JPH1180131A - Ethynylpyrimidine derivative - Google Patents
Ethynylpyrimidine derivativeInfo
- Publication number
- JPH1180131A JPH1180131A JP9251348A JP25134897A JPH1180131A JP H1180131 A JPH1180131 A JP H1180131A JP 9251348 A JP9251348 A JP 9251348A JP 25134897 A JP25134897 A JP 25134897A JP H1180131 A JPH1180131 A JP H1180131A
- Authority
- JP
- Japan
- Prior art keywords
- group
- mmol
- solution
- added
- alkyl
- 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
Links
- -1 (substituted) phenyl Chemical group 0.000 claims abstract description 130
- 150000001875 compounds Chemical class 0.000 claims abstract description 57
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 44
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 39
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 23
- 201000011510 cancer Diseases 0.000 claims abstract description 22
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 13
- 230000010261 cell growth Effects 0.000 claims abstract description 12
- 206010003210 Arteriosclerosis Diseases 0.000 claims abstract description 7
- 208000011775 arteriosclerosis disease Diseases 0.000 claims abstract description 7
- 229940124597 therapeutic agent Drugs 0.000 claims abstract description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 6
- 229940121363 anti-inflammatory agent Drugs 0.000 claims abstract description 5
- 239000002260 anti-inflammatory agent Substances 0.000 claims abstract description 5
- 229940127218 antiplatelet drug Drugs 0.000 claims abstract description 5
- 239000003966 growth inhibitor Substances 0.000 claims abstract description 5
- 229960003444 immunosuppressant agent Drugs 0.000 claims abstract description 5
- 239000003018 immunosuppressive agent Substances 0.000 claims abstract description 5
- 239000000106 platelet aggregation inhibitor Substances 0.000 claims abstract description 5
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 claims abstract description 4
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 0.000 claims abstract description 4
- 230000001861 immunosuppressant effect Effects 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims description 118
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 51
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 42
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 33
- 125000005843 halogen group Chemical group 0.000 claims description 26
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 24
- 125000003277 amino group Chemical group 0.000 claims description 24
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 24
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims description 19
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims description 19
- 230000000694 effects Effects 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 9
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 9
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- 125000003860 C1-C20 alkoxy group Chemical group 0.000 claims description 5
- 125000004423 acyloxy group Chemical group 0.000 claims description 5
- 239000002246 antineoplastic agent Substances 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 125000006833 (C1-C5) alkylene group Chemical group 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 230000000069 prophylactic effect Effects 0.000 claims description 2
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- 150000004677 hydrates Chemical class 0.000 claims 2
- BMNUHRHTDNKJII-UHFFFAOYSA-N 2-ethynylpyrimidine Chemical class C#CC1=NC=CC=N1 BMNUHRHTDNKJII-UHFFFAOYSA-N 0.000 claims 1
- 125000002993 cycloalkylene group Chemical group 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 abstract description 188
- 239000002904 solvent Substances 0.000 abstract description 108
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 abstract description 94
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 abstract description 54
- 230000002401 inhibitory effect Effects 0.000 abstract description 16
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 abstract description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract description 11
- 239000003795 chemical substances by application Substances 0.000 abstract description 6
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 abstract description 5
- 229910052763 palladium Inorganic materials 0.000 abstract description 4
- 125000002619 bicyclic group Chemical group 0.000 abstract description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 abstract description 2
- XUIIKFGFIJCVMT-GFCCVEGCSA-N D-thyroxine Chemical compound IC1=CC(C[C@@H](N)C(O)=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-GFCCVEGCSA-N 0.000 abstract 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 abstract 1
- 108091000080 Phosphotransferase Proteins 0.000 abstract 1
- 230000000903 blocking effect Effects 0.000 abstract 1
- 230000003327 cancerostatic effect Effects 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 102000020233 phosphotransferase Human genes 0.000 abstract 1
- 229940034208 thyroxine Drugs 0.000 abstract 1
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 251
- 239000000243 solution Substances 0.000 description 220
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 202
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 108
- 230000015572 biosynthetic process Effects 0.000 description 103
- 238000003786 synthesis reaction Methods 0.000 description 103
- 235000019439 ethyl acetate Nutrition 0.000 description 95
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 85
- 238000006243 chemical reaction Methods 0.000 description 85
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 84
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 83
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 82
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 80
- 239000000047 product Substances 0.000 description 75
- 238000010898 silica gel chromatography Methods 0.000 description 60
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 58
- 238000000034 method Methods 0.000 description 58
- 239000012044 organic layer Substances 0.000 description 56
- 239000007864 aqueous solution Substances 0.000 description 53
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 52
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 51
- 229910001868 water Inorganic materials 0.000 description 51
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 45
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 43
- 239000013078 crystal Substances 0.000 description 40
- 239000011734 sodium Substances 0.000 description 39
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 32
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 30
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 30
- 229920006395 saturated elastomer Polymers 0.000 description 30
- 239000000126 substance Substances 0.000 description 30
- 235000019441 ethanol Nutrition 0.000 description 28
- 238000001914 filtration Methods 0.000 description 27
- 239000000284 extract Substances 0.000 description 26
- PKDOHUMRKCAPRY-UHFFFAOYSA-N 6-fluoro-1h-pyrido[3,2-d]pyrimidin-4-one Chemical compound N1=CNC(=O)C2=NC(F)=CC=C21 PKDOHUMRKCAPRY-UHFFFAOYSA-N 0.000 description 25
- 238000003756 stirring Methods 0.000 description 25
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- 239000000460 chlorine Substances 0.000 description 23
- 239000010410 layer Substances 0.000 description 21
- 238000004519 manufacturing process Methods 0.000 description 21
- 229960001701 chloroform Drugs 0.000 description 20
- 235000019270 ammonium chloride Nutrition 0.000 description 19
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 18
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 18
- HGMQPDNSSYTATF-UHFFFAOYSA-N 4-chloro-6,7-diethoxyquinazoline Chemical compound C1=NC(Cl)=C2C=C(OCC)C(OCC)=CC2=N1 HGMQPDNSSYTATF-UHFFFAOYSA-N 0.000 description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- 238000001816 cooling Methods 0.000 description 16
- 235000017557 sodium bicarbonate Nutrition 0.000 description 16
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 16
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 15
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 15
- 239000002585 base Substances 0.000 description 14
- VXAWCKIQYKXJMD-UHFFFAOYSA-N ethynamine Chemical group NC#C VXAWCKIQYKXJMD-UHFFFAOYSA-N 0.000 description 14
- 239000003921 oil Substances 0.000 description 14
- 235000019198 oils Nutrition 0.000 description 14
- 238000000746 purification Methods 0.000 description 14
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 14
- 238000005406 washing Methods 0.000 description 14
- WMPTYRGXBUYONY-UHFFFAOYSA-N 2-chloroquinazoline Chemical class C1=CC=CC2=NC(Cl)=NC=C21 WMPTYRGXBUYONY-UHFFFAOYSA-N 0.000 description 13
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 13
- 238000004440 column chromatography Methods 0.000 description 13
- 150000002148 esters Chemical class 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- 238000010992 reflux Methods 0.000 description 12
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 11
- 238000005859 coupling reaction Methods 0.000 description 11
- 230000032050 esterification Effects 0.000 description 11
- 238000005886 esterification reaction Methods 0.000 description 11
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 11
- 239000005457 ice water Substances 0.000 description 11
- 239000002244 precipitate Substances 0.000 description 11
- 229910000104 sodium hydride Inorganic materials 0.000 description 11
- 239000007858 starting material Substances 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 10
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 10
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 10
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 10
- 235000011114 ammonium hydroxide Nutrition 0.000 description 10
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 10
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 150000001408 amides Chemical class 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 9
- 229910052801 chlorine Inorganic materials 0.000 description 9
- GWGVDNZFTPIGDY-UHFFFAOYSA-M magnesium;ethyne;chloride Chemical compound [Mg+2].[Cl-].[C-]#C GWGVDNZFTPIGDY-UHFFFAOYSA-M 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- 229940014800 succinic anhydride Drugs 0.000 description 9
- BDBRXILWISDQCT-UHFFFAOYSA-N 6,7-di(propan-2-yloxy)-1h-quinazolin-4-one Chemical compound N1=CNC(=O)C2=C1C=C(OC(C)C)C(OC(C)C)=C2 BDBRXILWISDQCT-UHFFFAOYSA-N 0.000 description 8
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 230000008878 coupling Effects 0.000 description 8
- 238000010168 coupling process Methods 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 8
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- CAKNVIMJJNHQLR-UHFFFAOYSA-N 6,7-diethoxy-1h-quinazolin-4-one Chemical compound N1=CNC(=O)C2=C1C=C(OCC)C(OCC)=C2 CAKNVIMJJNHQLR-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 7
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 7
- QMNUDYFKZYBWQX-UHFFFAOYSA-N 1H-quinazolin-4-one Chemical compound C1=CC=C2C(=O)N=CNC2=C1 QMNUDYFKZYBWQX-UHFFFAOYSA-N 0.000 description 6
- 102000001301 EGF receptor Human genes 0.000 description 6
- 108060006698 EGF receptor Proteins 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- AKGGYBADQZYZPD-UHFFFAOYSA-N benzylacetone Chemical compound CC(=O)CCC1=CC=CC=C1 AKGGYBADQZYZPD-UHFFFAOYSA-N 0.000 description 6
- 229940125904 compound 1 Drugs 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 6
- 239000011777 magnesium Substances 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 239000012312 sodium hydride Substances 0.000 description 6
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
- AJUAASWQUWIMHM-UHFFFAOYSA-N 1-(3,4-dichlorophenyl)propan-2-one Chemical compound CC(=O)CC1=CC=C(Cl)C(Cl)=C1 AJUAASWQUWIMHM-UHFFFAOYSA-N 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 5
- 150000008065 acid anhydrides Chemical class 0.000 description 5
- 150000001299 aldehydes Chemical class 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 125000001309 chloro group Chemical group Cl* 0.000 description 5
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 5
- 239000003701 inert diluent Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 229910052749 magnesium Inorganic materials 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 5
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 5
- YQUVCSBJEUQKSH-UHFFFAOYSA-N 3,4-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C(O)=C1 YQUVCSBJEUQKSH-UHFFFAOYSA-N 0.000 description 4
- CIRYMDFNFDJALS-UHFFFAOYSA-N 4-chloro-6,7-dimethoxyquinazolin-2-amine Chemical compound NC1=NC(Cl)=C2C=C(OC)C(OC)=CC2=N1 CIRYMDFNFDJALS-UHFFFAOYSA-N 0.000 description 4
- BWLOHIMQWHFSQF-UHFFFAOYSA-N 6-chloro-5-nitropyrimidin-4-amine Chemical compound NC1=NC=NC(Cl)=C1[N+]([O-])=O BWLOHIMQWHFSQF-UHFFFAOYSA-N 0.000 description 4
- PRPPZOGROOCHOG-UHFFFAOYSA-N 6-iodo-9-methylpurine Chemical compound N1=CN=C2N(C)C=NC2=C1I PRPPZOGROOCHOG-UHFFFAOYSA-N 0.000 description 4
- 239000004215 Carbon black (E152) Substances 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 4
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- RUJPPJYDHHAEEK-UHFFFAOYSA-N ethyl piperidine-4-carboxylate Chemical compound CCOC(=O)C1CCNCC1 RUJPPJYDHHAEEK-UHFFFAOYSA-N 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
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- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- JKANAVGODYYCQF-UHFFFAOYSA-N prop-2-yn-1-amine Chemical compound NCC#C JKANAVGODYYCQF-UHFFFAOYSA-N 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 150000003246 quinazolines Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 125000005920 sec-butoxy group Chemical group 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000011775 sodium fluoride Substances 0.000 description 1
- 235000013024 sodium fluoride Nutrition 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 108700026239 src Genes Proteins 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000005979 thermal decomposition reaction Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- CFOAUYCPAUGDFF-UHFFFAOYSA-N tosmic Chemical compound CC1=CC=C(S(=O)(=O)C[N+]#[C-])C=C1 CFOAUYCPAUGDFF-UHFFFAOYSA-N 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- KPZSTOVTJYRDIO-UHFFFAOYSA-K trichlorocerium;heptahydrate Chemical compound O.O.O.O.O.O.O.Cl[Ce](Cl)Cl KPZSTOVTJYRDIO-UHFFFAOYSA-K 0.000 description 1
- FWSPXZXVNVQHIF-UHFFFAOYSA-N triethyl(ethynyl)silane Chemical group CC[Si](CC)(CC)C#C FWSPXZXVNVQHIF-UHFFFAOYSA-N 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【0001】[0001]
【発明の属する技術分野】本発明は、新規なエチニルピ
リミジン誘導体に関する。さらに詳しくは、本発明はチ
ロシン特異的プロテインキナーゼ(以下、チロシンキナ
ーゼ)阻害活性を有するエチニルピリミジン誘導体に関
する。TECHNICAL FIELD The present invention relates to a novel ethynylpyrimidine derivative. More specifically, the present invention relates to an ethynylpyrimidine derivative having tyrosine-specific protein kinase (hereinafter, tyrosine kinase) inhibitory activity.
【0002】[0002]
【従来の技術および発明が解決しようとする課題】癌の
化学療法においては、DNA合成を阻害する薬剤や細胞
分裂を阻害する薬剤が多く用いられている。これらの薬
剤は一般には細胞に対し毒性を示し、急速に分裂する癌
細胞に対しその作用が有効である場合もあるが、多くの
場合その作用が癌細胞に限定されないため強い毒性を有
し、その結果それに基づく副作用が大きな問題になって
いるのが現状である。2. Description of the Related Art In cancer chemotherapy, drugs that inhibit DNA synthesis and drugs that inhibit cell division are often used. These drugs are generally toxic to cells, and their effects may be effective on rapidly dividing cancer cells.However, in many cases, their effects are not limited to cancer cells, so they have strong toxicity. As a result, the current situation is that side effects based on it have become a major problem.
【0003】チロシンキナーゼは細胞の分化・増殖や細
胞内情報伝達機構において中心的な機能を司ることが良
く知られている。したがって細胞内チロシンキナーゼ活
性の制御の破綻は細胞の分化増殖機構や細胞情報伝達機
構の異常をもたらし、多くの疾患の発症に直接的に関与
するものと考えられている。例えば動脈硬化(Am.
J.Physiol.1991,260(4−part
1),C721−C730.);Biochem.Bi
ophys.Res.Commun.1993,192
(3),1319−1326.等)、血小板凝集(FE
BS Letters.1990,263(1),10
4−108.;FEBS Letters.1992,
309(1),10−14.等)、免疫異常(FEBS
Letters.1991,279(2),319−
322.;J Immunol.1991,146
(9),2965−2971.;Nature,199
2,358,253−255.等)、乾癬(J.Inv
est.Deruatol.1990,95,75−9
5);炎症(Molecular Pharmacol
ogy.1990,37,519−525.;Inte
rnational Immunology.199
2,4(4),447−453.等)等である。またチ
ロシンキナーゼ活性は正常細胞に比べ、より頻繁に腫瘍
細胞において検出されることも知られている(Cel
l,1987,50,823)。なかでもHER2、E
GFレセプター等の増殖因子受容体チロシンキナーゼは
癌の形成への関与が大きいことが明らかとなってきてお
り、臨床的にもヒト癌細胞においてこの受容体チロシン
キナーゼ活性が特に亢進していることも見いだされてい
る(Cancer Res.1991,51,4430
−4435;Cancer Res.1992,52,
3636−3641.;Cancer Chemoth
er.Pharmacol.1993,32,1−1
9.等)。さらに、脳、肺、胃腸、頭頸部、膀胱、前立
腺、卵巣、食道、子宮等、数多くの腫瘍においてHER
2、EGFレセプターのチロシンキナーゼが過剰に発現
していることも示されている(Med.Bull.,1
991,47,87;Expert.Opin.Inv
est.Drugs,1994,3(6),577−5
95;特開平5−208911)。また癌の転移に関係
の深い血管新生においてもEGFレセプターの関与が示
されている(J.Biol.Chem.1995,12
9,895−898;Cancer Res.199
5,55,3772−3776)。従って、チロシンキ
ナーゼ活性を阻害する薬剤が動脈硬化等の上記に示した
チロシンキナーゼが関与する疾患の予防や治療の他、新
しい作用機序を有し、多くの癌種に適応しうる副作用の
少ない制癌剤として有用であると考えられる。[0003] It is well known that tyrosine kinases play a central role in cell differentiation / proliferation and intracellular signal transduction mechanisms. Therefore, disruption of the regulation of intracellular tyrosine kinase activity leads to abnormalities in cell differentiation and proliferation mechanisms and cell signaling mechanisms, and is considered to be directly involved in the development of many diseases. For example, arteriosclerosis (Am.
J. Physiol. 1991, 260 (4-part
1), C721-C730. ); Biochem. Bi
ophys. Res. Commun. 1993, 192
(3), 1319-1326. Etc.), platelet aggregation (FE
BS Letters. 1990, 263 (1), 10
4-108. FEBS Letters. 1992,
309 (1), 10-14. Etc.), immune abnormalities (FEBS)
Letters. 1991, 279 (2), 319-
322. J Immunol. 1991, 146
(9), 2965-2971. Nature, 199;
2,358,253-255. Etc.), psoriasis (J. Inv.
est. Deruatol. 1990, 95, 75-9
5); Inflammation (Molecular Pharmacol)
ogy. 1990, 37, 519-525. ; Inte
rational Immunology. 199
2,4 (4), 447-453. Etc.). It is also known that tyrosine kinase activity is more frequently detected in tumor cells than in normal cells (Cel).
1, 1987, 50, 823). Above all, HER2, E
Growth factor receptor tyrosine kinases such as GF receptor have been shown to be significantly involved in cancer formation. (Cancer Res. 1991, 51, 4430)
-4435; Cancer Res. 1992, 52,
3636-3641. ; Cancer Chemoth
er. Pharmacol. 1993, 32, 1-1
9. etc). In addition, HER in many tumors such as brain, lung, gastrointestinal, head and neck, bladder, prostate, ovary, esophagus, uterus, etc.
2. It has also been shown that the tyrosine kinase of the EGF receptor is overexpressed (Med. Bull., 1).
991, 47, 87; Expert. Opin. Inv
est. Drugs, 1994, 3 (6), 577-5.
95; JP-A-5-208911). The involvement of the EGF receptor has also been shown in angiogenesis closely related to cancer metastasis (J. Biol. Chem. 1995, 12).
9, 895-898; Cancer Res. 199
5, 55, 3772-3776). Therefore, a drug that inhibits tyrosine kinase activity has a new mechanism of action, in addition to the prevention and treatment of the above-mentioned tyrosine kinase-related diseases such as arteriosclerosis, and has few side effects that can be applied to many cancer types. It is considered to be useful as an anticancer agent.
【0004】従来のチロシンキナーゼ阻害物質として
は、例えば、アーブスタチン(Erbstatin)、
ラベンダスチン(Lavendustin)、ハービマ
イシンA(HerbimycinA)、ゲニスタイン
(Genistein)、ベンジリデンマロノニトリル
誘導体(特開平2−138238号公報)、α−シアノ
ケイ皮酸アミド誘導体(特開昭62−39523号公
報)、3,5−ジイソプロピル−4−ヒドロキシスチレ
ン誘導体(特開昭62−39522号公報)、3,5−
t−ブチル−4−ヒドロキシスチレン誘導体(特開昭6
2−39523号公報)等が挙げられ、また最近では、
キナゾリン誘導体(特開平6−73025号公報、特開
平5−208911号公報)に代表されるジアリルアミ
ン化合物(Exp.Opin.Ther.Patent
s,1995,5(12),1245−57;ibi
d,805−817)が報告されている。[0004] Conventional tyrosine kinase inhibitors include, for example, Erbstatin,
Lavendustin, Herbimycin A, Genistein, Benzylidenemalononitrile derivative (JP-A-2-138238), α-cyanocinnamic amide derivative (JP-A-62-39523), 3,5-diisopropyl-4-hydroxystyrene derivatives (JP-A-62-39522),
t-butyl-4-hydroxystyrene derivative (JP-A-6
2-39523) and the like, and recently,
Diallylamine compounds (Exp. Opin. Ther. Patent) represented by quinazoline derivatives (JP-A-6-73025 and JP-A-5-208911).
s, 1995, 5 (12), 1245-57; ibi.
d, 805-817).
【0005】[0005]
【課題を解決するための手段】本発明者らは、鋭意検討
の結果、特定構造のエチニルピリミジン誘導体が強力な
チロシンキナーゼ阻害活性と癌細胞増殖抑制作用を有す
ることを見い出し、本発明に到達した。即ち、本発明の
要旨は、下記一般式(I)で表されるエチニルピリミジ
ン誘導体並びにそれらの水和物、薬理学的に許容される
塩、光学活性形、ラセミ体およびジアステレオマー混合
物(以下、「本発明のエチニルピリミジン誘導体」とも
いう)、Means for Solving the Problems As a result of intensive studies, the present inventors have found that an ethynylpyrimidine derivative having a specific structure has potent tyrosine kinase inhibitory activity and cancer cell growth inhibitory activity, and has reached the present invention. . That is, the gist of the present invention is to provide an ethynylpyrimidine derivative represented by the following general formula (I), a hydrate thereof, a pharmacologically acceptable salt, an optically active form, a racemic mixture, and a diastereomer mixture (hereinafter, referred to as a mixture). , "Ethynylpyrimidine derivative of the present invention"),
【0006】[0006]
【化21】 Embedded image
【0007】〔但し、上記一般式(I)中、A、Bはそ
れぞれ独立して(1)ニトロ基;(2)−(CH2 )n'
NR3 R4 (式中、n′は0または1を表し、R3 、R
4 はそれぞれ独立して(a)水素原子;または(b)カ
ルボキシル基もしくはC1 〜C5 のアルコキシカルボニ
ル基で置換されていてもよいC1 〜C5 のアルキル基を
表す);またはA、Bが一緒になって環を形成し、
(3)[However, in the above general formula (I), A and B each independently represent (1) a nitro group; (2)-(CH 2 ) n ′
NR 3 R 4 (wherein, n ′ represents 0 or 1, and R 3 , R
4 represents each independently (a) a hydrogen atom; or (b) a carboxyl group or a C 1 -C 5 alkyl group optionally substituted with a C 1 -C 5 alkoxycarbonyl group); B together form a ring,
(3)
【0008】[0008]
【化22】 Embedded image
【0009】〔式中、X1 〜X4 はそれぞれ独立して
(a)水素原子、(b)ハロゲン原子、(c)ニトロ
基、(d)−OR′(式中、R′は(i)酸素原子を1
個含んでいてもよいC3 〜C8 のシクロアルキル基、ま
たは(ii)C1 〜C5 アルコキシ基、アミノ基もしくは
モルホリノ基で置換されていてもよいC1 〜C5 のアル
キル基を表す)、(e)C1 〜C5 のアルキル基で置換
されていてもよいアミノ基を表すか、または(f)隣接
する置換基が一緒になって環を形成し、C1 〜C5 のオ
キシアルキレン基を表す);(4)Wherein X 1 to X 4 are each independently (a) a hydrogen atom, (b) a halogen atom, (c) a nitro group, (d) —OR ′ (where R ′ is (i) ) 1 oxygen atom
A cycloalkyl group or (ii) C 1 ~C 5 alkoxy group, an alkyl group optionally C 1 -C 5 optionally substituted with an amino group or a morpholino group, a number include optionally C 3 be not -C 8 ), (e) C 1 ~C or an alkyl group substituted with an amino group which may be a 5, or (f) adjacent substituents together form a ring, the C 1 -C 5 (Representing an oxyalkylene group); (4)
【0010】[0010]
【化23】 Embedded image
【0011】(式中、X5 〜X7 はそれぞれ独立して水
素原子、ハロゲン原子、C1 〜C5 のアルコキシ基また
はC1 〜C5 のアルキル基で置換されていてもよいアミ
ノ基を表す);(5)(Wherein X 5 to X 7 each independently represent a hydrogen atom, a halogen atom, a C 1 to C 5 alkoxy group or an amino group which may be substituted by a C 1 to C 5 alkyl group) Represents); (5)
【0012】[0012]
【化24】 Embedded image
【0013】(式中、X8 〜X10はそれぞれ独立して水
素原子、ハロゲン原子、C1 〜C5 のアルコキシ基また
はC1 〜C5 のアルキル基で置換されていてもよいアミ
ノ基を表す);(6)(Wherein X 8 to X 10 each independently represent a hydrogen atom, a halogen atom, a C 1 -C 5 alkoxy group or a C 1 -C 5 alkyl group which may be substituted with an amino group. Represents); (6)
【0014】[0014]
【化25】 Embedded image
【0015】(式中、X11およびX12は水素原子;もし
くはC1 〜C5 のアルキル基を表す);(7)(Wherein X 11 and X 12 represent a hydrogen atom; or a C 1 -C 5 alkyl group);
【0016】[0016]
【化26】 Embedded image
【0017】〔式中、Wは窒素原子またはC−X15(式
中、X15は水素原子またはC1 〜C5のアルキル基を表
す)を表し、X13およびX14は水素原子またはC1 〜C
5 のアルキル基を表す〕;(8)Wherein W represents a nitrogen atom or C—X 15 (wherein X 15 represents a hydrogen atom or a C 1 -C 5 alkyl group), and X 13 and X 14 represent a hydrogen atom or C 1 to C
5 represents an alkyl group]; (8)
【0018】[0018]
【化27】 Embedded image
【0019】(式中、X16およびX17は水素原子または
C1 〜C5 のアルキル基を表す)を表し、R1 は(1)
水素原子;(2)ハロゲン原子;(3)ハロゲン原子で
置換されていてもよいフェニル基;(4)フェニル基で
置換されていてもよいC1 〜C5のアルキル基;(5)
カルボキシル基もしくはC1 〜C5 のアルコキシカルボ
ニル基で置換されていてもよいC1 〜C5 のアルコキシ
基;(6)ヒドロキシル基;または(7)C1 〜C5 の
アルキル基もしくはC1 〜C5 のアルカノイル基で置換
されていてもよいアミノ基を表し、R2 は(1)Wherein X 16 and X 17 represent a hydrogen atom or a C 1 -C 5 alkyl group, and R 1 is (1)
Hydrogen atom; (2) a halogen atom; (3) a phenyl group optionally substituted by a halogen atom; (4) an alkyl group optionally C 1 -C 5 substituted phenyl group; (5)
Alkoxy groups of the carboxyl group or C 1 -C 5 alkoxycarbonyl which may be substituted with a group C 1 ~C 5; (6) a hydroxyl group; or (7) C 1 alkyl or C 1 ~ of -C 5 R 2 represents an amino group which may be substituted with a C 5 alkanoyl group;
【0020】[0020]
【化28】 Embedded image
【0021】<式中、R3 、R4 はそれぞれ独立して、
(a)水素原子;(b)ハロゲン原子、ピリジル基、ピ
リダジニル基、もしくはC3 〜C8 のシクロアルキル基
で置換されていてもよいC1 〜C5 のアルキル基;
(c)−COR6 (式中、R6 は(i)ヒドロキシル
基;(ii)C1 〜C5 のアルコキシ基;(iii)C1 〜C
5 のアルキル基で置換されていてもよいアミノ基;また
は(iv)ハロゲン原子もしくはC1 〜C5 のアルコキシ
基で置換されていてもよいフェニル基を表す);(d)Wherein R 3 and R 4 are each independently
(A) hydrogen atom; (b) a halogen atom, a pyridyl group, an alkyl group of a pyridazinyl group or a C 3 -C 8 cycloalkyl group C 1 may be substituted with -C 5,;
(C) —COR 6 (wherein R 6 is (i) a hydroxyl group; (ii) a C 1 -C 5 alkoxy group; (iii) C 1 -C
An amino group optionally substituted with 5 alkyl groups; or (iv) a phenyl group optionally substituted with a halogen atom or a C 1 -C 5 alkoxy group);
【0022】[0022]
【化29】 Embedded image
【0023】(式中、jは0、1、2または3を表し、
Z1 、Z2 、Z3 はそれぞれ独立して、(i)水素原
子;(ii)ハロゲン原子;(iii)ヒドロキシル基;(i
v)C1 〜C5 のアルコキシ基;または(v)C1 〜C
5 のアルコキシカルボニル基を表す);または、R3 、
R4 が互いに環を形成し、(e)(i)C1 〜C5 のア
ルキル基、または(ii)−(CH2 )n ″R20(式中、
n″は0、1または2を表し、R20はカルボキシル基を
表すか、またはカルボキシル基もしくはC1 〜C5 のア
ルコキシカルボニル基で置換されていてもよいC3 〜C
8 のシクロアルキル基を表す)で置換されていてもよい
アミノ基;(f)(Where j represents 0, 1, 2 or 3;
Z 1 , Z 2 and Z 3 are each independently: (i) a hydrogen atom; (ii) a halogen atom; (iii) a hydroxyl group;
v) an alkoxy group having C 1 -C 5; or (v) C 1 -C
5 represents an alkoxycarbonyl group); or R 3 ,
R 4 is forms a ring together, (e) (i) alkyl groups of C 1 -C 5 or, (ii) - (CH 2 ) n "R 20 ( wherein,
n "is 0, 1 or 2, R 20 is either a carboxyl group or a carboxyl group or a C 1 -C 5 alkoxycarbonyl C 3 optionally substituted by a group -C
An amino group which may be substituted with (f) a cycloalkyl group of 8 );
【0024】[0024]
【化30】 Embedded image
【0025】(式中、R21はカルボキシル基またはC1
〜C5 のアルコキシカルボニル基を表す);(g)Wherein R 21 is a carboxyl group or C 1
An alkoxycarbonyl group ~C 5); (g)
【0026】[0026]
【化31】 Embedded image
【0027】(式中、kは1、2、3または4を表し、
R7 は(i)ヒドロキシル基;(ii)ヒドロキシル基も
しくはC1 〜C5 アルキル基で置換されていてもよいア
ミノ基;または(iii)C1 〜C5 のアルコキシ基を表
す);(h)(Where k represents 1, 2, 3 or 4;
R 7 is (i) a hydroxyl group; represents a or (iii) an alkoxy group having C 1 ~C 5);; ( ii) a hydroxyl group or a C 1 -C 5 alkyl amino group which may be substituted with group (h )
【0028】[0028]
【化32】 Embedded image
【0029】(i)(I)
【0030】[0030]
【化33】 Embedded image
【0031】(j)(J)
【0032】[0032]
【化34】 Embedded image
【0033】;または(k)Or (k)
【0034】[0034]
【化35】 Embedded image
【0035】を表す。R5 は(a)ヒドロキシル基;
(b)C1 〜C5 のアルキル基;(c)C1 〜C5 のア
ルコキシカルボニル基;(d)C1 〜C5 のアルカノイ
ルオキシ基;(e)カルボキシル基;(f)Represents R 5 is (a) a hydroxyl group;
(B) an alkyl group of C 1 ~C 5; (c) an alkoxycarbonyl group having C 1 ~C 5; (d) alkanoyloxy groups C 1 ~C 5; (e) a carboxyl group; (f)
【0036】[0036]
【化36】 Embedded image
【0037】〔式中、mは0または1を表し、nは0、
1、2または3を表し、Eは(i)酸素原子;(ii)−
NHSO2 −;(iii)−NHCO−;または(iv)−N
R7 −(式中、R7 は1)水素原子;2)C1 〜C5 の
アルキル基;もしくは3)ヒドロキシル基、カルボキシ
ル基、もしくはC1 〜C5 のアルコキシカルボニル基で
置換されていてもよいC1 〜C5 のアルキル基を表す)
を表し、Y1 、Y2 、Y3 はそれぞれ独立して、(i)
水素原子;(ii)ハロゲン原子;(iii)ヒドロキシル
基;(iv)C1 〜C5 のアルキル基;または(v)C1
〜C5 のアルコキシ基を表す〕;(g)−O−(CO)
p −G−COR8 〔式中、pは0または1を表し、Gは
(i)ヒドロキシル基もしくはアセトキシ基で置換され
ていてもよいC1 〜C5 のアルキレン基;または(ii)[Wherein m represents 0 or 1, n is 0,
1, 2, or 3, wherein E is (i) an oxygen atom; (ii)-
NHSO 2 —; (iii) —NHCO—; or (iv) —N
R 7 - (wherein, R 7 is 1) a hydrogen atom; 2) alkyl groups of C 1 -C 5; or 3) a hydroxyl group, a carboxyl group, or a substituted alkoxycarbonyl group of C 1 -C 5 Represents a C 1 -C 5 alkyl group)
Wherein Y 1 , Y 2 and Y 3 are each independently (i)
(Ii) halogen atom; (iii) hydroxyl group; (iv) C 1 -C 5 alkyl group; or (v) C 1
An alkoxy group -C 5]; (g) -O- (CO)
During p -G-COR 8 [wherein, p is 0 or 1, G is (i) an alkylene group having a hydroxyl group or optionally substituted with acetoxy group C 1 -C 5; or (ii)
【0038】[0038]
【化37】 Embedded image
【0039】を表し、R8 は(i)ヒドロキシル基;
(ii)C1 〜C5 のアルコキシ基;または(iii)C1 〜
C5 のアルキル基で置換されていてもよいアミノ基を表
す〕;(h)−NR9 R10{式中、R9 、R10はそれぞ
れ独立して、(i)水素原子;(ii)C1 〜C5 のアル
キル基;(iii)C1 〜C5 のアルコキシカルボニル基で
置換されていてもよいC3 〜C8 のシクロアルキル基;
または(iv)−(CO)q−L−(CO)r R11〔式
中、qおよびrは0または1を表し、Lは1)ヒドロキ
シル基もしくはアセトキシ基で置換されていてもよく、
酸素原子を介していてもよいC1 〜C5 のアルキレン
基;または2)C3 〜C8 のシクロアルキレン基を表
し、R11は1)ヒドロキシル基;2)C1 〜C20のアル
コキシ基;3)ピバロイルオキシメトキシ基;または
4)−NR12R13(式中、R12はa)水素原子;b)ヒ
ドロキシル基;またはc)C1 〜C5 のアルキル基を表
し、R13はa)水素原子;b)フェニル基、カルボキシ
ル基もしくはヒドロキシル基で置換されていてもよいC
1 〜C5 のアルキル基;c)C1 〜C7 のアルコキシカ
ルボニル基;d)シアノ基;e)フェニル基もしくはC
1 〜C5 のアルキル基で置換されていてもよいカルバモ
イル基;f)フェニル基もしくはC1 〜C5 のアルキル
基で置換されていてもよいスルホニル基;またはg)C
1 〜C5 のアルカノイル基を表す)〕を表すか、または
R9 、R10が一緒になって環を形成し、(v)Wherein R 8 is (i) a hydroxyl group;
(Ii) an alkoxy group having C 1 -C 5; or (iii) C 1 ~
Represents an alkyl group substituted with an amino group which may be the C 5]; 9 R 10 {wherein (h) -NR, R 9, R 10 are each independently, (i) a hydrogen atom; (ii) cycloalkyl group (iii) C 1 ~C 5 alkoxy optionally substituted by a carbonyl group C 3 ~C 8; C 1 ~C 5 alkyl group;
Or (iv)-(CO) q -L- (CO) r R 11 wherein q and r represent 0 or 1, and L is 1) which may be substituted with a hydroxyl group or an acetoxy group;
A C 1 -C 5 alkylene group which may be via an oxygen atom; or 2) a C 3 -C 8 cycloalkylene group, wherein R 11 is 1) a hydroxyl group; 2) a C 1 -C 20 alkoxy group. ; 12 R 13 (wherein or 4) -NR, R 12 is a) a hydrogen atom; 3) pivaloyloxymethoxy group b) a hydroxyl group; an alkyl group or c) C 1 ~C 5, R 13 is a) a hydrogen atom; b) C which may be substituted with a phenyl group, a carboxyl group or a hydroxyl group
Alkoxycarbonyl group c) C 1 ~C 7;; alkyl group 1 -C 5 d) a cyano group; e) phenyl or C
1 -C 5 carbamoyl group which may be substituted by an alkyl group; f) optionally a sulfonyl group which may be substituted with an alkyl group having a phenyl group or a C 1 -C 5; or g) C
Or represents represents)] alkanoyl group 1 -C 5, or R 9, R 10 are taken together to form a ring, (v)
【0040】[0040]
【化38】 Embedded image
【0041】〔式中、tおよびuは0、1または2を表
し、R14は1)ヒドロキシル基;2)C1 〜C20のアル
コキシ基;3)ピバロイルオキシメトキシ基;4)−N
R15R16(式中、R15はa)水素原子;b)ヒドロキシ
ル基;またはc)C1 〜C5 のアルキル基を表し、R16
はa)水素原子;b)フェニル基、カルボキシル基およ
び/またはヒドロキシル基で置換されていてもよいC1
〜C5 のアルキル基;またはc)シアノ基を表す)〕;
(vi)Wherein t and u represent 0, 1 or 2; R 14 represents 1) a hydroxyl group; 2) a C 1 -C 20 alkoxy group; 3) a pivaloyloxymethoxy group; N
(Wherein, R 15 is a) R 15 R 16 a hydrogen atom; b) a hydroxyl group; an alkyl group or c) C 1 ~C 5, R 16
Is a) a hydrogen atom; b) C 1 optionally substituted with a phenyl group, a carboxyl group and / or a hydroxyl group.
