isocyanates are all cheap and easy to get, compared to traditional multistep road
Line, synthesis step are simpler；Compared with Pinner condensation method, the reaction condition milder, the reaction time is short, and higher yields obtain
To target product.
(4) under the catalysis of transition metal ruthenium, acrylamide as homing device, Selective activation acrylamide it is cis- hydrocarbon
Key generates C (sp2)-Ru intermediate, nucleophilic addition, further cyclodehydration occurs with isocyanates.
(5) preparation method of pyrimidinone compound provided by the invention has good regioselectivity, functional group's tolerance
Property it is good, by introducing different substituent groups in substrate, can with a step construct polysubstituted pyrimidine ketone compound.
Therefore, the new synthesis route that the present invention provides pyrimidinone compound has efficient, Atom economy, reaction condition temperature
With and the advantages that wide application range of substrates, there is potential application prospect in pharmaceutical synthesis field.
Detailed description of the invention
Fig. 1 is the nuclear magnetic resonance of 2- methyl -6- phenyl -3- (p-methylphenyl) pyrimidine -4 (3H) -one in the embodiment of the present invention 1
Hydrogen spectrogram；
Fig. 2 is the nuclear magnetic resonance of 2- methyl -6- phenyl -3- (p-methylphenyl) pyrimidine -4 (3H) -one in the embodiment of the present invention 1
Carbon spectrogram；
Fig. 3 is the nuclear magnetic resonance of -4 (3H) -one of 2- methyl -3- p-methylphenyl -6- t-butyl pyrimidines in the embodiment of the present invention 8
Hydrogen spectrogram；
Fig. 4 is the nuclear magnetic resonance of -4 (3H) -one of 2- methyl -3- p-methylphenyl -6- t-butyl pyrimidines in the embodiment of the present invention 8
Carbon spectrogram.
Specific embodiment
Following will be combined with the drawings in the embodiments of the present invention, and technical solution in the embodiment of the present invention carries out clear, complete
Site preparation description, it is clear that described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.It is based on
Embodiment in the present invention, it is obtained by those of ordinary skill in the art without making creative efforts every other
Embodiment shall fall within the protection scope of the present invention.
Embodiment one
The synthesis of 2- methyl -6- phenyl -3- (p-methylphenyl) pyrimidine -4 (3H) -one:
Under nitrogen protection, to addition N- (1- phenyl vinyl) acetamide in 10mL Schlenk reaction tube
(0.75mmol, 120.9mg), (p -Methylisopropylbenzene base) ruthenium bis- to toluene diisocyanate (0.3mmol, 40.0mg), dichloro
Dimer (0.015mmol, 9.2mg), silver hexafluoroantimonate (0.06mmol, 20.9mg), 2,4,6- trimethylbenzoic acids
(0.45mmol, 73.9mg)；2mL tetrahydrofuran is added with syringe with nitrogen displacement reaction tube 3 times, and under nitrogen protection,
100 DEG C are heated to, 16h is stirred；After reaction, reaction solution is cooled to room temperature, is quenched with 10mL saturated sodium bicarbonate solution,
It is extracted 3 times with 10mL methylene chloride again；Merge organic phase and uses anhydrous Na2SO4Dry half an hour, be then filtered with it is dense
Contracting, and using the net product of the isolated white solid of silica gel column chromatography；Yield is 83%.
