JP7384926B2 - イミダゾ[1,2-a]ピリミジンの位置選択的合成 - Google Patents
イミダゾ[1,2-a]ピリミジンの位置選択的合成 Download PDFInfo
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- JP7384926B2 JP7384926B2 JP2021566476A JP2021566476A JP7384926B2 JP 7384926 B2 JP7384926 B2 JP 7384926B2 JP 2021566476 A JP2021566476 A JP 2021566476A JP 2021566476 A JP2021566476 A JP 2021566476A JP 7384926 B2 JP7384926 B2 JP 7384926B2
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- Prior art keywords
- aryl
- heteroaryl
- amino
- alkyl
- mmol
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- 230000015572 biosynthetic process Effects 0.000 title description 26
- 238000003786 synthesis reaction Methods 0.000 title description 24
- INSWZAQOISIYDT-UHFFFAOYSA-N imidazo[1,2-a]pyrimidine Chemical compound C1=CC=NC2=NC=CN21 INSWZAQOISIYDT-UHFFFAOYSA-N 0.000 title description 3
- -1 amino-imidazo-pyrimidine compound Chemical class 0.000 claims description 141
- 238000000034 method Methods 0.000 claims description 67
- 125000003118 aryl group Chemical group 0.000 claims description 50
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 49
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 43
- 125000001072 heteroaryl group Chemical group 0.000 claims description 38
- 125000000217 alkyl group Chemical group 0.000 claims description 28
- 239000000203 mixture Substances 0.000 claims description 28
- 229910052757 nitrogen Inorganic materials 0.000 claims description 24
- 125000003545 alkoxy group Chemical group 0.000 claims description 22
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 22
- 125000005843 halogen group Chemical group 0.000 claims description 21
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 19
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 19
- 125000004429 atom Chemical group 0.000 claims description 18
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 17
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 claims description 17
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 15
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 230000008878 coupling Effects 0.000 claims description 12
- 238000010168 coupling process Methods 0.000 claims description 12
- 238000005859 coupling reaction Methods 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
- 125000003342 alkenyl group Chemical group 0.000 claims description 10
- 125000001188 haloalkyl group Chemical group 0.000 claims description 10
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 claims description 9