It represents a or c) a cyano group)]; alkyl -C 5;
(Vi)
【0042】[0042]
【化39】 Embedded image
【0043】〔式中、sは0、1、または2を表し、R
17は1)ヒドロキシル基;2)C1 〜C20のアルコキシ
基;3)ピバロイルオキシメトキシ基;または4)ヒド
ロキシル基もしくはC1 〜C5 のアルキル基で置換され
ていてもよいアミノ基を表す〕を表す}を表す>を表す
か、または、(2)[Wherein, s represents 0, 1, or 2;
17 is 1) a hydroxyl group; 2) a C 1 -C 20 alkoxy group; 3) a pivaloyloxymethoxy group; or 4) an amino group optionally substituted with a hydroxyl group or a C 1 -C 5 alkyl group. Represents>) represents}, or represents (2)
【0044】[0044]
【化40】 Embedded image
【0045】(式中、CyAはベンゼン環、ピリジン
環、またはピロール環を表し、Qはハロゲン原子で置換
されていてもよいフェニル基を表し、Vは(1)水素原
子、(2)C1 〜C5 のアルコキシカルボニル基、
(3)カルボキシル基、または(4)C1 〜C5 のアル
コキシカルボニル基もしくはカルボキシル基で置換され
ていてもよいC1 〜C5 アルキル基を表す)を表す〕;
これらの化合物および薬学的に許容される担体を含んで
なる医薬組成物に存する。本発明の医薬組成物は、チロ
シンキナーゼの活性の亢進に起因する疾患に対する予防
及び/又は治療剤、具体的には、制癌剤、免疫抑制剤、
血小板凝集阻害剤、動脈硬化治療薬、抗炎症剤、癌細胞
増殖抑制薬として使用される。なお、以下、本発明にお
いてはこれらを単に「チロシンキナーゼ阻害薬」ともい
う。(Where CyA represents a benzene ring, a pyridine ring, or a pyrrole ring, Q represents a phenyl group optionally substituted with a halogen atom, V is (1) a hydrogen atom, (2) C 1 alkoxycarbonyl group -C 5,
(3) carboxyl represents group or a (4) represents a C 1 -C 5 alkoxycarbonyl group C 1 or may be substituted with a carboxyl group -C 5 alkyl group),];
A pharmaceutical composition comprising these compounds and a pharmaceutically acceptable carrier. The pharmaceutical composition of the present invention is a prophylactic and / or therapeutic agent for a disease caused by enhanced tyrosine kinase activity, specifically, an anticancer agent, an immunosuppressant,
It is used as a platelet aggregation inhibitor, a therapeutic agent for arteriosclerosis, an anti-inflammatory agent, and a cancer cell growth inhibitor. Hereinafter, in the present invention, these are also simply referred to as “tyrosine kinase inhibitors”.
【0046】[0046]
【発明の実施の形態】以下、本発明につき詳細に説明す
る。本発明の化合物は前記一般式(I)で表されるエチ
ニルピリミジン誘導体である。一般式(I)において、
定義されるハロゲン原子としては、フッ素原子、塩素原
子、臭素原子、ヨウ素原子が挙げられ、C1 〜C5 のア
ルキル基としては、メチル基、エチル基、n−プロピル
基、iso−プロピル基、n−ブチル基、iso−ブチ
ル基、sec−ブチル基、tert−ブチル基、n−ペ
ンチル基、ネオペンチル基等が挙げられ、C1 〜C5 の
アルコキシ基としては、メトキシ基、エトキシ基、n−
プロポキシ基、iso−プロポキシ基、n−ブトキシ
基、iso−ブトキシ基、sec−ブトキシ基、ter
t−ブトキシ基、n−ペンチルオキシ基、ネオペンチル
オキシ基等が挙げられる。C1 〜C5 のアルカノイル基
としては、ホルミル基、アセチル基、プロピオニル基、
ブチリル基、イソブチリル基、バレリル基等が挙げられ
る。DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail. The compound of the present invention is an ethynylpyrimidine derivative represented by the general formula (I). In the general formula (I),
Examples of the defined halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and the C 1 -C 5 alkyl group includes a methyl group, an ethyl group, an n-propyl group, an isopropyl group, n-butyl group, iso-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, neopentyl group and the like. Examples of the C 1 -C 5 alkoxy group include a methoxy group, an ethoxy group, and an n-butyl group. −
Propoxy group, iso-propoxy group, n-butoxy group, iso-butoxy group, sec-butoxy group, ter
Examples thereof include a t-butoxy group, an n-pentyloxy group, and a neopentyloxy group. Examples of the C 1 -C 5 alkanoyl group include a formyl group, an acetyl group, a propionyl group,
Butyryl, isobutyryl, valeryl and the like.
【0047】また前記一般式(I)で表される本発明の
エチニルピリミジン誘導体は、公知の方法により相当す
る酸または塩基によって塩に変換される。形成しうる塩
としては、例えば塩酸塩、硫酸塩、炭酸塩、リン酸塩等
の無機酸塩、あるいはぎ酸塩、酢酸塩、プロピオン酸
塩、乳酸塩、しゅう酸塩、フマル酸塩、マレイン酸塩、
クエン酸塩、酒石酸塩、安息香酸塩、フタル酸塩、メタ
ンスルホン酸塩、4−トルエンスルホン酸、イセチオン
酸塩、グルクロン酸塩、グルコン酸塩等の有機酸の塩が
挙げられる。また、エチニルピリミジン誘導体がカルボ
ン酸等の酸性基を有する場合には、ナトリウム塩、カリ
ウム塩等のアルカリ金属の塩、マグネシウム塩、カルシ
ウム塩等のアルカリ土類金属の塩、あるいは、アンモニ
ウム塩、薬理学的に許容される有機アミン(テトラメチ
ルアンモニウム、トリエチルアミン、シクロヘキシルア
ミン、ベンジルアミン、フェネチルアミン、モノエタノ
ールアミン、ジエタノールアミン、トリス(ヒドロキシ
エチル)アミン、リジン、アルギニン、N−メチル−D
−グルカミン等)の塩が挙げられる。なお、エチニルピ
リミジン誘導体が第3級のアミノ基および/またピリジ
ル基を有する場合には、それぞれ、アンモニウム塩、ピ
リジニウム塩を形成する場合もある。The ethynylpyrimidine derivative of the present invention represented by the above general formula (I) is converted into a salt with a corresponding acid or base by a known method. Salts that can be formed include, for example, inorganic acid salts such as hydrochloride, sulfate, carbonate, and phosphate, or formate, acetate, propionate, lactate, oxalate, fumarate, and maleate. Acid salts,
Examples include salts of organic acids such as citrate, tartrate, benzoate, phthalate, methanesulfonate, 4-toluenesulfonic acid, isethionate, glucuronate, and gluconate. When the ethynylpyrimidine derivative has an acidic group such as a carboxylic acid, a salt of an alkali metal such as a sodium salt or a potassium salt, a salt of an alkaline earth metal such as a magnesium salt or a calcium salt, or an ammonium salt or a drug. Physically acceptable organic amines (tetramethylammonium, triethylamine, cyclohexylamine, benzylamine, phenethylamine, monoethanolamine, diethanolamine, tris (hydroxyethyl) amine, lysine, arginine, N-methyl-D
-Glucamine and the like). When the ethynylpyrimidine derivative has a tertiary amino group and / or a pyridyl group, an ammonium salt and a pyridinium salt may be formed, respectively.
【0048】なお、本発明のエチニルピリミジン誘導体
は、水和物も形成することができる。以下、本発明の具
体例を示す。以下、Meは、メチル基を、Etはエチル
基を、Prはプロピル基を、Buはブチル基を、Phは
フェニル基を表す。The ethynylpyrimidine derivative of the present invention can also form a hydrate. Hereinafter, specific examples of the present invention will be described. Hereinafter, Me represents a methyl group, Et represents an ethyl group, Pr represents a propyl group, Bu represents a butyl group, and Ph represents a phenyl group.
【0049】[0049]
【表1】 [Table 1]
【0050】[0050]
【表2】 [Table 2]
【0051】[0051]
【表3】 [Table 3]
【0052】[0052]
【表4】 [Table 4]
【0053】[0053]
【表5】 [Table 5]
【0054】[0054]
【表6】 [Table 6]
【0055】[0055]
【表7】 [Table 7]
【0056】[0056]
【表8】 [Table 8]
【0057】[0057]
【表9】 [Table 9]
【0058】[0058]
【表10】 [Table 10]
【0059】[0059]
【表11】 [Table 11]
【0060】[0060]
【表12】 [Table 12]
【0061】[0061]
【表13】 [Table 13]
【0062】[0062]
【表14】 [Table 14]
【0063】[0063]
【表15】 [Table 15]
【0064】[0064]
【表16】 [Table 16]
【0065】[0065]
【表17】 [Table 17]
【0066】[0066]
【表18】 [Table 18]
【0067】[0067]
【表19】 [Table 19]
【0068】[0068]
【表20】 [Table 20]
【0069】[0069]
【表21】 [Table 21]
【0070】[0070]
【表22】 [Table 22]
【0071】[0071]
【表23】 [Table 23]
【0072】[0072]
【表24】 [Table 24]
【0073】[0073]
【表25】 [Table 25]
【0074】[0074]
【表26】 [Table 26]
【0075】[0075]
【表27】 [Table 27]
【0076】[0076]
【表28】 [Table 28]
【0077】[0077]
【表29】 [Table 29]
【0078】[0078]
【表30】 [Table 30]
【0079】[0079]
【表31】 [Table 31]
【0080】[0080]
【表32】 [Table 32]
【0081】[0081]
【表33】 [Table 33]
【0082】[0082]
【表34】 [Table 34]
【0083】[0083]
【表35】 [Table 35]
【0084】[0084]
【表36】 [Table 36]
【0085】[0085]
【表37】 [Table 37]
【0086】[0086]
【表38】 [Table 38]
【0087】[0087]
【表39】 [Table 39]
【0088】[0088]
【表40】 [Table 40]
【0089】[0089]
【表41】 [Table 41]
【0090】[0090]
【表42】 [Table 42]
【0091】[0091]
【表43】 [Table 43]
【0092】[0092]
【表44】 [Table 44]
【0093】[0093]
【表45】 [Table 45]
【0094】[0094]
【表46】 [Table 46]
【0095】[0095]
【表47】 [Table 47]
【0096】[0096]
【表48】 [Table 48]
【0097】[0097]
【表49】 [Table 49]
【0098】[0098]
【表50】 [Table 50]
【0099】[0099]
【表51】 [Table 51]
【0100】[0100]
【表52】 [Table 52]
【0101】[0101]
【表53】 [Table 53]
【0102】[0102]
【表54】 [Table 54]
【0103】[0103]
【表55】 [Table 55]
【0104】[0104]
【表56】 [Table 56]
【0105】[0105]
【表57】 [Table 57]
【0106】[0106]
【表58】 [Table 58]
【0107】[0107]
【表59】 [Table 59]
【0108】[0108]
【表60】 [Table 60]
【0109】[0109]
【表61】 [Table 61]
【0110】[0110]
【表62】 [Table 62]
【0111】[0111]
【表63】 [Table 63]
【0112】[0112]
【表64】 [Table 64]
【0113】[0113]
【表65】 [Table 65]
【0114】[0114]
【表66】 [Table 66]
【0115】[0115]
【表67】 [Table 67]
【0116】[0116]
【表68】 [Table 68]
【0117】[0117]
【表69】 [Table 69]
【0118】[0118]
【表70】 [Table 70]
【0119】[0119]
【表71】 [Table 71]
【0120】[0120]
【表72】 [Table 72]
【0121】[0121]
【表73】 [Table 73]
【0122】[0122]
【表74】 [Table 74]
【0123】[0123]
【表75】 [Table 75]
【0124】[0124]
【表76】 [Table 76]
【0125】[0125]
【表77】 [Table 77]
【0126】[0126]
【表78】 [Table 78]
【0127】[0127]
【表79】 [Table 79]
【0128】[0128]
【表80】 [Table 80]
【0129】[0129]
【表81】 [Table 81]
【0130】[0130]
【表82】 [Table 82]
【0131】[0131]
【表83】 [Table 83]
【0132】[0132]
【表84】 [Table 84]
【0133】[0133]
【表85】 [Table 85]
【0134】[0134]
【表86】 [Table 86]
【0135】[0135]
【表87】 [Table 87]
【0136】[0136]
【表88】 [Table 88]
【0137】[0137]
【表89】 [Table 89]
【0138】[0138]
【表90】 [Table 90]
【0139】[0139]
【表91】 [Table 91]
【0140】[0140]
【表92】 [Table 92]
【0141】[0141]
【表93】 [Table 93]
【0142】[0142]
【表94】 [Table 94]
【0143】[0143]
【表95】 [Table 95]
【0144】[0144]
【表96】 [Table 96]
【0145】[0145]
【表97】 [Table 97]
【0146】[0146]
【表98】 [Table 98]
【0147】[0147]
【表99】 [Table 99]
【0148】[0148]
【表100】 [Table 100]
【0149】[0149]
【表101】 [Table 101]
【0150】[0150]
【表102】 [Table 102]
【0151】[0151]
【表103】 [Table 103]
【0152】[0152]
【表104】 [Table 104]
【0153】[0153]
【表105】 [Table 105]
【0154】[0154]
【表106】 [Table 106]
【0155】[0155]
【表107】 [Table 107]
【0156】[0156]
【表108】 [Table 108]
【0157】[0157]
【表109】 [Table 109]
【0158】[0158]
【表110】 [Table 110]
【0159】[0159]
【表111】 [Table 111]
【0160】[0160]
【表112】 [Table 112]
【0161】[0161]
【表113】 [Table 113]
【0162】[0162]
【表114】 [Table 114]
【0163】[0163]
【表115】 [Table 115]
【0164】[0164]
【表116】 [Table 116]
【0165】[0165]
【表117】 [Table 117]
【0166】[0166]
【表118】 [Table 118]
【0167】[0167]
【表119】 [Table 119]
【0168】[0168]
【表120】 [Table 120]
【0169】[0169]
【表121】 [Table 121]
【0170】[0170]
【表122】 [Table 122]
【0171】[0171]
【表123】 [Table 123]
【0172】[0172]
【表124】 [Table 124]
【0173】[0173]
【表125】 [Table 125]
【0174】[0174]
【表126】 [Table 126]
【0175】[0175]
【表127】 [Table 127]
【0176】[0176]
【表128】 [Table 128]
【0177】[0177]
【表129】 [Table 129]
【0178】本発明化合物の製造法 1)上記一般式(I)で表される化合物のうち、R1 が
水素原子;塩素原子、臭素原子;フェニル基で置換され
ていてもよいC1 〜C5 のアルキル基;無置換のアミノ
基;ハロゲン原子で置換されていてもよいフェニル基を
表す化合物の製造法 例えばScheme 1の様なルートで製造できる。Method for Producing the Compound of the Present Invention 1) Among the compounds represented by the above general formula (I), R 1 is a hydrogen atom; a chlorine atom, a bromine atom; C 1 -C optionally substituted by a phenyl group. Method for producing compound representing alkyl group 5 ; unsubstituted amino group; phenyl group which may be substituted with a halogen atom The compound can be produced, for example, by a route such as Scheme 1.
【0179】[0179]
【化41】 Embedded image
【0180】(式中、LGは塩素原子、パラトルエンス
ルホニル基等の脱離基を表し、R1aは既に定義したR1
のうち、水素原子、塩素原子、臭素原子、アミノ基、フ
ェニル基で置換されていてもよいC1 〜C5 のアルキル
基、ハロゲン原子で置換されていてもよいフェニル基を
表す。A、B及びR2 は既に定義した通り。Meはリチ
ウム、ハロゲン化マグネシウム、トリアルキルスズ等の
金属原子団を表す) すなわち、化合物IIと化合物III をテトラヒドロフラ
ン、ジエチルエーテル等のエーテル系溶媒、ベンゼン、
トルエン等の炭化水素系溶媒、ジメチルホルムアミド、
ジメチルスルホキシド等の非プロトン性溶媒中、あるい
はそれらの混合溶媒中、1〜10当量のトリエチルアミ
ン、ジエチルアミン、ピリジン等の塩基、0.001〜
0.5当量のPd(PPh3 )4 、PdCl2 (PPh
3 )2 等のパラジウム錯体、0.001〜0.5当量の
CuI、CuCl等の銅(I)化合物の存在下、あるい
は非存在下、+20℃〜+200℃で5分間〜48時間
反応させることにより化合物Iを製造することができ
る。この際、化合物III の代わりに、化合物III をテト
ラヒドロフラン、ジエチルエーテル等のエーテル系溶
媒、ベンゼン、トルエン等の炭化水素系溶媒中でブチル
リチウム、臭化エチルマグネシウム等の有機金属化合物
を作用させて調整できるアセチリドIII ′(Met=リ
チウム、ハロゲン化マグネシウム)やさらにこれを塩化
トリアルキルスズ化合物やトリアルコキシホウ素化合物
と作用させて調整できるIII ′{Met=SnR3 、B
(OR)2 }(Rは低級アルキル基、または水素原子を
表す)を用いる事もできる。化合物IIはその構造に応
じ、次のようにして製造できる(Scheme 2−
4)。[0180] (wherein, LG represents a leaving group such as a chlorine atom, p-toluenesulfonyl group, R 1a is R 1 defined previously
Of these, a hydrogen atom, a chlorine atom, a bromine atom, an amino group, a C 1 -C 5 alkyl group which may be substituted with a phenyl group, and a phenyl group which may be substituted with a halogen atom. A, B and R 2 are as previously defined. Me represents a metal atom group such as lithium, magnesium halide, and trialkyltin. That is, compound II and compound III are converted to an ether solvent such as tetrahydrofuran or diethyl ether, benzene,
Hydrocarbon solvents such as toluene, dimethylformamide,
In an aprotic solvent such as dimethyl sulfoxide or a mixed solvent thereof, 1 to 10 equivalents of a base such as triethylamine, diethylamine, pyridine, 0.001 to
0.5 equivalents of Pd (PPh 3 ) 4 , PdCl 2 (PPh
3 ) Reaction at + 20 ° C. to + 200 ° C. for 5 minutes to 48 hours in the presence or absence of a palladium complex such as 2 or a copper (I) compound such as 0.001 to 0.5 equivalents of CuI or CuCl. Can produce compound I. At this time, instead of compound III, compound III is prepared by reacting an organometallic compound such as butyllithium or ethylmagnesium bromide in an ether solvent such as tetrahydrofuran or diethyl ether or a hydrocarbon solvent such as benzene or toluene. Acetylide III '(Met = lithium, magnesium halide) or a triacetyltin chloride compound or a trialkoxyboron compound, which can be adjusted to obtain III' @ Met = SnR 3 , B
(OR) 2 } (R represents a lower alkyl group or a hydrogen atom) can also be used. Compound II can be produced according to its structure as follows (Scheme 2-
4).
【0181】[0181]
【化42】 Embedded image
【0182】(式中、R1bは水素原子、フェニル基で置
換されていてもよいC1 〜C5 アルキル基、アミノ基、
ヒドロキシル基、ハロゲン原子で置換されていてもよい
フェニル基を表し、R1cは、水素原子、フェニル基で置
換されていてもよいC1 〜C5のアルカノイル基、ハロ
ゲン原子で置換されていてもよいベンゾイル基を表し、
R′はヒドロキシル基または低級アルコキシ基を表し、
R″はCNまたはCONH2 を表す) a)化合物IIが2環性縮合環(プテリジン環を除く、即
ち、A、Bが一緒になって環を形成するが(Wherein R 1b represents a hydrogen atom, a C 1 -C 5 alkyl group optionally substituted with a phenyl group, an amino group,
A hydroxyl group, a phenyl group optionally substituted with a halogen atom, and R 1c represents a hydrogen atom, a C 1 to C 5 alkanoyl group optionally substituted with a phenyl group, or a phenyl group optionally substituted with a halogen atom. Represents a good benzoyl group,
R ′ represents a hydroxyl group or a lower alkoxy group,
R ″ represents CN or CONH 2 ) a) Compound II is a bicyclic fused ring (excluding a pteridine ring, that is, A and B together form a ring,
【0183】[0183]
【化43】 Embedded image
【0184】以外を表す場合)を表す場合 化合物IIは対応する前駆体IVをベンゼン、トルエン等の
炭化水素系溶媒、ジクロロメタン、クロロホルム等のハ
ロゲン系炭化水素中、ジメチルホルムアミド等の適当な
溶媒中、または無溶媒で1〜10当量のジエチルアニリ
ン、ピリジン等の塩基存在下または非存在下、オキシ塩
化リン、五塩化リン、塩化チオニル、オキシ臭化リン
等、またはそれらの適当な混合物と+20℃〜+200
℃の温度で5分間〜48時間反応させる方法で製造する
ことができる{II(R1a=Cl、Br)の場合はIV(R
1b=OH)を用いる}。化合物IIの内、LGがパラトル
エンスルホニル基、メタンスルホニル基、トリフルオロ
メタンスルホニル基を表す化合物が必要な場合は対応す
るIVをテトラヒドロフラン、トルエン、ジメチルホルム
アミド等の適当な溶媒中、ピリジン等の塩基存在下、塩
化パラトルエンスルホニル、塩化メタンスルホニル、無
水トリフルオロメタンスルホン酸等をそれぞれ作用させ
ることによって製造できる。Compound II is obtained by converting the corresponding precursor IV into a hydrocarbon solvent such as benzene or toluene, a halogenated hydrocarbon such as dichloromethane or chloroform, or a suitable solvent such as dimethylformamide. Or in the absence or presence of 1 to 10 equivalents of a base such as diethylaniline or pyridine in the absence or presence of a solvent at + 20 ° C. with phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, phosphorus oxybromide, or a suitable mixture thereof; +200
5II (R 1a = Cl, Br) and IV (R
1b = OH). In the case where a compound in which LG represents a paratoluenesulfonyl group, a methanesulfonyl group, or a trifluoromethanesulfonyl group among the compound II is required, the corresponding IV is represented by a base such as pyridine in an appropriate solvent such as tetrahydrofuran, toluene, or dimethylformamide. It can be produced by reacting paratoluenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonic anhydride and the like.
【0185】さらに、化合物IVのうちR1bが水素原子、
フェニル基で置換されていてもよいC1 〜C5 アルキル
基、ハロゲン原子で置換されていてもよいフェニル基を
表す化合物の場合、アミノ酸V(R′=OH)もしくは
そのエステル体V(R′=低級アルコキシ基)と対応す
るアミド(R1b−CONH2 )、チオアミド(R1b−C
SNH2 )と適当な溶媒中、もしくは無溶媒または反応
剤を溶媒兼用として用い、+20℃〜+250℃の温度
で5分間〜48時間反応させる方法や、アミド体V(R
=NH2 )と反応剤であるエステル{R1b−CO2 R
(R=低級アルキル)}またはオルトエステル{R1b−
C(OR′)3 (R′=低級アルキル基)}と適当な溶
媒中、もしくは反応剤を溶媒兼用として用い、+20℃
〜+250℃の温度で5分間〜48時間反応させる方法
で製造できる。さらに対応するアミノニトリルVI(R″
=CN)を水酸化ナトリウム水溶液等のアルカリ存在
下、0.1〜5当量の過酸化水素を+20℃〜+250
℃の温度で5分間〜48時間反応させる方法で化合物IV
が製造できる。またアミノニトリルVI(R1c=H)とギ
酸と例えば無水酢酸の様な適当な酸無水物より調整でき
る混合酸無水物を+50℃〜+200℃の温度で5分間
〜48時間反応させる方法でもIV(R1b=H)を製造で
きる。化合物IVのうちR1bがアミノ基を表す化合物の場
合はエステル体(V;R′=低級アルコキシ基)をメタ
ノール、エタノール等適当な溶媒中、0.5〜100当
量のシアナミド(H2 NCN)を+20℃〜+150℃
の温度で5分間〜48時間反応させる方法で製造でき
る。また、化合物IVのうちR1bがアミノ基、またはヒド
ロキシル基を表す化合物の場合はscheme2′に示
す様に、V(R′=OH)をベンゼン、ジクロロメタ
ン、水等の適当な溶媒中、水酸化ナトリウム水溶液、ト
リエチルアミン等の塩基存在下ホスゲン、トリホスゲン
を反応させ、V′とした後、尿素およびグアニジン塩を
それぞれ作用させることでも製造できる。Further, in compound IV, R 1b is a hydrogen atom,
In the case of a compound representing a C 1 -C 5 alkyl group which may be substituted with a phenyl group or a phenyl group which may be substituted with a halogen atom, the amino acid V (R ′ = OH) or its ester V (R ′ = Lower alkoxy group) and the corresponding amide (R 1b -CONH 2 ), thioamide (R 1b -C
SNH 2 ) in an appropriate solvent, or without solvent or using a reactant as a solvent, at a temperature of + 20 ° C. to + 250 ° C. for 5 minutes to 48 hours, or an amide V (R
NHNH 2 ) and the ester {R 1b —CO 2 R as a reactant
(R = lower alkyl)} or orthoester {R 1b −
+ 20 ° C. in C (OR ′) 3 (R ′ = lower alkyl group)} and an appropriate solvent or using a reactant as a solvent
It can be produced by a method of reacting at a temperature of ~ 250C for 5 minutes to 48 hours. Furthermore, the corresponding aminonitrile VI (R ″
= CN) in the presence of an alkali such as an aqueous solution of sodium hydroxide in the presence of 0.1 to 5 equivalents of hydrogen peroxide at + 20 ° C to + 250 ° C.
Compound IV by reacting at a temperature of 5 ° C. for 5 minutes to 48 hours.
Can be manufactured. A method in which aminonitrile VI (R 1c = H), formic acid and a mixed acid anhydride which can be adjusted from a suitable acid anhydride such as acetic anhydride at a temperature of + 50 ° C. to + 200 ° C. for 5 minutes to 48 hours is also used. (R 1b = H). When R 1b represents an amino group among the compounds IV, the ester form (V; R ′ = lower alkoxy group) is converted to 0.5 to 100 equivalents of cyanamide (H 2 NCN) in a suitable solvent such as methanol or ethanol. + 20 ° C to + 150 ° C
At a temperature of 5 minutes to 48 hours. Further, in the case of compound IV in which R 1b represents an amino group or a hydroxyl group, as shown in scheme 2 ′, V (R ′ = OH) is hydroxylated in an appropriate solvent such as benzene, dichloromethane and water. It can also be produced by reacting phosgene and triphosgene in the presence of a base such as sodium aqueous solution and triethylamine to obtain V ', and then reacting with urea and a guanidine salt, respectively.
【0186】b)化合物IIがピリミジン単環を表す場合
{即ち、化合物IIでA、Bが−(CH2 )n'NR3 R4
(式中、n′、R3 およびR4 は既に定義した通り)、
またはニトロ基で表される場合} 化合物IIは化合物VII を水、メタノール、トルエン、ジ
エチルエーテル等の適当な溶媒中、0.1〜10当量の
H(CH2 )n'NR3 R4 (式中、n′、R3およびR
4 は既に定義した通り)と0℃〜+150℃の温度で5
分間〜48時間反応させる方法や、ここで得られる化合
物VIII(A=−(CH2 )n'NR3 R4)を水、メタノ
ール、トルエン、ジメチルホルムアミド等の適当な溶媒
中、亜鉛、鉄等の還元剤を用い、+20℃〜+200℃
の温度で5分間〜48時間反応させる方法でも製造でき
る。必要に応じ、化合物VIIIは化合物IXを濃硫酸と発煙
硝酸を用いるニトロ化で製造する事ができる(Sche
me3)。B) When compound II represents a pyrimidine monocyclic ring, that is, in compound II, A and B represent-(CH 2 ) n ' NR 3 R 4
Wherein n ′, R 3 and R 4 are as defined above,
Or a compound represented by a nitro group. Compound II is prepared by dissolving Compound VII in a suitable solvent such as water, methanol, toluene or diethyl ether in an amount of 0.1 to 10 equivalents of H (CH 2 ) n ′ NR 3 R 4 (formula Where n ′, R 3 and R
4 as defined above) and 5 at a temperature between 0 ° C. and + 150 ° C.
Minutes to 48 or a method of hours, where the resulting compound VIII (A = - (CH 2 ) n 'NR 3 R 4) water, methanol, toluene, a suitable solvent, such as dimethylformamide, zinc, iron, etc. + 20 ° C to + 200 ° C using a reducing agent of
At a temperature of 5 minutes to 48 hours. If necessary, compound VIII can be prepared by nitrating compound IX with concentrated sulfuric acid and fuming nitric acid (Sche
me3).
【0187】[0187]
【化44】 Embedded image
【0188】(式中、R1a及びAは前記と同義を表す) c)化合物IIがプテリジン環、即ちA、Bが一緒になっ
て環を形成し、(Wherein R 1a and A have the same meanings as described above) c) Compound II forms a pteridine ring, ie, A and B together form a ring,
【0189】[0189]
【化45】 Embedded image
【0190】を表す場合(Scheme4) 上記b)で製造できる化合物II(A=B=NH2 )をメ
タノール、エタノール等のアルコール系溶媒、ベンゼ
ン、トルエン等の炭化水素系溶媒、ジメチルホルムアミ
ド、ジメチルスルホキシド等の非プロトン性溶媒中、あ
るいはそれらの混合溶媒中、プテリジン環の場合は0.
5〜10当量のX11COCOX12(式中、X11、X12は
既に定義した通り))を、+20℃〜+200℃の温度
で5分間〜48時間反応させる方法で製造できる。同様
にプリン環の場合は上記a)の方法の他、化合物II(A
=B=NH2 )とX13CO2 HまたはX13C(OR′)
3 (X13、R′は既に定義した通り)を上記溶媒中、ま
たは反応剤を溶媒兼用として用い、+20℃〜+200
℃の温度で5分間〜48時間反応させる方法によっても
製造できる。さらにプリン環のアルキル化が必要な場合
は、例えばジメチルホルムアミド、テトラヒドロフラン
等の適当な溶媒中、水素化ナトリウム、ナトリウムメト
キシド、炭酸カリウム等の塩基存在下、X14−hal
(X14は既に定義した通り、halはヨウ素、臭素等の
ハロゲン原子を表す)を0℃〜+200℃の温度で5分
間〜48時間反応作用させる方法で製造できる。(Scheme 4) Compound II (A = B = NH 2 ) which can be produced in b) is converted to an alcohol solvent such as methanol or ethanol, a hydrocarbon solvent such as benzene or toluene, dimethylformamide, or dimethyl sulfoxide. In the case of a pteridine ring in an aprotic solvent such as
5~10 X 11 COCOX 12 (wherein, X 11, X 12 is as already defined) in equivalents), can be prepared by a method of reacting 48 hours 5 minutes at a temperature of + 20 ℃ ~ + 200 ℃. Similarly, in the case of a purine ring, a compound II (A)
= B = NH 2 ) and X 13 CO 2 H or X 13 C (OR ′)
3 (X 13 , R ′ is as defined above) in the above-mentioned solvent or using the reactant as a solvent, from + 20 ° C. to + 200 ° C.
It can also be produced by a method of reacting at a temperature of 5 ° C. for 5 minutes to 48 hours. When further alkylation of the purine ring is necessary, for example, X 14 -hal in a suitable solvent such as dimethylformamide or tetrahydrofuran in the presence of a base such as sodium hydride, sodium methoxide or potassium carbonate.
(X 14 is as previously defined, hal is iodine, halogen atom represents a bromine or the like) can be produced by a method for 5 minutes to 48 hours action of a temperature of 0 ℃ ~ + 200 ℃.
【0191】[0191]
【化46】 Embedded image
【0192】(式中、R1a、X11、X12、X13、X14、
R′は前記と同義を表し、halはハロゲン原子を表
す) 〔化合物III の製造法〕 a)対応するアルコールを酸化して製造できるアルデヒ
ドにジクロロメタン、四塩化炭素等適当な溶媒中、例え
ばそれぞれ0.1〜10当量の四臭化炭素およびトリフ
ェニルホスフィンを−20〜+50℃で5分間〜48時
間反応させる方法や、テトラヒドロフラン、ジエチルエ
ーテル等の溶媒あるいはそれらの混合溶媒中、例えば
(EtO)2 P(O)CCl3 とn−BuLiを−15
0℃〜+50℃で5分間〜48時間反応させて調製でき
るwittig反応剤を−150℃〜+100℃で5分
間〜48時間反応させる方法でハロアルケンを製造でき
る。このハロアルケンをさらにテトラヒドロフラン、ジ
エチルエーテル等の溶媒あるいはそれらの混合溶媒中、
例えばn−BuLi等の有機リチウム化合物を−100
℃〜+100℃で5分間〜48時間反応させることによ
り化合物III を製造できる。必要に応じ化合物に存在す
る官能基を保護してこの変換を行うこともできる(sc
heme5)。(Wherein R 1a , X 11 , X 12 , X 13 , X 14 ,
R 'has the same meaning as described above, and hal represents a halogen atom. [Production method of compound III] a) An aldehyde which can be produced by oxidizing the corresponding alcohol is converted to an aldehyde which can be prepared by adding an aldehyde to a suitable solvent such as dichloromethane, carbon tetrachloride or the like. 0.1 to 10 equivalents of carbon tetrabromide and triphenylphosphine at -20 to + 50 ° C. for 5 minutes to 48 hours, or in a solvent such as tetrahydrofuran or diethyl ether or a mixed solvent thereof, for example, (EtO) 2 P (O) CCl 3 and n-BuLi are converted to -15
A haloalkene can be produced by reacting a wittig reagent, which can be prepared by reacting at 0 ° C. to + 50 ° C. for 5 minutes to 48 hours, at −150 ° C. to + 100 ° C. for 5 minutes to 48 hours. This haloalkene is further added to a solvent such as tetrahydrofuran and diethyl ether or a mixed solvent thereof,
For example, an organic lithium compound such as n-BuLi is
The compound III can be produced by reacting at a temperature of from + 100 ° C to + 100 ° C for from 5 minutes to 48 hours. This conversion can also be carried out by protecting the functional group present in the compound if necessary (sc
heme5).
【0193】[0193]
【化47】 Embedded image
【0194】(式中、X18、X19は同時に臭素原子を表
すか、または、一方が塩素原子を表し、一方が水素原子
を表し、R2 は前記と同義を表す) b)R5 が特に、アミノ基、アニリノ基、フェノキシ
基、アルコキシ基、アルカノイルオキシ基(いずれも置
換されていてもよい)を表す場合。 上記a)の方法の他にもscheme6に示す方法でも
製造できる。すなわち対応するケトンにエチニルマグネ
シウムハライド、リチウムトリメチルシリルアセチリ
ド、あるいはこれらをCeCl3 と反応させて調製でき
るエチニルセリウム化合物等のエチニル化剤をテトラヒ
ドロフラン、ジエチルエーテル、トルエン、ヘキサン等
の溶媒あるいはそれらの混合溶媒中、−100℃〜+1
00℃で5分間〜48時間反応させることにより製造で
きるアルコール体IIIaを酸無水物、酸クロリド等のアシ
ル化剤をジクロロメタン、トルエン、アセトニトリル等
の適当な溶媒中、ピリジン、トリエチルアミン等の塩基
存在下もしくはこれら塩基を溶媒兼用で用い0℃〜+1
50℃で5分間〜48時間反応させることによりIIIb
(X20=アルカノイルオキシ基を表す、R18は水素原子
またはトリアルキルシリル基を表す)を製造できる。ま
たケトンにエチニル化剤を反応させ、系中に発生するア
ルコキシドを酸無水物、酸クロリド等のアシル化剤で直
接補足する方法によってもIIIb(X20、R18は既に定義
した通り)を製造できる。IIIbのうちR18がトリメチル
シリル等のシリル基を表す化合物に塩酸等の酸やテトラ
ブチルアンモニウムフロリド、フッ化セシウム等の脱シ
リル化剤を水、メタノール、テトラヒドロフラン等適当
な溶媒中、0℃〜+150℃で5分間〜48時間作用さ
せることで、IIIb(R18=水素原子)に変換できる。[0194] (wherein, either X 18, X 19 represents a simultaneous bromine atom, or one represents a chlorine atom, one represents a hydrogen atom, R 2 represents the same meaning) b) R 5 is In particular, when it represents an amino group, an anilino group, a phenoxy group, an alkoxy group, or an alkanoyloxy group (all may be substituted). In addition to the above method a), it can also be manufactured by the method shown in scheme 6. That is, an ethynylating agent such as ethynylmagnesium halide, lithium trimethylsilylacetylide, or an ethynylcerium compound that can be prepared by reacting these with CeCl 3 in a corresponding ketone in a solvent such as tetrahydrofuran, diethyl ether, toluene, hexane, or a mixed solvent thereof. -100 ° C to +1
An acylating agent such as an acid anhydride or an acid chloride can be prepared by reacting an alcohol IIIa, which can be produced by reacting at 00 ° C. for 5 minutes to 48 hours, in a suitable solvent such as dichloromethane, toluene or acetonitrile in the presence of a base such as pyridine or triethylamine. Alternatively, these bases are used also as a solvent, and
By reacting at 50 ° C. for 5 minutes to 48 hours, IIIb
(X 20 = alkanoyloxy group, R 18 represents a hydrogen atom or a trialkylsilyl group). IIIb (X 20 and R 18 are as defined above) can also be produced by reacting an ethynylating agent with a ketone and directly capturing the alkoxide generated in the system with an acylating agent such as an acid anhydride or an acid chloride. it can. In IIIb, a compound in which R 18 represents a silyl group such as trimethylsilyl is added with an acid such as hydrochloric acid or a desilylating agent such as tetrabutylammonium fluoride or cesium fluoride in a suitable solvent such as water, methanol or tetrahydrofuran at 0 ° C. By acting at + 150 ° C. for 5 minutes to 48 hours, it can be converted to IIIb (R 18 = hydrogen atom).
【0195】化合物IIIb(X20=アルカノイルオキシ基
を表し、R18は水素原子を表す)をテトラヒドロフラ
ン、ジエチルエーテル、ジクロロメタン、トルエン、ア
セトニトリル等の溶媒中、触媒量のCuCl、CuIあ
るいは銅粉等の銅化合物の存在下、対応するアミン、ア
ニリン、もしくはフェノール(いずれも置換されていて
よい)0℃〜+150℃で5分間〜48時間反応させる
ことによりIII を製造できる。Compound IIIb (X 20 = alkanoyloxy group, R 18 represents a hydrogen atom) is reacted in a solvent such as tetrahydrofuran, diethyl ether, dichloromethane, toluene or acetonitrile with a catalytic amount of CuCl, CuI or copper powder. III can be prepared by reacting at 0 ° C. to + 150 ° C. for 5 minutes to 48 hours at 0 ° C. to + 150 ° C., in the presence of a copper compound, with the corresponding amine, aniline or phenol (which may be substituted).
