CN112159411A - Trifluoromethyl substituted pyrimido [1,3] diaza compound and preparation method thereof - Google Patents
Trifluoromethyl substituted pyrimido [1,3] diaza compound and preparation method thereof Download PDFInfo
- Publication number
- CN112159411A CN112159411A CN202011105476.3A CN202011105476A CN112159411A CN 112159411 A CN112159411 A CN 112159411A CN 202011105476 A CN202011105476 A CN 202011105476A CN 112159411 A CN112159411 A CN 112159411A
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- CN
- China
- Prior art keywords
- dihydronaphthalenone
- perfluorobutyl
- compound
- hydrochloride
- mmol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 34
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- -1 amidine compound Chemical class 0.000 claims abstract description 43
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- 238000000034 method Methods 0.000 claims abstract description 25
- 239000000654 additive Substances 0.000 claims abstract description 23
- 239000003513 alkali Substances 0.000 claims abstract description 21
- 238000012546 transfer Methods 0.000 claims abstract description 21
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims abstract description 20
- 230000000996 additive effect Effects 0.000 claims abstract description 19
- 239000002904 solvent Substances 0.000 claims abstract description 17
- 238000004440 column chromatography Methods 0.000 claims abstract description 15
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 12
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims abstract description 10
- 229910000024 caesium carbonate Inorganic materials 0.000 claims abstract description 10
- 229910001629 magnesium chloride Inorganic materials 0.000 claims abstract description 10
- 238000001035 drying Methods 0.000 claims abstract description 7
- 238000003756 stirring Methods 0.000 claims abstract description 7
- 238000005406 washing Methods 0.000 claims abstract description 7
- 238000002156 mixing Methods 0.000 claims abstract description 4
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 238000001514 detection method Methods 0.000 claims abstract description 3
- 238000004809 thin layer chromatography Methods 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 238000000926 separation method Methods 0.000 claims description 11
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 235000011147 magnesium chloride Nutrition 0.000 claims description 8
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 claims description 8
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 8
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 8
- 230000005526 G1 to G0 transition Effects 0.000 claims description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- LZCZIHQBSCVGRD-UHFFFAOYSA-N benzenecarboximidamide;hydron;chloride Chemical compound [Cl-].NC(=[NH2+])C1=CC=CC=C1 LZCZIHQBSCVGRD-UHFFFAOYSA-N 0.000 claims description 6
- 230000008859 change Effects 0.000 claims description 6
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 claims description 6
- 125000001624 naphthyl group Chemical group 0.000 claims description 6
- 239000003208 petroleum Substances 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 239000000741 silica gel Substances 0.000 claims description 6
- 229910002027 silica gel Inorganic materials 0.000 claims description 6
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 5
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 claims description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- JQPHHPDUERQEGZ-UHFFFAOYSA-N n-propan-2-ylpropan-2-amine;sodium Chemical compound [Na].CC(C)NC(C)C JQPHHPDUERQEGZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000004323 potassium nitrate Substances 0.000 claims description 4
- 235000010333 potassium nitrate Nutrition 0.000 claims description 4
- 235000002639 sodium chloride Nutrition 0.000 claims description 4
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 3
- 239000005695 Ammonium acetate Substances 0.000 claims description 3
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- 150000001409 amidines Chemical class 0.000 claims description 3
- 229940043376 ammonium acetate Drugs 0.000 claims description 3
- 235000019257 ammonium acetate Nutrition 0.000 claims description 3
- 239000001099 ammonium carbonate Substances 0.000 claims description 3
- 235000012501 ammonium carbonate Nutrition 0.000 claims description 3
- CHQVQXZFZHACQQ-UHFFFAOYSA-M benzyl(triethyl)azanium;bromide Chemical compound [Br-].CC[N+](CC)(CC)CC1=CC=CC=C1 CHQVQXZFZHACQQ-UHFFFAOYSA-M 0.000 claims description 3
- BZRRQSJJPUGBAA-UHFFFAOYSA-L cobalt(ii) bromide Chemical compound Br[Co]Br BZRRQSJJPUGBAA-UHFFFAOYSA-L 0.000 claims description 3