- 125000000304 alkynyl group Chemical group 0.000 claims description 9
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 8
- 125000002883 imidazolyl group Chemical group 0.000 claims description 7
- 230000002194 synthesizing effect Effects 0.000 claims description 6
- SFMFACMIOWQIPR-ONEGZZNKSA-N (e)-3-ethoxyprop-2-enoyl chloride Chemical compound CCO\C=C\C(Cl)=O SFMFACMIOWQIPR-ONEGZZNKSA-N 0.000 claims description 5
- 239000003125 aqueous solvent Substances 0.000 claims description 5
- 239000012320 chlorinating reagent Substances 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 4
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 claims description 3
- 150000007942 carboxylates Chemical class 0.000 claims description 3
- UCQFCFPECQILOL-UHFFFAOYSA-N diethyl hydrogen phosphate Chemical compound CCOP(O)(=O)OCC UCQFCFPECQILOL-UHFFFAOYSA-N 0.000 claims description 3
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 claims description 2
- 229910006124 SOCl2 Inorganic materials 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 239000000010 aprotic solvent Substances 0.000 claims description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 claims description 2
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 claims description 2
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000005270 trialkylamine group Chemical group 0.000 claims 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 64
- 238000006243 chemical reaction Methods 0.000 description 56
- 238000005481 NMR spectroscopy Methods 0.000 description 51
- 239000007787 solid Substances 0.000 description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 38
- 238000004896 high resolution mass spectrometry Methods 0.000 description 34
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 31
- 239000000047 product Substances 0.000 description 28
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 26
- 238000002844 melting Methods 0.000 description 26
- 230000008018 melting Effects 0.000 description 26
- 125000000623 heterocyclic group Chemical group 0.000 description 25
- 239000003480 eluent Substances 0.000 description 24
- IWRSVGXUWRVXRW-UHFFFAOYSA-N pyrimido[1,2-a]benzimidazol-2-amine Chemical group C1=CC=C2N3C=CC(N)=NC3=NC2=C1 IWRSVGXUWRVXRW-UHFFFAOYSA-N 0.000 description 22
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 18
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 17
- 239000000741 silica gel Substances 0.000 description 17
- 229910002027 silica gel Inorganic materials 0.000 description 17