【0196】[0196]
【化48】 Embedded image
【0197】(式中、R18は水素原子、トリアルキルシ
リル等を表し、R3 、R4 、R5 、X20は前記と同義を
表す) c)R2 が置換フェニル基を表す場合(scheme
7) 上記a)の方法の他、対応するハロベンゼンを例えばn
−BuLi,Mg等を作用させ調製できるアリールリチ
ウムやアリールマグネシウムハライドの有機金属化合物
に例えばN,N′−ジメチルホルムアミド等を反応させ
る方法でアルデヒドXが製造でき、Xを上記a)の方法
に準じることによりIII を製造できる。また例えば、ハ
ロベンゼンとトリメチルシリルアセチレン、3−メチル
−1−ブチン−3−オールもしくはそれらの金属アセチ
リドをPd、Cu等の金属触媒存在下カップリング反応
を行い、脱シリル化の条件、もしくはブタノール等適当
な溶媒中、水酸化カリウム等の塩基を50℃〜+200
℃で5分間〜48時間反応させ、末端アセチレンを精製
させる方法でもIII を製造できる。(Wherein, R 18 represents a hydrogen atom, trialkylsilyl, etc., and R 3 , R 4 , R 5 , and X 20 have the same meanings as described above.) C) When R 2 represents a substituted phenyl group ( scheme
7) In addition to the above method a), the corresponding halobenzene is, for example, n
Aldehyde X can be produced by reacting an organometallic compound of aryllithium or arylmagnesium halide which can be prepared by the action of -BuLi, Mg or the like with, for example, N, N'-dimethylformamide or the like, wherein X is in accordance with the above method a). Thus, III can be produced. Further, for example, a coupling reaction is performed between halobenzene and trimethylsilylacetylene, 3-methyl-1-butyn-3-ol or a metal acetylide thereof in the presence of a metal catalyst such as Pd, Cu, or the like. In a suitable solvent, a base such as potassium hydroxide is added at 50 ° C to + 200 ° C.
III can also be produced by purifying terminal acetylene by reacting at 5 ° C. for 5 minutes to 48 hours.
【0198】[0198]
【化49】 Embedded image
【0199】2)上記一般式(I)で表される化合物の
うち、R1 がフッ素原子、ヨウ素原子;ヒドロキシル
基;無置換のフェニル基;C1 〜C5 のアルキルもしく
はC1〜C5 のアルカノイル基で置換されたアミノ基;
カルボキシル基もしくはC1 〜C5 のアルコキシカルボ
ニル基で置換されていてもよいC1 〜C5 アルコキシ基
を表す化合物の製造法 a)R1 がヒドロキシル基;無置換のフェニル基;C1
〜C5 のアルキル基で置換されたアミノ基;または無置
換のC1 〜C5 アルコキシ基を表す場合2) Among the compounds represented by the above general formula (I), R 1 is a fluorine atom, an iodine atom; a hydroxyl group; an unsubstituted phenyl group; a C 1 -C 5 alkyl or a C 1 -C 5 An amino group substituted with an alkanoyl group;
Process a) R 1 is a hydroxyl group of a carboxyl group or a C 1 -C 5 alkoxycarbonyl group compound representing the optionally substituted C 1 -C 5 alkoxy group; an unsubstituted phenyl group; C 1
When referring to C 1 -C 5 alkoxy group or unsubstituted; amino group substituted with an alkyl group -C 5
【0200】上記製造法1)で製造できる化合物I(R
1a=ClまたはBr)を水、メタノール、エタノール、
ジメチルホルムアミド等の極性溶媒中、トルエン等の芳
香族炭化水素系溶媒中、トリエチルアミン、ジアザビシ
クロウンデセン等の含窒素塩基、水酸化ナトリウム、水
素化ナトリウム等の塩基存在下あるいは非存在下、水ま
たはC1 〜C5 のアルコール、あるいはこれの金属塩、
または対応するHNR1eR1f(式中、R1e、R1fは水素
原子、フェニル基、またはC1 〜C5 のアルキル基を表
す)を0℃〜+150℃の温度で5分間〜48時間反応
させる方法で製造できる。この際、例えばn−Bu4 N
+ Br- 等の相関移動触媒を共存させてもよい。また、
ここでアンモニア水を反応させれば、化合物I(R1a=
NH2 )も製造できる。The compound I (R) which can be produced by the above production method 1)
1a = Cl or Br) in water, methanol, ethanol,
In a polar solvent such as dimethylformamide, in an aromatic hydrocarbon solvent such as toluene, in the presence or absence of a nitrogen-containing base such as triethylamine or diazabicycloundecene, or a base such as sodium hydroxide or sodium hydride, water or alcohols C 1 -C 5 or which metal salts,
Or a corresponding HNR 1e R 1f (wherein R 1e and R 1f represent a hydrogen atom, a phenyl group or a C 1 -C 5 alkyl group) at a temperature of 0 ° C. to + 150 ° C. for 5 minutes to 48 hours It can be manufactured by the method of causing. At this time, for example, n-Bu 4 N
+ Br - a phase transfer catalyst may coexist, such as. Also,
Here, by reacting aqueous ammonia, compound I (R 1a =
NH 2 ) can also be produced.
【0201】b)R1 がC1 〜C5 のアルカノイル基で
置換されたアミノ基の場合 上記製造法1)もしくは2)−a)で製造できる化合物
I(R1a=NH2 )を水、テトラヒドロフラン、ジメチ
ルホルムアミド等の極性溶媒中、トルエン等の芳香族炭
化水素系溶媒中、トリエチルアミン、ジメチルアミノピ
リジン等の含窒素塩基、あるいは水酸化ナトリウム等の
塩基存在下、対応する酸無水物(R1gCO)2 O、もし
くは酸クロリド(R1gCOCl)(いずれも式中、R1g
はC1 〜C5 のアルキル基を表す)を0℃〜+150℃
の温度で5分間〜48時間反応させる方法で製造でき
る。B) When R 1 is an amino group substituted with a C 1 -C 5 alkanoyl group: Compound I (R 1a = NH 2 ) which can be produced by the above-mentioned production method 1) or 2) -a) is converted to water, In a polar solvent such as tetrahydrofuran or dimethylformamide, in an aromatic hydrocarbon solvent such as toluene, in the presence of a nitrogen-containing base such as triethylamine or dimethylaminopyridine, or a base such as sodium hydroxide, the corresponding acid anhydride (R 1g CO) 2 O or acid chloride (R 1g COCl) (in each formula, R 1g
Represents a C 1 -C 5 alkyl group) at 0 ° C. to + 150 ° C.
At a temperature of 5 minutes to 48 hours.
【0202】c)R1 がフッ素原子、ヨウ素原子を表す
場合 上記製造法1)で製造できる化合物I(R1a=Clまた
はBr)をジメチルホルムアミド、ジメチルスルホキシ
ド等の極性溶媒中、あるいはトルエン等の芳香族炭化水
素系溶媒中、対応するフッ化カリ、フッ化ナトリウム等
のフッソ化剤、またはヨウ化カリ等のヨウ素化剤を0℃
〜+150℃の温度で5分間〜48時間反応させる方法
で製造できる。また化合物I(R1a=NH2 )を水、エ
タノール等の極性溶媒中、または無溶媒で亜硝酸ナトリ
ウム/塩酸もしくは酢酸等のジアゾ化反応の条件下、ヨ
ウ化カリウム等のヨウ素化剤を作用させることにより、
化合物I(R1a=I)を、ホウフッ化水素酸(HB
F4 )水溶液を作用させる事により、化合物I(R1a=
F)が製造できる。後者の場合、亜硝酸ナトリウム/H
BF4 水溶液を用いてもよい。C) When R 1 represents a fluorine atom or an iodine atom The compound I (R 1a = Cl or Br) which can be produced by the above production method 1) is dissolved in a polar solvent such as dimethylformamide or dimethylsulfoxide, or a compound such as toluene. In an aromatic hydrocarbon solvent, a corresponding fluorinating agent such as potassium fluoride or sodium fluoride or an iodinating agent such as potassium iodide is added at 0 ° C.
It can be produced by a method of reacting at a temperature of ~ 150C for 5 minutes to 48 hours. Compound I (R 1a = NH 2 ) is reacted with a iodinating agent such as potassium iodide in a polar solvent such as water or ethanol, or without solvent under the conditions of a diazotization reaction such as sodium nitrite / hydrochloric acid or acetic acid. By letting
Compound I (R 1a = I) was converted to borofluoric acid (HB
By acting an aqueous solution of F 4 ), compound I (R 1a =
F) can be manufactured. In the latter case, sodium nitrite / H
A BF 4 aqueous solution may be used.
【0203】d)R1 がカルボキシル基もしくはC1 〜
C5 のアルコキシカルボニル基で置換されていてもよい
C1 〜C5 アルコキシ基を表す場合 上記製造法1)で製造できる化合物I(R1a=Clまた
はBr)をジメチルホルムアミド、ジメチルスルホキシ
ド等の極性溶媒中、あるいはトルエン等の芳香族炭化水
素系溶媒中、対応するHO−(CH2 )W −COORw
(式中、wは1〜5の整数を表し、Rwは水素原子もし
くはC1 〜C5 のアルキル基を表す)と水素化ナトリウ
ム、水素化カリウム等、あるいはブチルリチウム等から
調製されるアルコキシドと反応させることにより製造で
きる。RwがC1 〜C5 のアルキル基を表すものはさら
に、メタノール、水、ジクロロメタン等の適当な溶媒
中、水酸化ナトリウム等の塩基または塩酸、トリフルオ
ロ酢酸等の酸を作用させ加水分解することによっても、
R1 がカルボン酸で置換されているC1 〜C5 アルコキ
シ基を表すものを製造できる。D) R 1 is a carboxyl group or C 1-
Compound I (R 1a = Cl or Br) in dimethyl formamide case can be produced by the above production method 1) representing the alkoxycarbonyl-substituted C 1 optionally -C 5 alkoxy group group of C 5, polarity such as dimethyl sulfoxide In a solvent or an aromatic hydrocarbon solvent such as toluene, the corresponding HO— (CH 2 ) W —COORw
(Wherein, w represents an integer of 1 to 5, Rw represents a hydrogen atom or a C 1 to C 5 alkyl group) and an alkoxide prepared from sodium hydride, potassium hydride or the like, or butyllithium or the like. It can be produced by reacting. Those in which Rw represents a C 1 -C 5 alkyl group can be further hydrolyzed in a suitable solvent such as methanol, water or dichloromethane by the action of a base such as sodium hydroxide or an acid such as hydrochloric acid or trifluoroacetic acid. By
Those wherein R 1 represents a C 1 -C 5 alkoxy group substituted with a carboxylic acid can be prepared.
【0204】3)上記一般式(I)で表される化合物の
うち分子内にエステル、アミド、スルホンアミド等を有
する化合物の製造法 上記製造法1)で示したようにIII (もしくはIII ′)
がエステル、アミド、スルホンアミド等を有したもので
カップリング反応を行う方法のほか、例えば対応するア
ルコール、カルボン酸、アミンを有するIII を製造法
1)の方法に従いカップリングの後、エステル化、アミ
ド化等を行うことにより目的物を製造することもでき
る。3) Method for producing compounds having ester, amide, sulfonamide and the like in the molecule among the compounds represented by the above general formula (I) As shown in the above production method 1), III (or III ′)
Is a compound having an ester, an amide, a sulfonamide or the like, and in addition to the method of performing a coupling reaction, for example, III having a corresponding alcohol, carboxylic acid, or amine is coupled according to the method of production method 1), followed by esterification, The target product can also be produced by amidation or the like.
【0205】本発明のエチニルピリミジン誘導体は、チ
ロシンキナーゼ阻害活性及び癌細胞増殖抑制作用を有
し、制癌剤、免疫抑制剤、血小板凝集阻害剤、動脈硬化
治療薬、抗炎症剤または癌細胞増殖抑制薬として使用す
ることが可能である。上記一般式(I)で示される本発
明化合物を上記の目的で用いるには、通常、全身的また
は局所的に、経口または非経口の形で投与される。投与
量は、年令、体重、症状、治療効果、投与方法、処理時
間等により異なる。通常、成人一人あたり、一回につ
き、1mgから1.0gの範囲で、一日一回から数回経
口投与されるか、または成人一人あたり、一回につき1
mgから5gの範囲で、一日一回から数回非経口投与さ
れるか、または、一日1時間から24時間の範囲で静脈
内に持続投与される。もちろん前記したように、投与量
は種々の条件により変動するので、上記投与量より少な
い量で十分な場合もあるし、また範囲を越えて投与の必
要な場合もある。The ethynylpyrimidine derivatives of the present invention have a tyrosine kinase inhibitory activity and a cancer cell growth inhibitory effect, and are used as anticancer agents, immunosuppressants, platelet aggregation inhibitors, therapeutic agents for arteriosclerosis, anti-inflammatory agents or cancer cell growth inhibitors. It can be used as In order to use the compound of the present invention represented by the above general formula (I) for the above purpose, it is usually administered systemically or locally in an oral or parenteral form. The dose varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, and the like. It is usually administered orally, once to several times daily, in the range of 1 mg to 1.0 g per adult per dose, or 1 to 4 times per adult per dose.
It is administered parenterally once to several times a day in the range of mg to 5 g, or continuously intravenously in the range of 1 hour to 24 hours a day. Of course, as described above, since the dose varies depending on various conditions, a dose smaller than the above-mentioned dose may be sufficient, or administration outside the range may be necessary.
【0206】本発明化合物を投与する際には、経口投与
のための固体組成物、液体組成物およびその他の組成
物、非経口投与のための注射剤、外用剤、坐剤等として
用いられる。経口投与のための固体組成物には、錠剤、
丸剤、カプセル剤、散剤、顆粒剤等が含まれる。カプセ
ル剤にはハードカプセルおよびソフトカプセルが含まれ
る。このような固体組成物においては、ひとつまたはそ
れ以上の活性物質が、少なくともひとつの不活性な希釈
剤、例えばラクトース、マンニトール、グルコース、ヒ
ドロキシプロピルセルロース、微結晶セルロース、デン
プン、ポリビニルピロリドン、メタケイ酸アルミン酸マ
グネシウムと混合される。組成物は、常法に従って、不
活性な希釈剤以外の添加物、例えばステアリン酸マグネ
シウムのような潤滑剤、繊維素グルコール酸カルシウム
のような崩壊剤、ラクトースのような安定化剤、グルタ
ミン酸またはアスパラギン酸のような溶解補助剤を含有
していてもよい。錠剤または丸剤は必要により白糖、ゼ
ラチン、ヒドロキシプロピルセルロース、ヒドロキシプ
ロピルメチルセルロースフタレートなどの胃溶性あるい
は腸溶性物質のフィルムで被膜してもよいし、また2以
上の層で被膜してもよい。さらにゼラチンのような吸収
されうる物質のカプセルも包含される。When the compound of the present invention is administered, it is used as a solid composition, liquid composition and other compositions for oral administration, injection, external preparation, suppository and the like for parenteral administration. Solid compositions for oral administration include tablets,
Pills, capsules, powders, granules and the like are included. Capsules include hard capsules and soft capsules. In such a solid composition, the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminum metasilicate. It is mixed with magnesium acid. The composition may contain, in a conventional manner, additives other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium cellulose glycolate, a stabilizer such as lactose, glutamic acid or asparagine. A solubilizing agent such as an acid may be contained. The tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc., if necessary, or with two or more layers. Also included are capsules of absorbable materials such as gelatin.
【0207】経口投与のための液体組成物は、薬剤的に
許容される溶液剤、乳濁剤、懸濁剤、シロップ剤、エリ
キシル剤等を含み、一般的に用いられる不活性な希釈剤
(精製水、エタノール)を含んでいてもよい。この組成
物は不活性な希釈剤以外に湿潤剤、懸濁剤のような補助
剤、甘味剤、風味剤、芳香剤、防腐剤を含有していても
よい。経口投与のためのその他の組成物としては、ひと
つまたはそれ以上の活性物質を含み、それ自体公知の方
法により処方されるスプレー剤が含まれる。この組成物
は不活性な希釈剤以外に亜硫酸水素ナトリウムのような
安定剤と等張性を与えるような緩衝剤、例えば塩化ナト
リウム、クエン酸ナトリウムあるいはクエン酸を含有し
てもよい。スプレー剤の製造方法は、例えば米国特許第
2868691号および同第3095355号明細書に
詳しく記載されている。Liquid compositions for oral administration include pharmaceutically acceptable solutions, emulsions, suspensions, syrups, elixirs and the like, and commonly used inert diluents ( Purified water, ethanol). The composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives. Other compositions for oral administration include sprays which contain one or more active substances and are formulated in a manner known per se. The composition may contain, in addition to the inert diluent, buffers such as sodium chloride, sodium citrate, or citric acid which provide isotonicity with stabilizers such as sodium bisulfite. The method of producing the spray is described in detail in, for example, U.S. Pat. Nos. 2,868,691 and 3,095,355.
【0208】本発明による非経口投与のための注射剤と
しては、無菌の水性または非水性の溶液剤、懸濁剤、乳
濁剤を包含する。水性の溶液剤、懸濁剤としては、例え
ば、注射用蒸留水および生理食塩水が含まれる。非水溶
性の溶液剤、懸濁剤としては、例えば、プロピレングリ
コール、ポリエチレングリコール、オリーブ油、エタノ
ール、ポリソルベート80等がある。このような組成物
は、さらに防腐剤、湿潤剤、乳化剤、分散剤、安定化剤
(例えば、ラクトース)、溶解補助剤(例えば、グルタ
ミン酸、アスパラギン酸)のような補助剤を含んでもよ
い。これらは例えばバクテリア保留フィルターを通す濾
過、殺菌剤の配合または照射によって無菌化される。こ
れらはまた無菌の固体組成物を製造し、例えば凍結乾燥
品の使用前に無菌化水または無菌の注射用溶媒に溶解し
て使用することもできる。非経口投与のためのその他の
組成物としては、ひとつまたはそれ以上の活性物質を含
み、常法により処方される外用液剤、軟コウ、塗布剤、
坐剤、およびペッサリー等が含まれる。Injections for parenteral administration according to the present invention include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Examples of the water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, olive oil, ethanol, polysorbate 80 and the like. Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, stabilizing (eg, lactose) and solubilizing agents (eg, glutamic acid, aspartic acid). These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. They can also be used in the production of a sterile solid composition, for example, dissolved in sterile water or a sterile solvent for injection before use of the freeze-dried product. Other compositions for parenteral administration include one or more active substances, topical solutions, molasses, liniments, formulated in a conventional manner.
Suppositories, pessaries and the like.
【0209】[0209]
【実施例】以下、本発明につき合成例および実施例を挙
げて具体的に説明するが、その要旨を越えないかぎり以
下に限定されるものではない。なお合成例および実施例
中、反応は特に記載がないかぎり窒素雰囲気下で行なっ
た。実施例、合成例中、溶媒、試薬、置換基等は次のよ
うに略記した。ジエチルエーテル(エーテル、またはE
t2 O);テトラヒドロフラン(THF);n−ヘキサ
ン(Hexまたはヘキサン);酢酸エチル(EtOA
c);ジメチルホルムアミド(DMF);ジメチルスル
ホキシド(DMSO);Hexamethylphos
phoramide(HMPA);Dimethyla
minopyridine(DMAP);1,8−Di
azabicyclo〔5,4,0〕undec−7−
ene;1,3−Dicyclohexylcarbo
diimide(DCC);Diisobutylal
uminum hydride(DIBAL);t−B
utoxycarbonyl(Boc);アセチル基
(Ac)と表記した。 合成例1The present invention will be described below in more detail with reference to Synthesis Examples and Examples. However, the present invention is not limited thereto without departing from the gist thereof. In the Synthesis Examples and Examples, the reactions were performed under a nitrogen atmosphere unless otherwise specified. In Examples and Synthesis Examples, solvents, reagents, substituents and the like are abbreviated as follows. Diethyl ether (ether or E
t 2 O); tetrahydrofuran (THF); n-hexane (Hex or hexane); ethyl acetate (EtOA
c); dimethylformamide (DMF); dimethylsulfoxide (DMSO); Hexamethylphos
phoramide (HMPA); Dimethyla
minopyridine (DMAP); 1,8-Di
azacyclo [5,4,0] undec-7-
ene; 1,3-Dicyclohexylcarbo
diimide (DCC); Diisobutyral
uminhydride (DIBAL); tB
Utoxycarbonyl (Boc); acetyl group (Ac). Synthesis Example 1
【0210】[0210]
【化50】 Embedded image
【0211】PhC(S)NH2 (5.0g、36.4
mmol)とアントラニル酸(5.0g、36.4mm
ol)を120℃で2時間、160℃で30分間加熱撹
拌した。シクロヘキサノン(15ml)を反応混合物に
加え、130℃で5分間撹拌した。室温まで冷却後、生
成物4aを濾取した(4.0g、49%)。4aに五塩
化リン(5.3g、25.2mmol)およびオキシ塩
化リン(4.8ml、51.5mmol)を加え、13
0℃で2時間撹拌した。減圧下、過剰のオキシ塩化リン
および低沸点物を除去し、残渣に氷水を少しずつ加え
た。生成物をエタノール(100ml×2)で抽出し、
炭酸水素ナトリウム飽和水溶液(50ml×2)で洗浄
し、エーテル抽出液を減圧下濃縮した。残渣をヘキサン
(50ml)に懸濁させ、加熱しながら撹拌した(以
下、この操作を「ヘキサンで懸洗する」と記す)。懸濁
液を室温まで冷却後、沈殿物を濾取し、目的物である4
−クロロ−2−フェニルキナゾリン(2a)(3.18
g、72%)を得た。 2a:1H NMR(250MHz,CDCl3 )δpp
m:7.53(m,3H),7.66(dt,J=0.
7,7.6Hz,1H),7.94(dt,J=1.
2,7.6Hz,1H),8.10(d,J=1.2,
8.2Hz,1H),8.58(m,2H). 合成例2 アミノアセチレン3aPhC (S) NH 2 (5.0 g, 36.4)
mmol) and anthranilic acid (5.0 g, 36.4 mm)
ol) was heated and stirred at 120 ° C. for 2 hours and at 160 ° C. for 30 minutes. Cyclohexanone (15 ml) was added to the reaction mixture and stirred at 130 ° C. for 5 minutes. After cooling to room temperature, the product 4a was collected by filtration (4.0 g, 49%). Phosphorus pentachloride (5.3 g, 25.2 mmol) and phosphorus oxychloride (4.8 ml, 51.5 mmol) were added to 4a, and 13
Stirred at 0 ° C. for 2 hours. Excess phosphorous oxychloride and low-boiling substances were removed under reduced pressure, and ice water was added little by little to the residue. The product was extracted with ethanol (100 ml × 2),
The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate (50 ml × 2), and the ether extract was concentrated under reduced pressure. The residue was suspended in hexane (50 ml) and stirred while heating (hereinafter, this operation is referred to as "washing with hexane"). After the suspension was cooled to room temperature, the precipitate was collected by filtration, and the target compound, 4
-Chloro-2-phenylquinazoline (2a) (3.18
g, 72%). 2a: 1 H NMR (250 MHz, CDCl 3 ) δpp
m: 7.53 (m, 3H), 7.66 (dt, J = 0.
7, 7.6 Hz, 1H), 7.94 (dt, J = 1.
2,7.6 Hz, 1H), 8.10 (d, J = 1.2,
8.2 Hz, 1H), 8.58 (m, 2H). Synthesis Example 2 Aminoacetylene 3a
【0212】[0212]
【化51】 Embedded image
【0213】G.F.Hennionらの方法(J.A
m.Chem.Soc.,1960,82,4908)
に従い製造した。 3a: 1H NMR(300MHz,CDCl3 )δp
pm:1.08(t,J=7.2Hz,6H),1.4
0(s,6H),2.21(s,1H),2.66
(q,J=7.2Hz,4H). 合成例3、4 合成例1と同様な方法でクロロキナゾリン2b、2cを
得た。G. F. The method of Hennion et al. (JA)
m. Chem. Soc. , 1960, 82, 4908)
Manufactured according to 3a: 1 H NMR (300 MHz, CDCl 3 ) δp
pm: 1.08 (t, J = 7.2 Hz, 6H), 1.4
0 (s, 6H), 2.21 (s, 1H), 2.66
(Q, J = 7.2 Hz, 4H). Synthesis Examples 3 and 4 Chloroquinazolines 2b and 2c were obtained in the same manner as in Synthesis Example 1.
【0214】[0214]
【表130】 [Table 130]
【0215】実施例1 エチニルキナゾリン1aExample 1 Ethinylquinazoline 1a
【0216】[0216]
【化52】 Embedded image
【0217】合成例2で製造したアミノアセチレン3a
(500mg、3.59mmol)のTHF溶液(10
ml)に室温でEtMgBr(3.55ml、3.55
mmol、1.0M THF溶液)を加え40分間還流
し、エチニルグリニヤを調製した。一方、Pd(PPh
3 )2 Cl2 (21mg、0.03mmol)とPPh
3 (31mg、1.2mmol)のTHF溶液(5m
l)を室温で40分間撹拌し、この溶液に2a(480
mg、2.00mmol)と上記エチニルグリニヤを室
温で加え、3時間撹拌した。反応液を冷却後、水を加え
減圧下濃縮した。残渣に炭酸水素ナトリウム飽和水溶液
(20ml)とEtOAc(30ml)を加え、有機層
を分離した。有機層をNa2 SO4 上で乾燥後、減圧下
溶媒を留去し得られる残渣をシリカゲルカラムクロマト
にて精製し、カップリング生成物1a(700mg、定
量的)を得た。 1a:1H NMR(300MHz,CDCl3 )δpp
m:1.19(t,J=7.2Hz,6H),1.64
(s,6H),2.88(q,J=7.2Hz,4
H),7.40−7.60(m,3H),7.61
(m,1H),7.88(m,1H),8.06(m,
1H),8.27(m,1H),8.60(m,2
H). 実施例2Aminoacetylene 3a produced in Synthesis Example 2
(500 mg, 3.59 mmol) in a THF solution (10
ml) at room temperature in EtMgBr (3.55 ml, 3.55 ml).
(mmol, 1.0 M THF solution) and refluxed for 40 minutes to prepare ethynyl Grignard. On the other hand, Pd (PPh
3 ) 2 Cl 2 (21 mg, 0.03 mmol) and PPh
3 (31 mg, 1.2 mmol) in THF (5 m
l) was stirred at room temperature for 40 minutes and 2a (480
mg, 2.00 mmol) and the above-mentioned ethynyl Grignard were added at room temperature and stirred for 3 hours. After cooling the reaction solution, water was added and the mixture was concentrated under reduced pressure. A saturated aqueous solution of sodium hydrogen carbonate (20 ml) and EtOAc (30 ml) were added to the residue, and the organic layer was separated. After drying the organic layer over Na 2 SO 4 , the solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography to obtain a coupling product 1a (700 mg, quantitative). 1a: 1 H NMR (300 MHz, CDCl 3 ) δpp
m: 1.19 (t, J = 7.2 Hz, 6H), 1.64
(S, 6H), 2.88 (q, J = 7.2 Hz, 4
H), 7.40-7.60 (m, 3H), 7.61
(M, 1H), 7.88 (m, 1H), 8.06 (m, 1H)
1H), 8.27 (m, 1H), 8.60 (m, 2
H). Example 2
【0218】[0218]
【化53】 Embedded image
【0219】実施例1で得られた1a(140mg、
0.4mmol)をEt2 O(2ml)に溶解し、氷浴
上撹拌しながら4N HCl/EtOAc溶液(0.1
ml、0.4mmol)をゆっくり滴下した。室温まで
昇温後、生成物を濾取、乾燥し、1aの塩酸塩(1a・
HCl)を白色粉末結晶(70mg、46%)として得
た。 1a・HCl:1H NMR(300MHz,CDC
l3 )δppm:1.66(m,6H),2.18
(m,6H),3.43(br s,2H),3.66
(br s,2H),7.50−7.60(m,3
H),7.69(m,1H),7.95(m,1H),
8.10−8.25(m,2H),8.60(m,2
H),12.6(br s,1H); IR(KBr)νcm-1;3449,2986,241
5,2236,1613,1562,1534,148
7,1022,768,706; mp 165−168℃The 1a obtained in Example 1 (140 mg,
0.4 mmol) was dissolved in Et 2 O (2 ml) and stirred in an ice bath with a 4N HCl / EtOAc solution (0.1 ml).
ml, 0.4 mmol) was slowly added dropwise. After warming to room temperature, the product was collected by filtration, dried, and hydrochloride of 1a (1a.
HCl) as white powder crystals (70 mg, 46%). 1a · HCl: 1 H NMR (300 MHz, CDC
l 3 ) δ ppm: 1.66 (m, 6H), 2.18
(M, 6H), 3.43 (brs, 2H), 3.66.
(Br s, 2H), 7.50-7.60 (m, 3
H), 7.69 (m, 1H), 7.95 (m, 1H),
8.10-8.25 (m, 2H), 8.60 (m, 2
H), 12.6 (brs, 1H); IR (KBr) νcm -1 ; 3449, 2986, 241
5,2236,1613,1562,1534,148
7,1022,768,706; mp 165-168C
【0220】実施例3〜6 合成例1〜4で製造したクロロキナゾリン2a〜2cと
アミノアセチレン3a、3b(3bの製造法は合成例8
に記す)を用い実施例1、2と同様な操作を行い目的化
合物を製造した。構造、収率および物性値を次に示す。Examples 3 to 6 The chloroquinazolines 2a to 2c prepared in Synthesis Examples 1 to 4 and the aminoacetylenes 3a and 3b (the method for preparing 3b is described in Synthesis Example 8).
And the same procedures as in Examples 1 and 2 were used to produce the target compound. The structure, yield and physical properties are shown below.
【0221】[0221]
【表131】 [Table 131]
【0222】[0222]
【表132】 [Table 132]
【0223】合成例5 4−クロロキナゾリン(2d) 1)Synthesis Example 5 4-Chloroquinazoline (2d) 1)
【0224】[0224]
【化54】 Embedded image
【0225】アントラニル酸(11.45g、83.5
mmol)およびホルムアミド(8.5ml)を135
℃で2時間撹拌し、冷却後、沈殿物を濾取した。アセト
ンで懸洗後、濾取して目的物であるキナゾリン−4−オ
ン(4d)(4.06g、33%)を得た。 4d:1H NMR(DMSO−d,250MHz)δp
pm:7.50(t,J=7.5Hz,1H),7.6
5(d,J=8.1Hz,1H),7.80(m,1
H),8.09(s,1H),8.10(d,J=8.
2Hz,1H),12.25(br s,1H). 2)Anthranilic acid (11.45 g, 83.5
mmol) and formamide (8.5 ml) in 135
The mixture was stirred at 2 ° C. for 2 hours, cooled, and the precipitate was collected by filtration. After washing with acetone, the precipitate was collected by filtration to obtain the desired product, quinazolin-4-one (4d) (4.06 g, 33%). 4d: 1 H NMR (DMSO-d, 250 MHz) δp
pm: 7.50 (t, J = 7.5 Hz, 1H), 7.6
5 (d, J = 8.1 Hz, 1H), 7.80 (m, 1
H), 8.09 (s, 1H), 8.10 (d, J = 8.
2Hz, 1H), 12.25 (brs, 1H). 2)
【0226】[0226]
【化55】 Embedded image
【0227】上記キナゾリン−4−オン(4d)(4.
15g、28.4mmol)にPCl5 (5.9g、2
8.4mmol)、POCl3 (30ml)を加え、2
時間還流した。減圧下、過剰のPOCl3 および低沸点
物を留去後、氷浴上撹拌しながらCHCl3 (50m
l)および飽和NaHCO3 水溶液(50ml)を加え
た。CHCl3 層を乾燥(Na2 CO3 )、濃縮し、ヘ
キサンで懸洗後、沈殿物を濾取し、クロロキナゾリン
(2d)(4.01g、86%)を得た。 2c:1H NMR(CDCl3 ,300MHz)δpp
m:7.73(m,1H),7.96(m,1H),
8.07(d,J=8.4Hz,1H),8.27
(d,J=8.4Hz,1H),9.05(s,1
H). 合成例6The quinazolin-4-one (4d) (4.
15 g (28.4 mmol) in PCl 5 (5.9 g, 2
8.4 mmol) and POCl 3 (30 ml).
Refluxed for hours. Under reduced pressure, excess POCl 3 and low-boiling substances were distilled off, and then CHCl 3 (50 m
l) and saturated aqueous NaHCO 3 (50 ml) were added. The CHCl 3 layer was dried (Na 2 CO 3 ), concentrated, washed with hexane, and the precipitate was collected by filtration to obtain chloroquinazoline (2d) (4.01 g, 86%). 2c: 1 H NMR (CDCl 3 , 300 MHz) δpp
m: 7.73 (m, 1H), 7.96 (m, 1H),
8.07 (d, J = 8.4 Hz, 1H), 8.27
(D, J = 8.4 Hz, 1H), 9.05 (s, 1
H). Synthesis Example 6
【0228】[0228]
【化56】 Embedded image
【0229】Johannsenらが報告している方法
(Chimica Scripta,1986,26,
347−351)に従い製造した5,6−Dimeth
ylfuro〔2,3−d〕pyrimidin−4
(3H)−one(1.08g、6.62mmol)に
POCl3 (4ml)を加え還流させた。減圧下、過剰
のPOCl3 と低沸点物を留去し、残渣をCHCl
3 (15ml)に溶解した。氷浴上撹拌しながら、液相
がアルカリ性になるまで28%アンモニア水を加えた。
CHCl3 (20ml×2)で抽出し、乾燥(Na2 S
O4 )、濃縮し、目的物である2e(960mg、79
%)を淡黄色固体として得た。 2e:1H NMR(CDCl3 ,300MHz)δpp
m:2.34(s,3H),2.45(s,3H),
8.63(s,1H). 合成例7 アセテート5The method reported by Johannsen et al. (Chimica Scripta, 1986, 26,
347-351)
ylfuro [2,3-d] pyrimidin-4
POCl 3 (4 ml) was added to (3H) -one (1.08 g, 6.62 mmol) and the mixture was refluxed. Under reduced pressure, excess POCl 3 and low boilers were distilled off, and the residue was washed with CHCl 3.
3 (15 ml). While stirring on an ice bath, 28% aqueous ammonia was added until the liquid phase became alkaline.
Extract with CHCl 3 (20 ml × 2) and dry (Na 2 S
O 4 ) and concentrated to give 2e (960 mg, 79
%) As a pale yellow solid. 2e: 1 H NMR (CDCl 3 , 300 MHz) δpp
m: 2.34 (s, 3H), 2.45 (s, 3H),
8.63 (s, 1H). Synthesis Example 7 Acetate 5
【0230】[0230]
【化57】 Embedded image
【0231】0.5MエチニルマグネシウムクロリドT
HF溶液(500ml、0.25mol)に氷冷下、フ
ェニルアセトン(30.0g、0.224mol)のT
HF溶液(20ml)を滴下した。1.5時間撹拌した
後、無水酢酸(30ml、0.316mol)を滴下し
1時間撹拌した。反応液を減圧下濃縮した後、塩化アン
モニウム飽和水溶液(500ml)を注いだ。反応混合
物をエーテル(300ml×1、100ml×1)で抽
出した後、有機層をNaHCO3 飽和水溶液、飽和食塩
水の順に洗浄し、無水硫酸ナトリウム上で乾燥後、減圧
下濃縮した。残渣をシリカゲルカラムクロマトグラフィ
ー(silica250g、ヘキサン→ヘキサン:Et
OAc=8:1)で精製しアセテート5(39.34
g、87%)を得た。0.5M ethynylmagnesium chloride T
The HF solution (500 ml, 0.25 mol) was cooled with ice and the phenylacetone (30.0 g, 0.224 mol) T
An HF solution (20 ml) was added dropwise. After stirring for 1.5 hours, acetic anhydride (30 ml, 0.316 mol) was added dropwise and stirred for 1 hour. After the reaction solution was concentrated under reduced pressure, a saturated aqueous solution of ammonium chloride (500 ml) was poured. After the reaction mixture was extracted with ether (300 ml × 1, 100 ml × 1), the organic layer was washed with a saturated aqueous solution of NaHCO 3 and saturated saline in this order, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (silica 250 g, hexane → hexane: Et)
OAc = 8: 1) and purified by acetate 5 (39.34).
g, 87%).
【0232】5:1H NMR(CDCl3 ,250MH
z)δppm:1.64(s,3H),2.38(s,
3H),2.60(s,1H),3.19(d,J=1
3.5Hz,1H),3.25(d,J=13.5H
z,1H),7.27−7.30(m,5H). 合成例8 アミノアセチレン3b5: 1 H NMR (CDCl 3 , 250 MH
z) δ ppm: 1.64 (s, 3H), 2.38 (s,
3H), 2.60 (s, 1H), 3.19 (d, J = 1
3.5 Hz, 1 H), 3.25 (d, J = 13.5 H)
z, 1H), 7.27-7.30 (m, 5H). Synthesis Example 8 Aminoacetylene 3b
【0233】[0233]
【化58】 Embedded image
【0234】合成例7で製造したアセテート5(1.3
9g、6.86mmol)、CuCl(47mg、0.
47mmol)およびEt2 NH(1.67ml、1
6.1mmol)のTHF溶液(15ml)を1時間還
流した。減圧下溶媒を留去しエーテル(10ml)を加
え3N HCl水溶液(10ml×2)で抽出した。抽
出液を氷浴上撹拌し、水層がアルカリ性になるまでK2
CO3 を少しずつ加え、生成物をCH2 Cl2 (10m
l)続いてEtOAc(20ml)で抽出した。有機層
を10%アンモニア水(15ml)で洗浄後、乾燥(N
a2 SO4 )、濃縮し、得られる残渣をシリカゲルカラ
ムクロマトグラフィー(silica 15g,ヘキサ
ン:EtOAc=9:1)で精製し、目的物3b(0.