- 229940043279 diisopropylamine Drugs 0.000 claims description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 3
- 235000019341 magnesium sulphate Nutrition 0.000 claims description 3
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 claims description 3
- 239000002808 molecular sieve Substances 0.000 claims description 3
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 235000011181 potassium carbonates Nutrition 0.000 claims description 3
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 3
- 235000011009 potassium phosphates Nutrition 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 239000001632 sodium acetate Substances 0.000 claims description 3
- 235000017281 sodium acetate Nutrition 0.000 claims description 3
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 3
- MCZDHTKJGDCTAE-UHFFFAOYSA-M tetrabutylazanium;acetate Chemical compound CC([O-])=O.CCCC[N+](CCCC)(CCCC)CCCC MCZDHTKJGDCTAE-UHFFFAOYSA-M 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- RXAOGVQDNBYURA-UHFFFAOYSA-N (4-chlorobenzenecarboximidoyl)azanium;chloride Chemical compound Cl.NC(=N)C1=CC=C(Cl)C=C1 RXAOGVQDNBYURA-UHFFFAOYSA-N 0.000 claims description 2
- JQDATBKJKUWNGA-UHFFFAOYSA-N 4-fluorobenzenecarboximidamide;hydrochloride Chemical compound Cl.NC(=N)C1=CC=C(F)C=C1 JQDATBKJKUWNGA-UHFFFAOYSA-N 0.000 claims description 2
- LTHONTNMNUUXOD-UHFFFAOYSA-N 4-iodobenzenecarboximidamide;hydrochloride Chemical compound Cl.NC(=N)C1=CC=C(I)C=C1 LTHONTNMNUUXOD-UHFFFAOYSA-N 0.000 claims description 2
- AJOSDIDPIBJFAI-UHFFFAOYSA-N 4-methoxybenzenecarboximidamide;hydrochloride Chemical compound Cl.COC1=CC=C(C(N)=N)C=C1 AJOSDIDPIBJFAI-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- YQLMHXJICJZZFV-UHFFFAOYSA-N [amino-(4-ethoxycarbonylphenyl)methylidene]azanium;chloride Chemical compound [Cl-].CCOC(=O)C1=CC=C(C([NH3+])=N)C=C1 YQLMHXJICJZZFV-UHFFFAOYSA-N 0.000 claims description 2
- NMVVJCLUYUWBSZ-UHFFFAOYSA-N aminomethylideneazanium;chloride Chemical compound Cl.NC=N NMVVJCLUYUWBSZ-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- WCQOBLXWLRDEQA-UHFFFAOYSA-N ethanimidamide;hydrochloride Chemical compound Cl.CC(N)=N WCQOBLXWLRDEQA-UHFFFAOYSA-N 0.000 claims description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 125000002541 furyl group Chemical class 0.000 claims description 2
- MTDUPZAXNYELOU-UHFFFAOYSA-N hydron;4-methylbenzenecarboximidamide;chloride Chemical compound Cl.CC1=CC=C(C(N)=N)C=C1 MTDUPZAXNYELOU-UHFFFAOYSA-N 0.000 claims description 2
- CJXJAUKCHHAJQN-UHFFFAOYSA-N hydron;4-nitrobenzenecarboximidamide;chloride Chemical compound Cl.NC(=N)C1=CC=C([N+]([O-])=O)C=C1 CJXJAUKCHHAJQN-UHFFFAOYSA-N 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- XDRYMKDFEDOLFX-UHFFFAOYSA-N pentamidine Chemical compound C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 XDRYMKDFEDOLFX-UHFFFAOYSA-N 0.000 claims description 2
- 229960004448 pentamidine Drugs 0.000 claims description 2
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 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
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- XHLHPRDBBAGVEG-UHFFFAOYSA-N 1-tetralone Chemical compound C1=CC=C2C(=O)CCCC2=C1 XHLHPRDBBAGVEG-UHFFFAOYSA-N 0.000 claims 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- 239000002585 base Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000003054 catalyst Substances 0.000 abstract description 3
- 229910052723 transition metal Inorganic materials 0.000 abstract description 3
- 150000003624 transition metals Chemical class 0.000 abstract description 3
- 229910001873 dinitrogen Inorganic materials 0.000 description 5
- 125000000623 heterocyclic group Chemical group 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000007789 sealing Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 208000019901 Anxiety disease Diseases 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- 229960004538 alprazolam Drugs 0.000 description 2
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 229960004782 chlordiazepoxide Drugs 0.000 description 2
- ANTSCNMPPGJYLG-UHFFFAOYSA-N chlordiazepoxide Chemical compound O=N=1CC(NC)=NC2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 ANTSCNMPPGJYLG-UHFFFAOYSA-N 0.000 description 2
- 229960003529 diazepam Drugs 0.000 description 2
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229960003528 flurazepam Drugs 0.000 description 2
- SAADBVWGJQAEFS-UHFFFAOYSA-N flurazepam Chemical compound N=1CC(=O)N(CCN(CC)CC)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1F SAADBVWGJQAEFS-UHFFFAOYSA-N 0.000 description 2
- 239000008204 material by function Substances 0.000 description 2
- 229960004535 oxazepam Drugs 0.000 description 2