- JWYUFVNJZUSCSM-UHFFFAOYSA-N 2-aminobenzimidazole Chemical compound C1=CC=C2NC(N)=NC2=C1 JWYUFVNJZUSCSM-UHFFFAOYSA-N 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 15
- 235000019439 ethyl acetate Nutrition 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- UPWOHLKTCYPXFE-UHFFFAOYSA-N NC1=NC2=C(N1P(OCC)(OCC)=O)C=CC=C2 Chemical compound NC1=NC2=C(N1P(OCC)(OCC)=O)C=CC=C2 UPWOHLKTCYPXFE-UHFFFAOYSA-N 0.000 description 14
- 238000003818 flash chromatography Methods 0.000 description 14
- 229910052717 sulfur Inorganic materials 0.000 description 14
- 239000011593 sulfur Substances 0.000 description 14
- QMCSYYZPVPDNTQ-JLHYYAGUSA-N C(C)O/C=C/C(=O)N1CCC(CC1)C1=CC=CC=C1 Chemical compound C(C)O/C=C/C(=O)N1CCC(CC1)C1=CC=CC=C1 QMCSYYZPVPDNTQ-JLHYYAGUSA-N 0.000 description 13
- 239000013078 crystal Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 229910052760 oxygen Inorganic materials 0.000 description 12
- 125000006413 ring segment Chemical group 0.000 description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 11
- KWLSGYGLZGECCI-UHFFFAOYSA-N n-diethoxyphosphoryl-1h-benzimidazol-2-amine Chemical compound C1=CC=C2NC(NP(=O)(OCC)OCC)=NC2=C1 KWLSGYGLZGECCI-UHFFFAOYSA-N 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 11
- 239000001301 oxygen Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- 125000004122 cyclic group Chemical group 0.000 description 10
- ICNMSUJSMUWXPF-UHFFFAOYSA-N pyrimido[1,2-a]benzimidazol-4-amine Chemical class C1=CC=C2N3C(N)=CC=NC3=NC2=C1 ICNMSUJSMUWXPF-UHFFFAOYSA-N 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- SYMAGJYJMLUEQE-ONEGZZNKSA-N (e)-3-ethoxyprop-2-enoic acid Chemical compound CCO\C=C\C(O)=O SYMAGJYJMLUEQE-ONEGZZNKSA-N 0.000 description 7
- 229910019213 POCl3 Inorganic materials 0.000 description 7
- 125000005842 heteroatom Chemical group 0.000 description 7
- 150000002460 imidazoles Chemical class 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 description 7
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 6
- JMMMQHDFFZCZOS-UHFFFAOYSA-N 3-ethoxyprop-2-enamide Chemical compound CCOC=CC(N)=O JMMMQHDFFZCZOS-UHFFFAOYSA-N 0.000 description 6
- WXHZPDUTOKEAHA-UHFFFAOYSA-N C(C)OP(=O)(OCC)NC=1NC=C(N=1)C(=O)OCC Chemical compound C(C)OP(=O)(OCC)NC=1NC=C(N=1)C(=O)OCC WXHZPDUTOKEAHA-UHFFFAOYSA-N 0.000 description 6
- SAQYIBUJXVFJFW-BUHFOSPRSA-N C(C1=CC=CC=C1)N(C(\C=C\OCC)=O)CC1=CC=CC=C1 Chemical compound C(C1=CC=CC=C1)N(C(\C=C\OCC)=O)CC1=CC=CC=C1 SAQYIBUJXVFJFW-BUHFOSPRSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229910052805 deuterium Inorganic materials 0.000 description 6