35g、24%)を油状物質として得た。Acetate 5 produced in Synthesis Example 7 (1.3
9g, 6.86mmol), CuCl (47mg, 0.
47 mmol) and Et 2 NH (1.67 ml, 1
(6.1 mmol) in THF (15 ml) was refluxed for 1 hour. The solvent was distilled off under reduced pressure, ether (10 ml) was added, and the mixture was extracted with a 3N aqueous HCl solution (10 ml × 2). The extract is stirred on an ice bath and K 2 until the aqueous layer is alkaline.
CO 3 was added in small portions and the product was washed with CH 2 Cl 2 (10 m
l) Subsequent extraction with EtOAc (20 ml). The organic layer was washed with 10% aqueous ammonia (15 ml) and then dried (N
a 2 SO 4 ), concentrated, and the resulting residue was purified by silica gel column chromatography (silica 15 g, hexane: EtOAc = 9: 1) to give the desired product 3b (0.
(35 g, 24%) as an oil.
【0235】3b:1H NMR(CDCl3 ,250M
Hz)δppm:1.13(t,J=7.2Hz,6
H),1.25(s,3H),2.29(s,1H),
2.75(d,J=13.0Hz,1H),2.78
(q,J=7.2Hz,4H),3.10(d,J=1
3.0Hz,1H),7.15−7.35(m,5
H). 合成例9 アミノアセチレン3c3b: 1 H NMR (CDCl 3 , 250M
Hz) δ ppm: 1.13 (t, J = 7.2 Hz, 6
H), 1.25 (s, 3H), 2.29 (s, 1H),
2.75 (d, J = 13.0 Hz, 1H), 2.78
(Q, J = 7.2 Hz, 4H), 3.10 (d, J = 1
3.0 Hz, 1 H), 7.15-7.35 (m, 5
H). Synthesis Example 9 Aminoacetylene 3c
【0236】[0236]
【化59】 Embedded image
【0237】出発物質としてベンジルアセトンを用い、
合成例7および8と同様な操作を行い3c(収率22
%)を油状物質として得た。 3c:1H NMR(300MHz,CDCl3 )δpp
m:1.09(t,J=7.2Hz,6H),1.42
(s,3H),1.84−2.40(m,2H),2.
72(s,1H),2.60−2.84(m,6H),
7.13−7.35(m,5H). 合成例10、11 アニリノアセチレン3d、3eUsing benzylacetone as a starting material,
The same operation as in Synthesis Examples 7 and 8 was performed to obtain 3c (yield: 22
%) As an oil. 3c: 1 H NMR (300 MHz, CDCl 3 ) δpp
m: 1.09 (t, J = 7.2 Hz, 6H), 1.42
(S, 3H), 1.84-2.40 (m, 2H), 2.
72 (s, 1H), 2.60-2.84 (m, 6H),
7.13-7.35 (m, 5H). Synthesis Examples 10 and 11 Anilinoacetylene 3d, 3e
【0238】[0238]
【化60】 Embedded image
【0239】R.S.Hanzelらの方法(J.A
m.Chem.Soc.,1960,82,4908)
でそれぞれ製造した。 3d:1H NMR(250MHz,CDCl3 )δpp
m:1.40(s,6H),2.39(s,1H),
2.85(s,3H),7.14(m,1H),7.2
2−7.40(m,4H). 3e:1H NMR(300MHz,CDCl3 )δpp
m:1.61(s,6H),2.35(s,1H),
6.79(t,J=7.4Hz,1H),6.94
(d,J=7.7Hz,2H),7.19(m,2
H). 合成例12 アミノアセチレン3fR.I. S. Hansel et al. (JA)
m. Chem. Soc. , 1960, 82, 4908)
Respectively. 3d: 1 H NMR (250 MHz, CDCl 3 ) δpp
m: 1.40 (s, 6H), 2.39 (s, 1H),
2.85 (s, 3H), 7.14 (m, 1H), 7.2
2-7.40 (m, 4H). 3e: 1 H NMR (300 MHz, CDCl 3 ) δpp
m: 1.61 (s, 6H), 2.35 (s, 1H),
6.79 (t, J = 7.4 Hz, 1H), 6.94
(D, J = 7.7 Hz, 2H), 7.19 (m, 2
H). Synthesis Example 12 Aminoacetylene 3f
【0240】[0240]
【化61】 Embedded image
【0241】1)Diethylamino−(3−p
yridyl)−acetonitrile Et2 NH(7.2g、98.6mmol)に濃塩酸を
少しずつ加え中和し、3−pyridinecarbo
xaldehyde(7.1ml、75.0mmol)
を加えた。KCN(4.88g)の水溶液(15ml)
を加え、3時間還流させた後、水(30ml)を加えエ
ーテルで抽出した(50ml×1、20ml×1)。有
機層を水(30ml×2)、飽和食塩水(30ml)で
洗浄、乾燥(Na2 SO4 )、濃縮しDiethyla
mino−(3−pyridyl)−acetonit
rile(12.55g、88%)を得た。 2)Diethylamino−(3−pyridy
l)−acetonitrile(888mg、4.6
9mmol)のTHF(15ml)−HMPA(5m
l)溶液を−68℃に冷却し、そこへ1.0MのLit
hium bis(trimethylsilyl)a
mide(7.0ml、7.0mmol)をゆっくり加
えた。この温度で45分間撹拌後、ベンジルブロミド
(0.67ml、5.63mmol)を滴下し、反応溶
液を徐々に室温まで昇温した。水を加え反応を停止させ
た後反応混合物を濃縮し、エーテル(50ml)で抽出
した。抽出液を水(40ml×2)で洗浄、乾燥(Na
2 SO4 )、濃縮した。残渣(1.90g)を氷浴上撹
拌しながら0.5MエチニルマグネシウムブロミドTH
F溶液(36.5ml、18.3mmol)を加え、室
温で2.5時間撹拌した。反応液を氷冷し、水を加えて
反応を停止させた後、濃縮しエーテル(50ml×2)
で抽出した。エーテル層を希塩酸で抽出し、抽出液に2
N水酸化ナトリウム水溶液を液相がアルカリ性を呈する
まで加え、ジクロロメタン(20ml×2)で抽出し
た。有機層を乾燥、濃縮し得られる残渣をシリカゲルカ
ラムクロマトグラフィー(ヘキサン:EtOAc=4:
1)で精製し、目的物3f(840mg、65%)を油
状物質として得た。1) Diethylamino- (3-p
Concentrated hydrochloric acid was added little by little to (yridyl) -acetonitrile Et 2 NH (7.2 g, 98.6 mmol) to neutralize, and 3-pyridinecarbo
xaldehyde (7.1 ml, 75.0 mmol)
Was added. An aqueous solution (15 ml) of KCN (4.88 g)
Was added, and the mixture was refluxed for 3 hours. Then, water (30 ml) was added, and the mixture was extracted with ether (50 ml × 1, 20 ml × 1). The organic layer was washed with water (30 ml × 2) and a saturated saline solution (30 ml), dried (Na 2 SO 4 ), concentrated and concentrated in Diethyla.
mino- (3-pyridyl) -acetonit
rifle (12.55 g, 88%) was obtained. 2) Diethylamino- (3-pyridy
l) -acetonitrile (888 mg, 4.6
9 mmol) of THF (15 ml) -HMPA (5 m
l) Cool the solution to -68 ° C and add 1.0M Lite
ium bis (trimethylsilyl) a
mid (7.0 ml, 7.0 mmol) was added slowly. After stirring at this temperature for 45 minutes, benzyl bromide (0.67 ml, 5.63 mmol) was added dropwise, and the reaction solution was gradually warmed to room temperature. After stopping the reaction by adding water, the reaction mixture was concentrated and extracted with ether (50 ml). The extract was washed with water (40 ml × 2) and dried (Na
2 SO 4 ) and concentrated. The residue (1.90 g) was stirred on an ice bath while stirring 0.5M ethynyl magnesium bromide TH.
An F solution (36.5 ml, 18.3 mmol) was added, and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was ice-cooled, the reaction was stopped by adding water, and the mixture was concentrated and ether (50 ml × 2).
Extracted. The ether layer was extracted with dilute hydrochloric acid.
An aqueous solution of N sodium hydroxide was added until the liquid phase became alkaline, and the mixture was extracted with dichloromethane (20 ml × 2). The organic layer is dried and concentrated, and the resulting residue is subjected to silica gel column chromatography (hexane: EtOAc = 4:
Purification in 1) gave the desired product 3f (840 mg, 65%) as an oil.
【0242】3f:1H NMR(300MHz,CDC
l3 )δppm:1.13(t,J=7.2Hz,3
H),2.54(2dq,J=14.0,7.1,2
H),2.63(s,1H),2.83(2dq,J=
14.0,7.1Hz,2H),2.93(d,J=1
2.2Hz,1H),3.46(d,J=12.2H
z,1H),6.67−6.76(m,2H),6.9
6−7.12(m,4H),7.63(dt,J=8.
0,2.0Hz,1H),8.40(dd,J=1.
7,4.7Hz,1H),8.69(m,1H). 合成例13 アミノアセチレン3g3f: 1 H NMR (300 MHz, CDC
l 3 ) δ ppm: 1.13 (t, J = 7.2 Hz, 3
H), 2.54 (2dq, J = 14.0, 7.1, 2)
H), 2.63 (s, 1H), 2.83 (2dq, J =
14.0, 7.1 Hz, 2H), 2.93 (d, J = 1
2.2 Hz, 1 H), 3.46 (d, J = 12.2 H)
z, 1H), 6.67-6.76 (m, 2H), 6.9.
6-7.12 (m, 4H), 7.63 (dt, J = 8.
0, 2.0 Hz, 1H), 8.40 (dd, J = 1.
7, 4.7 Hz, 1H), 8.69 (m, 1H). Synthesis Example 13 Aminoacetylene 3 g
【0243】[0243]
【化62】 Embedded image
【0244】1)Methyl 3−ethylami
nopropionate EtNH2 (33g、720mmol)のMeOH溶液
(150ml)に4〜6℃でアクリル酸メチル(54m
l、600mmol)を20分以上かけて滴下した。2
4時間後、常圧でMeOHを留去後さらに減圧で蒸留
し、Methyl3−ethylaminopropi
onate(32.94g、42%)を無色透明液体と
して得た。 bp70℃/20mmHg;1H NMR(300MH
z,CDCl3 )δppm:1.11(t,J=7.1
Hz,3H),2.52(t,J=6.6Hz,2
H),2.66(q,J=7.1Hz,2H),2.8
9(t,J=6.6Hz,2H),3.69(s,3
H).1) Methyl 3-ethylami
A solution of nopropionate EtNH 2 (33 g, 720 mmol) in MeOH (150 ml) at 4-6 ° C. was treated with methyl acrylate (54 m 2).
1, 600 mmol) was added dropwise over 20 minutes. 2
Four hours later, MeOH was distilled off at normal pressure, and further distilled under reduced pressure to obtain methyl3-ethylaminopropi.
Onate (32.94 g, 42%) was obtained as a clear, colorless liquid. bp 70 ° C./20 mmHg; 1 H NMR (300 MH
z, CDCl 3 ) δ ppm: 1.11 (t, J = 7.1)
Hz, 3H), 2.52 (t, J = 6.6 Hz, 2
H), 2.66 (q, J = 7.1 Hz, 2H), 2.8
9 (t, J = 6.6 Hz, 2H), 3.69 (s, 3
H).
【0245】2)出発物質としてMethyl 3−e
thylaminopropionateおよびアセテ
ート5(合成例7)を用い、合成例8と同様な操作を行
い3gを淡黄色油状物質として得た(収率41%)。 3g:1H NMR(300MHz,CDCl3 )δpp
m:1.12(t,J=7.2Hz,3H),1.25
(s,3H),2.31(s,1H),2.52−2.
62(m,2H),2.70−2.90(m,3H),
3.20−3.12(m,3H),3.67(s,3
H),7.18−7.35(m,5H). 合成例14 アミノアセチレン3h2) Methyl 3-e as starting material
The same operation as in Synthesis Example 8 was carried out using thylaminopropionate and acetate 5 (Synthesis Example 7) to obtain 3 g as a pale yellow oily substance (yield 41%). 3g: 1 H NMR (300 MHz, CDCl 3 ) δpp
m: 1.12 (t, J = 7.2 Hz, 3H), 1.25
(S, 3H), 2.31 (s, 1H), 2.52-2.
62 (m, 2H), 2.70-2.90 (m, 3H),
3.20-3.12 (m, 3H), 3.67 (s, 3
H), 7.18-7.35 (m, 5H). Synthesis Example 14 Aminoacetylene 3h
【0246】[0246]
【化63】 Embedded image
【0247】出発物質としてN−Methyletha
nolamineおよびアセテート5(合成例7)を用
い、合成例8と同様な操作を行い3hを淡黄色油状物質
として得た(収率77%)。 3h:1H NMR(300MHz,CDCl3 )δpp
m:1.26(s,3H),2.36(s,1H),
2.40(s,3H),2.74−2.83(m,3
H),3.09(d,J=13.2Hz,1H),3.
55−3.68(m,2H),7.20−7.40
(m,5H). 合成例15、16 アミノアセチレン3i、3jAs a starting material, N-methylethyla
The same operation as in Synthesis Example 8 was performed using nolamine and acetate 5 (Synthesis Example 7) to obtain 3h as a pale yellow oily substance (yield 77%). 3h: 1 H NMR (300 MHz, CDCl 3 ) δpp
m: 1.26 (s, 3H), 2.36 (s, 1H),
2.40 (s, 3H), 2.74-2.83 (m, 3
H), 3.09 (d, J = 13.2 Hz, 1H);
55-3.68 (m, 2H), 7.20-7.40
(M, 5H). Synthesis Examples 15, 16 Aminoacetylenes 3i, 3j
【0248】[0248]
【化64】 Embedded image
【0249】出発物質としてアセテート5(合成例1
7)と、Ethyl 4−piperidinecar
boxylateおよび1−(Ethoxycarbo
nylmethyl)piperazineを用い合成
例8と同様な操作を行い3iおよび3jをそれぞれ製造
した(精製法を化合物番号後のカッコ内に示す)。 3i:(ヘキサンで懸洗);収率59%;淡黄色結晶;
1H NMR(CDCl3 ,300MHz)δppm:
1.22(s,3H),1.26(t,J=7.1H
z,3H),1.78(m,2H),1.97(m,2
H),2.24−2.43(m,3H),2.36
(s,1H),2.84(d,J=13.3Hz,1
H),3.05(d,J=13.3Hz,1H),3.
10(m,1H),3.24(m,1H),4.14
(q,J=7.1Hz,2H),7.15−7.36
(m,5H).As a starting material, acetate 5 (Synthesis Example 1)
7) and Ethyl 4-piperidinecar
boxylate and 1- (Ethoxycarbo
The same operation as in Synthesis Example 8 was carried out using nylmethyl) piperazine to produce 3i and 3j, respectively (purification methods are shown in parentheses after the compound numbers). 3i: (washed with hexane); yield: 59%; pale yellow crystals;
1 H NMR (CDCl 3 , 300 MHz) δ ppm:
1.22 (s, 3H), 1.26 (t, J = 7.1H)
z, 3H), 1.78 (m, 2H), 1.97 (m, 2
H), 2.24-2.43 (m, 3H), 2.36.
(S, 1H), 2.84 (d, J = 13.3 Hz, 1
H), 3.05 (d, J = 13.3 Hz, 1H), 3.
10 (m, 1H), 3.24 (m, 1H), 4.14
(Q, J = 7.1 Hz, 2H), 7.15-7.36
(M, 5H).
【0250】3j:(EtOH−H2 Oで懸洗);収率
50%; 1H NMR(CDCl3,300MHz)δ
ppm:1.21(s,3H),1.28(t,J=
7.1Hz,3H),2.36(s,1H),2.61
−2.73(m,4H),2.80(d,J=13.2
Hz,1H),2.80−2.90(m,4H),3.
07(t,J=13.2Hz,1H),3.22(s,
2H),4.27(q,J=7.1Hz,2H),7.
20−7.40(m,5H). 合成例17 アミノアセチレン3k3j: (suspension with EtOH-H 2 O); yield 50%; 1 H NMR (CDCl 3 , 300 MHz) δ
ppm: 1.21 (s, 3H), 1.28 (t, J =
7.1 Hz, 3H), 2.36 (s, 1H), 2.61
-2.73 (m, 4H), 2.80 (d, J = 13.2)
Hz, 1H), 2.80-2.90 (m, 4H), 3.
07 (t, J = 13.2 Hz, 1H), 3.22 (s,
2H), 4.27 (q, J = 7.1 Hz, 2H), 7.
20-7.40 (m, 5H). Synthesis Example 17 Aminoacetylene 3k
【0251】[0251]
【化65】 Embedded image
【0252】合成例7のフェニルアセトンの代わりにフ
ェニルアセトアルデヒドを用い同様な操作で3−ace
toxy−4−phenyl−1−butyneに変換
し、さらにこれとEthyl 4−piperidin
e−carboxylateを用い、合成例8と同様な
操作で3kを製造した。 3k:収率22%; 1H NMR(CDCl3 ,300
MHz)δppm:1.25(t,J=7.1Hz,3
H),2.65−2.86(m,2H),2.86−
2.04(m,2H),2.24−2.40(m,3
H),2.50(dt,J=3.0,11.3Hz,1
H),2.70−2.80(m,1H),2.84−
3.07(m,3H),3.54(ddd,J=2.
2,5.6,9.3Hz,1H),4.14(q,J=
7.1Hz,2H),7.08−7.40(m,5
H). 合成例18 アニリノアセチレン3mIn the same manner as in Synthesis Example 7 except that phenylacetaldehyde was used instead of phenylacetone, 3-ace
Toxyl-4-phenyl-1-butyne was converted into Ethyl 4-piperidin.
Using e-carboxylate, 3k was produced in the same manner as in Synthesis Example 8. 3k: 22% yield; 1 H NMR (CDCl 3 , 300
MHz) δ ppm: 1.25 (t, J = 7.1 Hz, 3
H), 2.65-2.86 (m, 2H), 2.86-
2.04 (m, 2H), 2.24-2.40 (m, 3
H), 2.50 (dt, J = 3.0, 11.3 Hz, 1
H), 2.70-2.80 (m, 1H), 2.84-
3.07 (m, 3H), 3.54 (ddd, J = 2.
2,5.6,9.3 Hz, 1H), 4.14 (q, J =
7.1 Hz, 2H), 7.08-7.40 (m, 5
H). Synthesis Example 18 Anilinoacetylene 3 m
【0253】[0253]
【化66】 Embedded image
【0254】W.S.Johnsonらの方法(J.A
m.Chem.Soc.,1949,71,1901)
で製造したMethyl β−anilinoprop
ionateと3−Chloro−3−methyl−
1−butyneを用いて、合成例10{R.S.Ha
nzelらの方法(J.Am.Chem.Soc.,1
960,82,4908)}と同様な操作を行い3kを
製造した。 3m:収率28%; 1H NMR(CDCl3 ,300
MHz)δppm:1.31(s,6H),2.26
(t,J=7.2Hz,2H),2.39(s,1
H),3.45(t,J=7.2Hz,2H),3.6
2(s,3H),7.12(m,1H),7.25−
7.38(m,4H). 実施例7 化合物1の製造W. S. The method of Johnson et al.
m. Chem. Soc. , 1949, 71, 1901).
Β-anilinoprop manufactured by
ionate and 3-Chloro-3-methyl-
Synthesis Example 10 Using 1-butyne S. Ha
nzel et al. (J. Am. Chem. Soc., 1).
960, 82, 4908)} to produce 3k. 3m: 28% yield; 1 H NMR (CDCl 3 , 300
MHz) δ ppm: 1.31 (s, 6H), 2.26
(T, J = 7.2 Hz, 2H), 2.39 (s, 1
H), 3.45 (t, J = 7.2 Hz, 2H), 3.6
2 (s, 3H), 7.12 (m, 1H), 7.25-
7.38 (m, 4H). Example 7 Preparation of Compound 1
【0255】[0255]
【化67】 Embedded image
【0256】合成例15で製造したアミノアセチレン3
i(7.34g、24.6mmol)および4−クロロ
−6,7−ジエトキシキナゾリン(合成例)(6.21
g、24.6mmol)のDMF溶液(120ml)に
撹拌しながら窒素を40分間吹き込んだ。Et3 N
(8.2ml、59.0mmol)、Pd(PPh3 )
4(710mg、0.61mmol)およびCuI(3
70mg、1.94mmol)を加え、反応混合物を1
00℃で5時間加熱撹拌した。反応液を減圧下濃縮し、
飽和炭酸水素ナトリウム水溶液(100ml)とEtO
Ac(100ml)に分配した。有機層を乾燥(Na2
SO3 )、濃縮し、残渣をシリカゲルカラムクロマトグ
ラフィー(ヘキサン→ヘキサン:EtOAc=2:3)
で精製し、目的物を赤褐色タール状物質として得た(1
0.58g、83%)。Aminoacetylene 3 produced in Synthesis Example 15
i (7.34 g, 24.6 mmol) and 4-chloro-6,7-diethoxyquinazoline (Synthesis Example) (6.21)
g, 24.6 mmol) in DMF (120 ml) was bubbled with nitrogen for 40 minutes with stirring. Et 3 N
(8.2 ml, 59.0 mmol), Pd (PPh 3 )
4 (710 mg, 0.61 mmol) and CuI (3
70 mg, 1.94 mmol) and the reaction mixture was
The mixture was heated and stirred at 00 ° C. for 5 hours. The reaction solution was concentrated under reduced pressure,
Saturated aqueous sodium bicarbonate solution (100 ml) and EtO
Partitioned into Ac (100 ml). Dry the organic layer (Na 2
SO 3 ), concentrated, and the residue was subjected to silica gel column chromatography (hexane → hexane: EtOAc = 2: 3).
To give the desired product as a reddish brown tar-like substance (1
0.58 g, 83%).
【0257】1H NMR(CDCl3 ,300MH
z)δppm:1.26(t,J=7.1Hz,3
H),1.45(s,3H),1.50(t,J=7.
1Hz,3H),1.56(t,J=7.0Hz,3
H),1.72−1.95(m,2H),1.93−
2.10(m,2H),2.36(tt,J=4.0,
11.5Hz,1H),2.46(dt,J=2.5,
11.4Hz,1H),2.56(dt,J=2.5,
11.4Hz,1H),3.05(d,J=13.4H
z,1H),3.27(d,J=13.4Hz,1
H),3.22−3.35(m,1H),3.45(b
r d,J=11.2Hz,1H),4.05(q,J
=7.1Hz,2H),4.15(q,J=7.1H
z,2H),4.28(q,J=7.0Hz,2H),
7.10−7.30(m,5H),7.30−7.45
(m,2H),9.08(s,1H). IR(film)νcm-1:2982,2936,28
09,2213,1732,1613,1568,10
45,855,756,702. 実施例8 化合物1の製造 1 H NMR (CDCl 3 , 300 MH
z) δ ppm: 1.26 (t, J = 7.1 Hz, 3
H), 1.45 (s, 3H), 1.50 (t, J = 7.
1 Hz, 3H), 1.56 (t, J = 7.0 Hz, 3
H), 1.72-1.95 (m, 2H), 1.93-
2.10 (m, 2H), 2.36 (tt, J = 4.0,
11.5 Hz, 1 H), 2.46 (dt, J = 2.5,
11.4 Hz, 1 H), 2.56 (dt, J = 2.5,
11.4 Hz, 1H), 3.05 (d, J = 13.4H)
z, 1H), 3.27 (d, J = 13.4 Hz, 1
H), 3.22-3.35 (m, 1H), 3.45 (b
rd, J = 11.2 Hz, 1H), 4.05 (q, J
= 7.1 Hz, 2H), 4.15 (q, J = 7.1H)
z, 2H), 4.28 (q, J = 7.0 Hz, 2H),
7.10-7.30 (m, 5H), 7.30-7.45
(M, 2H), 9.08 (s, 1H). IR (film) νcm -1 : 2982, 2936, 28
09, 2213, 1732, 1613, 1568, 10
45,855,756,702. Example 8 Preparation of Compound 1
【0258】[0258]
【化68】 Embedded image
【0259】実施例7で製造したエステル(10.01
g、19.4mmol)のEtOH溶液(100ml)
に2N NaOH水溶液(25ml、50mmol)を
加え室温で1.5時間撹拌した。減圧下濃縮乾固し、残
渣にEtOH(2ml)を加え、撹拌しながら10%ク
エン酸水溶液(180ml)を加えた。室温で30分撹
拌した後、沈殿物を濾取、洗浄(水−EtOH)、乾燥
し、目的物を淡黄色粉末結晶として得た(9.04g、
96%)。さらにトルエンおよびEtOH−H2 Oで順
次懸洗し、精製物を白色粉末結晶として得た。The ester prepared in Example 7 (10.01
g, 19.4 mmol) in EtOH (100 ml)
To the mixture was added a 2N aqueous solution of NaOH (25 ml, 50 mmol), and the mixture was stirred at room temperature for 1.5 hours. The mixture was concentrated to dryness under reduced pressure, EtOH (2 ml) was added to the residue, and a 10% aqueous citric acid solution (180 ml) was added with stirring. After stirring at room temperature for 30 minutes, the precipitate was collected by filtration, washed (water-EtOH), and dried to obtain the desired product as pale yellow powdery crystals (9.04 g,
96%). Further successively suspension washing with toluene and EtOH-H 2 O, to give a purified product as a white powder crystals.
【0260】1: 1H NMR(CDCl3 ,300M
Hz)δppm:1.44(t,J=7.0Hz,3
H),1.49(s,3H),1.56(t,J=7.
0Hz,3H),1.84−2.08(m,2H),
2.07−2.29(m,2H),2.50−2.70
(m,2H),2.77(br t,J=10.7H
z,1H),2.97(d,J=13.1Hz,1
H),3.28−3.56(m,2H),3.38
(d,J=13.1Hz,1H),3.89(m,2
H),4.28(q,J=7.0Hz,2H),7.0
9(s,1H),7.18−7.44(m,6H),
9.20(s,1H). IR(KBr)cm-1:3409,2984,293
7,2213,1717,1612,1499,145
8,1235,1204,1032,936,704,
662. m.p. 212−215℃ P−SIMS m/z 488(M+H)+ 1: 1 H NMR (CDCl 3 , 300M
Hz) δ ppm: 1.44 (t, J = 7.0 Hz, 3
H), 1.49 (s, 3H), 1.56 (t, J = 7.
0 Hz, 3H), 1.84-2.08 (m, 2H),
2.07-2.29 (m, 2H), 2.50-2.70
(M, 2H), 2.77 (br t, J = 10.7H
z, 1H), 2.97 (d, J = 13.1 Hz, 1
H), 3.28-3.56 (m, 2H), 3.38
(D, J = 13.1 Hz, 1H), 3.89 (m, 2
H), 4.28 (q, J = 7.0 Hz, 2H), 7.0
9 (s, 1H), 7.18-7.44 (m, 6H),
9.20 (s, 1H). IR (KBr) cm -1 : 3409, 2984, 293
7,2213,1717,1612,1499,145
8,1235,1204,1032,936,704,
662. m. p. 212-215 ° C P-SIMS m / z 488 (M + H) +
【0261】実施例9〜90 上記合成例で製造したハロゲン化含窒素化合物とアセチ
レン化合物(後述のものを含む)を用い発明化合物を製
造した。構造、方法、収率、物性値等を次に示すが、方
法の欄は用いた方法と精製法を示し、次の様に表すこと
とする。 方法 (カップリング反応)実施例1、7の方法をそれぞれ
A、Bとし、反応溶媒やパラジウム触媒に変更があった
場合は使用したものをカッコ内に記した。Examples 9 to 90 Inventive compounds were produced using the halogenated nitrogen-containing compound and the acetylene compound (including those described below) produced in the above Synthesis Examples. The structure, method, yield, physical properties and the like are shown below. The method column shows the method used and the purification method, and is represented as follows. Method (Coupling reaction) The methods of Examples 1 and 7 were A and B, respectively. When there was a change in the reaction solvent or palladium catalyst, the one used was indicated in parentheses.
【0262】(塩酸塩化)実施例2の操作をCとし、反
応溶媒に変更があった場合はカッコ内に記した。 (加水分解反応)実施例8の操作をDとし、反応溶媒に
変更があった場合はカッコ内に記した。 精製法 シリカゲルカラムクロマトグラフィーによる精製で、溶
出液がヘキサン−EtOAc系であるものをP1a、溶
出液がCHCl3 −MeOH系であるものをP1bと記
した。ODSカラムクロマトグラフィーによる精製をP
2と記した。懸洗または再結晶による精製をP3とし、
その際の使用溶媒をカッコ内に記した。いずれの場合も
最終精製物は減圧下乾燥した。(Hydrochlorination) The procedure of Example 2 was designated as C, and the case where the reaction solvent was changed was described in parentheses. (Hydrolysis reaction) The operation of Example 8 was designated as D, and the case where the reaction solvent was changed was described in parentheses. Purification method In purification by silica gel column chromatography, an eluate of hexane-EtOAc system was designated as P1a, and an eluate of CHCl 3 -MeOH system was designated as P1b. Purification by ODS column chromatography
Marked as 2. P3 means purification by suspension washing or recrystallization,
The solvent used at that time is shown in parentheses. In each case, the final purified product was dried under reduced pressure.
【0263】[0263]
【表133】 [Table 133]
【0264】[0264]
【表134】 [Table 134]
【0265】[0265]
【表135】 [Table 135]
【0266】[0266]
【表136】 [Table 136]
【0267】[0267]
【表137】 [Table 137]
【0268】[0268]
【表138】 [Table 138]
【0269】[0269]
【表139】 [Table 139]
【0270】[0270]
【表140】 [Table 140]
【0271】[0271]
【表141】 [Table 141]
【0272】[0272]
【表142】 [Table 142]
【0273】[0273]
【表143】 [Table 143]
【0274】[0274]
【表144】 [Table 144]
【0275】[0275]
【表145】 [Table 145]
【0276】[0276]
【表146】 [Table 146]
【0277】[0277]
【表147】 [Table 147]
【0278】[0278]
【表148】 [Table 148]
【0279】[0279]
【表149】 [Table 149]
【0280】[0280]
【表150】 [Table 150]
【0281】[0281]
【表151】 [Table 151]
【0282】[0282]
【表152】 [Table 152]
【0283】[0283]
【表153】 [Table 153]
【0284】[0284]
【表154】 [Table 154]
【0285】[0285]
【表155】 [Table 155]
【0286】[0286]
【表156】 [Table 156]
【0287】[0287]
【表157】 [Table 157]
【0288】[0288]
【表158】 [Table 158]
【0289】[0289]
【表159】 [Table 159]
【0290】[0290]
【表160】 [Table 160]
【0291】[0291]
【表161】 [Table 161]
【0292】[0292]
【表162】 [Table 162]
【0293】[0293]
【表163】 [Table 163]
【0294】[0294]
【表164】 [Table 164]
【0295】[0295]
【表165】 [Table 165]
【0296】[0296]
【表166】 [Table 166]
【0297】[0297]
【表167】 [Table 167]
【0298】[0298]
【表168】 [Table 168]
【0299】[0299]
【表169】 [Table 169]
【0300】[0300]
【表170】 [Table 170]
【0301】[0301]
【表171】 [Table 171]
【0302】[0302]
【表172】 [Table 172]
【0303】[0303]
【表173】 [Table 173]
【0304】実施例91Embodiment 91
【0305】[0305]
【化69】 Embedded image
【0306】実施例8で製造したカルボン酸(389m
g、0.8mmol)、ClCH2OCO−t−Bu
(138μl、0.96mmol)およびDBV(13
2μl、0.96mmol)のトルエン溶液(10m
l)を80℃で2時間撹拌した。反応液に水(40m
l)、EtOAc(40ml)を加え有機層を分離し
た。抽出液を洗浄(飽和NaHCO3 水溶液、10%ク
エン酸水溶液、水)、乾燥(Na2 SO4 )、濃縮し、
残渣をシリカゲルカラムクロマトグラフィー(ヘキサ
ン:EtOAc=4:1→2:3)で精製し、エステル
体をアモルファスとして得た(405mg、84%)。The carboxylic acid prepared in Example 8 (389 m
g, 0.8 mmol), ClCH 2 OCO-t-Bu
(138 μl, 0.96 mmol) and DBV (13
2 μl, 0.96 mmol) in toluene (10 m
l) was stirred at 80 ° C for 2 hours. Water (40m
1) and EtOAc (40 ml) were added, and the organic layer was separated. The extract was washed (saturated aqueous NaHCO 3 , 10% aqueous citric acid, water), dried (Na 2 SO 4 ), concentrated,
The residue was purified by silica gel column chromatography (hexane: EtOAc = 4: 1 → 2: 3) to give an ester as an amorphous (405 mg, 84%).
【0307】1H NMR(CDCl3 ,300MH
z)δppm:1.21(s,9H),1.45(s,
3H),1.49(t,J=7.0Hz,3H),1.
56(t,J=7.0Hz,3H),1.73−1.9
4(m,2H),1.95−2.12(m,2H),
2.37−2.62(m,3H),3.04(d,J=
13.3Hz,1H),3.27(d,J=13.3H
z,1H),3.22−3.32(m,1H),3.4
4(m,1H),4.03(br q,J=7.0H
z,2H),4.28(q,J=7.0Hz,1H),
5.77(s,2H),7.16−7.30(m,5
H),7.30−7.40(m,2H),9.07
(s,1H). 実施例92 1 H NMR (CDCl 3 , 300 MH
z) δ ppm: 1.21 (s, 9H), 1.45 (s,
3H), 1.49 (t, J = 7.0 Hz, 3H), 1.
56 (t, J = 7.0 Hz, 3H), 1.73-1.9
4 (m, 2H), 1.95-2.12 (m, 2H),
2.37-2.62 (m, 3H), 3.04 (d, J =
13.3 Hz, 1 H), 3.27 (d, J = 13.3 H)
z, 1H), 3.22-3.32 (m, 1H), 3.4
4 (m, 1H), 4.03 (br q, J = 7.0H
z, 2H), 4.28 (q, J = 7.0 Hz, 1H),
5.77 (s, 2H), 7.16-7.30 (m, 5
H), 7.30-7.40 (m, 2H), 9.07
(S, 1H). Example 92
【0308】[0308]
【化70】 Embedded image
【0309】実施例39で製造した2−アミノ体(20
0mg、0.48mmol)に42%HBF4 水溶液
(4ml)およびこん跡量のEtOHを加え−20℃に
冷却し、5.1MのNaNO2 水溶液(150μl、
0.75mmol)を加えた。ゆっくりと昇温し、反応
液が+20℃になる間に数回にわけて5.1MのNaN
O2 水溶液(1.55ml)、7.8MのNaNO2 水
溶液(0.5ml)を加えた。HBF4 水溶液(2m
l)加え室温で30分間撹拌後、0℃で6N NaOH
水溶液と10%Na2 CO3 水溶液を液性が中性になる
まで加えた。生成物をEtOAc(30ml×1、20
ml×1)で抽出し、抽出液を洗浄(飽和NaHCO3
水溶液)、乾燥(Na2 SO4 )、濃縮した。残渣をシ
リカゲルカラムクロマトグラフィー(ヘキサン:EtO
Ac=1:0→1/1,クロロホルム:メタノール=
1:0→30:1)で精製し、2−フッ素体(21m
g、10%)を得た。The 2-amino compound (20) produced in Example 39
0 mg, 0.48 mmol), a 42% aqueous HBF 4 solution (4 ml) and a trace amount of EtOH were added, cooled to −20 ° C., and a 5.1 M aqueous NaNO 2 solution (150 μl,
0.75 mmol) was added. The temperature was slowly increased, and the reaction solution was divided into several portions of 5.1 M NaN while the temperature reached + 20 ° C.
O 2 aqueous solution (1.55 ml), was added NaNO 2 aqueous solution of 7.8 M (0.5 ml). HBF 4 aqueous solution (2m
1) Addition and stirring at room temperature for 30 minutes, followed by 6N NaOH at 0 ° C.
An aqueous solution and a 10% aqueous solution of Na 2 CO 3 were added until the solution became neutral. The product was treated with EtOAc (30 ml × 1, 20
ml × 1), and the extract is washed (saturated NaHCO 3).
Aqueous solution), dried (Na 2 SO 4 ) and concentrated. The residue is subjected to silica gel column chromatography (hexane: EtO
Ac = 1: 0 → 1/1, chloroform: methanol =
1: 0 → 30: 1) to give 2-fluoride (21m
g, 10%).
【0310】1H NMR(CDCl3 ,300MH
z)δppm:1.20(t,J=7.1Hz,6
H),1.48(s,3H),2.86−3.05
(m,5H),3.31(d,J=13.2Hz,1
H),3.84(s,3H),4.05(s,3H),
7.17−7.30(m,5H),7.32−7.40
(m,2H).19 F NMR(CDCl3 ,280MHz)δppm:
−49.3 実施例93 1 H NMR (CDCl 3 , 300 MH
z) δ ppm: 1.20 (t, J = 7.1 Hz, 6
H), 1.48 (s, 3H), 2.86-3.05.