- ADIMAYPTOBDMTL-UHFFFAOYSA-N oxazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(O)N=C1C1=CC=CC=C1 ADIMAYPTOBDMTL-UHFFFAOYSA-N 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical class N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
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- 208000029650 alcohol withdrawal Diseases 0.000 description 1
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- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 229940005530 anxiolytics Drugs 0.000 description 1
- 238000005899 aromatization reaction Methods 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000003326 hypnotic agent Substances 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 125000001477 organic nitrogen group Chemical group 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
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Abstract
The invention discloses a trifluoromethyl substituted pyrimido [1,3]]Diaza derivatives
Compounds and methods for their preparation. Adding a phase transfer promoter, an alkali promoter, an additive and a solvent into a reaction raw material formed by mixing a 2-perfluorobutyl dihydronaphthalenone compound and an amidine compound, stirring and reacting for 1-24 hours at the temperature of 20-100 ℃, determining the reaction process by TLC (thin layer chromatography) detection, obtaining a reaction product after the reaction is finished, washing, extracting and drying the reaction product, and separating by column chromatography to obtain trifluoromethyl substituted pyrimido [1,3]Diaza derivatives
A compound is provided. The invention synthesizes trifluoromethyl substituted pyrimido [1,3] from simple and easily obtained 2-perfluorobutyl dihydronaphthalenone compound and amidine compound raw materials]Diaza derivatives
The preparation method of the compound has mild reaction conditions, does not need expensive transition metal catalysts, only uses cesium carbonate as alkali and magnesium chloride as additives, and meets the requirements of green and economic chemistry.
Description
Technical Field
The invention belongs to the field of organic chemistry and pharmaceutical chemistry, and particularly relates to trifluoromethyl substituted pyrimido [1,3]Diaza derivatives
Compounds, methods of making the same.
Background
Nitrogen atoms are the most common heteroatoms in FDA-approved small molecule drugs. Nitrogen-containing heterocyclic compounds are the most important class of substances in organic chemistry. In view of the core role of organic nitrogen-containing heterocyclic compounds in chemistry and biology, chemists have been working on developing efficient and highly chemoselective methods for constructing heterocycles. The synthetic studies of pyrido-conjugated five-membered rings (e.g., indolizine) and pyrido-conjugated six-membered rings (e.g., quinolizine salts) as two of the classical aromatic skeletons widely present in bioactive molecules and functional materials have led to fruitful results. However, the pyrido-conjugated seven-membered rings closely related thereto, in particular pyrido [1,3]]Diaza derivatives
The synthesis of (2) is rare. Fused benzodiazepines
The compounds, including chlordiazepoxide, diazepam, flurazepam, alprazolam, oxazepam and the like, can be used as sedatives and anxiolytics, are mainly used for anxiety, tension and agitation, can be used as hypnotics or auxiliary drugs for anxiety, can be used as anti-panic drugs, and can relieve acute alcohol withdrawal symptoms and the like.
Traditional methods of constructing polycyclic systems require multi-step syntheses, and these reactions are primarily limited by poor atom economy, step economy, and the need for expensive metal catalysts. Therefore, development of more economical and efficient fused ring dinitrogen
The synthesis method of the compounds is very goodAs necessary. Moreover, specific small molecular skeleton trifluoromethyl is introduced while constructing the heterocyclic skeleton, and the function of obviously improving the physical and chemical properties of the heterocyclic skeleton can also be achieved. And synthesizing trifluoromethyl substituted pyrimido [1,3]]Diaza derivatives
Methods for the compounds have not been reported.
Disclosure of Invention
The invention aims at providing trifluoromethyl substituted pyrimido [1,3]Diaza derivatives
The compound aims to introduce specific small molecular skeleton trifluoromethyl while constructing a heterocyclic skeleton so as to obviously improve the physical and chemical properties of the compound.
It is a secondary object of the present invention to provide the above trifluoromethyl-substituted pyrimido [1,3]]Diaza derivatives
The preparation method of the compound aims to overcome various defects of the traditional method for constructing a polycyclic system.