The nucleus magnetic hydrogen spectrum data of the product are as follows:1H NMR (400MHz, CDCl3): δ 8.04-7.98 (m, 2H), 7.51-
7.46 (m, 3H), 7.39-7.34 (m, 2H), 7.14 (d, J=8.3Hz, 2H), 6.89 (s, 1H), 2.44 (s, 3H), 2.28 (s,
3H)。
Embodiment two
The synthesis of -4 (3H) -one of 2- methyl -3,6- di-p-tolyl pyrimidine:
Under nitrogen protection, to addition N- (1- p-methylphenyl vinyl) acetamide in 10mL Schlenk reaction tube
(0.75mmol, 131.4mg), (p -Methylisopropylbenzene base) ruthenium bis- to toluene diisocyanate (0.3mmol, 40.0mg), dichloro
Dimer (0.015mmol, 9.2mg), silver hexafluoroantimonate (0.06mmol, 20.9mg), 2,4,6- trimethylbenzoic acids
(0.45mmol, 73.9mg)；2mL tetrahydrofuran is added with syringe with nitrogen displacement reaction tube 3 times, and under nitrogen protection,
100 DEG C are heated to, 16h is stirred；After reaction, reaction solution is cooled to room temperature, is quenched with 10mL saturated sodium bicarbonate solution,
It is extracted 3 times with 10mL methylene chloride again；Merge organic phase and uses anhydrous Na2SO4Dry half an hour, be then filtered with it is dense
Contracting, and using the net product of the isolated white solid of silica gel column chromatography；Yield is 50%.
The nucleus magnetic hydrogen spectrum data of the product are as follows:1H NMR (400MHz, CDCl3): δ 7.91 (d, J=8.2Hz, 2H),
7.40-7.34 (m, 2H), 7.31-7.26 (m, 2H), 7.14 (d, J=8.3Hz, 2H), 6.86 (s, 1H), 2.44 (s, 3H),
2.42 (s, 3H), 2.27 (s, 3H).
Embodiment three
Synthesis of the 2- methyl -3- p-methylphenyl -6- to cyano-phenyl pyrimidine -4 (3H) -one:
Under nitrogen protection, to addition N- (1- is to cyano-phenyl vinyl) acetamide in 10mL Schlenk reaction tube
(0.75mmol, 139.7mg), (p -Methylisopropylbenzene base) ruthenium bis- to toluene diisocyanate (0.3mmol, 40.0mg), dichloro
Dimer (0.015mmol, 9.2mg), silver hexafluoroantimonate (0.06mmol, 20.9mg), 2,4,6- trimethylbenzoic acids
(0.4mmol, 73.9mg)；2mL tetrahydrofuran is added with syringe with nitrogen displacement reaction tube 3 times, and under nitrogen protection, adds
Heat stirs 16h to 100 DEG C；After reaction, reaction solution is cooled to room temperature, is quenched with 10mL saturated sodium bicarbonate solution, then
It is extracted 3 times with 10mL methylene chloride；Merge organic phase and uses anhydrous Na2SO4It dry half an hour, is then filtered and is concentrated,
And using the net product of the isolated yellow solid of silica gel column chromatography；Yield is 70%.
The nucleus magnetic hydrogen spectrum data of the product are as follows:1H NMR (400MHz, CDCl3): δ 8.14-8.07 (m, 2H), 7.81-
7.71 (m, 2H), 7.37 (d, J=8.2Hz, 2H), 7.17-7.08 (m, 2H), 6.91 (s, 1H), 2.44 (s, 3H), 2.28 (s,
3H)。
Example IV
The synthesis of -4 (3H) -one of 2- methyl -3- p-methylphenyl -6- rubigan pyrimidine:
Under nitrogen protection, to addition N- (1- rubigan vinyl) acetamide in 10mL Schlenk reaction tube
(0.75mmol, 146.7mg), (p -Methylisopropylbenzene base) ruthenium bis- to toluene diisocyanate (0.3mmol, 40.0mg), dichloro
Dimer (0.015mmol, 9.2mg), silver hexafluoroantimonate (0.06mmol, 20.9mg), 2,4,6- trimethylbenzoic acids
(0.45mmol, 73.9mg)；2mL tetrahydrofuran is added with syringe with nitrogen displacement reaction tube 3 times, and under nitrogen protection,
100 DEG C are heated to, 16h is stirred；After reaction, reaction solution is cooled to room temperature, is quenched with 10mL saturated sodium bicarbonate solution,
It is extracted 3 times with 10mL methylene chloride again；Merge organic phase and uses anhydrous Na2SO4Dry half an hour, be then filtered with it is dense
Contracting, and using the net product of the isolated white solid of silica gel column chromatography；Yield is 98%.