(M, 5H), 3.31 (d, J = 13.2 Hz, 1
H), 3.84 (s, 3H), 4.05 (s, 3H),
7.17-7.30 (m, 5H), 7.32-7.40
(M, 2H). 19 F NMR (CDCl 3 , 280 MHz) δ ppm:
-49.3 Example 93
【0311】[0311]
【化71】 Embedded image
【0312】実施例92で製造した2−フッ素体を用い
実施例2と同様な操作を行ない目的とする塩酸塩を白色
粉末結晶として得た(収率74%)。1 H NMR(CDCl3 ,300MHz)δppm:
1.67(t,J=7.7Hz,3H),1.69
(t,J=8.2Hz,3H),1.96(s,3
H),3.25−3.55(m,2H),3.55−
3.80(m,4H),3.86(s,3H),4.0
6(s,3H),7.10−7.34(m,5H),
7.37−7.50(m,2H),12.90(s,1
H).19 F NMR(CDCl3 ,280MHz)δppm:
−49.4 IR(KBR)νcm-1:3430,2980,294
0,2450,2238,1618,1580,154
9,1306,1242,1015,1001,84
3,770,708. m.p. 182−187℃ 実施例94The same operation as in Example 2 was carried out using the 2-fluorinated compound produced in Example 92 to obtain the desired hydrochloride as white powder crystals (yield 74%). 1 H NMR (CDCl 3 , 300 MHz) δ ppm:
1.67 (t, J = 7.7 Hz, 3H), 1.69
(T, J = 8.2 Hz, 3H), 1.96 (s, 3
H), 3.25-3.55 (m, 2H), 3.55-
3.80 (m, 4H), 3.86 (s, 3H), 4.0
6 (s, 3H), 7.10-7.34 (m, 5H),
7.37-7.50 (m, 2H), 12.90 (s, 1
H). 19 F NMR (CDCl 3 , 280 MHz) δ ppm:
−49.4 IR (KBR) νcm −1 : 3430,2980,294
0,2450,2238,1618,1580,154
9,1306,1242,1015,1001,84
3,770,708. m. p. 182-187 ° C Example 94
【0313】[0313]
【化72】 Embedded image
【0314】実施例39で製造した2−アミノ体(60
mg、0.14mmol)のピリジン(0.5ml)−
無水酢酸(0.5ml)溶液を一晩放置した後80℃で
1時間加熱撹拌した。反応液を濃縮し、残渣をシリカゲ
ルカラムクロマト(ヘキサン:EtOAc=4:1→
0:1)で精製し、目的とする2−アセチルアミノ体
(24mg、36%)を得た。1 H NMR(CDCl3 ,300MHz)δppm:
1.20(t,J=7.1Hz,3H),1.46
(s,3H),2.56(br s,3H),2.85
−3.05(m,5H),3.30(d,J=13.2
Hz,1H),3.84(s,3H),4.04(s,
3H),7.12−7.30(m,5H),7.30−
7.48(m,2H),8.14(br s,1H). 実施例95The 2-amino compound (60) produced in Example 39
mg, 0.14 mmol) of pyridine (0.5 ml)
The acetic anhydride (0.5 ml) solution was left overnight, and then heated and stirred at 80 ° C. for 1 hour. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography (hexane: EtOAc = 4: 1 →
0: 1) to give the desired 2-acetylamino form (24 mg, 36%). 1 H NMR (CDCl 3 , 300 MHz) δ ppm:
1.20 (t, J = 7.1 Hz, 3H), 1.46
(S, 3H), 2.56 (br s, 3H), 2.85
-3.05 (m, 5H), 3.30 (d, J = 13.2)
Hz, 1H), 3.84 (s, 3H), 4.04 (s,
3H), 7.12-7.30 (m, 5H), 7.30-
7.48 (m, 2H), 8.14 (brs, 1H). Example 95
【0315】[0315]
【化73】 Embedded image
【0316】実施例25で製造した2−クロロ体(15
6mg、0.36mmol)のメタノール溶液(4m
l)を氷浴上撹拌し、28%NaOMeメタノール溶液
(0.5ml)を加えた。80℃で30分間加熱撹拌し
た後、濃縮し、水とCH2 Cl2 を加え有機層を分離し
た。有機層を乾燥(Na2 SO4 )、濃縮し、目的とす
る2−メトキシ体(160mg、定量的)を得た。1 H NMR(CDCl3 ,300MHz)δppm:
1.19(t,J=7.1Hz,3H),1.45
(s,3H),2.85−3.10(m,5H),3.
31(d,J=13.2Hz,1H),3.81(s,
3H),4.03(s,3H),4.09(s,3
H),7.12(s,1H),7.17−7.30
(m,4H),7.35−7.42(m,2H). 実施例96The 2-chloro compound (15) produced in Example 25
6 mg, 0.36 mmol) in methanol (4 m
1) was stirred on an ice bath and a 28% NaOMe methanol solution (0.5 ml) was added. After heating and stirring at 80 ° C. for 30 minutes, the mixture was concentrated, water and CH 2 Cl 2 were added, and the organic layer was separated. The organic layer was dried (Na 2 SO 4 ) and concentrated to obtain the desired 2-methoxy compound (160 mg, quantitative). 1 H NMR (CDCl 3 , 300 MHz) δ ppm:
1.19 (t, J = 7.1 Hz, 3H), 1.45
(S, 3H), 2.85-3.10 (m, 5H), 3.
31 (d, J = 13.2 Hz, 1H), 3.81 (s,
3H), 4.03 (s, 3H), 4.09 (s, 3
H), 7.12 (s, 1H), 7.17-7.30
(M, 4H), 7.35-7.42 (m, 2H). Example 96
【0317】[0317]
【化74】 Embedded image
【0318】実施例95で製造した2−メトキシ体を用
い実施例2と同様な操作を行ない目的とする塩酸塩を白
色粉末結晶として得た(収率78%)。1 H NMR(CDCl3 ,300MHz)δppm:
1.64(t,J=7.5Hz,3H),1.71
(t,J=7.4Hz,3H),1.95(s,3
H),3.33−3.90(m,4H),3.59
(d,J=12.4Hz,1H),3.76(s,3
H),3.90(d,J=12.4Hz,1H),4.
05(s,3H),4.10(s,3H),6.97
(br s,1H),7.15(s,1H),7.25
−7.35(m,3H),7.42−7.50(m,2
H),12.65(br s,1H). IR(KBr)νcm-1:3426,2990,294
6,2361,1620,1555,1501,147
4,1426,1410,1310,1061,100
1,860,791,708. m.p. 172−175℃ 実施例97The same operation as in Example 2 was carried out using the 2-methoxy compound prepared in Example 95 to obtain the desired hydrochloride as white powder crystals (yield 78%). 1 H NMR (CDCl 3 , 300 MHz) δ ppm:
1.64 (t, J = 7.5 Hz, 3H), 1.71
(T, J = 7.4 Hz, 3H), 1.95 (s, 3
H), 3.33-3.90 (m, 4H), 3.59
(D, J = 12.4 Hz, 1H), 3.76 (s, 3
H), 3.90 (d, J = 12.4 Hz, 1H), 4.
05 (s, 3H), 4.10 (s, 3H), 6.97
(Br s, 1H), 7.15 (s, 1H), 7.25
-7.35 (m, 3H), 7.42-7.50 (m, 2
H), 12.65 (brs, 1H). IR (KBr) νcm -1 : 3426,2990,294
6,2361,1620,1555,1501,147
4,1426,1410,1310,1061,100
1,860,791,708. m. p. 172-175 ° C Example 97
【0319】[0319]
【化75】 Embedded image
【0320】実施例25で製造した2−クロロ体(36
0mg、0.82mmol)のベンゼン溶液(4ml)
にn−Bu4 N+ Br- (30mg)と50%NaOH
水溶液(3ml)を加え、48時間還流した。濃塩酸を
加え中和した後、飽和NaHCO3 水溶液を加え生成物
をEtOAc(20ml×2)で抽出した。抽出液を濃
縮し、残渣にMeOH(15ml)を加え生成する沈殿
物を濾取し、目的物である2−ヒドロキシ(2−オキ
ソ)体(130mg、38%)を白色粉結晶として得
た。The 2-chloro compound (36) produced in Example 25
0mg, 0.82mmol) benzene solution (4ml)
The n-Bu 4 N + Br - (30mg) and 50% NaOH
An aqueous solution (3 ml) was added, and the mixture was refluxed for 48 hours. After neutralization by adding concentrated hydrochloric acid, a saturated aqueous solution of NaHCO 3 was added, and the product was extracted with EtOAc (20 ml × 2). The extract was concentrated, MeOH (15 ml) was added to the residue, and the resulting precipitate was collected by filtration to give the desired 2-hydroxy (2-oxo) compound (130 mg, 38%) as white powder crystals.
【0321】1H NMR(CDCl3 ,300MH
z)δppm:1.19(br peak,6H),
1.43(s,3H),2.40−3.20(br p
eak,4H),3.09(d,J=13.5Hz,1
H),3.58(d,J=13.5Hz,1H),4.
00(s,3H),4.10(s,3H),5.66
(s,1H),6.72−6.85(m,2H),7.
05−7.20(m,3H),7.58(s,1H),
7.64(s,1H). 実施例98 化合物2の製造 1 H NMR (CDCl 3 , 300 MH
z) δ ppm: 1.19 (br peak, 6H),
1.43 (s, 3H), 2.40-3.20 (br p
eak, 4H), 3.09 (d, J = 13.5 Hz, 1
H), 3.58 (d, J = 13.5 Hz, 1H), 4.
00 (s, 3H), 4.10 (s, 3H), 5.66
(S, 1H), 6.72-6.85 (m, 2H), 7.
05-7.20 (m, 3H), 7.58 (s, 1H),
7.64 (s, 1H). Example 98 Preparation of compound 2
【0322】[0322]
【化76】 Embedded image
【0323】グリコール酸エチル(210mg、2.0
mmol)のDMF溶液(2ml)に室温で60%Na
H(10mg、0.25mmol)と2−クロロ体1
(130mg、0.30mmol)を加え80℃に加熱
撹拌した。1時間後、さらにグリコール酸エチル620
mg(5.96mmol)、60%NaH(240m
g、6.0mmol)および2−クロロ体1(100m
g、0.23mmol)を加え室温で10分間撹拌し
た。反応液に水とEtOAcを加え、水層を濃縮し、2
N NaOH水溶液(5ml)を加えた。室温で2時間
撹拌後、水層をEt2O(10ml)で洗浄し10%ク
エン酸水溶液(20ml)を加え中和した。生成物をE
tOAc(20ml×2)で抽出し、乾燥(Na2 SO
4 )濃縮し、残渣をシリカゲルカラムクロマトグラフィ
ーで精製し目的とする2−(カルボキシメチル)オキシ
体2(46mg、16%)を得た。 2: 1H NMR(CDCl3 ,250MHz)δpp
m:1.27(t,J=7.1Hz,3H),1.55
(s,3H),3.00−3.25(m,5H),3.
30(d,J=15.4Hz,1H),3.70(s,
3H),3.89(s,3H),5.00(s,2
H),6.90(s,1H),6.99(s,1H),
7.10−7.40(m,5H),12.55(br
s,1H). 実施例99Ethyl glycolate (210 mg, 2.0 mg
mmol) in DMF solution (2 ml) at room temperature with 60% Na
H (10 mg, 0.25 mmol) and 2-chloro form 1
(130 mg, 0.30 mmol) was added and the mixture was heated and stirred at 80 ° C. After one hour, further ethyl glycolate 620
mg (5.96 mmol), 60% NaH (240 m
g, 6.0 mmol) and 2-chloro form 1 (100 m
g, 0.23 mmol) and stirred at room temperature for 10 minutes. Water and EtOAc were added to the reaction, the aqueous layer was concentrated,
An aqueous solution of N NaOH (5 ml) was added. After stirring at room temperature for 2 hours, the aqueous layer was washed with Et 2 O (10 ml) and neutralized with a 10% aqueous citric acid solution (20 ml). The product is E
Extract with tOAc (20 ml × 2), dry (Na 2 SO 4)
4 ) After concentration, the residue was purified by silica gel column chromatography to obtain the desired 2- (carboxymethyl) oxy form 2 (46 mg, 16%). 2: 1 H NMR (CDCl 3 , 250 MHz) δpp
m: 1.27 (t, J = 7.1 Hz, 3H), 1.55
(S, 3H), 3.00-3.25 (m, 5H), 3.
30 (d, J = 15.4 Hz, 1H), 3.70 (s,
3H), 3.89 (s, 3H), 5.00 (s, 2
H), 6.90 (s, 1H), 6.99 (s, 1H),
7.10-7.40 (m, 5H), 12.55 (br
s, 1H). Example 99
【0324】[0324]
【化77】 Embedded image
【0325】実施例11で製造したアルコール体(40
0mg、1.47mmol)のCH2 Cl2 溶液(6m
l)に室温で無水フタル酸(327mg、2.2mmo
l)、トリエチルアミン(0.30ml、2.2mmo
l)およびDMAP(44mg、0.36mmol)を
加え12時間撹拌した後、3日間放置した。飽和NaH
CO3 水溶液(10ml)とEtOAc(30ml)を
加え、よく撹拌した。混合物を濾過して得られる沈殿物
と有機層を希塩酸で洗浄した際生じる沈殿物を合わせて
水で洗浄すると目的とするハーフエステル体(336m
g、54%)が白色粉末固体として得られた。The alcohol compound (40) produced in Example 11
0 mg, 1.47 mmol) in CH 2 Cl 2 solution (6 m
1) phthalic anhydride (327 mg, 2.2 mmol) at room temperature
l), triethylamine (0.30 ml, 2.2 mmol
l) and DMAP (44 mg, 0.36 mmol) were added, stirred for 12 hours, and left for 3 days. Saturated NaH
An aqueous solution of CO 3 (10 ml) and EtOAc (30 ml) were added, and the mixture was stirred well. The precipitate obtained by filtering the mixture and the precipitate formed when the organic layer is washed with dilute hydrochloric acid are combined and washed with water to obtain the desired half-ester (336 m
g, 54%) as a white powder solid.
【0326】1H NMR(DMSO−d6 ,300M
Hz)δppm:1.91(s,6H),3.86
(s,3H),4.00(s,3H),7.38(s,
1H),7.62(s,1H),7.63−7.80
(m,4H),9.05(s,1H),13.35(b
r s,1H). IR(KBr)νcm-1:3434,2986,294
0,2477,2234,1912,1730,150
5,1430,1368,1240,1119,107
3,993,918,885,801,745. m.p. 162−165℃ 実施例100 1 H NMR (DMSO-d 6 , 300 M
Hz) δ ppm: 1.91 (s, 6H), 3.86
(S, 3H), 4.00 (s, 3H), 7.38 (s,
1H), 7.62 (s, 1H), 7.63-7.80.
(M, 4H), 9.05 (s, 1H), 13.35 (b
rs, 1H). IR (KBr) νcm -1 : 3434,2986,294
0, 2477, 2234, 1912, 1730, 150
5,1430,1368,1240,1119,107
3,993,918,885,801,745. m. p. 162-165 ° C Example 100
【0327】[0327]
【化78】 Embedded image
【0328】実施例8で製造したカルボン酸(439m
g、0.90mmol)およびEt3 N(0.19m
l、1.37mmol)のTHF溶液(15ml)を−
5℃に冷却しi−BuOCOCl(0.126ml、
0.99mmol)を滴下し、0℃で5分間撹拌した
後、シアナミド(63mg、1.50mmol)を加え
た。反応混合物を−5〜0℃で30分間撹拌し室温まで
徐々に昇温した後水を加え反応を停止した。生成物をE
tOAc(20ml×2)で抽出し、乾燥(Na2 SO
4 )濃縮した。残渣にEtOAcを加えて生じる固体を
EtOAcで懸洗、濾取し目的とするアミド体(98m
g、21%)を白色粉末結晶として得た。The carboxylic acid prepared in Example 8 (439 m
g, 0.90 mmol) and Et 3 N (0.19 m
l, 1.37 mmol) in a THF solution (15 ml)
After cooling to 5 ° C, i-BuOCOCl (0.126 ml,
0.99 mmol) was added dropwise, and the mixture was stirred at 0 ° C. for 5 minutes, and then cyanamide (63 mg, 1.50 mmol) was added. The reaction mixture was stirred at −5 to 0 ° C. for 30 minutes, gradually heated to room temperature, and then water was added to stop the reaction. The product is E
Extract with tOAc (20 ml × 2), dry (Na 2 SO 4)
4 ) Concentrated. EtOAc was added to the residue, and the resulting solid was washed with EtOAc and collected by filtration.
g, 21%) as white powder crystals.
【0329】1H NMR(CDCl3 +D2 O,30
0MHz)δppm:1.46(t,J=6.9Hz,
3H),1.56(t,J=7.0Hz,3H),1.
65(s,3H),2.00−2.30(m,4H),
2.63(m,1H),2.78−3.10(m,2
H),3.20(d,J=13.1Hz,1H),3.
44(d,J=13.1Hz,1H),3.58−3.
82(m,2H),3.93(q,J=7.0Hz,2
H),4.27(q,J=6.9Hz,2H),7.0
4(s,1H),7.20−7.50(m,7H),
9.05(s,1H). IR(KBr)νcm-1:3395,2984,293
8,2654,2513,2249,2166,172
5,1613,1543,1499,1460,139
7,1366,1231,1032,706. m.p. 141−145℃ 実施例101 1 H NMR (CDCl 3 + D 2 O, 30
0 MHz) δ ppm: 1.46 (t, J = 6.9 Hz,
3H), 1.56 (t, J = 7.0 Hz, 3H), 1.
65 (s, 3H), 2.00-2.30 (m, 4H),
2.63 (m, 1H), 2.78-3.10 (m, 2
H), 3.20 (d, J = 13.1 Hz, 1H), 3.
44 (d, J = 13.1 Hz, 1H), 3.58-3.
82 (m, 2H), 3.93 (q, J = 7.0 Hz, 2
H), 4.27 (q, J = 6.9 Hz, 2H), 7.0.
4 (s, 1H), 7.20-7.50 (m, 7H),
9.05 (s, 1H). IR (KBr) νcm -1 : 3395,2984,293
8,2654,2513,2249,2166,172
5,1613,1543,1499,1460,139
7, 1366, 1231, 1032, 706. m. p. 141-145 ° C Example 101
【0330】[0330]
【化79】 Embedded image
【0331】実施例60で製造したカルボン酸(100
mg、0.21mmol)のクロロホルム溶液(5m
l)を−10℃に冷却し、i−BuOCOCl(27μ
l、0.21mmol)とEt3 N(30μl、0.2
1mmol)を加え、15分間撹拌した。ノニルアルコ
ール(50μl、0.28mmol)を加え、室温まで
30分かけて昇温し反応液をCH2 Cl2 で希釈した。
有機層を洗浄(NaHCO3 飽和水溶液、クエン酸水溶
液、飽和食塩水)、乾燥(MgSO4 )、濃縮した。残
渣をシリカゲルカラムクロマトグラフィー(ヘキサン:
EtOAc=15:1→3:1)で精製し目的とするエ
ステル体(45mg、36%)を黄茶油状物質として得
た。The carboxylic acid prepared in Example 60 (100
mg, 0.21 mmol) in chloroform solution (5 m
l) was cooled to -10 ° C and i-BuOCOCl (27
1, 0.21 mmol) and Et 3 N (30 μl, 0.21 mmol).
1 mmol) and stirred for 15 minutes. Nonyl alcohol (50 μl, 0.28 mmol) was added, the temperature was raised to room temperature over 30 minutes, and the reaction solution was diluted with CH 2 Cl 2 .
The organic layer was washed (NaHCO 3 saturated aqueous solution, citric acid aqueous solution, saturated saline), dried (MgSO 4 ) and concentrated. The residue was subjected to silica gel column chromatography (hexane:
Purification by EtOAc = 15: 1 → 3: 1) gave the desired ester (45 mg, 36%) as a yellow-brown oil.
【0332】1H NMR(CDCl3 ,300MH
z)δppm:0.90(t,J=6.5Hz,3
H),1.20−1.70(m,26H),2.60
(t,J=6.8Hz,2H),2.90(m,4
H),3.20(m,2H),4.10(m,4H),
4.30(q,J=8.6Hz,2H),7.23
(m,5H),7.38(s,1H),7.4(s,1
H),9.05(s,1H). IR(film)νcm-1:2928,2214,17
32,1613,1568,1535,1497,13
64,1308,1229,1046,934,85
5,702. Rf=0.6{ヘキサン:EtOAc=1:1,Sil
icagel 60F254 (MERCK)}. 実施例102 1 H NMR (CDCl 3 , 300 MH
z) δ ppm: 0.90 (t, J = 6.5 Hz, 3
H), 1.20-1.70 (m, 26H), 2.60
(T, J = 6.8 Hz, 2H), 2.90 (m, 4
H), 3.20 (m, 2H), 4.10 (m, 4H),
4.30 (q, J = 8.6 Hz, 2H), 7.23
(M, 5H), 7.38 (s, 1H), 7.4 (s, 1
H), 9.05 (s, 1H). IR (film) νcm -1 : 2928,2214,17
32, 1613, 1568, 1535, 1497, 13
64, 1308, 1229, 1046, 934, 85
5,702. Rf=0.6@hexane: EtOAc = 1: 1, Sil
icagel 60F 254 (MERCK)}. Example 102
【0333】[0333]
【化80】 Embedded image
【0334】実施例60で製造したカルボン酸(150
mg、0.32mmol)のジクロロメタン溶液(5m
l)にN,N′−ジシクロヘキシルカルボジイミド(7
4mg、0.35mmol)、N−ヒドロキシスクシン
イミド(40mg、0.34mmol)を加えた。混合
物を室温で1時間撹拌してから生じた沈殿物を濾別し、
濾液を濃縮した。残渣をEtOH(7ml)およびジク
ロロメタン(7ml)で希釈し28%NH4 OH水溶液
を加え室温で1時間撹拌した。溶媒を留去したのち残渣
をCH2 Cl2 (100ml)に溶解し洗浄(飽和Na
HCO3 水溶液、飽和食塩水)、乾燥(MgSO4 )、
濃縮した。残渣をシリカゲルカラムクロマトグラフィー
(CHCl3 :MeOH=50:1)で精製しアミド体
(127mg、81%)を赤茶色フォーム状物質として
得た。The carboxylic acid prepared in Example 60 (150
mg, 0.32 mmol) in dichloromethane (5 m
l) is N, N'-dicyclohexylcarbodiimide (7
4 mg, 0.35 mmol) and N-hydroxysuccinimide (40 mg, 0.34 mmol) were added. The mixture was stirred for 1 hour at room temperature and the resulting precipitate was filtered off,
The filtrate was concentrated. The residue was diluted with EtOH (7 ml) and dichloromethane (7 ml), and a 28% aqueous NH 4 OH solution was added, followed by stirring at room temperature for 1 hour. After the solvent was distilled off, the residue was dissolved in CH 2 Cl 2 (100 ml) and washed (sat.
HCO 3 aqueous solution, saturated saline), dried (MgSO 4 ),
Concentrated. The residue was purified by silica gel column chromatography (CHCl 3 : MeOH = 50: 1) to give an amide (127 mg, 81%) as a reddish brown foam.
【0335】1H NMR(CDCl3 ,300MH
z)δppm:1.24(t,J=7.0Hz,3
H),1.47(t,J=7.0Hz,3H),1.5
3−1.58(m,6H),2.58(m,2H),
2.98(m,3H),3.27(m,3H),3.9
6(q,J=7.0Hz,2H),4.27(q,J=
7.0Hz,2H),5.30(br s,2H),
7.10−7.45(m,7H),9.00(s,1
H). IR(KBr)νcm-1:3347,3187,298
2,2934,2213,1672,1612,147
4,1366,1308,1231,1202,110
9,1044,934,853,702. Rf=0.5{CHCl3 :MeOH=15:1,Si
licagel 60F254 (MERCK)} 実施例103 1 H NMR (CDCl 3 , 300 MH
z) δ ppm: 1.24 (t, J = 7.0 Hz, 3
H), 1.47 (t, J = 7.0 Hz, 3H), 1.5
3-1.58 (m, 6H), 2.58 (m, 2H),
2.98 (m, 3H), 3.27 (m, 3H), 3.9
6 (q, J = 7.0 Hz, 2H), 4.27 (q, J =
7.0 Hz, 2H), 5.30 (brs, 2H),
7.10-7.45 (m, 7H), 9.00 (s, 1
H). IR (KBr) νcm -1 : 3347,3187,298
2,2934,2213,1672,1612,147
4,1366,1308,1231,1202,110
9, 1044, 934, 853, 702. Rf = 0.5 {CHCl 3 : MeOH = 15: 1, Si
licagel 60F 254 (MERCK)} Example 103
【0336】[0336]
【化81】 Embedded image
【0337】実施例61で製造したアルコール体1(3
5mg、0.086mmol)のジクロロメタン(2m
l)溶液に室温下で無水コハク酸(34mg、0.34
4mmol)ジメチルアミノピリジン(52mg、0.
043mmol)、トリエチルアミン(35mg、0.
344mmol)を加えて撹拌した。8日後、反応溶液
をシリカゲルカラムクロマトグラフィー(展開溶媒 H
ex→クロロホルム〜メタノール系)と懸洗(溶媒、E
t2 O)で精製して目的物2(17mg、39%)を得
た。 目的物2The alcohol derivative 1 (3) produced in Example 61
5 mg, 0.086 mmol) of dichloromethane (2 m
1) Succinic anhydride (34 mg, 0.34
4 mmol) dimethylaminopyridine (52 mg, 0.1 mg).
043 mmol), triethylamine (35 mg, 0.1 mg).
344 mmol) and stirred. Eight days later, the reaction solution was subjected to silica gel column chromatography (developing solvent H
ex → chloroform-methanol system) and suspended washing (solvent, E
Purification by t 2 O) gave the desired product 2 (17 mg, 39%). Object 2
【0338】m.p.:175℃1 H NMR(CDCl3 ,300MHz)δppm:
1.43〜1.47(m,2H),1.79(s,3
H),2.69(s,4H),3.42(s,2H),
4.68−4.75(m,1H),4.83−4.91
(m,1H),7.22−7.35(m,6H),7.
46(s,1H),8.79(s,1H). IR(KBr)νcm-1:3426,2980,293
6,2728,2523,2363,2234,189
0,1740,1609,1574,1497,143
7,1370,1314,1236,1155,110
9,1082,1061,955,928,835,7
43,702,588,569,515. 実施例104M. p. 175 ° C. 1 H NMR (CDCl 3 , 300 MHz) δ ppm:
1.43 to 1.47 (m, 2H), 1.79 (s, 3
H), 2.69 (s, 4H), 3.42 (s, 2H),
4.68-4.75 (m, 1H), 4.83-4.91
(M, 1H), 7.22-7.35 (m, 6H), 7.
46 (s, 1H), 8.79 (s, 1H). IR (KBr) νcm -1 : 3426,2980,293
6,2728,2523,2363,2234,189
0,1740,1609,1574,1497,143
7, 1370, 1314, 1236, 1155, 110
9,1082,1061,955,928,835,7
43,702,588,569,515. Example 104
【0339】[0339]
【化82】 Embedded image
【0340】実施例66で製造したニトロピリミジン体
1(457mg、0.87mmol)のエタノール(1
0ml)溶液に亜鉛粉末(561mg)とH2 O(2m
l)を加え還流した。5時間後、濾過した後、母液にH
2 O(50ml)を加え、EtOAc(200ml)で
抽出し、飽和食塩水で洗浄、乾燥(Na2 SO4 )、濃
縮後得られた残渣をシリカゲルカラムクロマトグラフィ
ー(Hex−EtOAc系)で精製し目的物2(100
mg、23%)を得た。 2The nitropyrimidine derivative 1 (457 mg, 0.87 mmol) produced in Example 66 was treated with ethanol (1
0 ml) solution and zinc powder (561 mg) and H 2 O (2 m
l) was added and refluxed. Five hours later, after filtration, H
2 O (50 ml) was added, extracted with EtOAc (200 ml), washed with saturated saline, dried (Na 2 SO 4 ), and concentrated. The residue obtained was purified by silica gel column chromatography (Hex-EtOAc). Object 2 (100
mg, 23%). 2
【0341】油状物質1 H NMR(CDCl3 ,300MHz)δppm:
1.26(t,J=7.2Hz,3H),1.31
(t,J=7.2Hz,3H),1.38(s,3
H),1.75−1.83(m,2H),2.00−
2.04(m,2H),2.34−2.50(m,3
H),2.94(d,J=13.5Hz,1H),3.
19(d,J=13.5Hz,1H),3.17−3.
22(m,1H),3.35−3.38(m,1H),
3.44(s,2H),4.14(q,J=7.2H
z,2H),4.26(q,J=7.2Hz,2H),
4.23(s,2H),5.20(m,1H),7.2
4−7.36(m,5H),8.21(s,1H). IR(neat)νcm-1:3349,3243,29
82,2936,2812,2367,2211,17
30,1589,1468,1263,1188,11
25,1046,752,702. 実施例105Oil 1 H NMR (CDCl 3 , 300 MHz) δ ppm:
1.26 (t, J = 7.2 Hz, 3H), 1.31
(T, J = 7.2 Hz, 3H), 1.38 (s, 3
H), 1.75-1.83 (m, 2H), 2.00-
2.04 (m, 2H), 2.34-2.50 (m, 3
H), 2.94 (d, J = 13.5 Hz, 1H), 3.
19 (d, J = 13.5 Hz, 1H), 3.17-3.
22 (m, 1H), 3.35-3.38 (m, 1H),
3.44 (s, 2H), 4.14 (q, J = 7.2H)
z, 2H), 4.26 (q, J = 7.2 Hz, 2H),
4.23 (s, 2H), 5.20 (m, 1H), 7.2
4-7.36 (m, 5H), 8.21 (s, 1H). IR (neat) νcm -1 : 3349,3243,29
82,2936,2812,2367,2211,17
30, 1589, 1468, 1263, 1188, 11
25,1046,752,702. Example 105
【0342】[0342]
【化83】 Embedded image
【0343】実施例8で製造したイソニペコチン酸体1
(250mg、0.5mmol)のDMF(4ml)溶
液中に1−ペンタデカノール(171mg、0.75m
mol)のDMF(2ml)溶液を加え室温で撹拌した
中にトリエチルアミン(152mg、1.5mmo
l)、1−ヒドロキシベンゾトリアゾール(101m
g、0.75mmol)、N,N′−ジシクロヘキシル
カルボジイミド(129mg、0.625mmol)を
氷浴下で加え、60℃で撹拌した。3時間後、減圧濃縮
してNaHCO3 飽和水溶液を加え、EtOAcで抽出
した後、飽和食塩水で洗浄、乾燥(Na2 SO4 )、濃
縮して残渣(0.63g)を得た。これをシリカゲルカ
ラムクロマトグラフィー(展開溶媒Hex−EtOAc
系)、懸洗(溶媒、Et2 O)で精製して目的物の長鎖
エステル体2(135mg、39%)を得た。Isonipecotinic acid compound 1 produced in Example 8
1-pentadecanol (171 mg, 0.75 m) in a DMF (4 ml) solution of (250 mg, 0.5 mmol)
mol) in DMF (2 ml) and stirred at room temperature while triethylamine (152 mg, 1.5 mmol) was added.
l), 1-hydroxybenzotriazole (101 m
g, 0.75 mmol) and N, N'-dicyclohexylcarbodiimide (129 mg, 0.625 mmol) were added in an ice bath, and the mixture was stirred at 60 ° C. After 3 hours, the mixture was concentrated under reduced pressure, a saturated aqueous solution of NaHCO 3 was added thereto, extracted with EtOAc, washed with saturated saline, dried (Na 2 SO 4 ), and concentrated to obtain a residue (0.63 g). This was subjected to silica gel column chromatography (developing solvent Hex-EtOAc).
The resulting product was purified by suspending and washing (solvent, Et 2 O) to obtain the desired long-chain ester 2 (135 mg, 39%).
【0344】長鎖エステル体2 油状物質1 H NMR(CDCl3 ,300MHz)δppm:
0.88(t,J=6.9Hz,3H),1.26−
1.30(m,26H),1.45(s,3H),1.
50(t,J=7.2Hz,3H),1.56(t,J
=7.2Hz,3H),1.76−1.88(m,2
H),1.97−2.03(m,2H),2.32−
2.60(m,3H),3.05(d,J=13.5H
z,1H),3.28(d,J=13.5Hz,1
H),3.52〜3.30(m,1H),3.43−
3.48(m,1H),4.03−4.10(m,4
H),4.28(q,J=7.2Hz,2H),7.2
2−7.29(m,5H),7.34−737(m,2
H),9.07(s,1H). IR(neat)νcm-1:2926,2855,28
09,2751,2361,2213,1890,17
32,1613,1497,1456,1397,13
64,1304,1262,1231,1202,11
28,1046,959,934,855,760,7
02,440. 実施例106Long-chain ester 2 oily substance 1 H NMR (CDCl 3 , 300 MHz) δ ppm:
0.88 (t, J = 6.9 Hz, 3H), 1.26
1.30 (m, 26H), 1.45 (s, 3H), 1.
50 (t, J = 7.2 Hz, 3H), 1.56 (t, J
= 7.2 Hz, 3H), 1.76-1.88 (m, 2
H), 1.97-2.03 (m, 2H), 2.32-
2.60 (m, 3H), 3.05 (d, J = 13.5H)
z, 1H), 3.28 (d, J = 13.5 Hz, 1
H), 3.52-3.30 (m, 1H), 3.43-
3.48 (m, 1H), 4.03-4.10 (m, 4
H), 4.28 (q, J = 7.2 Hz, 2H), 7.2
2-7.29 (m, 5H), 7.34-737 (m, 2
H), 9.07 (s, 1H). IR (neat) νcm -1 : 2926,2855,28
09,2751,2361,223,1890,17
32, 1613, 1497, 1456, 1397, 13
64, 1304, 1262, 1231, 1202, 11
28,1046,959,934,855,760,7
02,440. Example 106
【0345】[0345]
【化84】 Embedded image
【0346】実施例8で製造したイソニペコチン酸体1
(268mg、0.54mmol)のTHF(20m
l)溶液に−5℃下でクロルギ酸イソブチルエステル
(88mg、0.65mmol)のTHF(1ml)溶
液を滴下した。10分間撹拌の後トリエチルアミン(6
6mg、0.65mmol)のTHF(1ml)溶液を
滴下して10分間撹拌した後、28%アンモニア水溶液
(4ml)を滴下した。10分後、減圧濃縮して得られ
た残渣にNaHCO3 飽和水溶液(10ml)を加え、
EtOAc(30ml)で抽出、飽和食塩水(10m
l)で洗浄、乾燥(Na2 SO4 )、減圧濃縮して粗結
晶(278mg)を得た。これを懸洗(溶媒EtOA
c)で精製し目的物のアミド体(164mg、63%)
を得た。Isonipecotinic acid compound 1 prepared in Example 8
(268 mg, 0.54 mmol) in THF (20 m
l) A solution of isobutyl chloroformate (88 mg, 0.65 mmol) in THF (1 ml) was added dropwise to the solution at -5 ° C. After stirring for 10 minutes, triethylamine (6
(6 mg, 0.65 mmol) in THF (1 ml) was added dropwise, and the mixture was stirred for 10 minutes, and then a 28% aqueous ammonia solution (4 ml) was added dropwise. Ten minutes later, a saturated aqueous solution of NaHCO 3 (10 ml) was added to the residue obtained by concentration under reduced pressure.
Extracted with EtOAc (30 ml), saturated brine (10 m
1), dried (Na 2 SO 4 ) and concentrated under reduced pressure to obtain crude crystals (278 mg). Wash this (solvent EtOA)
Purified in c), the desired amide (164 mg, 63%)
I got
【0347】白色結晶 m.p.:198℃1 H NMR(CDCl3 ,300MHz)δppm:
1.45(s,3H),1.49(t,J=6.9H
z,3H),1.56(t,J=6.9Hz,3H),
1.68−2.04(m,4H),2.20−2.30
(m,1H),2.42−2.46(m,1H),2.
53−2.57(m,1H),3.05(d,J=1
3.5Hz,1H),3.28(d,J=13.5H
z,1H),3.30−3.35(m,1H),3.4
9−3.53(m,1H),4.02(q,J=6.9
Hz,2H),4.28(q,J=6.9Hz,2
H),5.39(s,1H),5.51(s,1H),
7.22−7.29(m,5H),7.34−7.37
(m,2H),9.07(s,1H). IR(KBr)νcm-1:3304,3135,298
0,2938,2814,2367,2209,169
0,1611,1564,1535,1497,145
8,1360,1310,1231,1109,102
8,932,858,826,762,704,65
4. 実施例107White crystals m. p. 198 ° C. 1 H NMR (CDCl 3 , 300 MHz) δ ppm:
1.45 (s, 3H), 1.49 (t, J = 6.9H)
z, 3H), 1.56 (t, J = 6.9 Hz, 3H),
1.68-2.04 (m, 4H), 2.20-2.30
(M, 1H), 2.42-2.46 (m, 1H), 2.
53-2.57 (m, 1H), 3.05 (d, J = 1
3.5 Hz, 1 H), 3.28 (d, J = 13.5 H)
z, 1H), 3.30-3.35 (m, 1H), 3.4
9-3.53 (m, 1H), 4.02 (q, J = 6.9)
Hz, 2H), 4.28 (q, J = 6.9 Hz, 2
H), 5.39 (s, 1H), 5.51 (s, 1H),
7.22-7.29 (m, 5H), 7.34-7.37
(M, 2H), 9.07 (s, 1H). IR (KBr) νcm −1 : 3304,3135,298
0,2938,2814,2367,2209,169
0, 1611, 1564, 1535, 1497, 145
8, 1360, 1310, 1231, 1109, 102
8,932,858,826,762,704,65
4. Example 107
【0348】[0348]
【化85】 Embedded image
【0349】実施例8で製造したカルボン酸体1(25
0mg、0.50mmol)のN,N−ジメチルホルム
アミド溶液(6ml)にイソプロピルアミン(44m
g、0.75mmol)、トリエチルアミン(152m
g、15mmol)、1−ヒドロキシビンゾトリアゾー
ル(102mg、0.75mmol)、N,N−ジシク
ロカルボジイミド(129mg、0.625mmol)
を室温下で順次加えた後、50℃で撹拌した。1時間
後、減圧濃縮した後、NaHCO3 飽和水溶液を加え酢
酸エチルで抽出し、飽和食塩水で洗浄、乾燥(Na2 S
O4 )、濃縮して得られた残渣をシリカゲルカラムクロ
マトグラフィー(溶媒:酢酸エチル−メタノール系)、
懸洗(溶媒:メタノール−ジエチルエーテル系)で精製
して目的物2(65mg、24%)を得た。The carboxylic acid derivative 1 prepared in Example 8 (25
0 mg, 0.50 mmol) in N, N-dimethylformamide solution (6 ml).
g, 0.75 mmol), triethylamine (152 m
g, 15 mmol), 1-hydroxyvinzotriazole (102 mg, 0.75 mmol), N, N-dicyclocarbodiimide (129 mg, 0.625 mmol)
Was added successively at room temperature, followed by stirring at 50 ° C. One hour later, the mixture was concentrated under reduced pressure, a saturated aqueous solution of NaHCO 3 was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried (Na 2 S).