The present invention is achieved by a trifluoromethyl-substituted pyrimido [1,3]]Diaza derivatives
A compound having the chemical formula (I):
in the formula (I), R1Any one selected from C1-C5 alkyl, C1-C5 alkoxy, halogen, benzyl, phenyl, cyano, nitro, acetyl, ethoxycarbonyl, hydroxyl and amino;
R2any one selected from C1-C5 alkyl, benzyl, phenyl, naphthyl, thienyl and pyridyl;
R3any one selected from C1-C5 alkyl, benzyl, phenyl, naphthyl, thienyl and pyridyl;
R4any one selected from the group consisting of C1-C5 alkyl, benzyl, phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, halogen-substituted phenyl, cyano-substituted phenyl, nitro-substituted phenyl, alkoxycarbonyl-substituted phenyl, naphthyl, furyl, and pyridyl.
Preferably, in the formula (I), the C1-C5 alkyl group is selected from any one of methyl, ethyl, propyl, isopropyl, tert-butyl and pentyl.
Preferably, in the formula (i), the C1-C5 alkoxy group is selected from any one of methoxy, ethoxy, isopropoxy, tert-butoxy and pentyloxy.
Preferably, in formula (i), the halogen is selected from any one of fluorine, chlorine, bromine and iodine.
The invention further discloses the trifluoromethyl substituted pyrimido [1,3]]Diaza derivatives
A process for the preparation of a compound, the process comprising the steps of:
(1) adding a phase transfer promoter, an alkali promoter, an additive and a solvent into a reaction raw material formed by mixing a 2-perfluorobutyl dihydronaphthalenone compound and an amidine compound, stirring and reacting for 1-24 hours at the temperature of 20-100 ℃, determining the reaction process by TLC (thin layer chromatography) detection, and obtaining a reaction product after the reaction is finished; wherein the molar volume ratio of the 2-perfluorobutyl dihydronaphthalenone compound to the amidine compound to the phase transfer promoter to the alkali promoter to the additive to the solvent is 1 mmol: 2-5 mmol: 1 mmol: 3-5 mmol: 3-5 mmol: 4-6 mL;
(2) washing, extracting and drying the reaction product, and separating by column chromatography to obtain trifluoromethyl substituted pyrimido [1,3]Diaza derivatives
A compound is provided.
Preferably, in the step (1), the molar volume ratio of the 2-perfluorobutyl dihydronaphthalenone compound, the amidine compound, the phase transfer promoter, the alkali promoter, the additive and the solvent is 1 mmol: 3 mmol: 1 mmol: 4 mmol: 4 mmol: 5 mL.
Preferably, in the step (1), the 2-perfluorobutyl dihydronaphthalenone compound is selected from the group consisting of 7-methyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-ethyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-isopropyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-tert-butyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-pentyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-methoxy-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-ethoxy-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-isopropoxy-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-tert-butoxy-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-pentyloxy-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-fluoro-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-chloro-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-bromo-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-iodo-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-benzyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-phenyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-cyano-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-nitro-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-acetyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-ethoxycarbonyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-hydroxy-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-amino-2-perfluorobutyl-3, 4-dihydronaphthalenone, 4-methyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 4-ethyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 4-isopropyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 4-tert-butyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 4-pentyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 4-benzyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 4-phenyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 4-naphthyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 4-thienyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 4-pyridyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 3-methyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 3-ethyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 3-isopropyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 3-tert-butyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 3-pentyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, any one of 3-benzyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 3-phenyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 3-naphthyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 3-thienyl-2-perfluorobutyl-3, 4-dihydronaphthalenone and 3-pyridyl-2-perfluorobutyl-3, 4-dihydronaphthalenone;
the amidine compound is selected from one of formamidine hydrochloride, acetamidine hydrochloride, cyclopropyl amidine hydrochloride, butylamidine hydrochloride, pentamidine hydrochloride, phenethylamidine hydrochloride, benzamidine hydrochloride, 4-methylbenzamidine hydrochloride, 4-methoxybenzamidine hydrochloride, 4-fluorobenzamidine hydrochloride, 4-chlorobenzamidine hydrochloride, 4-bromobenzylamidine hydrochloride, 4-iodobenzamidine hydrochloride, 4-cyanobenzylamidine hydrochloride, 4-nitrobenzamidine hydrochloride, 4-ethoxycarbonylbenzamidine hydrochloride, 4-naphthylbenzamidine hydrochloride, 4-furyl benzamidine hydrochloride and 4-pyridyl benzamidine hydrochloride.