- LGTLXDJOAJDFLR-UHFFFAOYSA-N diethyl chlorophosphate Chemical compound CCOP(Cl)(=O)OCC LGTLXDJOAJDFLR-UHFFFAOYSA-N 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 150000005237 imidazopyrimidines Chemical group 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- GUCXVPPWYUBPQD-CMDGGOBGSA-N (E)-N-benzyl-3-ethoxyprop-2-enamide Chemical compound CCO\C=C\C(=O)NCc1ccccc1 GUCXVPPWYUBPQD-CMDGGOBGSA-N 0.000 description 5
- DEPDDPLQZYCHOH-UHFFFAOYSA-N 1h-imidazol-2-amine Chemical compound NC1=NC=CN1 DEPDDPLQZYCHOH-UHFFFAOYSA-N 0.000 description 5
- QRZMXADUXZADTF-UHFFFAOYSA-N 4-aminoimidazole Chemical compound NC1=CNC=N1 QRZMXADUXZADTF-UHFFFAOYSA-N 0.000 description 5
- TVTIKJUTFJHYND-MDZDMXLPSA-N C(C)O/C=C/C(=O)N(C)C1=CC=C(C=C1)OC Chemical compound C(C)O/C=C/C(=O)N(C)C1=CC=C(C=C1)OC TVTIKJUTFJHYND-MDZDMXLPSA-N 0.000 description 5
- ZDDRPVIBRPOGOL-MDZDMXLPSA-N C(C)O/C=C/C(=O)N(C1=CC=CC=C1)C Chemical compound C(C)O/C=C/C(=O)N(C1=CC=CC=C1)C ZDDRPVIBRPOGOL-MDZDMXLPSA-N 0.000 description 5
- TWGRQBXEBPUYRJ-UHFFFAOYSA-N C1(=CC=CC=C1)C1CCN(CC1)C1=NC=2N(C=C1)C1=C(N=2)C=CC=C1 Chemical compound C1(=CC=CC=C1)C1CCN(CC1)C1=NC=2N(C=C1)C1=C(N=2)C=CC=C1 TWGRQBXEBPUYRJ-UHFFFAOYSA-N 0.000 description 5
- KYKKFYBNCFQGSJ-UHFFFAOYSA-N C1(=CC=CC=C1)C1CCN(CC1)C1=NC=2N(C=C1)C=CN=2 Chemical compound C1(=CC=CC=C1)C1CCN(CC1)C1=NC=2N(C=C1)C=CN=2 KYKKFYBNCFQGSJ-UHFFFAOYSA-N 0.000 description 5
- DPDFLETZELXVID-UHFFFAOYSA-N COC1=CC2=C(N/C(/N2)=N/P(OCC)(OCC)=O)C=C1 Chemical compound COC1=CC2=C(N/C(/N2)=N/P(OCC)(OCC)=O)C=C1 DPDFLETZELXVID-UHFFFAOYSA-N 0.000 description 5
- SYSBHGVOYQBJEU-CMDGGOBGSA-N ClC1=CC=C(C=C1)N(C(\C=C\OCC)=O)C Chemical compound ClC1=CC=C(C=C1)N(C(\C=C\OCC)=O)C SYSBHGVOYQBJEU-CMDGGOBGSA-N 0.000 description 5
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 5
- 238000002441 X-ray diffraction Methods 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 125000002619 bicyclic group Chemical group 0.000 description 5
- 125000000524 functional group Chemical group 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 description 5
- 150000008298 phosphoramidates Chemical class 0.000 description 5
- 238000006366 phosphorylation reaction Methods 0.000 description 5
- HOHWYQSDLRTVDK-UHFFFAOYSA-N pyrimido[1,2-a]benzimidazole Chemical group N1=CC=CN2C3=CC=CC=C3N=C21 HOHWYQSDLRTVDK-UHFFFAOYSA-N 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- CGXOYOUTLGBSNN-UHFFFAOYSA-N BrC1=CC=CC=2N/C(/NC=21)=N/P(OCC)(OCC)=O Chemical compound BrC1=CC=CC=2N/C(/NC=21)=N/P(OCC)(OCC)=O CGXOYOUTLGBSNN-UHFFFAOYSA-N 0.000 description 4