The nucleus magnetic hydrogen spectrum data of the product are as follows:1H NMR (400MHz, CDCl3): δ 7.95 (d, J=8.5Hz, 2H),
7.45 (d, J=8.6Hz, 2H), 7.36 (dt, J=8.5,0.7Hz, 2H), 7.13 (d, J=8.2Hz, 2H), 6.85 (s, 1H),
2.44 (s, 3H), 2.27 (s, 3H).
Embodiment five
The synthesis of 2- methyl -3- p-methylphenyl -6- (2- fluorophenyl) pyrimidine -4 (3H) -one:
Under nitrogen protection, to addition N- (1- (2- fluorophenyl) vinyl) acetamide in 10mL Schlenk reaction tube
(0.75mmol, 134.4mg), (p -Methylisopropylbenzene base) ruthenium bis- to toluene diisocyanate (0.3mmol, 40.0mg), dichloro
Dimer (0.015mmol, 9.2mg), silver hexafluoroantimonate (0.06mmol, 20.9mg), 2,4,6- trimethylbenzoic acids
(0.45mmol, 73.9mg)；2mL tetrahydrofuran is added with syringe with nitrogen displacement reaction tube 3 times, and under nitrogen protection,
120 DEG C are heated to, 16h is stirred；After reaction, reaction solution is cooled to room temperature, is quenched with 10mL saturated sodium bicarbonate solution,
It is extracted 3 times with 10mL methylene chloride again；Merge organic phase and uses anhydrous Na2SO4Dry half an hour, be then filtered with it is dense
Contracting, and using the net product of the isolated light yellow solid of silica gel column chromatography；Yield is 54%.
The nucleus magnetic hydrogen spectrum data of the product are as follows:1H NMR (400MHz, CDCl3): δ 8.09 (td, J=7.9,2.0Hz,
1H), 7.46-7.38 (m, 1H), 7.36 (d, J=8.0Hz, 2H), 7.30-7.24 (m, 1H), 7.16-7.13 (m, 3H), 7.03
(s, 1H), 2.43 (s, 3H), 2.26 (s, 3H).
Embodiment six
The synthesis of 2- methyl -3- p-methylphenyl -6- (3- methoxyphenyl) pyrimidine -4 (3H) -one:
Under nitrogen protection, to addition N- (1- (3- methoxyphenyl) vinyl) acetyl in 10mL Schlenk reaction tube
Amine (0.75mmol, 143.4mg), (p -Methylisopropylbenzene bases) bis- to toluene diisocyanate (0.3mmol, 40.0mg), dichloro
Ruthenium dimer (0.015mmol, 9.2mg), silver hexafluoroantimonate (0.06mmol, 20.9mg), 2,4,6- trimethylbenzoic acids
(0.45mmol, 73.9mg)；2mL tetrahydrofuran is added with syringe with nitrogen displacement reaction tube 3 times, and under nitrogen protection,
100 DEG C are heated to, 16h is stirred；After reaction, reaction solution is cooled to room temperature, is quenched with 10mL saturated sodium bicarbonate solution,
It is extracted 3 times with 10mL methylene chloride again；Merge organic phase and uses anhydrous Na2SO4Dry half an hour, be then filtered with it is dense
Contracting, and using the net product of the isolated white solid of silica gel column chromatography；Yield is 53%.
The nucleus magnetic hydrogen spectrum data of the product are as follows:1H NMR (400MHz, CDCl3): δ 7.57 (dt, J=5.0,1.8Hz,
2H), 7.43-7.33 (m, 3H), 7.14 (d, J=8.2Hz, 2H), 7.02 (ddd, J=8.2,2.6,1.0Hz, 1H), 6.87 (s,
1H), 3.88 (s, 3H), 2.44 (s, 3H), 2.27 (s, 3H).