Preferably, in step (1), the phase transfer promoter comprises tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, tetrabutylammonium acetate, benzyltriethylammonium bromide, hexadecyltrimethylammonium bromide, methyltrioctylammonium chloride;
the alkali promoter comprises pyridine, triethylene diamine, diisopropylamine, triethylamine, diazabicyclo, diisopropylamine sodium, sodium hydride, cesium carbonate, potassium carbonate, ammonium carbonate, potassium phosphate, sodium acetate, sodium hydroxide and lithium hydroxide;
the additive comprises sodium chloride, potassium nitrate, ammonium acetate, magnesium chloride, zinc chloride, cobalt bromide, cuprous iodide, a molecular sieve and magnesium sulfate;
the solvent comprises dimethyl sulfoxide, acetonitrile, tert-butyl alcohol, nitromethane, ethanol, toluene, tetrahydrofuran, cyclohexane and ethyl acetate.
Preferably, in step (1), the phase transfer promoter is tetrabutylammonium bromide; the alkali promoter is cesium carbonate; the additive is magnesium chloride; the solvent is dimethyl sulfoxide.
Preferably, in the step (1), the reaction is stirred at 25 ℃; in the step (2), the washing is water washing, the extraction is ethyl acetate extraction, the drying is anhydrous sodium sulfate drying, and the column chromatography separation conditions of the column chromatography separation are as follows: the stationary phase is silica gel powder of 300-400 meshes, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change procedure (A: B) is that 1: 20 → 1: 6.
functionalized aza ring
The invention provides a trifluoromethyl substituted pyrimido [1,3] compound, which overcomes the defects of the prior art and is always the hotspot research field of organic synthetic chemistry and pharmaceutical chemistry]Diaza derivatives
Compounds, methods of preparation and uses thereof. The invention develops a novel trifluoromethyl substituted pyrimido [1,3]]Diaza derivatives
The intermolecular cyclization synthesis method of the compound comprises the following synthesis reaction processes:
the invention efficiently synthesizes trifluoromethyl substituted pyrimido [1,3] by simply mixing and stirring a 2-perfluorobutyl dihydronaphthalenone compound and an amidine compound under the condition of no transition metal participation and by intermolecular continuous C-F bond functionalization-cyclization-aromatization series reaction]Diaza derivatives
A compound is provided. The scheme adopts a one-pot method to construct the target pyrimido [1,3]]Diaza derivatives
The compound simultaneously realizes the introduction of a regioselective trifluoromethyl group.
In the preparation method, a series of trifluoro-fluorine can be efficiently synthesized by regulating and controlling a series of conditions such as the proportion of reactants, the types of selected phase transfer promoters, the types of selected alkalis, the types of selected additives, a solvent for reaction, reaction temperature and the likeMethyl-substituted pyrimido [1,3]Diaza derivatives
A compound is provided.
In the condition screening process of the preparation method, different phase transfer promoters, such as: tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, tetrabutylammonium acetate, benzyltriethylammonium bromide, hexadecyltrimethylammonium bromide and methyltrioctylammonium chloride can obtain expected results, but the tetrabutylammonium bromide has the optimal effect; for different alkali promoters, such as: pyridine, triethylene diamine, diisopropylamine, triethylamine, diazabicyclo, diisopropylamine sodium, sodium hydride, cesium carbonate, potassium carbonate, ammonium carbonate, potassium phosphate, sodium acetate, sodium hydroxide and lithium hydroxide can obtain expected results, but the cesium carbonate effect is optimal; for different additives, such as: the expected results can be obtained by sodium chloride, potassium nitrate, ammonium acetate, magnesium chloride, zinc chloride, cobalt bromide, cuprous iodide, molecular sieves and magnesium sulfate, but the effect of the magnesium chloride is optimal; different ratios between 2-perfluorobutyl dihydronaphthalenone compound and amidine compound 1: (2-5), adding 1: 3, optimizing; for different solvents, such as: dimethyl sulfoxide, acetonitrile, tert-butyl alcohol, nitromethane, ethanol, toluene, tetrahydrofuran, cyclohexane and ethyl acetate can obtain expected products, but the effect of the dimethyl sulfoxide is optimal; the target product can be obtained at different temperatures within the range of 25-100 ℃, and the room temperature of 25 ℃ is optimal.
Compared with the defects and shortcomings of the prior art, the invention has the following beneficial effects:
(1) the invention provides a method for synthesizing trifluoromethyl substituted pyrimido [1,3] by starting from simple and easily obtained 2-perfluorobutyl dihydronaphthalenone compound and amidine compound]Diaza derivatives
A novel process for the preparation of compounds wherein 6/6/7/6 multiple fused rings are simultaneously constructed and trifluoromethyl is regioselectively introduced to construct a trifluoromethyl-functionalized trifluoromethyl-substituted pyrimido [1,3]]DinitrogenHetero compound
Heterocycles have not been reported before;
(2) the preparation method has mild reaction conditions, does not need expensive transition metal catalysts, only uses cesium carbonate as alkali and magnesium chloride as additives, and meets the requirements of green and economic chemistry;
(3) the preparation method of the invention completes the selective cutting of C-F bonds at three different positions on the polyfluoroalkyl carbon chain, and forms a plurality of new C-N bonds and heterocyclic systems;
(4) the invention relates to trifluoromethyl substituted pyrimido [1,3]]Diaza derivatives
The compound can be used for preparing bioactive molecules and functional materials, including chlordiazepoxide, diazepam, flurazepam, alprazolam, oxazepam and the like.