- SUMUUQCDUKPBAL-MDZDMXLPSA-N C(C)O/C=C/C(=O)N(C1=C(C=CC=C1)C)C Chemical compound C(C)O/C=C/C(=O)N(C1=C(C=CC=C1)C)C SUMUUQCDUKPBAL-MDZDMXLPSA-N 0.000 description 4
- KSCOLABKFXDUNN-UHFFFAOYSA-N C(C1=CC=CC=C1)N(C1=NC=2N(C=C1)C1=C(N=2)C=CC=C1)CC1=CC=CC=C1 Chemical compound C(C1=CC=CC=C1)N(C1=NC=2N(C=C1)C1=C(N=2)C=CC=C1)CC1=CC=CC=C1 KSCOLABKFXDUNN-UHFFFAOYSA-N 0.000 description 4
- XFXMZEUTONIRKE-UHFFFAOYSA-N C(C1=CC=CC=C1)NC1=NC=2N(C=C1)C1=C(N=2)C=CC=C1 Chemical compound C(C1=CC=CC=C1)NC1=NC=2N(C=C1)C1=C(N=2)C=CC=C1 XFXMZEUTONIRKE-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- 238000004364 calculation method Methods 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- 238000013480 data collection Methods 0.000 description 4
- 229910001873 dinitrogen Inorganic materials 0.000 description 4
- 238000005562 fading Methods 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 150000002829 nitrogen Chemical class 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 125000004076 pyridyl group Chemical group 0.000 description 4
- 150000003230 pyrimidines Chemical class 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- QOTJXDDCGLHDTO-UHFFFAOYSA-N tert-butyl 2-(diethoxyphosphorylamino)-1H-benzimidazole-4-carboxylate Chemical compound C(C)OP(=O)(OCC)\N=C\1/NC2=C(N/1)C=CC=C2C(=O)OC(C)(C)C QOTJXDDCGLHDTO-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- HAUALPXATQXYAP-CMDGGOBGSA-N C(C)O/C=C/C(=O)N(C1=CC=C(C=C1)C(F)(F)F)C Chemical compound C(C)O/C=C/C(=O)N(C1=CC=C(C=C1)C(F)(F)F)C HAUALPXATQXYAP-CMDGGOBGSA-N 0.000 description 3
- IHXGBTOHNYCWNB-UHFFFAOYSA-N ClC1=CC=C(C=C1)N(C1=CC=NC=2N1C1=C(N=2)C=CC=C1)C Chemical compound ClC1=CC=C(C=C1)N(C1=CC=NC=2N1C1=C(N=2)C=CC=C1)C IHXGBTOHNYCWNB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-GUEYOVJQSA-N acetic acid-d4 Chemical compound [2H]OC(=O)C([2H])([2H])[2H] QTBSBXVTEAMEQO-GUEYOVJQSA-N 0.000 description 3
- 150000003926 acrylamides Chemical class 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 230000000155 isotopic effect Effects 0.000 description 3
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 238000005457 optimization Methods 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 230000026731 phosphorylation Effects 0.000 description 3
- 230000000865 phosphorylative effect Effects 0.000 description 3
- 125000002098 pyridazinyl group Chemical group 0.000 description 3
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- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