Embodiment seven
The synthesis of 2- methyl -3- p-methylphenyl -6- (2- naphthalene) pyrimidine -4 (3H) -one:
Under nitrogen protection, to addition N- (1- (3- methoxyphenyl) vinyl) acetyl in 10mLSchlenk reaction tube
Amine (0.75mmol, 158.4mg), (p -Methylisopropylbenzene bases) bis- to toluene diisocyanate (0.3mmol, 40.0mg), dichloro
Ruthenium dimer (0.015mmol, 9.2mg), silver hexafluoroantimonate (0.06mmol, 20.9mg), 2,4,6- trimethylbenzoic acids
(0.45mmol, 73.9mg)；2mL tetrahydrofuran is added with syringe with nitrogen displacement reaction tube 3 times, and under nitrogen protection,
100 DEG C are heated to, 16h is stirred；After reaction, reaction solution is cooled to room temperature, is quenched with 10mL saturated sodium bicarbonate solution,
It is extracted 3 times with 1mL methylene chloride again；Merge organic phase and uses anhydrous Na2SO4Dry half an hour, be then filtered with it is dense
Contracting, and using the net product of the isolated light yellow solid of silica gel column chromatography；Yield is 87%.
The nucleus magnetic hydrogen spectrum data of the product are as follows:1H NMR (400MHz, CDCl3): δ 8.64-8.59 (m, 1H), 8.04
(dd, J=8.6,1.8Hz, 1H), 8.00-7.85 (m, 3H), 7.58-7.52 (m, 2H), 7.38 (dt, J=7.8,0.7Hz,
2H), 7.17 (d, J=8.3Hz, 2H), 7.04 (s, 1H), 2.45 (s, 3H), 2.33 (s, 3H).
Embodiment eight
The synthesis of -4 (3H) -one of 2- methyl -3- p-methylphenyl -6- t-butyl pyrimidines:
Under nitrogen protection, to addition N- (1- tert-butyl vinyl base) acetamide in 10mL Schlenk reaction tube
(0.75mmol, 105.9mg), (p -Methylisopropylbenzene base) ruthenium bis- to toluene diisocyanate (0.3mmol, 40.0mg), dichloro
Dimer (0.015mmol, 9.2mg), silver hexafluoroantimonate (0.06mmol, 20.9mg), 2,4,6- trimethylbenzoic acids
(0.45mmol, 73.9mg)；2mL tetrahydrofuran is added with syringe with nitrogen displacement reaction tube 3 times, and under nitrogen protection,
100 DEG C are heated to, 16h is stirred；After reaction, reaction solution is cooled to room temperature, is quenched with 10mL saturated sodium bicarbonate solution,
It is extracted 3 times with 10mL methylene chloride again；Merge organic phase and uses anhydrous Na2SO4Dry half an hour, be then filtered with it is dense
Contracting, and using the net product of the isolated white solid of silica gel column chromatography；Yield is 64%.
The nucleus magnetic hydrogen spectrum data of the product are as follows:1H NMR (400MHz, CDCl3): δ 7.36-7.28 (m, 2H), 7.09 (d,
J=8.3Hz, 2H), 6.41 (s, 1H), 2.41 (s, 3H), 2.16 (s, 3H), 1.28 (s, 9H).