Drawings
FIG. 1 shows a target compound 2, 6-diphenyl-4- (trifluoromethyl) -1H-naphtho [1,2-d]Pyrido [4,5-f][1,3]Dinitrogen
Hydrogen spectrum of (a);
FIG. 2 shows a target compound 2, 6-diphenyl-4- (trifluoromethyl) -1H-naphtho [1,2-d]Pyrido [4,5-f][1,3]Dinitrogen
The fluorine spectrum of (a);
FIG. 3 shows the target compound 2, 6-diphenyl-4- (trifluoromethyl) -1H-naphtho [1,2-d]Pyrido [4,5-f][1,3]Dinitrogen
The carbon spectrum of (a).
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
(1) 1mmol of 2-perfluorobutyl dihydronaphthalenone compound (0.364 g), 3mmol of amidine compound (0.470 g), 1mmol of phase transfer promoter (0.322 g), 4mmol of alkali promoter (1.303 g) and 4mmol of additive (0.381g) are added into a test tube reaction tube with the specification of 20mL, 5mL of dimethyl sulfoxide is added into the reaction tube as a solvent, the reaction tube is sealed and sealed, and the reaction is stirred at room temperature for 24 hours to obtain trifluoromethyl substituted pyrimido [1,3]]Diaza derivatives
A compound; wherein the 2-perfluorobutyl dihydronaphthalenone compound is 2-perfluorobutyl-3, 4-dihydronaphthalenone; the amidine compound is benzamidine hydrochloride; the phase transfer promoter is tetrabutylammonium bromide; the alkali promoter is cesium carbonate; the additive is magnesium chloride;
(2) after the reaction in the step (1) is finished, the reaction solution is sequentially dried by water, ethyl acetate and anhydrous sodium sulfate and separated by column chromatography (under the conditions of column chromatography separation, the stationary phase is silica gel powder of 300-400 meshes, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change procedure (A: B) is 1: 20 → 1: 6, so that 0.327 g of reaction product 1 is obtained.
The reaction product is characterized, as shown in fig. 1-3, the result is: a yellow solid;1H NMR(400MHz,DMSO-d6)9.51(s,1H),8.59(d,J＝8.5Hz,1H),8.39(dd,J＝6.6,3.1Hz,2H),8.10–7.99(m,3H),7.95(d,J＝7.5Hz,1H),7.73(td,J＝8.6,2.5Hz,2H),7.69–7.62(m,2H),7.61–7.52(m,5H)ppm.
according to the characterization data, the reaction product 1 is 2, 6-diphenyl-4- (trifluoromethyl) -1H-naphtho [1, 2-d%]Pyrido [4,5-f][1,3]Dinitrogen
(purity > 98%); the product yield was calculated to be 70%.
Example 2
Examples 2-62 are substantially the same as example 1 above, except as shown in Table 1 below:
TABLE 1 examples 2 to 62
Example 63
(1) Adding 1mmol of 2-perfluorobutyl dihydronaphthalenone compound, 2mmol of amidine compound, 1mmol of phase transfer promoter, 3mmol of alkali promoter and 5mmol of additive into a test tube reaction tube with the specification of 20mL, adding 4mL of dimethyl sulfoxide as a solvent into the reaction tube, sealing, stirring at 20 ℃ for reaction for 2 hours to obtain trifluoromethyl substituted pyrimido [1,3 ℃]Diaza derivatives
A compound; wherein the 2-perfluorobutyl dihydronaphthalenone compound is 2-perfluorobutyl-3, 4-dihydronaphthalenone; the amidine compound is benzamidine hydrochloride; the phase transfer promoter is tetrabutyl ammonium iodide; the alkali promoter is triethylene diamine; the additive is potassium nitrate;
(2) after the reaction in the step (1) is finished, the reaction solution is sequentially dried by water, ethyl acetate and anhydrous sodium sulfate and subjected to column chromatography separation (under the column chromatography separation conditions, the stationary phase is silica gel powder of 300-400 meshes, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change procedure (A: B) is 1: 20 → 1: 6, so that a reaction product 63 is obtained.