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- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/22—Amides of acids of phosphorus
- C07F9/24—Esteramides
- C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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- Y02P20/50—Improvements relating to the production of bulk chemicals
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Description
本出願は、いずれも参照によりその全体が本明細書に組み込まれる、2019年5月9日に出願された米国仮特許出願第62/845,840号及び2019年11月18日に出願された米国仮特許出願第62/937,069号に対する35U.S.C.§119(e)の下での優先権の利益を主張する。
その方法は、
式XX-P1a又はXX-P1bの第1のアミノ-イミダゾール化合物を式XX-P2の第2のアクリルアミド化合物とカップリングすることを含む。
定義
合成方法の概要
アミノ-イミダゾピリミジンの合成
全ての新規化合物を、1H NMR、13C NMR、IR、融点及びHRMSによって特徴付けた。
実施例1:2-(1-(ベンゾ[4,5]イミダゾ[1,2-a]ピリジン-3-イル)ピペリジン-4-イル)エチル-1,1,2,2-d4 4-メチルベンゼンスルホネートの合成
工程1-ジエチル(1H-ベンゾ[d]イミダゾール-2-イル)ホスホルアミダートの形成
ステップ2-2-(1-(ベンゾ[4,5]イミダゾ[1,2-a]ピリミジン-2-イル)ピペリジン-4-イル)エチル-1,1-d2ベンゾエート
実施例2:2-(1-(ベンゾ[4,5]イミダゾ[1,2-a]ピリジン-3-イル)ピペリジン-4-イル)エチル-1,1,2,2-d4 4-メチルベンゼンスルホネートの合成
工程1-ジエチル(1H-ベンゾ[d]イミダゾール-2-イル)ホスホルアミダートの調製
工程2-(E)-3-エトキシアクリロイルクロリドの調製
工程3-(E)-2-(1-(3-エトキシアクリロイル)ピペリジン-4-イル)エチル-1,1,2,2-d4ベンゾエート
工程4-2-(1-(ベンゾ[4,5]イミダゾ[1,2-a]ピリミジン-2-イル)ピペリジン-4-イル)エチル-1,1,2,2-d4ベンゾエート
実施例3.0:2-アミノ-イミダゾ[1,2-a]ピリミジン(R1=R2=R3=R4=H)の合成
実施例3.1:2-(4-フェニルピペリジン-1-イル)ベンゾ[4,5]イミダゾ[1,2-a]ピリミジンの合成
実施例3.2:7-(4-フェニルピペリジン-1-イル)イミダゾ[1,2-a]ピリミジンの合成
実施例3.3:エチル2-(4-フェニルピペリジン-1-イル)ベンゾ[4,5]イミダゾ[1,2-a]ピリミジン-8-カルボキシレートの合成
実施例3.4:N-ベンジルベンゾ[4,5]イミダゾ[1,2-a]ピリミジン-2-アミンの合成
実施例3.5:N,N-ジベンジルベンゾ[4,5]イミダゾ[1,2-a]ピリミジン-2-アミンの合成
実施例4:環化反応の最適化
a 反応は、0.25mmol規模、アクリルアミド(1.0当量)、アミノベンズイミダゾール(1.1当量)、活性化剤(2.2当量)、0.5Mで行った。
b A%=254nmでのHPLC面積パーセント。
c 254nmでの粗反応混合物のHPLC分析によって決定された6a:6bの比。
d 1と2bの両方を0℃で30分間POCl3と反応させた後に合わせて、次いで70℃に加熱した。
e 5をPOCl3で前処理し、20分間70℃に加熱し、次いで室温に冷却した後、3.0当量に添加した。2b.次いで、反応混合物を50℃に加熱した。
実施例5:β-エトキシアクリルアミドのバリエーション
実施例6:アミノ(ベンツ)イミダゾールのバリエーション
実施例7:4-アミノイミダゾ[1,2-a]ピリミジンの形成
実施例8:ジエチル(2-アミノ-1H-ベンゾ[d]イミダゾール-1-イル)ホスホネート(2b)
実施例9:ジエチル(Z)-(5-メトキシ-1,3-ジヒドロ-2H-ベンゾ[d]イミダゾール-2-イリデン)ホスホルアミダート(19):
実施例10:ジエチル(Z)-(4-ブロモ-1,3-ジヒドロ-2H-ベンゾ[d]イミダゾール-2-イリデン)ホスホルアミダート(20):
実施例11:tert-ブチル(Z)-2-((ジエトキシホスホリル)イミノ)-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-4-カルボキシレート(21)
実施例12:ジエチル(1,3-ジヒドロ-2H-イミダゾール-2-イリデン)ホスホルアミダート(22)
実施例13:エチル(Z)-2-((ジエトキシホスホリル)イミノ)-2,3-ジヒドロ-1H-イミダゾール-4-カルボキシレート(23)
実施例15:(E)-3-エトキシ-N-メチル-N-フェニルアクリルアミド(25)
実施例16:(E)-3-エトキシ-N-(4-メトキシフェニル)-N-メチルアクリルアミド(26)
実施例17:(E)-3-エトキシ-N-メチル-N-(4-(トリフルオロメチル)フェニル)アクリルアミド(27)
実施例18:(E)-N-(4-クロロフェニル)-3-エトキシ-N-メチルアクリルアミド(28)
実施例19:(E)-3-エトキシ-N-メチル-N-(o-トリル)アクリルアミド(29)
実施例20:(E)-N,N-ジベンジル-3-エトキシアクリルアミド(30)
実施例21:(E)-N-ベンジル-3-エトキシアクリルアミド(31)