Embodiment nine
The synthesis of -4 (3H) -one of 2- ethyl -3- p-methylphenyl -6- phenyl pyrimidine:
Under nitrogen protection, to addition N- (1- phenyl vinyl) propionamide in 10mL Schlenk reaction tube
(0.75mmol, 131.4mg), (p -Methylisopropylbenzene base) ruthenium bis- to toluene diisocyanate (0.3mmol, 40.0mg), dichloro
Dimer (0.015mmol, 9.2mg), silver hexafluoroantimonate (0.06mmol, 20.9mg), 2,4,6- trimethylbenzoic acids
(0.45mmol, 73.9mg)；2mL tetrahydrofuran is added with syringe with nitrogen displacement reaction tube 3 times, and under nitrogen protection,
100 DEG C are heated to, 16h is stirred；After reaction, reaction solution is cooled to room temperature, is quenched with 10mL saturated sodium bicarbonate solution,
It is extracted 3 times with 10mL methylene chloride again；Merge organic phase and uses anhydrous Na2SO4Dry half an hour, be then filtered with it is dense
Contracting, and using the net product of the isolated light yellow solid of silica gel column chromatography；Yield is 91%.
The nucleus magnetic hydrogen spectrum data of the product are as follows:1H NMR (400MHz, CDCl3): δ 8.08 (dd, J=6.8,2H), 7.49
(dd, J=4.8,3H), 7.36 (d, J=8.1Hz, 2H), 7.19-7.09 (m, 2H), 6.92 (s, 1H), 2.49-2.43 (m,
5H), 1.28 (t, J=7.3Hz, 3H).
Embodiment ten
The synthesis of 2- methyl -3- (4- methoxyphenyl) -6- phenyl pyrimidine -4 (3H) -one:
Under nitrogen protection, to addition N- (1- phenyl vinyl) acetamide in 10mL Schlenk reaction tube
(0.75mmol, 131.4mg), 4- methoxybenzene isocyanates (0.3mmol, 44.7mg), the bis- (p -Methylisopropylbenzenes of dichloro
Base) ruthenium dimer (0.015mmol, 9.2mg), silver hexafluoroantimonate (0.06mmol, 20.9mg), 2,4,6- trimethylbenzoic acids
(0.45mmol, 73.9mg)；2mL tetrahydrofuran is added with syringe with nitrogen displacement reaction tube 3 times, and under nitrogen protection,
100 DEG C are heated to, 16h is stirred；After reaction, reaction solution is cooled to room temperature, is quenched with 10mL saturated sodium bicarbonate solution,
It is extracted 3 times with 10mL methylene chloride again；Merge organic phase and uses anhydrous Na2SO4Dry half an hour, be then filtered with it is dense
Contracting, and using the net product of the isolated light yellow solid of silica gel column chromatography；Yield is 84%.
The nucleus magnetic hydrogen spectrum data of the product are as follows:1H NMR (400MHz, CDCl3): δ 8.04-7.97 (m, 2H), 7.50-
7.45 (m, 3H), 7.17 (d, J=8.9Hz, 2H), 7.05 (d, J=8.9Hz, 2H), 6.88 (s, 1H), 3.85 (s, 3H), 2.27
(s, 3H).
Embodiment 11
The synthesis of 2- methyl -3- (3- bromophenyl) -6- phenyl pyrimidine -4 (3H) -one:
Under nitrogen protection, to addition N- (1- phenyl vinyl) acetamide in 10mL Schlenk reaction tube
(0.75mmol, 131.4mg), 3- bromobenzene isocyanates (0.3mmol, 59.4mg), bis- (p -Methylisopropylbenzene base) rutheniums of dichloro
Dimer (0.015mmol, 9.2mg), silver hexafluoroantimonate (0.06mmol, 20.9mg), 2,4,6- trimethylbenzoic acids
(0.45mmol, 73.9mg)；2mL tetrahydrofuran is added with syringe with nitrogen displacement reaction tube 3 times, and under nitrogen protection,
100 DEG C are heated to, 16h is stirred；After reaction, reaction solution is cooled to room temperature, is quenched with 10mL saturated sodium bicarbonate solution,
It is extracted 3 times with 10mL methylene chloride again；Merge organic phase and uses anhydrous Na2SO4Dry half an hour, be then filtered with it is dense
Contracting, and using the net product of the isolated light tan solid of silica gel column chromatography；Yield is 85%.