O 4 ), and the residue obtained by concentration was subjected to silica gel column chromatography (solvent: ethyl acetate-methanol system),
Purification by hanging washing (solvent: methanol-diethyl ether system) gave the desired product 2 (65 mg, 24%).
【0350】m.p.:149℃1 H NMR(CDCl3 ,300MHz)δppm:
1.14(d,J=6.6Hz,6H),1.45
(s,3H),1.49(t,J=7.2Hz,3
H),1.56(t,J=6.9Hz,3H),1.7
7−2.11(m,5H),2.37−2.57(m,
2H),3.04(d,J=13.5Hz,1H),
3.28(d,J=13.5Hz,1H),3.26−
3.34(m,1H),3.51−3.52(m,1
H),4.02(q,J=6.9Hz,2H),4.0
9(q,J=6.6Hz,1H),4.28(q,J=
7.2Hz,2H),5.22−5.25(m,1
H),7.24−7.26(m,5H),7.35−
7.36(m,2H),9.07(s,1H). IR(KBr)νcm-1:3283,3063,297
6,2936,2811,2211,1730,164
0,1537,1499,1474,1456,136
4,1231,1202,1128,1111,104
6,853,828,702,666,569. 実施例108 化合物5の製造M. p. 149 ° C. 1 H NMR (CDCl 3 , 300 MHz) δ ppm:
1.14 (d, J = 6.6 Hz, 6H), 1.45
(S, 3H), 1.49 (t, J = 7.2 Hz, 3
H), 1.56 (t, J = 6.9 Hz, 3H), 1.7
7-2.11 (m, 5H), 2.37-1.57 (m, 5H)
2H), 3.04 (d, J = 13.5 Hz, 1H),
3.28 (d, J = 13.5 Hz, 1H), 3.26-
3.34 (m, 1H), 3.51-3.52 (m, 1
H), 4.02 (q, J = 6.9 Hz, 2H), 4.0.
9 (q, J = 6.6 Hz, 1H), 4.28 (q, J =
7.2 Hz, 2H), 5.22-5.25 (m, 1
H), 7.24-7.26 (m, 5H), 7.35-
7.36 (m, 2H), 9.07 (s, 1H). IR (KBr) νcm -1 : 3283,3063,297
6,2936,2811,2121,1730,164
0, 1537, 1499, 1474, 1456, 136
4,1231,1202,1128,1111,104
6,853,828,702,666,569. Example 108 Preparation of compound 5
【0351】[0351]
【化86】 Embedded image
【0352】1)水素化ナトリウム(460mg、1
1.5mmol、60% in oil)を乾燥ヘキサ
ンで洗浄し、DMF(30ml)を加え、氷浴上撹拌し
た。化合物1(1.90g、9.8mmol)を加え室
温で30分間撹拌後、プロパギルブロマイド(0.8m
l、10.6mmol)を氷冷下加えた。室温で1時間
撹拌後、氷冷下水を加え反応を停止させ、生成物をエー
テル(60ml)で抽出した。抽出液を乾燥、濃縮し残
渣をシリカゲルカラムクロマトグラフィーで精製し、化
合物2(1.51g、66%)を得た。 2: 1H NMR(CDCl3 ,300MHz)δpp
m:1.46(s,9H),2.24(t,J=2.4
Hz,1H),4.36(d,J=2.4Hz,2
H),7.10−7.50(m,5H).1) Sodium hydride (460 mg, 1
(1.5 mmol, 60% in oil) was washed with dry hexane, DMF (30 ml) was added, and the mixture was stirred on an ice bath. Compound 1 (1.90 g, 9.8 mmol) was added and the mixture was stirred at room temperature for 30 minutes, and then propargyl bromide (0.8 m
1, 10.6 mmol) was added under ice cooling. After stirring at room temperature for 1 hour, water was added under ice cooling to stop the reaction, and the product was extracted with ether (60 ml). The extract was dried and concentrated, and the residue was purified by silica gel column chromatography to obtain Compound 2 (1.51 g, 66%). 2: 1 H NMR (CDCl 3 , 300 MHz) δpp
m: 1.46 (s, 9H), 2.24 (t, J = 2.4
Hz, 1H), 4.36 (d, J = 2.4 Hz, 2
H), 7.10-7.50 (m, 5H).
【0353】2)PdCl2 (PPh3 )2 (10m
g、0.014mmol)とPPh3(15mg、0.
056mmol)、のTHF溶液(7ml)を室温でし
ばらく撹拌した後、これに化合物1(250mg、1.
1mmol)、4−ヨード−6,7−ジメトキシキナゾ
リン(3)(144mg、0.5mmol)、CuI
(10mg、0.053mmol)およびEt3 N
(0.5ml、3.6mmol)を加え1時間還流後、
室温で一晩放置した。反応液にNH4 Cl水溶液、Na
HCO3 飽和水溶液を加え、生成物をEtOAcで抽出
した。抽出液を乾燥、濃縮し、残渣をシリカゲルカラム
クロマトグラフィーで精製し化合物4(100mg、5
0%)を得た。 4: 1H NMR(CDCl3 ,300MHz)δpp
m:1.46(s,9H),3.96(s,3H),
4.06(s,3H),4.80(s,2H),7.2
0−7.50(m,7H),9.09(s,1H).2) PdCl 2 (PPh 3 ) 2 (10 m
g, 0.014 mmol) and PPh 3 (15 mg, 0.1 g).
056 mmol) in THF (7 ml) was stirred at room temperature for a while and then added to Compound 1 (250 mg, 1.
1 mmol), 4-iodo-6,7-dimethoxyquinazoline (3) (144 mg, 0.5 mmol), CuI
(10 mg, 0.053 mmol) and Et 3 N
(0.5 ml, 3.6 mmol) and refluxed for 1 hour.
Left at room temperature overnight. NH 4 Cl aqueous solution, Na
A saturated aqueous solution of HCO 3 was added and the product was extracted with EtOAc. The extract was dried and concentrated, and the residue was purified by silica gel column chromatography to give compound 4 (100 mg, 5 mg).
0%). 4: 1 H NMR (CDCl 3 , 300 MHz) δpp
m: 1.46 (s, 9H), 3.96 (s, 3H),
4.06 (s, 3H), 4.80 (s, 2H), 7.2
0-7.50 (m, 7H), 9.09 (s, 1H).
【0354】3)化合物3(100mg、0.245m
mol)を氷冷上冷却し4N HCl AcOEt溶液
(2ml)を加えた。撹拌しながら30分以上かけて室
温に昇温し、反応液を濃縮した。Et2 O(10ml)
を加え、生成物を濾取した。残渣をCH2 Cl2 (40
ml)−NaHCO3 飽和水溶液(20ml)に分配
し、CH2 Cl2 層を乾燥、濃縮した。得られる残渣を
EtOAc−Et2 Oで懸洗し、目的とする化合物5
(40mg、53%)を得た。 5: 1H NMR(CDCl3 ,250MHz)δpp
m:4.06(s,3H),4.08(s,3H),
5.38(d,J=2.4Hz,2H),6.98
(t,J=2.4Hz,1H),7.15−7.40
(m,3H),7.47(t,J=7.9Hz,2
H),7.72(d,J=7.9Hz,2H),9.0
8(s,1H). IR(KBr)νcm-1:3395,2182,179
0,1665,1576,1503,1431,138
5,1300,1238,1115,974,845,
758. 実施例1093) Compound 3 (100 mg, 0.245 m
mol) was cooled on ice and 4N HCl AcOEt solution (2 ml) was added. The temperature was raised to room temperature over 30 minutes with stirring, and the reaction solution was concentrated. Et 2 O (10 ml)
Was added and the product was collected by filtration. The residue was washed with CH 2 Cl 2 (40
ml) -NaHCO 3 saturated aqueous solution (20 ml), and the CH 2 Cl 2 layer was dried and concentrated. The resulting residue was washed with EtOAc-Et 2 O to give the desired compound 5
(40 mg, 53%). 5: 1 H NMR (CDCl 3 , 250 MHz) δpp
m: 4.06 (s, 3H), 4.08 (s, 3H),
5.38 (d, J = 2.4 Hz, 2H), 6.98
(T, J = 2.4 Hz, 1H), 7.15-7.40
(M, 3H), 7.47 (t, J = 7.9 Hz, 2
H), 7.72 (d, J = 7.9 Hz, 2H), 9.0
8 (s, 1H). IR (KBr) νcm −1 : 3395,2182,179
0, 1665, 1576, 1503, 1431, 138
5,1300,1238,1115,974,845,
758. Example 109
【0355】[0355]
【化87】 Embedded image
【0356】ジイソプロピルアミン(43mg、0.4
3mmol)のTHF溶液(2mM)に−78℃にて
1.6M nBuLiヘキサン溶液(0.268ml、
0.43mmol)を滴下した。これを実施例33で得
たアルコール体(100mg、0.287mmol)の
THF(1ml)溶液に加え、室温とした後、無水フタ
ル酸(44mg、0.3mmol)を加えた。反応液に
塩化アンモニウム水溶液を加え、酢酸エチルで抽出し
た。有機層を食塩水で洗浄し、減圧下溶媒を留去した。
残渣をカラムクロマトグラフィーで精製し、Et2 Oを
注ぎ生じた結晶を濾取し、半エステル体(16.7m
g、0.034mmol、収率12%)を得た。以後、
この半エステル合成法をエステル化A法と記す。Diisopropylamine (43 mg, 0.4
3 mmol) in a THF solution (2 mM) at -78 ° C at 1.6 M nBuLi in hexane (0.268 ml,
0.43 mmol) was added dropwise. This was added to a solution of the alcohol form (100 mg, 0.287 mmol) obtained in Example 33 in THF (1 ml), and the mixture was brought to room temperature. Then, phthalic anhydride (44 mg, 0.3 mmol) was added. An aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and the solvent was distilled off under reduced pressure.
The residue was purified by column chromatography, and the resulting crystals were poured into Et 2 O and collected by filtration.
g, 0.034 mmol, yield 12%). Since then
This half ester synthesis method is referred to as esterification method A.
【0357】1H NMR(CDCl3 ,250MH
z)δppm:1.95(s,3H),3.47(d,
J=13.7Hz,1H),3.62(d,J=13.
7Hz,1H),3.99(s,3H),4.00
(s,3H),6.98(s,1H),7.36−7.
41(m,5H),7.49−7.60(m,4H),
7.93−8.0(m,1H),8.66(s,1
H). 実施例110 1 H NMR (CDCl 3 , 250 MH
z) δ ppm: 1.95 (s, 3H), 3.47 (d,
J = 13.7 Hz, 1H), 3.62 (d, J = 13.
7 Hz, 1H), 3.99 (s, 3H), 4.00
(S, 3H), 6.98 (s, 1H), 7.36-7.
41 (m, 5H), 7.49-7.60 (m, 4H),
7.93-8.0 (m, 1H), 8.66 (s, 1
H). Example 110
【0358】[0358]
【化88】 Embedded image
【0359】実施例33で得たアルコール体(100m
g、0.29mmol)と無水コハク酸(45mg、
0.29mmol)をエステル化A法にて反応を行い、
目的物(19mg、0.042mmol、15%)を得
た。1 H NMR(CDCl3 ,250MHz)δppm:
1.83(s,3H),2.68−2.79(m,4
H),3.38−3.52(m,2H),3.90
(s,3H),4.12(s,3H),7.15(s,
1H),7.27−7.43(m,6H),8.69
(s,1H). 実施例111The alcohol compound obtained in Example 33 (100 m
g, 0.29 mmol) and succinic anhydride (45 mg,
0.29 mmol) by the esterification A method,
The desired product (19 mg, 0.042 mmol, 15%) was obtained. 1 H NMR (CDCl 3 , 250 MHz) δ ppm:
1.83 (s, 3H), 2.68-2.79 (m, 4
H), 3.38-3.52 (m, 2H), 3.90
(S, 3H), 4.12 (s, 3H), 7.15 (s,
1H), 7.27-7.43 (m, 6H), 8.69.
(S, 1H). Example 111
【0360】[0360]
【化89】 Embedded image
【0361】実施例22で得たアルコール体(120m
g、0.33mmol)と無水コハク酸(33mg、
0.33mmol)をエステル化A法にて反応を行い、
目的物(8mg、0.017mmol、5%)を得た。1 H NMR(CDCl3 ,250MHz)δppm:
1.82(s,3H),2.63−2.75(m,4
H),3.37(s,2H),3.90(s,3H),
4.13(s,3H),6.70−7.07(m,2
H),7.16(s,1H),7.33〜7.38
(m,2H),7.45(s,1H),8.72(s,
1H). 実施例112The alcohol compound obtained in Example 22 (120 m
g, 0.33 mmol) and succinic anhydride (33 mg,
0.33 mmol) by the esterification A method,
The desired product (8 mg, 0.017 mmol, 5%) was obtained. 1 H NMR (CDCl 3 , 250 MHz) δ ppm:
1.82 (s, 3H), 2.63-2.75 (m, 4
H), 3.37 (s, 2H), 3.90 (s, 3H),
4.13 (s, 3H), 6.70-7.07 (m, 2
H), 7.16 (s, 1H), 7.33-7.38.
(M, 2H), 7.45 (s, 1H), 8.72 (s,
1H). Example 112
【0362】[0362]
【化90】 Embedded image
【0363】プロパルジルアルコール体(3z)と4−
フルオロフェニルアセトンの3:1混合物(560m
g、2.4mmol)とクロロキナゾリン(2j)(5
00mg、1.98mmol)を実施例7と同様の方法
で反応を行い、目的化合物(720mg、92%)を得
た。1 H NMR(CDCl3 ,250MHz)δppm:
1.52(t,J=7.0Hz,3H),1.57
(t,J=7.0Hz,3H),1.75(s,3
H),3.07−3.22(m,2H),4.06
(q,2H,J=7.0Hz),4.27(q,2H,
J=7.0Hz),7.01(dd,J=8.7,8.
7Hz,2H),7.14(s,1H),7.26
(s,1H),7.38(dd,J=8.7,5.4H
z,2H),9.06(s,1H). 実施例113The propargyl alcohol compound (3z) and 4-
3: 1 mixture of fluorophenylacetone (560 m
g, 2.4 mmol) and chloroquinazoline (2j) (5
(00 mg, 1.98 mmol) was reacted in the same manner as in Example 7 to obtain the desired compound (720 mg, 92%). 1 H NMR (CDCl 3 , 250 MHz) δ ppm:
1.52 (t, J = 7.0 Hz, 3H), 1.57
(T, J = 7.0 Hz, 3H), 1.75 (s, 3
H), 3.07-3.22 (m, 2H), 4.06.
(Q, 2H, J = 7.0 Hz), 4.27 (q, 2H,
J = 7.0 Hz), 7.01 (dd, J = 8.7, 8.
7 Hz, 2H), 7.14 (s, 1H), 7.26
(S, 1H), 7.38 (dd, J = 8.7, 5.4H
z, 2H), 9.06 (s, 1H). Example 113
【0364】[0364]
【化91】 Embedded image
【0365】実施例112で得たアルコール体(720
mg、1.83mmol)のCH2Cl2 溶液(5m
l)に、無水コハク酸(400mg、4mmol)、4
−ジメチルアミノピリジン(50mg、0.41mmo
l)、トリエチルアミン(1.5ml、10.8mmo
l)を加え室温で18時間撹拌した。反応液をクロロホ
ルムと1N塩酸水溶液に分配し、有機層を飽和食塩水で
洗浄し、Na2 SO4 上で乾燥後減圧下溶媒を留去し
た。残渣をカラムクロマトグラフィーにより精製後、エ
ーテル−ヘキサン(1:1)溶媒にて、懸洗し(215
mg、0.434mmol、収率24%)で半エステル
体を得た。The alcohol compound obtained in Example 112 (720
mg, 1.83 mmol) in CH 2 Cl 2 (5 m
l) has succinic anhydride (400 mg, 4 mmol), 4
-Dimethylaminopyridine (50 mg, 0.41 mmol
l), triethylamine (1.5 ml, 10.8 mmol)
l) was added and the mixture was stirred at room temperature for 18 hours. The reaction solution was partitioned between chloroform and a 1N aqueous hydrochloric acid solution, and the organic layer was washed with saturated saline, dried over Na 2 SO 4 , and the solvent was distilled off under reduced pressure. After the residue was purified by column chromatography, the residue was washed with ether-hexane (1: 1) solvent (215).
(mg, 0.434 mmol, 24% yield).
【0366】以後、この半エステル合成法をエステル化
B法と記す。 単黄色結晶 m.p.129−131℃1 H NMR(CDCl3 ,250MHz)δppm:
1.55(t,J=6.8Hz,3H),1.57
(t,J=6.8Hz,3H),1.79(s,3
H),2.64−2.84(m,4H),3.30−
3.50(m,2H),4.13(q,2H,J=6.
8Hz),4.25−4.50(m,2H),6.99
−7.06(m,2H),7.15(s,1H),7.
25−7.36(m,3H),8.68(s,1H). IR(KBr)νcm-1:3423,2984,293
7,2363,1741,1371,1315,123
6,1157,1062,937,827,653,5
69,420. 実施例114Hereinafter, this half ester synthesis method is referred to as esterification method B. Single yellow crystal m. p. 129-131 ° C. 1 H NMR (CDCl 3 , 250 MHz) δ ppm:
1.55 (t, J = 6.8 Hz, 3H), 1.57
(T, J = 6.8 Hz, 3H), 1.79 (s, 3
H), 2.64-2.84 (m, 4H), 3.30-
3.50 (m, 2H), 4.13 (q, 2H, J = 6.
8Hz), 4.25-4.50 (m, 2H), 6.99
-7.06 (m, 2H), 7.15 (s, 1H), 7.
25-7.36 (m, 3H), 8.68 (s, 1H). IR (KBr) νcm -1 : 3423,2984,293
7, 2363, 1741, 1371, 1315, 123
6,1157,1062,937,827,653,5
69, 420. Example 114
【0367】[0367]
【化92】 Embedded image
【0368】プロパルジルアルコール(3ae)(32
0mg、2.0mmol)と、クロロキナゾリン(2
j)(500mg、1.98mmol)を実施例7と同
様の方法で反応を行い、目的化合物(594mg、1.
56mmol、80%)を得た。1 H NMR(CDCl3 ,250MHz)δppm:
1.50(t,J=7.0Hz,3H),1.56
(t,J=7.0Hz,3H),1.68(s,3
H),3.12(d,J=13.3Hz,1H),3.
22(d,J=13.3Hz,1H),4.03(q,
J=7.0Hz,2H),4.27(q,J=7.0H
z,2H),7.15(s,1H),7.27−7.3
2(m,4H),7.39−7.44(m,2H),
9.07(s,1H). 実施例115Propardyl alcohol (3ae) (32
0 mg, 2.0 mmol) and chloroquinazoline (2
j) (500 mg, 1.98 mmol) was reacted in the same manner as in Example 7 to give the target compound (594 mg, 1.98 mmol).
(56 mmol, 80%). 1 H NMR (CDCl 3 , 250 MHz) δ ppm:
1.50 (t, J = 7.0 Hz, 3H), 1.56
(T, J = 7.0 Hz, 3H), 1.68 (s, 3
H), 3.12 (d, J = 13.3 Hz, 1H), 3.
22 (d, J = 13.3 Hz, 1H), 4.03 (q,
J = 7.0 Hz, 2H), 4.27 (q, J = 7.0H)
z, 2H), 7.15 (s, 1H), 7.27-7.3.
2 (m, 4H), 7.39-7.44 (m, 2H),
9.07 (s, 1H). Example 115
【0369】[0369]
【化93】 Embedded image
【0370】実施例114で得たアルコール体(300
mg、0.80mmol)と無水コハク酸(80mg、
0.80mmol)をエステル化B法にて反応を行い目
的物(28mg、0.059mmol、7.4%)を得
た。 白色結晶 m.p.148〜150℃1 H NMR(CDCl3 ,300MHz)δppm:
1.52−1.58(m,6H),1.81(s,3
H),2.60−2.80(m,4H),3.35−
3.50(m,2H),7.16(s,1H),7.2
6−7.40(m,6H),8.70(s,1H). IR(KBr)νcm-1:3427,2984,293
7,2363,1612,1577,1500,146
7,1439,1400,1371,1059,93
9,827,706 実施例116The alcohol compound obtained in Example 114 (300
mg, 0.80 mmol) and succinic anhydride (80 mg,
0.80 mmol) was reacted by the esterification B method to obtain the desired product (28 mg, 0.059 mmol, 7.4%). White crystals m. p. 148-150 ° C 1 H NMR (CDCl 3 , 300 MHz) δ ppm:
1.52-1.58 (m, 6H), 1.81 (s, 3
H), 2.60-2.80 (m, 4H), 3.35-
3.50 (m, 2H), 7.16 (s, 1H), 7.2
6-7.40 (m, 6H), 8.70 (s, 1H). IR (KBr) νcm -1 : 3427,2984,293
7, 2363, 1612, 1577, 1500, 146
7, 1439, 1400, 1371, 1059, 93
9,827,706 Example 116
【0371】[0371]
【化94】 Embedded image
【0372】3,4−ジクロロフェニルアセトン(1
g、6.0mmol)のTHF(10ml)溶液にエチ
ニルマグネシウムクロリド(0.5M in THF
12ml、6mmol)を加えた。これに塩化アンモニ
ウム水溶液を加えた後、酢酸エチルで抽出後、有機層を
飽和食塩水で洗浄し、硫酸ナトリウムで乾燥し減圧下溶
媒を留去した。出発物質3,4−ジクロロフェニルアセ
トンとプロパルジルアルコールの混合物(NMR比、
1:2)(1.21g)が得られた(65%)。この混
合物(200mg、0.64mmol)とクロロキナゾ
リン(2j)(176mg、0.70mmol)を実施
例7と同様の反応を行い、カップリング生成物とDMF
の1:1混合物(164mg、49%)を得た。3,4-dichlorophenylacetone (1
g, 6.0 mmol) in THF (10 ml) was added to ethynylmagnesium chloride (0.5 M in THF).
12 ml, 6 mmol). An aqueous ammonium chloride solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Mixture of starting materials 3,4-dichlorophenylacetone and propargyl alcohol (NMR ratio,
1: 2) (1.21 g) was obtained (65%). This mixture (200 mg, 0.64 mmol) and chloroquinazoline (2j) (176 mg, 0.70 mmol) were reacted in the same manner as in Example 7 to obtain a coupling product and DMF.
To give a 1: 1 mixture (164 mg, 49%).
【0373】1H NMR(CDCl3 ,250MH
z)δppm:1.52(t,J=6.9Hz,3
H),1.56(t,J=7.9Hz,3H),1.7
4(s,3H),3.07(d,J=13.8Hz,1
H),3.14(d,J=13.8Hz,1H),4.
05(q,J=6.9Hz,2H),4.26(q,J
=7.0Hz,2H),7.11(s,1H),7.2
3(m,2H),7.36(d,J=8.2Hz,1
H),7.51(d,J=1.8Hz,1H),9.0
5(s,1H). 実施例117 1 H NMR (CDCl 3 , 250 MH
z) δ ppm: 1.52 (t, J = 6.9 Hz, 3
H), 1.56 (t, J = 7.9 Hz, 3H), 1.7
4 (s, 3H), 3.07 (d, J = 13.8 Hz, 1
H), 3.14 (d, J = 13.8 Hz, 1H), 4.
05 (q, J = 6.9 Hz, 2H), 4.26 (q, J
= 7.0 Hz, 2H), 7.11 (s, 1H), 7.2
3 (m, 2H), 7.36 (d, J = 8.2 Hz, 1
H), 7.51 (d, J = 1.8 Hz, 1H), 9.0
5 (s, 1H). Example 117
【0374】[0374]
【化95】 Embedded image
【0375】実施例116で得たアルコール体とDMF
の混合物(164mg)をエステル化B法で反応を行
い、目的物(122mg、65%)を得た。 淡黄色結晶 m.p.124〜126℃1 H NMR(CDCl3 ,300MHz)δppm:
1.54(t,J=6.9Hz,3H),1.58
(t,J=7.0Hz,3H),1.82(s,3
H),2.60−2.88(m,4H),3.31
(d,J=13.8Hz,1H),3.39(d,J=
13.8Hz,1H),4.14(q,J=6.9H
z,2H),4.28−4.38(m,2H),7.1
7(s,1H),7.24(dd,J=8.1,1.8
Hz,1H),7.38(s,1H),7.41(d,
J=8.1Hz,1H),7.47(d,J=1.8H
z,1H),8.72(s,1H). IR(KBr)νcm-1:3427,2984,293
7,2364,2235,1741,1612,157
5,1500,1469,1371,1236,115
3,1032,933,825,652,567. 実施例118The alcohol compound obtained in Example 116 and DMF
(164 mg) was reacted by the esterification method B to obtain the desired product (122 mg, 65%). Pale yellow crystals m. p. 124-126 ° C 1 H NMR (CDCl 3 , 300 MHz) δ ppm:
1.54 (t, J = 6.9 Hz, 3H), 1.58
(T, J = 7.0 Hz, 3H), 1.82 (s, 3
H), 2.60-2.88 (m, 4H), 3.31.
(D, J = 13.8 Hz, 1H), 3.39 (d, J =
13.8 Hz, 1 H), 4.14 (q, J = 6.9 H)
z, 2H), 4.28-4.38 (m, 2H), 7.1
7 (s, 1H), 7.24 (dd, J = 8.1, 1.8
Hz, 1H), 7.38 (s, 1H), 7.41 (d,
J = 8.1 Hz, 1H), 7.47 (d, J = 1.8H)
z, 1H), 8.72 (s, 1H). IR (KBr) νcm -1 : 3427,2984,293
7, 2364, 2235, 1741, 1612, 157
5,1500,1469,1371,1236,115
3, 1032, 933, 825, 652, 567. Example 118
【0376】[0376]
【化96】 Embedded image
【0377】クロロキナゾリン(2i)(100mg、
0.55mmol)とプロパルジルアルコール(3z)
(157mg、0.664mmol)を実施例7と同様
の方法で反応を行いカップリング生成物を含む油状物質
(180mg)を得た。1 H NMR(CDCl3 ,250MHz)δppm:
1.75(s,3H),3.05−3.20(m,2
H),6.19(s,2H),7.04(dd,J=
8.5,8.5Hz,2H),7.13(s,1H),
7.38(dd,J=8.5,5.5Hz,2H),
9.04(s,1H). 実施例119Chloroquinazoline (2i) (100 mg,
0.55 mmol) and propargyl alcohol (3z)
(157 mg, 0.664 mmol) was reacted in the same manner as in Example 7 to obtain an oily substance (180 mg) containing a coupling product. 1 H NMR (CDCl 3 , 250 MHz) δ ppm:
1.75 (s, 3H), 3.05-3.20 (m, 2
H), 6.19 (s, 2H), 7.04 (dd, J =
8.5, 8.5 Hz, 2H), 7.13 (s, 1H),
7.38 (dd, J = 8.5, 5.5 Hz, 2H),
9.04 (s, 1H). Example 119
【0378】[0378]
【化97】 Embedded image
【0379】実施例118で得たカップリング生成物を
含む油状物質(180mg)と無水コハク酸(163m
g、1.63mmol)をエステル化B法にて反応を行
い、目的物(65mg、0.14mmol、実施例11
7の2iより26%)を得た。 淡黄色結晶 m.p.152〜154℃1 H NMR(CDCl3 ,250MHz)δppm:
1.81(s,3H),2.60−2.85(m,4
H),3.36(s,2H),6.14(s,2H),
7.02(t,J=8.6Hz,2H),7.05
(s,1H),7.27(s,1H),7.31(t,
J=8.6Hz,1H),7.34(t,J=8.6H
z,1H),8.96(s,1H). IR(KBr)νcm-1:3425,3055,293
2,2364,2237,1901,1736,161
6,1545,1510,1467,1367,121
9,1153,1066,1035,906,877,
841,652,611,565. 実施例120The oil containing the coupling product obtained in Example 118 (180 mg) and succinic anhydride (163 m
g, 1.63 mmol) was reacted by the esterification method B, and the desired product (65 mg, 0.14 mmol, Example 11) was obtained.
7 from 2i). Pale yellow crystals m. p. 152-154 ° C. 1 H NMR (CDCl 3 , 250 MHz) δ ppm:
1.81 (s, 3H), 2.60-2.85 (m, 4
H), 3.36 (s, 2H), 6.14 (s, 2H),
7.02 (t, J = 8.6 Hz, 2H), 7.05
(S, 1H), 7.27 (s, 1H), 7.31 (t,
J = 8.6 Hz, 1 H), 7.34 (t, J = 8.6 H)
z, 1H), 8.96 (s, 1H). IR (KBr) νcm -1 : 3425,3055,293
2,2364,2237,1901,1736,161
6,1545,1510,1467,1367,121
9,1153,1066,1035,906,877,
841,652,611,565. Example 120
【0380】[0380]
【化98】 Embedded image
【0381】合成例137で得たプロパルジルアルコー
ル3w(280mg、1.19mmol)とクロロキナ
ゾリン(2j)(250mg、0.99mmol)を、
実施例7と同様の方法で反応を行い、カップリング生成
物(530mg、含溶媒AcOEt)を得た。1 H NMR(CDCl3 ,250MHz)δppm:
1.43(t,J=7.0Hz,3H),1.55
(t,J=7.0Hz,3H),3.19(d,J=1
3.4Hz,1H),3.26(d,J=13.4H
z,1H),3.79(q,J=7.0Hz,2H),
4.24(q,J=7.0Hz,2H),6.90
(s,1H),7.22−7.34(m,7H),7.
41−7.46(m,4H),9.04(s,1H). 実施例121The propargyl alcohol 3w (280 mg, 1.19 mmol) obtained in Synthesis Example 137 and chloroquinazoline (2j) (250 mg, 0.99 mmol) were
The reaction was carried out in the same manner as in Example 7 to obtain a coupling product (530 mg, AcOEt containing a solvent). 1 H NMR (CDCl 3 , 250 MHz) δ ppm:
1.43 (t, J = 7.0 Hz, 3H), 1.55
(T, J = 7.0 Hz, 3H), 3.19 (d, J = 1
3.4 Hz, 1 H), 3.26 (d, J = 13.4 H)
z, 1H), 3.79 (q, J = 7.0 Hz, 2H),
4.24 (q, J = 7.0 Hz, 2H), 6.90
(S, 1H), 7.22-7.34 (m, 7H), 7.
41-7.46 (m, 4H), 9.04 (s, 1H). Example 121
【0382】[0382]
【化99】 Embedded image
【0383】実施例120で得た生成物(530mg)
を、無水コハク酸(150mg、1.5mmol)とエ
ステル化B法にて反応を行い、目的物(107mg、
0.19mmol、実施例119の2jより19%)を
得た。 白色結晶 m.p.156.5〜158℃1 H NMR(CDCl3 ,250MHz)δppm:
1.51(t,J=6.9Hz,3H),1.54
(t,J=6.9Hz,3H),2.61−2.73
(m,4H),3.44(s,4H),4.11(q,
J=6.9Hz,2H),4.18(q,J=6.9H
z,2H),7.07(s,1H),7.21(s,1
H),7.29−7.41(m,10H),8.27
(m,1H). IR(KBr)νcm-1:3429,2982,293
5,2498,2233,1919,1739,161
2,1575,1500,1471,1439,137
1,1317,1238,1163,1039,93
3,877,827,746,700,565. 実施例122The product obtained in Example 120 (530 mg)
Was reacted with succinic anhydride (150 mg, 1.5 mmol) by esterification method B, and the target product (107 mg,
0.19 mmol, 19% from 2j of Example 119). White crystals m. p. 156.5-158 ° C. 1 H NMR (CDCl 3 , 250 MHz) δ ppm:
1.51 (t, J = 6.9 Hz, 3H), 1.54
(T, J = 6.9 Hz, 3H), 2.61-2.73
(M, 4H), 3.44 (s, 4H), 4.11 (q,
J = 6.9 Hz, 2H), 4.18 (q, J = 6.9H)
z, 2H), 7.07 (s, 1H), 7.21 (s, 1
H), 7.29-7.41 (m, 10H), 8.27.
(M, 1H). IR (KBr) νcm -1 : 3429,2982,293
5,2498,2233,1919,1739,161
2,1575,1500,1471,1439,137
1,1317,1238,1163,1039,93
3,877,827,746,700,565. Example 122
【0384】[0384]
【化100】 Embedded image
【0385】合成例38で得たプロパルジルアルコール
3x(315mg、1.8mmol)とクロロキナゾリ
ン(2j)(380mg、1.5mmol)を、実施例
7と同様の方法で反応を行い、カップリング生成物(5
88mg、1.5mmol、定量的)を得た。1 H NMR(CDCl3 ,250MHz)δppm:
1.27(t,J=7.4Hz,3H),1.50
(t,J=7.0Hz,3H),1.56(t,J=
7.0Hz,3H),3.07(d,J=13.4H
z,1H),3.23(d,J=13.4Hz,1
H),4.04(q,J=7.0Hz,2H),4.2
7(q,J=7.0Hz,2H),7.19(s,1
H),7.25−7.36(m,4H),7.40−
7.44(m,2H),9.06(s,1H). 実施例123The propargyl alcohol 3x (315 mg, 1.8 mmol) obtained in Synthesis Example 38 and chloroquinazoline (2j) (380 mg, 1.5 mmol) were reacted in the same manner as in Example 7 to couple them. Product (5
88 mg, 1.5 mmol, quantitative). 1 H NMR (CDCl 3 , 250 MHz) δ ppm:
1.27 (t, J = 7.4 Hz, 3H), 1.50
(T, J = 7.0 Hz, 3H), 1.56 (t, J =
7.0 Hz, 3H), 3.07 (d, J = 13.4H)
z, 1H), 3.23 (d, J = 13.4 Hz, 1
H), 4.04 (q, J = 7.0 Hz, 2H), 4.2
7 (q, J = 7.0 Hz, 2H), 7.19 (s, 1
H), 7.25-7.36 (m, 4H), 7.40-
7.44 (m, 2H), 9.06 (s, 1H). Example 123
【0386】[0386]
【化101】 Embedded image
【0387】実施例122で得たカップリング生成物
(588mg、1.5mmol)と、無水コハク酸(2
25mg、2.25mmol)とエステル化B法にて反
応を行い、目的物(347mg、0.707mmol、
47%)を得た。 白色結晶 m.p.158〜159℃1 H NMR(CDCl3 ,250MHz)δppm:
1.22(t,J=7.3Hz,3H),1.55
(t,J=6.9Hz,3H),1.60(t,J=
6.9Hz,3H),2.04(dq,J=7.3,
9.3Hz,2H),2.58−2.75(m,4
H),3.42(d,J=13.7Hz,1H),3.
57(d,J=13.7Hz,1H),4.05−4.
13(m,2H),4.28−4.46(m,2H),
7.16(s,1H),7.27−7.30(m,5
H),7.48(s,1H),8.66(s,1H). IR(KBr)νcm-1:3429,2982,293
7,2363,1739,1612,1577,150
0,1467,1439,1373,1317,123
8,1170,1035,978,939,702,6
52,567. 実施例124The coupling product (588 mg, 1.5 mmol) obtained in Example 122 was combined with succinic anhydride (2
Reaction with 25 mg, 2.25 mmol) by esterification method B, and the desired product (347 mg, 0.707 mmol,
47%). White crystals m. p. 158-159 ° C 1 H NMR (CDCl 3 , 250 MHz) δ ppm:
1.22 (t, J = 7.3 Hz, 3H), 1.55
(T, J = 6.9 Hz, 3H), 1.60 (t, J =
6.9 Hz, 3H), 2.04 (dq, J = 7.3,
9.3 Hz, 2H), 2.58-2.75 (m, 4
H), 3.42 (d, J = 13.7 Hz, 1H), 3.
57 (d, J = 13.7 Hz, 1H), 4.05-4.