実施例22:ベンゾ[4,5]イミダゾ[1,2-a]ピリミジン-2-アミンの合成のための一般的手順
実施例23:2-(4-フェニルピペリジン-1-イル)ベンゾ[4,5]イミダゾ[1,2-a]ピリミジン(6a)
実施例24:N-メチル-N-フェニルベンゾ[4,5]イミダゾ[1,2-a]ピリミジン-2-アミン(7a)
実施例25:N-(4-メトキシフェニル)-N-メチルベンゾ[4,5]イミダゾ[1,2-a]ピリミジン-2-アミン(8a)
実施例26:N-メチル-N-(4-(トリフルオロメチル)フェニル)ベンゾ[4,5]イミダゾ[1,2-a]ピリミジン-2-アミン(9a)
実施例27:N-(4-クロロフェニル)-N-メチルベンゾ[4,5]イミダゾ[1,2-a]ピリミジン-2-アミン(10a)
実施例28:N-メチル-N-(o-トリル)ベンゾ[4,5]イミダゾ[1,2-a]ピリミジン-2-アミン(11a)
実施例29:N,N-ジベンジルベンゾ[4,5]イミダゾ[1,2-a]ピリミジン-2-アミン(12a)
実施例30:N-ベンジルベンゾ[4,5]イミダゾ[1,2-a]ピリミジン-2-アミン(13a)
実施例31:8-メトキシ-2-(4-フェニルピペリジン-1-イル)ベンゾ[4,5]イミダゾ[1,2-a]ピリミジン(14a)
実施例32:7-メトキシ-2-(4-フェニルピペリジン-1-イル)ベンゾ[4,5]イミダゾ[1,2-a]ピリミジン(14a’)
実施例33:9-ブロモ-2-(4-フェニルピペリジン-1-イル)ベンゾ[4,5]イミダゾ[1,2-a]ピリミジン(15a)
実施例34:tert-ブチル2-(4-フェニルピペリジン-1-イル)ベンゾ[4,5]イミダゾ[1,2-a]ピリミジン-9-カルボキシレート(16a)
実施例35:7-(4-フェニルピペリジン-1-イル)イミダゾ[1,2-a]ピリミジン(17a)
実施例36:エチル7-(4-フェニルピペリジン-1-イル)イミダゾ[1,2-a]ピリミジン-2-カルボキシレート(18a)
実施例37:ベンゾ[4,5]イミダゾ[1,2-a]ピリミジン-4-アミンの合成のための一般的手順
実施例38:4-(4-フェニルピペリジン-1-イル)ベンゾ[4,5]イミダゾ[1,2-a]ピリミジン(6b)
実施例39:N-メチル-N-フェニルベンゾ[4,5]イミダゾ[1,2-a]ピリミジン-4-アミン(7b)
実施例40:N-(4-メトキシフェニル)-N-メチルベンゾ[4,5]イミダゾ[1,2-a]ピリミジン-4-アミン(8b)
実施例41:N-(4-クロロフェニル)-N-メチルベンゾ[4,5]イミダゾ[1,2-a]ピリミジン-4-アミン(10b)
実施例42:N,N-ジベンジルベンゾ[4,5]イミダゾ[1,2-a]ピリミジン-4-アミン(12b)
実施例43:計算
実施例44:2aのX線分析
実施例45:2bのX線分析
実施例46:6aのX線分析
実施例47:6bのX線分析
Claims (10)
- 式(XXa)のアミノ-イミダゾ-ピリミジン化合物を合成する方法であって、
式XX-P1aの第1の化合物を式XX-P2の第2の化合物とカップリングすることを含み、
ここで、
R1及びR2は、それぞれ独立して、アルキル、アルケニル、アルキニル、カルボシクリル、アリール、又はヘテロアリールから選択され、任意のそのような基は、その利用可能な位置の1つ以上において、ヒドロキシル、アミノ、アルコキシ、アミノアルキル、チオ、カルボキシ、シアノ、ハロ、アルキル、シクロアルキル、アリール、及びヘテロアリールから選択される基によって独立して置換されていてもよく、又は
R1及びR2は、それらが結合している窒素と一緒になって、3~12個の原子を有する環を形成し、この環は、その利用可能な位置のいずれか1つ以上において、ヒドロキシル、アミノ、アルコキシ、アミノアルキル、カルボキシ、シアノ、チオ、ハロ、アルキル、ハロアルキル、シクロアルキル、アリール、及びヘテロアリールから選択される基によって、場合により且つ独立して置換されており、
R3及びR4は、それぞれ独立して、アルキル、アルケニル、アルキニル、ハロアルキル、カルボキシレート、カルボシクリル、アリール、及びヘテロアリールから選択され、任意のそのような基は、その利用可能な位置の1つ以上において、ヒドロキシル、アミノ、アルコキシ、アミノアルキル、チオ、シアノ、ハロ、アリール、及びヘテロアリールから選択される基によって独立して置換されていてもよく、又は、
R3及びR4は、それらがそれぞれ結合しているイミダゾール環の2つの炭素原子と一緒になってフェニル環を形成し、フェニル環は、その4つの利用可能な位置のいずれか1つ以上において、ヒドロキシル、アミノ、アルコキシ、アミノアルキル、チオ、ニトロ、スルホニル、カルボキシ、シアノ、ハロ、アルキル、シクロアルキル、アリール、及びヘテロアリールから選択される基によって、場合により且つ独立して置換されており、任意のそのような基は、その利用可能な位置の1つ以上において、ヒドロキシル、アミノ、アルコキシ、アミノアルキル、チオ、ニトロ、ハロアルキル、スルホニル、シアノ、ハロ、アルキル、シクロアルキル、アリール、及びヘテロアリールから選択される基によって、独立して置換されていてもよく;
前記カップリングは、PCl5又はPOCl3、塩基、及び非水性溶媒の存在下で行われる、方法。 - 前記塩基がトリアルキルアミンである、請求項1に記載の方法。
- R3及びR4が、それらがそれぞれ結合しているイミダゾール環の2つの炭素原子と一緒になってフェニル環を形成する、請求項1に記載の方法。
- 前記PCl(O)(OEt)2は、リン酸水素ジエチルを1,3,5-トリクロロ-1,3,5-トリアジナン-2,4,6-トリオンと反応させることによって形成される、請求項4に記載の方法。
- 前記式XX-P2の化合物を、以下:
(E)-3-エトキシアクリル酸を、塩化オキサリル、SOCl2から選択される塩素化剤と、クロロギ酸メチル、クロロギ酸エチル、クロロギ酸イソプロピル、及びクロロギ酸イソブチルから選択されるクロロギ酸アルキルと反応させて、(E)-3-エトキシアクリロイルクロリドを形成すること;及び
(E)-3-エトキシアクリロイルクロリドを、非プロトン性溶媒中、アミンR1R2NHと反応させること
で形成する、請求項1に記載の方法。 - 前記塩素化剤がSOCl2である、請求項6に記載の方法。
- 前記非水性溶媒がMeCN、MeTHF又はそれらの混合物である、請求項1に記載の方法。
- 式(XXb)のアミノ-イミダゾ-ピリミジン化合物を合成する方法であって、
式XX-P1bの第1の化合物を式XX-P2の第2の化合物とカップリングすることを含み、
ここで、
R1及びR2は、それぞれ独立して、アルキル、アルケニル、アルキニル、カルボシクリル、アリール又はヘテロアリールから選択され、任意のそのような基は、その利用可能な位置の1つ以上において、ヒドロキシル、アミノ、アルコキシ、アミノアルキル、チオ、カルボキシ、シアノ、ハロ、アルキル、シクロアルキル、アリール、及びヘテロアリールから選択される基によって独立して置換されていてもよく、又は
R1及びR2は、それらが結合している窒素と一緒になって、3~12個の原子を有する環を形成し、この環は、その利用可能な位置のいずれか1つ以上において、ヒドロキシル、アミノ、アルコキシ、アミノアルキル、カルボキシ、シアノ、チオ、ハロ、アルキル、ハロアルキル、シクロアルキル、アリール、及びヘテロアリールから選択される基によって、場合により且つ独立して置換されており、
R3及びR4は、それぞれ独立して、アルキル、アルケニル、アルキニル、ハロアルキル、カルボキシレート、カルボシクリル、アリール、及びヘテロアリールから選択され、任意のそのような基は、その利用可能な位置の1つ以上において、ヒドロキシル、アミノ、アルコキシ、アミノアルキル、チオ、シアノ、ハロ、アリール、及びヘテロアリールから選択される基によって独立して置換されていてもよく、又は、
R3及びR4は、それらがそれぞれ結合しているイミダゾール環の2つの炭素原子と一緒になってフェニル環を形成し、フェニル環は、その4つの利用可能な位置のいずれか1つ以上において、ヒドロキシル、アミノ、アルコキシ、アミノアルキル、チオ、ニトロ、スルホニル、カルボキシ、シアノ、ハロ、アルキル、シクロアルキル、アリール、及びヘテロアリールから選択される基によって、場合により且つ独立して置換されており、任意のそのような基は、その利用可能な位置の1つ以上において、ヒドロキシル、アミノ、アルコキシ、アミノアルキル、チオ、ニトロ、ハロアルキル、スルホニル、シアノ、ハロ、アルキル、シクロアルキル、アリール、及びヘテロアリールから選択される基によって独立して置換されていてもよく;
前記カップリングは、POCl3、塩基、及び非水性溶媒の存在下で行われる、方法。 - 前記塩基がトリアルキルアミンである、請求項9に記載の方法。
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JP2013522365A (ja) | 2010-03-23 | 2013-06-13 | シーメンス メディカル ソリューションズ ユーエスエー インコーポレイテッド | 神経性疾患の検出のためのイメージング剤 |
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Bioorganic & Medicinal Chemistry Letters,2014年,24(1),P.254-257 |
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WO2020227575A1 (en) | 2020-11-12 |
US20200354369A1 (en) | 2020-11-12 |
JP7369208B2 (ja) | 2023-10-25 |
JP2022531936A (ja) | 2022-07-12 |
WO2020227576A1 (en) | 2020-11-12 |
TWI751548B (zh) | 2022-01-01 |
EP3966215A1 (en) | 2022-03-16 |
BR112021022395A2 (pt) | 2021-12-28 |
TW202235420A (zh) | 2022-09-16 |
CN114026092A (zh) | 2022-02-08 |
SG11202112064XA (en) | 2021-11-29 |
CA3138873A1 (en) | 2020-11-12 |
CN114423763A (zh) | 2022-04-29 |
US11325912B2 (en) | 2022-05-10 |
EP3966216A1 (en) | 2022-03-16 |
US20200369670A1 (en) | 2020-11-26 |
IL287887A (en) | 2022-01-01 |
TW202108586A (zh) | 2021-03-01 |
TWI804079B (zh) | 2023-06-01 |
MX2021013574A (es) | 2021-12-10 |
AU2020267664B2 (en) | 2023-04-27 |
US11136330B2 (en) | 2021-10-05 |
CA3138873C (en) | 2024-01-09 |
KR20220005065A (ko) | 2022-01-12 |
JP2022531011A (ja) | 2022-07-05 |
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