The nucleus magnetic hydrogen spectrum data of the product are as follows:1H NMR (400MHz, CDCl3): δ 8.04-7.97 (m, 2H), 7.66
(ddd, J=8.1,1.9,1.0Hz, 1H), 7.52-7.42 (m, 5H), 7.23 (ddd, J=7.9,2.0,1.0Hz, 1H), 6.88
(s, 1H), 2.29 (s, 3H).
Embodiment 12
The synthesis of -4 (3H) -one of 2- methyl -3- benzyl -6- phenyl pyrimidine:
Under nitrogen protection, to addition N- (1- phenyl vinyl) acetamide in 10mL Schlenk reaction tube
(0.75mmol, 131.4mg), benzyl mustard oil (0.3mmol, 40.0mg), bis- (p -Methylisopropylbenzene base) the ruthenium dimerization of dichloro
Body (0.015mmol, 9.2mg), silver hexafluoroantimonate (0.06mmol, 20.9mg), 2,4,6- trimethylbenzoic acids (0.45mmol,
73.9mg)；2mL tetrahydrofuran is added with syringe with nitrogen displacement reaction tube 3 times, and under nitrogen protection, is heated to 100
DEG C, stir 16h；After reaction, reaction solution is cooled to room temperature, is quenched with 10mL saturated sodium bicarbonate solution, then use 10mL
Methylene chloride extracts 3 times；Merge organic phase and uses anhydrous Na2SO4It dry half an hour, is then filtered and is concentrated, and use
The net product of the isolated white solid of silica gel column chromatography；Yield is 72%.
The nucleus magnetic hydrogen spectrum data of the product are as follows:1H NMR (400MHz, CDCl3): δ 8.02-7.96 (m, 2H), 7.50-
7.44 (m, 3H), 7.39-7.32 (m, 2H), 7.32-7.28 (m, 1H), 7.25-7.21 (m, 2H), 6.88 (s, 1H), 5.35 (s,
2H), 2.55 (s, 3H).
Embodiment 13
The synthesis of -4 (3H) -one of 2- methyl -3- ethyl -6- phenyl pyrimidine:
Under nitrogen protection, to addition N- (1- phenyl vinyl) acetamide in 10mL Schlenk reaction tube
(0.75mmol, 131.4mg), ethyl isocyanate (0.3mmol, 21.3mg), bis- (p -Methylisopropylbenzene base) the ruthenium dimerization of dichloro
Body (0.015mmol, 9.2mg), silver hexafluoroantimonate (0.06mmol, 20.9mg), 2,4,6- trimethylbenzoic acids (0.45mmol,
73.9mg)；2mL tetrahydrofuran is added with syringe with nitrogen displacement reaction tube 3 times, and under nitrogen protection, is heated to 100
DEG C, stir 16h；After reaction, reaction solution is cooled to room temperature, is quenched with 10mL saturated sodium bicarbonate solution, then use 10mL
Methylene chloride extracts 3 times；Merge organic phase and uses anhydrous Na2SO4It dry half an hour, is then filtered and is concentrated, and use
The net product of the isolated white solid of silica gel column chromatography；Yield is 66%.
The nucleus magnetic hydrogen spectrum data of the product are as follows:1H NMR (400MHz, CDCl3): δ 7.96-7.90 (m, 2H), 7.47-
7.41 (m, 3H), 6.75 (s, 1H), 4.11 (q, J=7.2Hz, 2H), 2.64 (s, 3H), 1.35 (t, J=7.2Hz, 3H).
Although the present invention is described in detail referring to the foregoing embodiments, for those skilled in the art,
It is still possible to modify the technical solutions described in the foregoing embodiments, or part of technical characteristic is carried out etc.
With replacement, all within the spirits and principles of the present invention, any modification, equivalent replacement, improvement and so on should be included in this
Within the protection scope of invention.