13 (m, 2H), 4.28-4.46 (m, 2H),
7.16 (s, 1H), 7.27-7.30 (m, 5
H), 7.48 (s, 1H), 8.66 (s, 1H). IR (KBr) νcm -1 : 3429,2982,293
7, 2363, 1739, 1612, 1577, 150
0, 1467, 1439, 1373, 1317, 123
8, 1170, 1035, 978, 939, 702, 6
52,567. Example 124
【0388】[0388]
【化102】 Embedded image
【0389】プロパルジルアルコール(3Y)(1.7
g,9.8mmol)とクロロキナゾリン(2j)
(2.5g,9.8mmol)を、実施例7と同様に反
応を行い、カップリング生成物(2.55g、6.5m
mol、67%)を得た。1 H NMR(CDCl3 ,250MHz)δppm:
1.43−1.50(m,3H),1.53−1.60
(m,3H),1.77(s,3H),2.21(d
d,J=10.1,6.9Hz,2H),2.99−
3.09(m,2H),4.10−4.21(m,2
H),4.23−4.32(m,2H),7.15−
7.33(m,6H),7.39−7.41(m,1
H),9.08(bs,1H). 実施例125Propardyl alcohol (3Y) (1.7
g, 9.8 mmol) and chloroquinazoline (2j)
(2.5 g, 9.8 mmol) was reacted in the same manner as in Example 7, and the coupling product (2.55 g, 6.5 m) was obtained.
mol, 67%). 1 H NMR (CDCl 3 , 250 MHz) δ ppm:
1.43-1.50 (m, 3H), 1.53-1.60
(M, 3H), 1.77 (s, 3H), 2.21 (d
d, J = 10.1, 6.9 Hz, 2H), 2.99−
3.09 (m, 2H), 4.10-4.21 (m, 2
H), 4.23-4.32 (m, 2H), 7.15-
7.33 (m, 6H), 7.39-7.41 (m, 1
H), 9.08 (bs, 1H). Example 125
【0390】[0390]
【化103】 Embedded image
【0391】実施例124で得た生成物(950mg、
2.43mmol)を無水コハク酸(500mg、5m
mol)とエステル化B法にて反応を行い、目的物(6
42mg、1.31mmol、54%)を得た。 白色結晶 mp.123〜125℃1 H NMR(CDCl3 ,250MHz)δppm:
1.42(t,3H,J=6.9Hz),1.44
(t,3H,J=6.9Hz),1.86(s,3
H),2.30−2.38(m,2H),2.49−
2.68(m,5H),2.80−2.95(m,2
H),3.28−3.46(m,1H),4.25
(q,J=6.9Hz,2H),4.28(q,J=
6.9Hz,2H),7.13−7.35(m,5
H),7.36(s,1H),7.54(s,1H),
9.03(s,1H). IR(KBr)νcm-1:3416,2984,293
7,2507,2366,2233,1896,174
1,1612,1575,1500,1467,137
1,1317,1236,1153,1087,103
2,933,827,748,700,567,54
3,412. 実施例126The product obtained in Example 124 (950 mg,
2.43 mmol) with succinic anhydride (500 mg, 5 m
mol) with the esterification B method, and the desired product (6
42 mg, 1.31 mmol, 54%). White crystals mp. 123-125 ° C 1 H NMR (CDCl 3 , 250 MHz) δ ppm:
1.42 (t, 3H, J = 6.9 Hz), 1.44
(T, 3H, J = 6.9 Hz), 1.86 (s, 3
H), 2.30-2.38 (m, 2H), 2.49-
2.68 (m, 5H), 2.80-2.95 (m, 2
H), 3.28-3.46 (m, 1H), 4.25
(Q, J = 6.9 Hz, 2H), 4.28 (q, J =
6.9 Hz, 2H), 7.13-7.35 (m, 5
H), 7.36 (s, 1H), 7.54 (s, 1H),
9.03 (s, 1H). IR (KBr) νcm -1 : 3416,2984,293
7,2507,2366,2233,1896,174
1,1612,1575,1500,1467,137
1,1317,1236,1153,1087,103
2,933,827,748,700,567,54
3,412. Example 126
【0392】[0392]
【化104】 Embedded image
【0393】カルボン酸(実施例79で製造)(350
mg、0.69mmol)、L−アラニンメチルエステ
ル塩酸塩(96mg、0.69mmol)、1−(3−
ジメチルアミノプロピル)−3−エチルカルボジイミド
塩酸塩(133mg、0.69mmol)、1−ヒドロ
キシベンゾトリアゾール(93mg、0.69mmo
l)、トリエチルアミン(96μl、0.69mmo
l)を、ジクロロメタン(2ml)に溶解させ、12時
間室温で撹拌した。反応液に塩化アンモニウム水溶液を
加え、ジクロロメタンで抽出した。有機層を飽和食塩水
で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下溶
媒を留去した。残渣をシリカゲルカラムクロマトグラフ
ィーにより精製し、アミド(310mg)を得た。これ
(250mg)を実施例8と同様に反応を行い、目的物
(159mg、0.28mmol、50%)を収率で得
た。Carboxylic acid (prepared in Example 79) (350
mg, 0.69 mmol), L-alanine methyl ester hydrochloride (96 mg, 0.69 mmol), 1- (3-
Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (133 mg, 0.69 mmol), 1-hydroxybenzotriazole (93 mg, 0.69 mmol)
l), triethylamine (96 μl, 0.69 mmol)
l) was dissolved in dichloromethane (2 ml) and stirred for 12 hours at room temperature. An aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain an amide (310 mg). This (250 mg) was reacted in the same manner as in Example 8 to obtain the desired product (159 mg, 0.28 mmol, 50%) in a yield.
【0394】黄色結晶 m.p.162〜172℃1 H NMR(d6 −DMSO,250MHz)δpp
m:1.20(d,J=7Hz,3H),1.35
(s,3H),1.41(t,J=6.9Hz,3
H),1.42(t,J=6.9Hz,3H),1.5
0−1.90(m,4H),2.10−2.42(m,
3H),3.40−3.58(m,1H),3.99−
4.18(m,3H),4.25(q,J=6.9H
z,2H),7.10(dd,J=8.9,8.9H
z,2H),7.25(s,1H),7.32−7.4
0(m,3H),7.62−7.66(m,1H),
9.00(s,1H). IR(KBr)νcm-1:3406,2984,293
5,2812,2363,2214,1612,149
8,1458,1396,1365,1305,123
0,1157,1109,1043,958,933,
854,825,653,569,424. 実施例127Yellow crystals m. p. 162 ° -172 ° C. 1 H NMR (d 6 -DMSO, 250 MHz) δpp
m: 1.20 (d, J = 7 Hz, 3H), 1.35
(S, 3H), 1.41 (t, J = 6.9 Hz, 3
H), 1.42 (t, J = 6.9 Hz, 3H), 1.5
0-1.90 (m, 4H), 2.10-2.42 (m, 4H)
3H), 3.40-3.58 (m, 1H), 3.99-
4.18 (m, 3H), 4.25 (q, J = 6.9H
z, 2H), 7.10 (dd, J = 8.9, 8.9H
z, 2H), 7.25 (s, 1H), 7.32-7.4.
0 (m, 3H), 7.62-7.66 (m, 1H),
9.00 (s, 1H). IR (KBr) νcm -1 : 3406,2984,293
5,2812,2363,2214,1612,149
8, 1458, 1396, 1365, 1305, 123
0,1157,1109,1043,958,933,
854, 825, 653, 569, 424. Example 127
【0395】[0395]
【化105】 Embedded image
【0396】カルボン酸(実施例60で製造)(400
mg、0.84mmol)、L−アラニンメチルエステ
ル塩酸塩(117mg、0.84mmol)、1−(3
−ジメチルアミノプロピル)−3−エチルカルボジイミ
ド塩酸塩(161mg、0.84mmol)、1−ヒド
ロキシベンゾトリアゾール(114mg、0.84mm
ol)、トリエチルアミン(118μl、0.84mm
ol)を、ジクロロメタン(2ml)に溶解させ、16
時間撹拌した。反応液に塩化アンモニウム水溶液を注
ぎ、クロロホルムで抽出した。有機層を飽和食塩水で洗
浄後、無水硫酸ナトリウムで乾燥させ、減圧下溶媒を留
去した。残渣をシリカゲルカラムクロマトグラフィーに
より精製し、アミド体(440mg)を得た。これ(4
30mg)を実施例8と同様に反応を行い、目的物(1
06mg、0.19mmol、24%)を得た。The carboxylic acid (prepared in Example 60) (400
mg, 0.84 mmol), L-alanine methyl ester hydrochloride (117 mg, 0.84 mmol), 1- (3
-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (161 mg, 0.84 mmol), 1-hydroxybenzotriazole (114 mg, 0.84 mm)
ol), triethylamine (118 μl, 0.84 mm)
ol) in dichloromethane (2 ml) and 16
Stirred for hours. An aqueous ammonium chloride solution was poured into the reaction solution, and extracted with chloroform. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain an amide (440 mg). This (4
30 mg) was reacted in the same manner as in Example 8 to give the desired product (1
(06 mg, 0.19 mmol, 24%).
【0397】単黄色結晶 m.p.129〜142℃1 H NMR(d6 −DMSO,250MHz)δpp
m:1.13(t,J=6.9Hz,3H),1.19
(t,J=5.8Hz,3H),1.35−1.45
(m,9H),2.33−2.51(m,2H),2.
80−3.0(m,3H),3.02−3.20(m,
2H),3.22−3.38(m,1H),3.98−
4.17(m,3H),4.25(q,J=7.0H
z,2H),7.19−7.30(m,4H),7.3
3(s,1H),7.34−7.40(m,2H). IR(KBr)νcm-1:3406,2982,293
5,2361,2341,2214,1612,149
8,1458,1437,1396,1365,130
7,1230,1109,1043,933,854,
763,702,669,569,420. 合成例19 4−クロロ−6,7−ジメトキシキナゾリ
ン(2f)の製造 1)Single yellow crystal m. p. 129-142 ° C 1 H NMR (d 6 -DMSO, 250 MHz) δpp
m: 1.13 (t, J = 6.9 Hz, 3H), 1.19
(T, J = 5.8 Hz, 3H), 1.35-1.45
(M, 9H), 2.33-2.51 (m, 2H), 2.
80-3.0 (m, 3H), 3.02-3.20 (m,
2H), 3.22-3.38 (m, 1H), 3.98-
4.17 (m, 3H), 4.25 (q, J = 7.0H
z, 2H), 7.19-7.30 (m, 4H), 7.3.
3 (s, 1H), 7.34-7.40 (m, 2H). IR (KBr) νcm -1 : 3406, 2982, 293
5,2361,2341,214,1612,149
8, 1458, 1437, 1396, 1365, 130
7,1230,1109,1043,933,854,
763, 702, 669, 569, 420. Synthesis Example 19 Production of 4-chloro-6,7-dimethoxyquinazoline (2f) 1)
【0398】[0398]
【化106】 Embedded image
【0399】4,5−ジメトキシアントラニル酸メチル
エステル(51.85g、264mmol)にホルムア
ミド(264ml)を加え、170℃で10時間反応さ
せた。冷却後水を加え、生成する沈殿物を濾過し、残渣
を水で洗浄し、6,7−ジメトキシキナゾリン−4−オ
ン(34.52g、63%)を得た。1 H NMR(CDCl3 ,300MHz)δppm:
3.87(s,3H),3.90(s,3H),7.1
3(s,1H),7.44(s,1H),7.98
(s,1H),12.04(br s,1H).Formamide (264 ml) was added to 4,5-dimethoxyanthranilic acid methyl ester (51.85 g, 264 mmol), and the mixture was reacted at 170 ° C. for 10 hours. After cooling, water was added, the resulting precipitate was filtered and the residue was washed with water to give 6,7-dimethoxyquinazolin-4-one (34.52 g, 63%). 1 H NMR (CDCl 3 , 300 MHz) δ ppm:
3.87 (s, 3H), 3.90 (s, 3H), 7.1
3 (s, 1H), 7.44 (s, 1H), 7.98
(S, 1H), 12.04 (br s, 1H).
【0400】2)6,7−ジメトキシキナゾリン−4−
オン(34.5g、167mmol)にトルエン(34
0ml)およびPOCl3 (56.44g、368mm
ol)を加え3時間還流させた。減圧下、溶媒を留去し
氷水を加えた後、K2 CO3を水層がアルカリ性になる
まで加えクロロホルム(500ml×2)で抽出した。
抽出液を濃縮し、残渣をエーテルで懸洗し標題化合物
(31.09g、83%)を得た。 2f: 1H NMR(CDCl3 ,300MHz)δp
pm:4.07(s,3H),4.08(s,3H),
7.34(s,1H),7.40(s,1H),8.8
7(s,1H). 合成例20 4,6,7−トリクロロキナゾリン(2
g)の製造2) 6,7-dimethoxyquinazoline-4-
On (34.5 g, 167 mmol) in toluene (34
0 ml) and POCl 3 (56.44 g, 368 mm)
ol) and refluxed for 3 hours. After evaporating the solvent under reduced pressure and adding ice water, K 2 CO 3 was added until the aqueous layer became alkaline, and the mixture was extracted with chloroform (500 ml × 2).
The extract was concentrated, and the residue was washed with ether to give the title compound (31.09 g, 83%). 2f: 1 H NMR (CDCl 3 , 300 MHz) δp
pm: 4.07 (s, 3H), 4.08 (s, 3H),
7.34 (s, 1H), 7.40 (s, 1H), 8.8
7 (s, 1H). Synthesis Example 20 4,6,7-Trichloroquinazoline (2
g) manufacture
【0401】[0401]
【化107】 Embedded image
【0402】文献記載の方法(Synth.Commu
n.1992,22,3067−3074)と同様な方
法で4,5−ジクロロアントラニル酸(1)を製造した
(収率85%)。1(2g、11.7mmol)とホル
ムアミド(5ml)を200℃で12時間加熱還流し
た。反応液を水で希釈し生じた結晶を濾取し、減圧下乾
燥し、結晶(3.7g)を得た。これをトルエン(20
ml)混液としオキシ塩化リン(2.2ml、23.6
mmol)を加え、4時間加熱還流した。減圧下、反応
液を濃縮し、炭酸水素ナトリウム水溶液を注ぎ、クロロ
ホルムで抽出した。不溶物をセライトを用いて濾去した
後、有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾
燥後、減圧下溶媒を留去し、4,6,7−トリクロロキ
ナゾリン(2g)(683mg、25%)を得た。 2g: 1H NMR(DMSO−d6 ,250MHz)
δppm:8.50(s,1H),8.54(s,1
H),9.18(s,1H). 合成例21 2−アミノ−4−クロロ−6,7−ジメト
キシキナゾリン(2h)の製造The method described in the literature (Synth. Commu)
n. 1992, 22 , 3067-3074) to give 4,5-dichloroanthranilic acid (1) (yield 85%). 1 (2 g, 11.7 mmol) and formamide (5 ml) were heated under reflux at 200 ° C. for 12 hours. The reaction solution was diluted with water, and the resulting crystals were collected by filtration and dried under reduced pressure to obtain crystals (3.7 g). This is added to toluene (20
ml) and mixed with phosphorus oxychloride (2.2 ml, 23.6 ml).
mmol) and heated to reflux for 4 hours. The reaction solution was concentrated under reduced pressure, an aqueous sodium hydrogen carbonate solution was poured, and the mixture was extracted with chloroform. After filtering off the insolubles using Celite, the organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to give 4,6,7-trichloroquinazoline (2 g) (683 mg, 25%). 2g: 1 H NMR (DMSO- d 6, 250MHz)
δ ppm: 8.50 (s, 1H), 8.54 (s, 1
H), 9.18 (s, 1H). Synthesis Example 21 Production of 2-amino-4-chloro-6,7-dimethoxyquinazoline (2h)
【0403】[0403]
【化108】 Embedded image
【0404】1)4,5−ジメトキシアントラニル酸メ
チル(1)(2.11g、10.0mmol)のメタノ
ール溶液(20ml)を還流下撹拌しながらH2 NCN
(0.40g、9.5mmol)と濃塩酸(0.1m
l)を2時間ごとに加え、計10回加えた。濃塩酸
(1.0ml)を加え、約30分間撹拌した後、氷冷し
た。生成物を濾別し、冷水(10ml)、メタノール
(10ml)、Et2 O(10ml)で洗浄、減圧下乾
燥し、2−アミノ−6,7−ジメトキシキナゾリン−4
−オン(4h)(1.92g、86%)を得た。1) A solution of methyl 4,5-dimethoxyanthranilate (1) (2.11 g, 10.0 mmol) in methanol (20 ml) was stirred under reflux while stirring with H 2 NCN.
(0.40 g, 9.5 mmol) and concentrated hydrochloric acid (0.1 m
l) was added every 2 hours for a total of 10 additions. Concentrated hydrochloric acid (1.0 ml) was added, the mixture was stirred for about 30 minutes, and then cooled with ice. The product was separated by filtration, washed with cold water (10 ml), methanol (10 ml), Et 2 O (10 ml), dried under reduced pressure, and dried with 2-amino-6,7-dimethoxyquinazoline-4
-On (4h) (1.92 g, 86%) was obtained.
【0405】4h: 1H NMR(DMSO−d6 ,2
50MHz)δppm:3.84(s,3H),3.8
9(s,3H),6.99(s,1H),7.34
(s,1H),8.38(br s,2H),12.7
0(br s,1H). 2)上記で得た化合物4h(1.916g、8.62m
mol)、POCl3(13ml)、Me2 NPh
(0.26ml)を2時間還流後濃縮し、氷冷下氷水を
残渣に加えた。生成する固体を濾別し、10%Na2 C
O3 水溶液−THFに分配し、THF層を分離した。水
層を数回THFで抽出し、合わせた抽出液を乾燥、濃縮
した。残渣をシリカゲルカラムクロマトグラフィーで精
製し目的とする2−アミノ−4−クロロ−6,7−ジメ
トキシキナゾリン(2h)(580mg、28%)を得
た。 2h; 1H NMR(CDCl3 ,300MHz)δp
pm:3.99(s,3H),4.00(s,3H),
5.06(br s,2H),6.93(s,1H),
7.23(s,1H). 合成例22 2−アミノ−4−クロロ−6,7−ジエト
キシキナゾリンの製造 1)4h: 1 H NMR (DMSO-d 6 , 2
50 MHz) δ ppm: 3.84 (s, 3H), 3.8
9 (s, 3H), 6.99 (s, 1H), 7.34
(S, 1H), 8.38 (br s, 2H), 12.7
0 (br s, 1H). 2) Compound 4h obtained above (1.916 g, 8.62 m)
mol), POCl 3 (13 ml), Me 2 NPh
(0.26 ml) was refluxed for 2 hours and concentrated, and ice water was added to the residue under ice cooling. The resulting solid is filtered off and 10% Na 2 C
The mixture was partitioned between O 3 aqueous solution and THF, and the THF layer was separated. The aqueous layer was extracted several times with THF, and the combined extracts were dried and concentrated. The residue was purified by silica gel column chromatography to obtain the desired 2-amino-4-chloro-6,7-dimethoxyquinazoline (2h) (580 mg, 28%). 2h; 1 H NMR (CDCl 3 , 300 MHz) δp
pm: 3.99 (s, 3H), 4.00 (s, 3H),
5.06 (br s, 2H), 6.93 (s, 1H),
7.23 (s, 1H). Synthesis Example 22 Production of 2-amino-4-chloro-6,7-diethoxyquinazoline 1)
【0406】[0406]
【化109】 Embedded image
【0407】合成例22と同様な操作で反応を行ない、
生成物を濾別し、これを7%アンモニア水に懸濁させ、
しばらく撹拌後、濾取、乾燥し、2−アミノ−6,7−
ジエトキシキナゾロンを得た(収率88%)。1 H NMR(DMSO−d6 ,300MHz)δpp
m:1.34(t,J=7.2Hz,3H),1.36
(t,J=7.2Hz,3H),4.02(q,J=
6.9Hz,2H),4.09(q,J=6.9Hz,
2H),6.16(br s,2H),6.66(s,
1H),7.24(s,1H),11.80(br
s,1H). 2)The reaction was carried out in the same manner as in Synthesis Example 22.
The product was filtered off, suspended in 7% aqueous ammonia,
After stirring for a while, the mixture was collected by filtration, dried, and treated with 2-amino-6,7-
Diethoxyquinazolone was obtained (88% yield). 1 H NMR (DMSO-d 6 , 300 MHz) δpp
m: 1.34 (t, J = 7.2 Hz, 3H), 1.36
(T, J = 7.2 Hz, 3H), 4.02 (q, J =
6.9 Hz, 2H), 4.09 (q, J = 6.9 Hz,
2H), 6.16 (br s, 2H), 6.66 (s,
1H), 7.24 (s, 1H), 11.80 (br
s, 1H). 2)
【0408】[0408]
【化110】 Embedded image
【0409】2−アミノ−6,7−ジエトキシキナゾロ
ン(5.55g、22.25mmol)、N,N′−ジ
メチルアニリン(7ml)、POCl3 (7.3ml、
78.3mmol)をトルエン(100ml)に溶解
し、2時間還流させた。反応液を濃縮後、残渣に氷水、
NaHCO3 水溶液を加えEtOAcで抽出(200m
l×4)し、抽出液を飽和NaHCO3 水溶液で洗浄
(300ml)した。抽出液を乾燥、濃縮後シリカゲル
カラムクロマトグラフィーで精製し、目的とする4−ク
ロロ−6,7−ジエトキシキナゾリン(370mg、
6.2%)を得た。2-Amino-6,7-diethoxyquinazolone (5.55 g, 22.25 mmol), N, N'-dimethylaniline (7 ml), POCl 3 (7.3 ml,
78.3 mmol) was dissolved in toluene (100 ml) and refluxed for 2 hours. After concentrating the reaction solution, the residue was iced water,
NaHCO 3 aqueous solution was added and extracted with EtOAc (200 m
1 × 4), and the extract was washed with a saturated aqueous solution of NaHCO 3 (300 ml). The extract was dried and concentrated, and then purified by silica gel column chromatography. The desired 4-chloro-6,7-diethoxyquinazoline (370 mg,
6.2%).
【0410】1H NMR(CDCl3 ,300MH
z)δppm:3.99(s,3H),4.00(s,
3H),5.10(br s,2H),6.93(s,
1H),7.23(s,1H).13 C NMR(CDCl3 ,75MHz)δppm:5
6.1,56.3,103.6,104.6,113.
4,147.9,151.0,157.2,158.
3,160.2 合成例23 4−クロロ−6,7−メチレンジオキシキ
ナゾリン(2i)の製造 1 H NMR (CDCl 3 , 300 MH
z) δ ppm: 3.99 (s, 3H), 4.00 (s,
3H), 5.10 (brs, 2H), 6.93 (s,
1H), 7.23 (s, 1H). 13 C NMR (CDCl 3 , 75 MHz) δ ppm: 5
6.1, 56.3, 103.6, 104.6, 113.
4,147.9,151.0,157.2,158.
3,160.2 Synthesis Example 23 Production of 4-chloro-6,7-methylenedioxyquinazoline (2i)
【0411】[0411]
【化111】 Embedded image
【0412】Methyl 4,5−methylen
edioxy−2−Nitrobenzoate(1)
(4.5g、20.0mmol)のMeOH(20m
l)−EtOAc(40ml)溶液に10%パラジウム
カーボン(170mg)を加え水素雰囲気下一晩撹拌し
た。不溶物を濾過し、濾液を濃縮して2(2.99g、
定量的)を得た。 2: 1H NMR(CDCl3 ,300MHz)δpp
m:3.82(s,3H),5.73(br s,2
H),5.88(s,2H),6.16(s,1H),
7.25(s,1H).[0412] Methyl 4,5-methylen
edoxy-2-Nitrobenzoate (1)
(4.5 g, 20.0 mmol) in MeOH (20 m
l) 10% palladium carbon (170 mg) was added to a -EtOAc (40 ml) solution, and the mixture was stirred overnight under a hydrogen atmosphere. The insolubles were filtered and the filtrate was concentrated to 2 (2.99 g,
Quantitative). 2: 1 H NMR (CDCl 3 , 300 MHz) δpp
m: 3.82 (s, 3H), 5.73 (brs, 2
H), 5.88 (s, 2H), 6.16 (s, 1H),
7.25 (s, 1H).
【0413】2を合成例19と同様な操作を行ない6,
7−メチレンジオキシ−キナゾリン−4−オン(4i)
(67%)および4−クロロ−6,7−メチレンジオキ
シキナゾリン(2i)(16%)を得た。 4i: 1H NMR(DMSO−d6 ,250MHz)
δppm:6.20(s,2H),7.12(s,1
H),7.41(s,1H),7.98(s,1H),
12.20(br s,1H). 合成例24 4−クロロ−6,7−ジエトキシキナゾリ
ン3の合成The same operation as in Synthesis Example 19 was performed for 2,
7-methylenedioxy-quinazolin-4-one (4i)
(67%) and 4-chloro-6,7-methylenedioxyquinazoline (2i) (16%). 4i: 1 H NMR (DMSO-d 6 , 250 MHz)
δ ppm: 6.20 (s, 2H), 7.12 (s, 1
H), 7.41 (s, 1H), 7.98 (s, 1H),
12.20 (br s, 1H). Synthesis Example 24 Synthesis of 4-chloro-6,7-diethoxyquinazoline 3
【0414】[0414]
【化112】 Embedded image
【0415】目的物4−クロロ−6,7−ジエトキシキ
ナゾリン(2j)は上に示す様に出発物質アントラニル
酸メチルエステル体1から2段階の反応で合成した。 1)6,7−ジエトキシキナゾリン−4−オン(4j)
の合成 アントラニル酸メチルエステル体1(138g、0.5
9mol)にホルムアミド(763ml)を加え還流し
た。3.5時間後氷水(1.1リットル)を加えて氷浴
中で1時間撹拌した後、濾過して得られる残渣を氷水
(1リットル)で洗浄した後、トルエン(350ml×
2)を加え残渣に含まれる水を共沸留去した。減圧乾燥
後6,7−ジエトキシキナゾリン−4−オン(118
g、87%)を得た。The desired product, 4-chloro-6,7-diethoxyquinazoline (2j), was synthesized from the starting material anthranilic acid methyl ester 1 in a two-step reaction as shown above. 1) 6,7-diethoxyquinazolin-4-one (4j)
Synthesis of anthranilic acid methyl ester 1 (138 g, 0.5
9 mol), and refluxed with formamide (763 ml). After 3.5 hours, ice water (1.1 liter) was added, and the mixture was stirred in an ice bath for 1 hour. The residue obtained by filtration was washed with ice water (1 liter), and then toluene (350 ml ×
2) was added and water contained in the residue was azeotropically distilled off. After drying under reduced pressure, 6,7-diethoxyquinazolin-4-one (118
g, 87%).
【0416】6,7−ジエトキシキナゾリン−4−オン
(4j):1 H NMR(CDCl3 ,300MHz)δppm:
1.38(t,J=6.9Hz,3H),1.39
(t,J=6.9Hz,3H),4.13(t,J=
6.9Hz,2H),4.17(t,J=6.9Hz,
2H),7.11(s,1H),7.43(s,1
H),7.96(s,1H),12.03(s,1
H).6,7-diethoxyquinazolin-4-one (4j): 1 H NMR (CDCl 3 , 300 MHz) δ ppm:
1.38 (t, J = 6.9 Hz, 3H), 1.39
(T, J = 6.9 Hz, 3H), 4.13 (t, J =
6.9 Hz, 2H), 4.17 (t, J = 6.9 Hz,
2H), 7.11 (s, 1H), 7.43 (s, 1
H), 7.96 (s, 1H), 12.03 (s, 1H)
H).
【0417】2)目的物4−クロロ−6,7−ジエトキ
シキナゾリン(2j)の合成 6,7−ジエトキシキナゾリン−4−オン(4j)(2
06.47g、0.881mol)をトルエン(1.4
リットル)に懸濁させ、オキシ塩化リン(167ml)
を室温下で滴下してトルエン(0.1リットル)を加え
た後、還流した。2時間後、過剰のオキシ塩化リンとト
ルエンを減圧留去し、残渣に氷水(1リットル)を氷浴
中でゆっくり加えた後、クロロホルム(2リットル)で
抽出した。この抽出液を10%Na2 CO3 水溶液(1
リットル×2)、飽和食塩水(1リットル×2)で洗
浄、乾燥(MgSO4 )、濃縮し粗結晶(247g)を
得た。2) Synthesis of the desired product 4-chloro-6,7-diethoxyquinazoline (2j) 6,7-diethoxyquinazolin-4-one (4j) (2j)
06.47 g, 0.881 mol) in toluene (1.4).
Liter) and phosphorus oxychloride (167 ml)
Was added dropwise at room temperature, toluene (0.1 liter) was added, and the mixture was refluxed. Two hours later, excess phosphorus oxychloride and toluene were distilled off under reduced pressure, and ice water (1 liter) was slowly added to the residue in an ice bath, followed by extraction with chloroform (2 liter). This extract was added to a 10% aqueous Na 2 CO 3 solution (1
Liter × 2), washed with saturated saline (1 liter × 2), dried (MgSO 4 ), and concentrated to obtain crude crystals (247 g).
【0418】得られた粗結晶のクロロホルム溶液(60
0ml)に活性炭(5g)を加え30分間室温で撹拌し
た後、シリカゲルカラムクロマトグラフィー(溶媒、ク
ロロホルム−メタノール系)と懸洗(溶媒:Hex−E
t2 O系)により精製して目的物4−クロロ−6,7−
ジエトキシキナゾリン(2j)(168.49g、76
%)を得た。 4−クロロ−6,7−ジエトキシキナゾリン(2j):1 H NMR(CDCl3 ,300MHz)δppm:
1.57(t,J=6.9Hz,3H),1.58
(t,J=6.9Hz,3H),4.28(q,J=
6.9Hz,2H),4.29(q,J=6.9Hz,
2H),7.30(s,1H),7.37(s,1
H),8.84(s,1H). 合成例25 4−クロロ−6,7−ジイソプロポキシキ
ナゾリン(2k)の合成A solution of the obtained crude crystals in chloroform (60
0 ml), activated carbon (5 g) was added thereto, and the mixture was stirred at room temperature for 30 minutes.
t 2 O) to purify the desired product 4-chloro-6,7-
Diethoxyquinazoline (2j) (168.49 g, 76
%). 4-Chloro-6,7-diethoxyquinazoline (2j): 1 H NMR (CDCl 3 , 300 MHz) δ ppm:
1.57 (t, J = 6.9 Hz, 3H), 1.58
(T, J = 6.9 Hz, 3H), 4.28 (q, J =
6.9 Hz, 2H), 4.29 (q, J = 6.9 Hz,
2H), 7.30 (s, 1H), 7.37 (s, 1
H), 8.84 (s, 1H). Synthesis Example 25 Synthesis of 4-chloro-6,7-diisopropoxyquinazoline (2k)
【0419】[0419]
【化113】 Embedded image
【0420】上に示す様に出発物質3,4−ジヒドロキ
シ安息香酸(1)から6工程で目的物を合成した。以下
に各々の工程の合成例を示す。 1)3,4−ジイソプロポキシ安息香酸(2)の合成 3,4−ジヒドロキシ安息香酸1(10.9g、71m
mol)のテトラヒドロフラン溶液(48ml)に2規
定水酸化ナトリウム水溶液(142ml、282mmo
l)を加えた中に0℃下でヨウ化イソプロピル(30
g、177mmol)のテトラヒドロフラン溶液(48
ml)を20分間で滴下した後、還流した。As shown above, the desired compound was synthesized from the starting material 3,4-dihydroxybenzoic acid (1) in 6 steps. The synthesis example of each step is shown below. 1) Synthesis of 3,4-diisopropoxybenzoic acid (2) 3,4-dihydroxybenzoic acid 1 (10.9 g, 71 m
mol) in a tetrahydrofuran solution (48 ml) and a 2N aqueous sodium hydroxide solution (142 ml, 282 mmol).
l) and isopropyl iodide (30
g, 177 mmol) in tetrahydrofuran (48
ml) was added dropwise over 20 minutes and then refluxed.
【0421】4日後、反応溶媒中のテトラヒドロフラン
を減圧留去した後、ノルマルヘキサン(300ml)で
洗浄した。得られる水層に濃塩酸を加えて酸性にした
後、酢酸エチル(600ml)で抽出、飽和食塩水で洗
浄、乾燥(MgSO4 )、濃縮の後得られた残渣をシリ
カゲルカラムクロマトグラフィー(溶媒、クロロホルム
−メタノール系)で精製し目的物2(2.9g、17
%)を得た。 3,4−ジイソプロポキシ安息香酸21 H NMR(CDCl3 ,300MHz)δppm:
1.36(d,J=6.1Hz,12H),4.51
(dq,J=6.1,6.1Hz,1H),4.62
(dq,J=6.1,6.1Hz,1H),6.93
(d,J=8.5,1H),7.65(d,J=1.9
Hz,1H),7.72(dd,J=8.5,1.9H
z,1H).Four days later, tetrahydrofuran in the reaction solvent was distilled off under reduced pressure, and the residue was washed with normal hexane (300 ml). The resulting aqueous layer was acidified by adding concentrated hydrochloric acid, extracted with ethyl acetate (600 ml), washed with brine, dried (MgSO 4 ), and concentrated, and the resulting residue was subjected to silica gel column chromatography (solvent, Purified with chloroform-methanol system, and the desired product 2 (2.9 g, 17
%). 3,4-diisopropoxybenzoic acid 2 1 H NMR (CDCl 3 , 300 MHz) δ ppm:
1.36 (d, J = 6.1 Hz, 12H), 4.51
(Dq, J = 6.1, 6.1 Hz, 1H), 4.62
(Dq, J = 6.1, 6.1 Hz, 1H), 6.93
(D, J = 8.5, 1H), 7.65 (d, J = 1.9
Hz, 1H), 7.72 (dd, J = 8.5, 1.9H)
z, 1H).
【0422】2)4,5−ジイソプロポキシ−2−ニト
ロ安息香酸(3)の合成 3,4−ジイソプロポキシ安息香酸(2)(2.4g、
10.0mmol)のジクロロメタン(50ml)溶液
中に−55〜65℃の温度内で、発煙硝酸(1ml)の
ジクロロメタン(20ml)溶液に無水硫酸第二スズ
(1.4ml)のジクロロメタン溶液(20ml)を1
5分間で同時に滴下した。30分後、氷水(100m
l)をゆっくり加え、ジクロロメタン(300ml)で
抽出し飽和食塩水(100ml)で洗浄、乾燥(MgS
O4 )、濃縮して得られた残渣をシリカゲルカラムクロ
マトグラフィー(溶媒クロロホルム−メタノール系)で
精製し目的物3(2.42g、80%)を得た。 4,5−ジイソプロポキシ−2−ニトロ安息香酸31 H NMR(DMSO−d6 ,300MHz)δpp
m:1.28−1.33(m,12H),4.68−
4.76(m,2H),7.29(s,1H),7.5
7(s,1H).2) Synthesis of 4,5-diisopropoxy-2-nitrobenzoic acid (3) 3,4-diisopropoxybenzoic acid (2) (2.4 g,
10.0 mmol) in dichloromethane (50 ml) at a temperature of -55 to 65 ° C. in a dichloromethane (20 ml) solution of fuming nitric acid (1 ml) in anhydrous dichloromethane (1.4 ml) in dichloromethane (20 ml). 1
It was dropped simultaneously over 5 minutes. 30 minutes later, ice water (100m
l) was slowly added, extracted with dichloromethane (300 ml), washed with saturated saline (100 ml), and dried (MgSO4).
O 4 ) and the residue obtained by concentration were purified by silica gel column chromatography (solvent: chloroform-methanol system) to obtain the desired product 3 (2.42 g, 80%). 4,5-diisopropoxy-2-nitrobenzoic acid 3 1 H NMR (DMSO-d 6 , 300 MHz) δpp
m: 1.28-1.33 (m, 12H), 4.68-
4.76 (m, 2H), 7.29 (s, 1H), 7.5
7 (s, 1H).
【0423】3)4,5−ジイソプロポキシ−2−ニト
ロ安息香酸メチルエステル(4)の合成 4,5−ジイソプロポキシ−2−ニトロ安息香酸(2.
4g、8.4mmol)にメタノール(10ml)とジ
エチルエーテル(40ml)を加え、室温下でジメチル
アミノピリジン(51.3mg、5mol%)とジシク
ロヘキシルカルボジイミド(1.91g、9.2mmo
l)を加え撹拌した。5時間後、セライト濾過をして、
ジエチルエーテルで洗い込んだ後、母液を10%Na2
CO3 水溶液(40ml)、飽和食塩水(20ml)で
洗浄し、乾燥(MgSO4 )濃縮し得られた残渣をシリ
カゲルカラムクロマトグラフィー(溶媒、クロロホルム
−メタノール系)で精製目的物4(1.74g、69
%)を得た。3) Synthesis of 4,5-diisopropoxy-2-nitrobenzoic acid methyl ester (4) 4,5-diisopropoxy-2-nitrobenzoic acid (2.
Methanol (10 ml) and diethyl ether (40 ml) were added to dimethylaminopyridine (51.3 mg, 5 mol%) and dicyclohexylcarbodiimide (1.91 g, 9.2 mmol) at room temperature.
l) was added and stirred. After 5 hours, filter through celite,
After washing with diethyl ether, the mother liquor was washed with 10% Na 2
The residue was washed with a CO 3 aqueous solution (40 ml) and a saturated saline solution (20 ml), dried (MgSO 4 ) and concentrated, and the obtained residue was purified by silica gel column chromatography (solvent, chloroform-methanol system). , 69
%).
【0424】4,5−ジイソプロポキシ−2−ニトロ安
息香酸メチルエステル(4)1 H NMR(CDCl3 ,300MHz)δppm:
1.36−1.44(m,12H),3.90(s,3
H),4.59(dt,J=6.1Hz,1H),4.
63(dt,J=6.1Hz,1H),7.08(s,
1H),7.46(s,1H).4,5-diisopropoxy-2-nitrobenzoic acid methyl ester (4) 1 H NMR (CDCl 3 , 300 MHz) δ ppm:
1.36-1.44 (m, 12H), 3.90 (s, 3
H), 4.59 (dt, J = 6.1 Hz, 1H), 4.
63 (dt, J = 6.1 Hz, 1H), 7.08 (s,
1H), 7.46 (s, 1H).
【0425】4)3,4−ジイソプロポキシアントラニ
ル酸メチルエステル(5)の合成 4,5−ジイソプロポキシ−2−ニトロ安息香酸メチル
エステル(4)(1.32g,4.4mmol)のメタ
ノール溶液(40ml)を窒素置換した後、パラジウム
炭素(60mg)を加え、水素に置換して室温で激しく
撹拌した。7時間後、セライト濾過をおこない、メタノ
ールで洗い込んだ後、濾液を濃縮し目的物5(1.18
g、99%)を得た。4) Synthesis of 3,4-diisopropoxyanthranilic acid methyl ester (5) Methanol of 4,5-diisopropoxy-2-nitrobenzoic acid methyl ester (4) (1.32 g, 4.4 mmol) After the solution (40 ml) was replaced with nitrogen, palladium carbon (60 mg) was added, the mixture was replaced with hydrogen, and the mixture was vigorously stirred at room temperature. After 7 hours, the mixture was filtered through celite, washed with methanol, and the filtrate was concentrated to give the desired product 5 (1.18).
g, 99%).