Example 64
(1) Adding 1mmol of 2-perfluorobutyl dihydronaphthalenone compound, 5mmol of amidine compound, 1mmol of phase transfer promoter, 5mmol of alkali promoter and 4mmol of additive into a test tube reaction tube with specification of 20mL, and adding the reaction tubeAdding 6mL of dimethyl sulfoxide as a solvent, sealing, stirring at room temperature for 24 hours to obtain trifluoromethyl substituted pyrimido [1, 3%]Diaza derivatives
A compound; wherein the 2-perfluorobutyl dihydronaphthalenone compound is 2-perfluorobutyl-3, 4-dihydronaphthalenone; the amidine compound is benzamidine hydrochloride; the phase transfer promoter is hexadecyl trimethyl ammonium bromide; the alkali accelerator is diisopropylamine sodium; the additive is cuprous iodide;
(2) after the reaction in the step (1) is finished, the reaction solution is sequentially dried by water, ethyl acetate and anhydrous sodium sulfate and subjected to column chromatography separation (under the column chromatography separation conditions, the stationary phase is silica gel powder of 300-400 meshes, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change procedure (A: B) is 1: 20 → 1: 6, so that a reaction product 64 is obtained.
Example 65
(1) Adding 1mmol of 2-perfluorobutyl dihydronaphthalenone compound, 3mmol of amidine compound, 1mmol of phase transfer promoter, 4mmol of alkali promoter and 4mmol of additive into a test tube reaction tube with the specification of 20mL, adding 5mL of dimethyl sulfoxide as a solvent into the reaction tube, sealing, stirring at 100 ℃ for reaction for 10 hours to obtain trifluoromethyl substituted pyrimido [1,3]]Diaza derivatives
A compound; wherein the 2-perfluorobutyl dihydronaphthalenone compound is 2-perfluorobutyl-3, 4-dihydronaphthalenone; the amidine compound is benzamidine hydrochloride; the phase transfer promoter is tetrabutylammonium bromide; the alkali promoter is cesium carbonate; the additive is magnesium chloride;
(2) after the reaction in the step (1) is finished, the reaction solution is sequentially dried by water, ethyl acetate and anhydrous sodium sulfate and subjected to column chromatography separation (under the column chromatography separation conditions, the stationary phase is silica gel powder of 300-400 meshes, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change procedure (A: B) is 1: 20 → 1: 6, so that a reaction product 65 is obtained.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (10)
1. Trifluoromethyl substituted pyrimido [1,3]Diaza derivatives
A compound characterized by the chemical structural formula (I):
in the formula (I), R1Any one selected from C1-C5 alkyl, C1-C5 alkoxy, halogen, benzyl, phenyl, cyano, nitro, acetyl, ethoxycarbonyl, hydroxyl and amino;
R2any one selected from C1-C5 alkyl, benzyl, phenyl, naphthyl, thienyl and pyridyl;
R3any one selected from C1-C5 alkyl, benzyl, phenyl, naphthyl, thienyl and pyridyl;
R4any one selected from the group consisting of C1-C5 alkyl, benzyl, phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, halogen-substituted phenyl, cyano-substituted phenyl, nitro-substituted phenyl, alkoxycarbonyl-substituted phenyl, naphthyl, furyl, and pyridyl.
2. Trifluoromethyl-substituted pyrimido [1,3] according to claim 1]Diaza derivatives
The compound is characterized in that in the formula (I), the C1-C5 alkyl is selected from any one of methyl, ethyl, propyl, isopropyl, tert-butyl and pentyl.
3. Trifluoromethyl group as claimed in claim 1Substituted pyrimido [1,3]]Diaza derivatives
The compound is characterized in that in the formula (I), the C1-C5 alkoxy is selected from any one of methoxy, ethoxy, isopropoxy, tert-butoxy and pentoxy.
4. Trifluoromethyl-substituted pyrimido [1,3] according to claim 1]Diaza derivatives
A compound characterized in that, in formula (i), the halogen is selected from any one of fluorine, chlorine, bromine and iodine.
5. A process for the preparation of a compound according to any one of claims 1 to 4, characterized in that it comprises the following steps:
(1) adding a phase transfer promoter, an alkali promoter, an additive and a solvent into a reaction raw material formed by mixing a 2-perfluorobutyl dihydronaphthalenone compound and an amidine compound, stirring and reacting for 1-24 hours at the temperature of 20-100 ℃, determining the reaction process by TLC (thin layer chromatography) detection, and obtaining a reaction product after the reaction is finished; wherein the molar volume ratio of the 2-perfluorobutyl dihydronaphthalenone compound to the amidine compound to the phase transfer promoter to the alkali promoter to the additive to the solvent is 1 mmol: 2-5 mmol: 1 mmol: 3-5 mmol: 3-5 mmol: 4-6 mL;
(2) washing, extracting and drying the reaction product, and separating by column chromatography to obtain trifluoromethyl substituted pyrimido [1,3]Diaza derivatives
A compound is provided.