Claims (7)
1. a kind of polysubstituted pyrimidine ketone compound, it is characterised in that: shown under its structure such as formula:
In formula, R1For p-trifluoromethyl phenyl, 1,2- methylene dioxy phenyl group, p-methylphenyl, to cyano-phenyl, m-methoxyphenyl,
P-bromophenyl, o-fluorophenyl, 2- naphthalene, tert-butyl, 2- thienyl, p-fluorophenyl, rubigan, 3,4- ihydro naphthyl, Buddha's warrior attendant
Alkyl；R2For methyl, ethyl, propyl, isobutyl group, cyclohexyl, styryl；R3For p-methylphenyl, o-tolyl, normal-butyl, neighbour
Chlorphenyl, ethyl, cyclohexyl, rubigan, tolyl, p-methoxyphenyl, benzyl, p-fluorophenyl, 1- naphthalene, to trifluoro
Aminomethyl phenyl, acetylphenyl, to cyano-phenyl, n-octyl.
2. the preparation method of polysubstituted pyrimidine ketone compound according to claim 1, it is characterised in that: including following step
It is rapid:
(1) under nitrogen protection, to the substitution alkene acyl for being separately added into 0.45~0.75mmol in the Schlenk reaction tube of 10mL
Amine, the isocyanates of 0.3mmol, the ruthenium catalyst of 5mol%, the additive one of 20mol% and 0.45mmol additive two；
(2) with nitrogen displacement reaction tube 3 times, and under nitrogen protection, the solvent of 2mL is added into reaction tube with syringe, and
Heating and stirring are carried out, and are heated to 60~120 DEG C, mixing time is 12~for 24 hours；
(3) when the reaction solution in (2) after reaction, reaction solution is cooled to room temperature, is quenched with 10mL saturated sodium bicarbonate solution
It goes out, then is extracted 3 times with 10mL methylene chloride；
(4) merge organic phase, and use anhydrous Na2SO4It dry half an hour, is then filtered and is concentrated, then use silica gel column layer
Analysis carries out isolated net product.
3. the preparation method of polysubstituted pyrimidine ketone compound according to claim 2, it is characterised in that: the substitution alkene acyl
Amine, isocyanates, ruthenium catalyst, additive one, additive two and organic solvent molal volume than correspond to 1.5 respectively~
2.5mmol:1.0mmol:0.05mmol:0.2mmol:0.45mmol:2mL.
4. the preparation method of polysubstituted pyrimidine ketone compound according to claim 2, it is characterised in that: the solvent is non-
Protonic solvent, and solvent is acetonitrile, Isosorbide-5-Nitrae-dioxane, chlorobenzene, tetrahydrofuran, methylene chloride, 1,2- tetrachloroethanes, toluene
One of.
5. the preparation method of polysubstituted pyrimidine ketone compound according to claim 2, it is characterised in that: the ruthenium catalyst
For bis- (p -Methylisopropylbenzene base) the ruthenium dimers of ten dicarbapentaborane, three ruthenium, hydrate ruthenium trichloride, acetylacetone,2,4-pentanedione ruthenium, dichloro and (1,
One of 5- cyclo-octadiene) ruthenous chloride.
6. the preparation method of polysubstituted pyrimidine ketone compound according to claim 2, it is characterised in that: the additive one
For one of silver trifluoromethanesulfonate, silver acetate, silver tetrafluoroborate, silver hexafluoroantimonate and bis-trifluoromethylsulfoandimide silver.
7. the preparation method of polysubstituted pyrimidine ketone compound according to claim 2, it is characterised in that: the additive two
For organic acid, such as acetic acid, trifluoroacetic acid, pivalic acid, adamantanecarboxylic acid, benzoic acid, 2,4,6- trimethylbenzoic acid, 2,6- bis-
One of methyl benzoic acid and salicylic acid.
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| CN113563270A (en) * | 2021-08-10 | 2021-10-29 | 苏州小栗医药科技有限公司 | Synthetic method of 2-bromopyrimidine |
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