6. The method for preparing the compound according to claim 5, wherein in the step (1), the molar volume ratio of the 2-perfluorobutyldihydronaphthalenone compound, the amidine compound, the phase transfer promoter, the base promoter, the additive, and the solvent is 1 mmol: 3 mmol: 1 mmol: 4 mmol: 4 mmol: 5 mL.
7. The method for producing a compound according to claim 5, wherein in the step (1), the 2-perfluorobutyl dihydronaphthalenone compound is selected from the group consisting of 7-methyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-ethyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-isopropyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-tert-butyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-pentyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-methoxy-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-ethoxy-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-isopropoxy-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-tert-butoxy-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-pentyloxy-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-fluoro-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-chloro-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-bromo-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-iodo-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-benzyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, methyl-ethyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, methyl-2, 7-phenyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-cyano-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-nitro-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-acetyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-ethoxycarbonyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-hydroxy-2-perfluorobutyl-3, 4-dihydronaphthalenone, 7-amino-2-perfluorobutyl-3, 4-dihydronaphthalenone, 4-methyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 4-ethyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 4-isopropyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 4-tert-butyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 4-pentyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 4-benzyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 4-phenyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 4-naphthyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 4-thienyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 4-pyridyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 3-methyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 3-ethyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 3-isopropyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 3-tert-butyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 3-pentyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 3-benzyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 3-phenyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 3-naphthyl-2-perfluorobutyl-3, 4-dihydronaphthalenone, 3-thienyl-2-perfluorobutyl-3, any one of 4-dihydronaphthalenone and 3-pyridyl-2-perfluorobutyl-3, 4-dihydronaphthalenone;
the amidine compound is selected from one of formamidine hydrochloride, acetamidine hydrochloride, cyclopropyl amidine hydrochloride, butylamidine hydrochloride, pentamidine hydrochloride, phenethylamidine hydrochloride, benzamidine hydrochloride, 4-methylbenzamidine hydrochloride, 4-methoxybenzamidine hydrochloride, 4-fluorobenzamidine hydrochloride, 4-chlorobenzamidine hydrochloride, 4-bromobenzylamidine hydrochloride, 4-iodobenzamidine hydrochloride, 4-cyanobenzylamidine hydrochloride, 4-nitrobenzamidine hydrochloride, 4-ethoxycarbonylbenzamidine hydrochloride, 4-naphthylbenzamidine hydrochloride, 4-furyl benzamidine hydrochloride and 4-pyridyl benzamidine hydrochloride.
8. The method for preparing a compound according to claim 5, wherein in the step (1), the phase transfer promoter comprises tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, tetrabutylammonium hydrogensulfate, tetrabutylammonium acetate, benzyltriethylammonium bromide, hexadecyltrimethylammonium bromide, methyltrioctylammonium chloride;
the alkali promoter comprises pyridine, triethylene diamine, diisopropylamine, triethylamine, diazabicyclo, diisopropylamine sodium, sodium hydride, cesium carbonate, potassium carbonate, ammonium carbonate, potassium phosphate, sodium acetate, sodium hydroxide and lithium hydroxide;
the additive comprises sodium chloride, potassium nitrate, ammonium acetate, magnesium chloride, zinc chloride, cobalt bromide, cuprous iodide, a molecular sieve and magnesium sulfate;
the solvent comprises dimethyl sulfoxide, acetonitrile, tert-butyl alcohol, nitromethane, ethanol, toluene, tetrahydrofuran, cyclohexane and ethyl acetate.
9. The method of claim 8, wherein in step (1), the phase transfer promoter is tetrabutylammonium bromide; the alkali promoter is cesium carbonate; the additive is magnesium chloride; the solvent is dimethyl sulfoxide.
10. The method for preparing a compound according to claim 5, wherein in the step (1), the reaction is stirred at 25 ℃;
in the step (2), the washing is water washing, the extraction is ethyl acetate extraction, the drying is anhydrous sodium sulfate drying, and the column chromatography separation conditions of the column chromatography separation are as follows: the stationary phase is silica gel powder of 300-400 meshes, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change procedure (A: B) is that 1: 20 → 1: 6.
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