【0426】3,4−ジイソプロポキシアントラニル酸
メチルエステル(5)1 H NMR(CDCl3 ,300MHz)δppm:
1.28(d,J=6.2Hz,6H),1.36
(d,J=6.2Hz,6H),3.83(s,3
H),6.13(s,1H),7.42(s,1H). 5)6,7−ジイソプロポキシキナゾリン−4−オン
(6)の合成 4,5−ジイソプロポキシアントラニル酸メチルエステ
ル(5)(1.4g、5.2mmol)にホルムアミド
(10ml)を加えて還流した。2時間後、氷水(30
ml)を加え、濾過して得られる残渣を氷水で洗い乾燥
して目的物6(876mg、64%)を得た。3,4-diisopropoxyanthranilic acid methyl ester (5) 1 H NMR (CDCl 3 , 300 MHz) δ ppm:
1.28 (d, J = 6.2 Hz, 6H), 1.36
(D, J = 6.2 Hz, 6H), 3.83 (s, 3
H), 6.13 (s, 1H), 7.42 (s, 1H). 5) Synthesis of 6,7-diisopropoxyquinazolin-4-one (6) Formamide (10 ml) was added to 4,5-diisopropoxyanthranilic acid methyl ester (5) (1.4 g, 5.2 mmol). Refluxed. Two hours later, ice water (30
ml), and the residue obtained by filtration was washed with ice water and dried to obtain the desired product 6 (876 mg, 64%).
【0427】6,7−ジイソプロポキシキナゾリン−4
−オン(6)1 H NMR(DMSO−d6 ,300MHz)δpp
m:1.30(d,J=6.3Hz,6H),1.33
(d,J=6.3Hz,6H),4.59(dt,J=
6.3,6.3Hz,1H),4.76(dt,J=
6.3,6.3Hz,1H),7.13(s,1H),
7.46(s,1H),7.95(s,1H),12.
02(s,1H). 6)4−クロロ−6,7−ジイソプロポキシキナゾリン
(2k)の合成 6,7−ジイソプロポキシキナゾリン−4−オン6(8
76mg、3.34mmol)のトルエン(30ml)
液中にオキシ塩化リン(7ml)を室温下で加えた後、
還流した。2時間後、濃縮後、10%Na2 CO3 水溶
液を加えクロロホルムで抽出し飽和食塩水で洗浄、乾燥
(MgSO4 )、濃縮して得られた残渣をシリカゲルカ
ラムクロマトグラフィー(溶媒、ノルマルヘキサン−酢
酸エチル)で精製して目的物2k(577mg、61
%)を得た。6,7-diisopropoxyquinazoline-4
-On (6) 1 H NMR (DMSO-d 6 , 300 MHz) δpp
m: 1.30 (d, J = 6.3 Hz, 6H), 1.33
(D, J = 6.3 Hz, 6H), 4.59 (dt, J =
6.3, 6.3 Hz, 1H), 4.76 (dt, J =
6.3, 6.3 Hz, 1H), 7.13 (s, 1H),
7.46 (s, 1H), 7.95 (s, 1H), 12.
02 (s, 1H). 6) Synthesis of 4-chloro-6,7-diisopropoxyquinazoline (2k) 6,7-diisopropoxyquinazolin-4-one 6 (8
76 mg, 3.34 mmol) of toluene (30 ml)
After adding phosphorus oxychloride (7 ml) to the solution at room temperature,
Refluxed. Two hours later, after concentration, an aqueous 10% Na 2 CO 3 solution was added, extracted with chloroform, washed with brine, dried (MgSO 4 ), and concentrated. The residue obtained was purified by silica gel column chromatography (solvent, n-hexane- The residue was purified with ethyl acetate to give the desired product 2k (577 mg, 61
%).
【0428】4−クロロ−6,7−ジイソプロポキシキ
ナゾリン(2k)1 H NMR(CDCl3 ,300MHz)δppm:
1.46(d,J=6.1Hz,6H),1.48
(d,J=6.1Hz,6H),4.72(dt,J=
6.1,6.1Hz,1H),4.76(dt,J=
6.1,6.1Hz,1H),7.31(s,1H),
7.44(s,1H),8.83(s,1H).4-Chloro-6,7-diisopropoxyquinazoline (2k) 1 H NMR (CDCl 3 , 300 MHz) δ ppm:
1.46 (d, J = 6.1 Hz, 6H), 1.48
(D, J = 6.1 Hz, 6H), 4.72 (dt, J =
6.1, 6.1 Hz, 1H), 4.76 (dt, J =
6.1, 6.1 Hz, 1H), 7.31 (s, 1H),
7.44 (s, 1H), 8.83 (s, 1H).
【0429】合成例26 4−クロロ−6−ジメチルア
ミノピリド〔3,2−d〕ピリミジン2Lの合成Synthesis Example 26 Synthesis of 2 L of 4-chloro-6-dimethylaminopyrido [3,2-d] pyrimidine
【0430】[0430]
【化114】 Embedded image
【0431】目的物4−クロロ−6−ジメチルアミノピ
リド〔3,2−d〕ピリミジン(3)は上に示す様に出
発物質6−フルオロピリド〔3,2−d〕ピリミジン−
4−オン(1)から2段階で合成した。 (1)6−ジメチルアミノピリド(3,2−d〕ピリミ
ジン(2)の合成 W.A.Dennyらの方法に従い(J.Med.Ch
em.1996,39,1823−1835)製造した
6−フルオロピリド〔3,2−d〕ピリミジン−4−オ
ン(1)(540mg、3.27mmol)に50%ジ
メチルアミノ水溶液(7ml)、エタノール(50m
l)を加えて封管して100℃で撹拌した。The desired product 4-chloro-6-dimethylaminopyrido [3,2-d] pyrimidine (3) is a starting material 6-fluoropyrido [3,2-d] pyrimidine-
It was synthesized in two steps from 4-one (1). (1) Synthesis of 6-dimethylaminopyrido (3,2-d) pyrimidine (2) According to the method of WA Denney et al. (J. Med. Ch.
em. 1996, 39, 1823-1835) To a prepared 6-fluoropyrido [3,2-d] pyrimidin-4-one (1) (540 mg, 3.27 mmol) was added a 50% aqueous dimethylamino solution (7 ml), and ethanol (50 m
l) was added, and the mixture was sealed and stirred at 100 ° C.
【0432】4時間後室温に戻し一晩放置した後、濃縮
して2(527mg)を得た。 6−ジメチルアミノピリド〔3,2−d〕ピリミジン−
4−オン(2)1 H NMR(DMSO−d6 ,300MHz)δpp
m:3.13(s,6H),7.19(d,J=9.3
Hz,1H),7.77(d,J=9.3Hz,1
H),7.84(s,1H).After 4 hours, the temperature was returned to room temperature and the mixture was allowed to stand overnight, and then concentrated to obtain 2 (527 mg). 6-dimethylaminopyrido [3,2-d] pyrimidine-
4-one (2) 1 H NMR (DMSO-d 6 , 300 MHz) δpp
m: 3.13 (s, 6H), 7.19 (d, J = 9.3)
Hz, 1H), 7.77 (d, J = 9.3 Hz, 1
H), 7.84 (s, 1H).
【0433】(2)4−クロロ−6−ジメチルアミノピ
リド〔3,2−d〕ピリミジン(2L)の合成 6−ジメチルアミノピリド〔3,2−d〕ピリミジン−
4−オン(2)(360mg、2.04mmol)にオ
キシ塩化リン(15ml)を加えて還流した。30分後
過剰のオキシ塩化リンを減圧留去し、氷浴下でゆっくり
氷水(100ml)を加えた。EtOAc(200m
l)で抽出して、洗浄(飽和食塩水)乾燥(Na2 SO
4 )、濃縮して目的物2L(203mg、51%)を得
た。 4−クロロ−6ジメチルアミノピリド〔3,2−d〕ピ
リミジン(2L)1 H NMR(DMSO−d6 ,300MHz)δpp
m:3.25(s,6H),7.62(d,J=9.3
Hz,1H),8.07(d,J=9.3Hz,1
H),8.74(s,1H). 合成例27 4−クロロピリド〔2,3−d〕ピリミジ
ン(2m)の合成(2) Synthesis of 4-chloro-6-dimethylaminopyrido [3,2-d] pyrimidine (2 L) 6-dimethylaminopyrido [3,2-d] pyrimidine-
Phosphorous oxychloride (15 ml) was added to 4-one (2) (360 mg, 2.04 mmol) and the mixture was refluxed. After 30 minutes, excess phosphorus oxychloride was distilled off under reduced pressure, and ice water (100 ml) was slowly added in an ice bath. EtOAc (200m
1), washed (saturated saline) and dried (Na 2 SO 4)
4 ) and concentrated to obtain 2 L of the desired product (203 mg, 51%). 4-chloro-6-dimethylaminopyrido [3,2-d] pyrimidine (2 L) 1 H NMR (DMSO-d 6 , 300 MHz) δpp
m: 3.25 (s, 6H), 7.62 (d, J = 9.3)
Hz, 1H), 8.07 (d, J = 9.3 Hz, 1
H), 8.74 (s, 1H). Synthesis Example 27 Synthesis of 4-chloropyrido [2,3-d] pyrimidine (2m)
【0434】[0434]
【化115】 Embedded image
【0435】R.K.Robins,G.H.Hitc
hingsの方法に従い(J.Am.Chem.So
c.,77,2256(1995)目的物2mを合成し
た。 4−クロロピリド〔2,3−d〕ピリミジン(2m)1 H NMR(DMSO−d6 ,300MHz)δpp
m:7.92(dd,J=8.3,4.3Hz,1
H),8.75(dd,J=8.3,1.7Hz,1
H),9.30(s,1H),9.38(dd,J=
4.3,1.7Hz,1H). 合成例28 エチル 4−クロロ−5−アミノ−6−ピ
リミジルアミノアセテート(2n)の合成[0435] R. K. Robins, G .; H. Hitc
hings method (J. Am. Chem. So
c. , 77, 2256 (1995). 4-chloropyrido [2,3-d] pyrimidine (2 m) 1 H NMR (DMSO-d 6 , 300 MHz) δpp
m: 7.92 (dd, J = 8.3, 4.3 Hz, 1
H), 8.75 (dd, J = 8.3, 1.7 Hz, 1
H), 9.30 (s, 1H), 9.38 (dd, J =
4.3, 1.7 Hz, 1H). Synthesis Example 28 Synthesis of ethyl 4-chloro-5-amino-6-pyrimidylaminoacetate (2n)
【0436】[0436]
【化116】 Embedded image
【0437】W.R.Boonらの方法に従い(J.C
hem.Soc.96(1951))目的物エチル 4
−クロロ−5−アミノ−6−ピリミジルアミノアセテー
ト(2n)を合成した。 エチル 4−クロロ−5−アミノ−6−ピリミジルアミ
ノアセテート(2n)1 H NMR(DMSO−d6 ,300MHz)δpp
m:1.19(t,J=7.1Hz,3H),4.13
(q,J=7.1Hz,2H),4.19(d,J=
5.7Hz,2H),8.49(s,1H),8.82
(t,J=7.1Hz,1H). 合成例29 アセチレン体3nの合成[0437] W. R. According to the method of Boon et al.
hem. Soc. 96 (1951)) Ethyl 4
-Chloro-5-amino-6-pyrimidylaminoacetate (2n) was synthesized. Ethyl 4-chloro-5-amino-6-pyrimidylaminoacetate (2n) 1 H NMR (DMSO-d 6 , 300 MHz) δpp
m: 1.19 (t, J = 7.1 Hz, 3H), 4.13
(Q, J = 7.1 Hz, 2H), 4.19 (d, J =
5.7 Hz, 2H), 8.49 (s, 1H), 8.82
(T, J = 7.1 Hz, 1H). Synthesis Example 29 Synthesis of acetylene compound 3n
【0438】[0438]
【化117】 Embedded image
【0439】60%NaH(1.4g、34.4mmo
l)をTHFで洗浄し、THF(10ml)の懸濁液と
した中に1(1.38g、8.61mmol)のTHF
溶液(10ml)を室温下で滴下した。10分間撹拌の
後、ブロモ酢酸(1.79g、12.9mmol)のT
HF溶液(10ml)を室温下で滴下した。更にTHF
(15ml)を加えて懸濁状態のまま撹拌した。2日
後、H2 O(60ml)を加えてEt2 O(30ml)
で洗浄した後、水層を希硫酸でpH2とし、EtOAc
100mlで抽出した。抽出液を飽和食塩水で洗浄、乾
燥(Na2 SO4 )濃縮し、2のカルボン酸体の粗結晶
(2.04g)を得た。60% NaH (1.4 g, 34.4 mmol)
l) was washed with THF to give a suspension of THF (10 ml) in 1 (1.38 g, 8.61 mmol) of THF.
The solution (10 ml) was added dropwise at room temperature. After stirring for 10 minutes, the bromoacetic acid (1.79 g, 12.9 mmol) T
An HF solution (10 ml) was added dropwise at room temperature. Further THF
(15 ml) and the mixture was stirred in a suspended state. Two days later, H 2 O (60 ml) was added, and Et 2 O (30 ml) was added.
After washing with water, the aqueous layer was adjusted to pH 2 with dilute sulfuric acid and EtOAc
Extracted with 100 ml. The extract was washed with a saturated saline solution, dried (Na 2 SO 4 ) and concentrated to obtain crude crystals of the carboxylic acid compound (2.04 g).
【0440】得られた粗結晶(640mg)のメタノー
ル溶液(8ml)中にトリメチルシリルジアゾメタン、
10%ヘキサン溶液(14ml)を滴下した。これを濃
縮した後、シリカゲルカラムクロマトグラフィー(el
uent:Hex/EtOAc=10/1)で精製し、
目的物3n(505mg、80%)を得た。 アセチレン体3n;1 H NMR(CDCl3 ,300MHz)δppm:
1.42(s,3H),2.53(s,1H),2.9
7(d,J=13.2Hz,1H),3.10(d,J
=13.2Hz,1H),3.75(s,3H),4.
24(d,J=10.8Hz,1H),4.29(d,
J=10.8Hz,1H),7.26−7.34(m,
5H). 合成例30 アセチレン化合物3pの製造In a methanol solution (8 ml) of the obtained crude crystals (640 mg), trimethylsilyldiazomethane was added.
A 10% hexane solution (14 ml) was added dropwise. After concentrating this, silica gel column chromatography (el
uent: Hex / EtOAc = 10/1)
The desired product 3n (505 mg, 80%) was obtained. Acetylene derivative 3n; 1 H NMR (CDCl 3 , 300 MHz) δ ppm:
1.42 (s, 3H), 2.53 (s, 1H), 2.9
7 (d, J = 13.2 Hz, 1H), 3.10 (d, J
= 13.2 Hz, 1H), 3.75 (s, 3H), 4.
24 (d, J = 10.8 Hz, 1H), 4.29 (d,
J = 10.8 Hz, 1H), 7.26-7.34 (m,
5H). Synthesis Example 30 Production of acetylene compound 3p
【0441】[0441]
【化118】 Embedded image
【0442】Methyl 4−hydroxyben
zoate(2.10g、13.8mmol)のCH3
CN溶液(30ml)を氷冷下撹拌し、DBV(2.7
ml、17.9mmol)、CuCl2 −2H2 O
(2.5mg、0.014mmol)を加え次いで3−
Chloro−3−methyl−1−butyne
(1.84g、17.9mmol)のCH3 CN溶液
(8ml)を20分以上かけて滴下した。室温まで昇温
し、一晩放置した後、CuCl2 ・2H2 O(6mg)
および3−Chloro−3−methyl−1−bu
tyne(0.5ml)を加え室温で1.5時間撹拌し
た。反応液を濃縮し、残渣を1N HCl水溶液(30
ml)とトルエン(50ml)に分配し、有機層を1N
HCl水溶液(30ml×2)、10%Na2 CO3
水溶液(30ml×2)、飽和食塩水(30ml)で洗
浄し、乾燥(MgSO4 )後、減圧下溶媒を留去し、目
的とするアセチレン3p(2.93g、定量的)を得
た。 3p: 1H NMR(CDCl3 ,300MHz)δp
pm:1.69(s,6H),2.62(s,1H),
3.88(s,3H),7.24(d,J=8.9H
z,2H),7.97(d,J=8.9Hz,2H). 合成例31 アセチレン化合物3qの製造[0442] Methyl 4-hydroxyben
Zoate (2.10 g, 13.8 mmol) in CH 3
The CN solution (30 ml) was stirred under ice-cooling, and DBV (2.7
ml, 17.9 mmol), CuCl 2 -2H 2 O
(2.5 mg, 0.014 mmol) and then 3-
Chloro-3-methyl-1-butyne
A solution of (1.84 g, 17.9 mmol) in CH 3 CN (8 ml) was added dropwise over 20 minutes. After the temperature was raised to room temperature and allowed to stand overnight, CuCl 2 .2H 2 O (6 mg) was used.
And 3-Chloro-3-methyl-1-bu
Tyne (0.5 ml) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated, and the residue was treated with a 1N aqueous HCl solution (30%).
ml) and toluene (50 ml).
HCl aqueous solution (30 ml × 2), 10% Na 2 CO 3
After washing with an aqueous solution (30 ml × 2) and a saturated saline solution (30 ml), drying (MgSO 4 ), the solvent was distilled off under reduced pressure to obtain the target acetylene 3p (2.93 g, quantitative). 3p: 1 H NMR (CDCl 3 , 300 MHz) δp
pm: 1.69 (s, 6H), 2.62 (s, 1H),
3.88 (s, 3H), 7.24 (d, J = 8.9H)
z, 2H), 7.97 (d, J = 8.9 Hz, 2H). Synthesis Example 31 Production of acetylene compound 3q
【0443】[0443]
【化119】 Embedded image
【0444】出発物質としてサリチル酸エチルを用い上
記合成例と同様な操作を行なった。粗精製物をシリカゲ
ルカラムクロマトグラフィー(ヘキサン:EtOAc=
1:0→6/1)で精製し目的とするアセチレン3q
(1.95g、72%)を得た。 3q: 1H NMR(CDCl3 ,300MHz)δp
pm:1.39(t,J=7.2Hz,3H),1.6
8(s,6H),2.57(s,1H),4.35
(q,J=7.2Hz,2H),7.09(dd,J=
1.1,7.6Hz,1H),7.36−7.43
(m,1H),7.58(dd,J=1.1,8.3H
z,1H),7.75(dd,J=1.8,7.7H
z,1H). 合成例32 アミノアセチレン3rの製造The same operation as in the above Synthesis Example was performed using ethyl salicylate as a starting material. The crude product is purified by silica gel column chromatography (hexane: EtOAc =
1: 0 → 6/1) and purified acetylene 3q
(1.95 g, 72%). 3q: 1 H NMR (CDCl 3 , 300 MHz) δp
pm: 1.39 (t, J = 7.2 Hz, 3H), 1.6
8 (s, 6H), 2.57 (s, 1H), 4.35
(Q, J = 7.2 Hz, 2H), 7.09 (dd, J =
1.1, 7.6 Hz, 1H), 7.36-7.43
(M, 1H), 7.58 (dd, J = 1.1, 8.3H
z, 1H), 7.75 (dd, J = 1.8, 7.7H
z, 1H). Synthesis Example 32 Production of aminoacetylene 3r
【0445】[0445]
【化120】 Embedded image
【0446】NaH(435mg、10.9mmol、
60% in mineral oil)を乾燥ヘキサ
ンで洗浄し、DMF(5ml)を加え氷浴上撹拌した。
合成例14で製造したアミノアセチレン3h(591m
g、2.72mmol)のTHF溶液(2ml)を加え
た後、BrCH2 CO2 H(567mg、4.08mm
ol)を滴下し一晩室温で撹拌した。減圧下溶媒を留去
し、10%クエン酸水溶液に反応液をあけた。生成物を
CH2 Cl2 (20ml×2)で抽出し、抽出液を乾燥
(Na2 SO4 )、濃縮すると目的物3rのDMF溶液
(79wt%)が得られた(210mg、換算収率22
%)。NaH (435 mg, 10.9 mmol,
60% in mineral oil was washed with dry hexane, DMF (5 ml) was added, and the mixture was stirred on an ice bath.
The aminoacetylene 3h (591m) produced in Synthesis Example 14
g, 2.72 mmol) in THF (2 ml) was added, followed by BrCH 2 CO 2 H (567 mg, 4.08 mm).
ol) was added dropwise and stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and the reaction solution was poured into a 10% aqueous citric acid solution. The product was extracted with CH 2 Cl 2 (20 ml × 2), and the extract was dried (Na 2 SO 4 ) and concentrated to obtain a DMF solution (79 wt%) of the desired product 3r (210 mg, reduced yield 22).
%).
【0447】3r: 1H NMR(CDCl3 ,300
MHz)δppm:1.41(s,3H),2.54
(s,1H),2.69(s,3H),2.93(d,
J=12.7Hz,1H),2.92−3.18(m,
2H),3.27(d.J=12.7Hz,1H),
3.81(m,2H),4.14(2d,J=17.5
Hz,2H),7.27−7.40(m,5H). 合成例33 アセチレン3sの製造3r: 1 H NMR (CDCl 3 , 300
MHz) δ ppm: 1.41 (s, 3H), 2.54
(S, 1H), 2.69 (s, 3H), 2.93 (d,
J = 12.7 Hz, 1H), 2.92-3.18 (m,
2H), 3.27 (d.J = 12.7 Hz, 1H),
3.81 (m, 2H), 4.14 (2d, J = 17.5)
Hz, 2H), 7.27-7.40 (m, 5H). Synthesis Example 33 Production of acetylene 3s
【0448】[0448]
【化121】 Embedded image
【0449】下記スキームに従い製造した。The compound was produced according to the following scheme.
【0450】[0450]
【化122】 Embedded image
【0451】1)Ethyl 4−piperidin
ecarboxylate(4.45g、28.3mm
ol)およびEt3 N(4.7ml、34.0mmo
l)のTHF溶液(50ml)を氷浴上撹拌し、(t−
BuOCO)2 O(6.80g、31.1mmol)お
よびDMAP(73mg)を加え、室温で一晩放置し
た。反応液を濃縮し、水(50ml)およびEtOAc
(100ml)を加え、有機層を飽和炭酸水素ナトリウ
ム水溶液、1N塩酸水溶液、続いて飽和炭酸水素ナトリ
ウム水溶液で順次洗浄し、乾燥(Na2 SO4 )、濃縮
し目的物1を薄茶色油状物として得た(7.22g、9
9%)。1) Ethyl 4-piperidin
ecarboxylate (4.45 g, 28.3 mm
ol) and Et 3 N (4.7 ml, 34.0 mmol)
l) THF solution (50 ml) was stirred on an ice bath, and (t-
(BuOCO) 2 O (6.80 g, 31.1 mmol) and DMAP (73 mg) were added, and the mixture was allowed to stand at room temperature overnight. The reaction was concentrated, water (50 ml) and EtOAc
(100 ml), and the organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate, a 1N aqueous solution of hydrochloric acid, and then with a saturated aqueous solution of sodium hydrogencarbonate, dried (Na 2 SO 4 ) and concentrated to give the intended product 1 as a pale brown oil (7.22 g, 9
9%).
【0452】1: 1H NMR(CDCl3 ,300M
Hz)δppm:1.26(t,J=7.0Hz,3
H),1.46(s,9H),1.52−1.70
(m,2H),1.80−1.95(m,2H),2.
43(tt,J=3.9,11.0Hz,1H),2.
84(m,2H),4.01(br d,J=12.8
Hz,2H),4.14(q,J=7.0Hz,2
H). 2)上記1のTHF溶液(40ml)を−65℃に冷却
し、1MのLithium bis(trimethy
lsilyl)amide THF溶液(14.7m
l、14.7mmol)を滴下した。40分後、ベンジ
ルブロミド(1.67ml、14.1mmol)を滴下
し、−65℃で30分撹拌後、ゆっくりと室温まで昇温
した。反応液を0℃に冷却し、飽和NH4 Cl水溶液を
加え反応を停止させ、濃縮した。残渣を水(40ml)
−EtOAc(40ml)に分配し、水層をEtOAc
(30ml)で抽出した。有機層を乾燥(Na2 S
O4 )、濃縮後残渣をシリカゲルカラムクロマトグラフ
ィー(ヘキサン:EtOAc=9:1)で精製し2を得
た(4.23g、91%)。1: 1 H NMR (CDCl 3 , 300M
Hz) δ ppm: 1.26 (t, J = 7.0 Hz, 3
H), 1.46 (s, 9H), 1.52-1.70.
(M, 2H), 1.80-1.95 (m, 2H), 2.
43 (tt, J = 3.9, 11.0 Hz, 1H);
84 (m, 2H), 4.01 (br d, J = 12.8)
Hz, 2H), 4.14 (q, J = 7.0 Hz, 2
H). 2) The above THF solution (40 ml) was cooled to −65 ° C., and 1M lithium bis (trimethy) was added.
lsilyl) amide THF solution (14.7m
1, 14.7 mmol) was added dropwise. After 40 minutes, benzyl bromide (1.67 ml, 14.1 mmol) was added dropwise, and the mixture was stirred at -65 ° C for 30 minutes, and then slowly heated to room temperature. The reaction solution was cooled to 0 ° C., a saturated NH 4 Cl aqueous solution was added to stop the reaction, and the mixture was concentrated. The residue was water (40 ml)
-Partitioned between EtOAc (40 ml) and the aqueous layer was separated with EtOAc
(30 ml). Dry the organic layer (Na 2 S
O 4 ) and after concentration, the residue was purified by silica gel column chromatography (hexane: EtOAc = 9: 1) to give 2 (4.23 g, 91%).
【0453】2: 1H NMR(CDCl3 ,250M
Hz)δppm:1.18(t,J=7.1Hz,3
H),1.44(s,9H),1.32−1.65
(m,4H),2.09(br d,J=12.7H
z,2H),2.70−2.90(m,2H),2.8
2(s,2H),3.80−4.00(m,2H),
4.10(q,J=7.1Hz,2H),7.00−
7.10(m,2H),7.18−7.30(m,3
H). 3)2のトルエン溶液(20ml)を−65℃に冷却
し、1.1MのDIBALトルエン溶液(8.0ml、
8.77mmol)を滴下した。5分後希塩酸を加え、
室温でしばらく撹拌した。有機層を乾燥(Na2 S
O4 )濃縮し、残渣をシリカゲルカラムクロマトグラフ
ィーで精製するとアルデヒド4(381mg、17%)
およびアルコール3(306mg、14%)が生成物と
して得られた。2: 1 H NMR (CDCl 3 , 250M
Hz) δ ppm: 1.18 (t, J = 7.1 Hz, 3
H), 1.44 (s, 9H), 1.32-1.65.
(M, 4H), 2.09 (br d, J = 12.7H
z, 2H), 2.70-2.90 (m, 2H), 2.8
2 (s, 2H), 3.80-4.00 (m, 2H),
4.10 (q, J = 7.1 Hz, 2H), 7.00-
7.10 (m, 2H), 7.18-7.30 (m, 3
H). 3) The toluene solution of 2 (20 ml) was cooled to −65 ° C., and a 1.1 M DIBAL toluene solution (8.0 ml,
8.77 mmol) was added dropwise. After 5 minutes, add dilute hydrochloric acid,
Stirred at room temperature for a while. Dry the organic layer (Na 2 S
O 4 ) concentrated and the residue purified by silica gel column chromatography to give aldehyde 4 (381 mg, 17%)
And alcohol 3 (306 mg, 14%) were obtained as product.
【0454】4: 1H NMR(CDCl3 ,300M
Hz)δppm:1.44(s,9H),1.40−
1.66(m,4H),1.93(br d,J=1
3.7Hz,2H),2.78(s,2H),2.85
(br t,J=12.7Hz,2H),3.87(b
r d,J=13.2Hz,2H),7.02−7.1
0(m,2H),7.18−7.35(m,3H),
9.57(s,1H). 3: 1H NMR(CDCl3 ,300MHz)δpp
m:1.46(s,9H),1.40−1.50(m,
4H),2.72(s,2H),3.33−3.58
(m,4H),3.40(s,2H),7.12−7.
32(m,5H).4: 1 H NMR (CDCl 3 , 300M
Hz) δ ppm: 1.44 (s, 9H), 1.40 −
1.66 (m, 4H), 1.93 (br d, J = 1
3.7 Hz, 2H), 2.78 (s, 2H), 2.85
(Br t, J = 12.7 Hz, 2H), 3.87 (b
rd, J = 13.2 Hz, 2H), 7.02-7.1.
0 (m, 2H), 7.18-7.35 (m, 3H),
9.57 (s, 1H). 3: 1 H NMR (CDCl 3 , 300 MHz) δpp
m: 1.46 (s, 9H), 1.40-1.50 (m,
4H), 2.72 (s, 2H), 3.33-3.58
(M, 4H), 3.40 (s, 2H), 7.12-7.
32 (m, 5H).
【0455】4)アルコール3(306mg、1.4m
mol)、NaBr(430mg、4.2mmol)お
よび4−Hydroxy−2,2′,6,6′−tet
ramethylpiperidine−N−oxid
e(25mg)のジクロロメタン(6ml)−飽和Na
HCO3 水溶液(10ml)の混合溶液を氷浴上撹拌
し、これに5%NaOCl水溶液(2ml)を滴下し
た。10分後EtOH(0.5ml)を加えた後、有機
層を分離し、水層をジクロロメタン(10ml)で抽出
した。抽出液をMgSO4 上で乾燥し、減圧下溶媒を留
去し、残渣をシリカゲルカラムクロマトで精製し、アル
デヒド2を得た(287mg、68%)。4) Alcohol 3 (306 mg, 1.4 m)
mol), NaBr (430 mg, 4.2 mmol) and 4-Hydroxy-2,2 ', 6,6'-tet
ramethylpiperidine-N-oxid
e (25 mg) in dichloromethane (6 ml) -saturated Na
A mixed solution of an aqueous HCO 3 solution (10 ml) was stirred on an ice bath, and a 5% aqueous NaOCl solution (2 ml) was added dropwise thereto. After 10 minutes, EtOH (0.5 ml) was added, the organic layer was separated, and the aqueous layer was extracted with dichloromethane (10 ml). The extract was dried over MgSO 4 , the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain aldehyde 2 (287 mg, 68%).
【0456】5)(EtO)2 P(O)CCl3 (J.
Am.Chem.Soc.,1947,69,100
2)(766mg、3.0mmol)のTHF(4m
l)−Et2 O(6ml)溶液を−100℃に冷却し、
1.61Mのn−BuLiヘキサン溶液(1.8ml、
2.9mmol)を滴下した。これにアルデヒド2(3
78mg、1.25mmol)のTHF(2.5ml)
−Et2 O(2.5ml)溶液を滴下し、反応混合物を
5時間かけて室温まで昇温した後、15分間還流させ
た。反応混合物を−30℃に冷却し、NH4 Cl水溶液
を加え、EtOAc(20ml×2)で抽出した。抽出
液を乾燥(Na2 SO4 )濃縮し、残渣をシリカゲルカ
ラムクロマトグラフィーで精製し、ジクロロ体5を得た
(414mg、48%)。 5: 1H NMR(CDCl3 ,300MHz)δpp
m:1.45(s,9H),1.22−1.52(m,
2H),1.98(br d,J=12.4Hz,2
H),1.75−1.93(m,2H),2.83
(s,2H),3.82−4.00(m,2H),5.
59(s,1H),7.07−7.17(m,2H),
7.20−7.35(m,3H).5) (EtO) 2 P (O) CCl 3 (J.
Am. Chem. Soc. , 1947, 69, 100
2) (766 mg, 3.0 mmol) in THF (4m
l) Cool the -Et 2 O (6 ml) solution to -100 ° C,
1.61 M n-BuLi hexane solution (1.8 ml,
2.9 mmol) was added dropwise. Add aldehyde 2 (3
78mg, 1.25mmol) THF (2.5ml)
It was added dropwise -Et 2 O (2.5ml) solution, after raising the temperature to room temperature over the reaction mixture for 5 hours, refluxed for 15 minutes. The reaction mixture was cooled to −30 ° C., aqueous NH 4 Cl was added, and extracted with EtOAc (20 ml × 2). The extract was dried (Na 2 SO 4 ) and concentrated, and the residue was purified by silica gel column chromatography to obtain dichloro form 5 (414 mg, 48%). 5: 1 H NMR (CDCl 3 , 300 MHz) δpp
m: 1.45 (s, 9H), 1.22-1.52 (m,
2H), 1.98 (br d, J = 12.4 Hz, 2
H), 1.75-1.93 (m, 2H), 2.83.
(S, 2H), 3.82-4.00 (m, 2H), 5.
59 (s, 1H), 7.07-7.17 (m, 2H),
7.20-7.35 (m, 3H).
【0457】6)氷冷下、5(394mg、1.1mm
ol)のTHF溶液(10ml)に1.6Mのn−Bu
Liヘキサン溶液(1.52ml、2.43mmol)
を滴下し、ゆっくりと室温まで昇温した。反応混合液に
NH4 Cl水溶液を加え反応を停止し、生成物をヘキサ
ン−EtOAc混合液で抽出した。抽出液を乾燥(Na
2 SO4 )、濃縮し、6aを得た。6aをEtOAc
(0.5ml)に溶解し、氷冷下4N HCl/EtO
Ac溶液(2ml)を加え、10分間撹拌した。室温で
さらに1時間撹拌後、Et2 O(4ml)を加え生成す
る沈殿物を濾取し、6b・HClを白色粉末結晶として
得た(210mg、81%)。 6b・HCl: 1H NMR(DMSO−d6 ,300
MHz)δppm:1.70−1.95(m,4H),
2.81(s,2H),2.86(s,1H),3.0
0−3.20(m,2H),3.22−3.35(m,
2H),7.27(m,5H),9.12(br s,
1H),9.30(br s,1H).6) Under ice cooling, 5 (394 mg, 1.1 mm)
ol) in a THF solution (10 ml) of 1.6 M n-Bu.
Li hexane solution (1.52 ml, 2.43 mmol)
Was added dropwise, and the temperature was slowly raised to room temperature. An aqueous NH 4 Cl solution was added to the reaction mixture to stop the reaction, and the product was extracted with a hexane-EtOAc mixture. The extract is dried (Na
2 SO 4 ) and concentrated to give 6a. 6a to EtOAc
(0.5 ml) and 4N HCl / EtO under ice-cooling.
An Ac solution (2 ml) was added and stirred for 10 minutes. After further stirring at room temperature for 1 hour, Et 2 O (4 ml) was added and the resulting precipitate was collected by filtration to give 6b · HCl as white powder crystals (210 mg, 81%). 6b · HCl: 1 H NMR (DMSO-d 6 , 300
MHz) δ ppm: 1.70-1.95 (m, 4H),
2.81 (s, 2H), 2.86 (s, 1H), 3.0
0-3.20 (m, 2H), 3.22-3.35 (m,
2H), 7.27 (m, 5H), 9.12 (brs,
1H), 9.30 (brs, 1H).
【0458】7)6b・HCl(203mg、0.86
mmol)、K2 CO3 (178mg、1.29mmo
l)、BrCH2 CO2 Et(114μl、1.03m
mol)のトルエン混合溶液(5ml)を室温で2時間
撹拌した。K2 CO3 (178mg)を加え、一晩室温
に放置した後、不溶物を濾別した。濾液を濃縮し、残渣
にNaHCO3 飽和水溶液(10ml)およびEtOA
c(10ml)を加えた。有機層を乾燥(Na2 S
O4 )、濃縮し、残渣をシリカゲルカラムクロマトグラ
フィーで精製し目的とするアセチレン3sを油状物質と
して得た(130mg、53%)。 3s: 1H NMR(CDCl3 ,300MHz)δp
pm:1.26(t,J=7.1Hz,3H),1.5
8−1.78(m,4H),2.24(s,1H),
2.51(2dt,J=3.5,11.3Hz,2
H),2.76(s,2H),2.81(m,2H),
3.21(s,2H),4.18(q,J=7.1H
z,2H),7.16−7.32(m,5H). 合成例34 アセチレン化合物3tの製造7) 6b · HCl (203 mg, 0.86
mmol), K 2 CO 3 (178 mg, 1.29 mmol)
l), BrCH 2 CO 2 Et (114 μl, 1.03 m
mol) of toluene (5 ml) was stirred at room temperature for 2 hours. After K 2 CO 3 (178 mg) was added and the mixture was allowed to stand at room temperature overnight, insolubles were removed by filtration. The filtrate was concentrated and the residue was combined with a saturated aqueous solution of NaHCO 3 (10 ml) and EtOAc.
c (10 ml) was added. Dry the organic layer (Na 2 S
O 4 ), concentrated, and the residue was purified by silica gel column chromatography to obtain the target acetylene 3s as an oil (130 mg, 53%). 3s: 1 H NMR (CDCl 3 , 300 MHz) δp
pm: 1.26 (t, J = 7.1 Hz, 3H), 1.5
8-1.78 (m, 4H), 2.24 (s, 1H),
2.51 (2 dt, J = 3.5, 11.3 Hz, 2
H), 2.76 (s, 2H), 2.81 (m, 2H),
3.21 (s, 2H), 4.18 (q, J = 7.1H)
z, 2H), 7.16-7.32 (m, 5H). Synthesis Example 34 Production of acetylene compound 3t
【0459】[0459]
【化123】 Embedded image
【0460】下記スキームに従い製造した。The compound was produced according to the following scheme.
【0461】[0461]
【化124】 Embedded image
【0462】1)出発物質としてN−(t−Butox
ycarbonyl)−4−piperidone
(1)を用い合成例7、8と同様な操作で2(定量的)
および4を粗精製物として得た。 2: 1H NMR(CDCl3 ,250MHz)δpp
m:1.46(s,9H),1.93(2ddd,J=
3.9,9.4,13.2Hz,2H),2.07
(s,3H),2.15−2.25(m,2H),2.
67(s,1H),3.34(2ddd,J=3.6,
9.7,13.5Hz,2H),3.72(m,2
H).1) N- (t-Butox) as a starting material
ycarbonyl) -4-piperidone
2 (quantitative) by the same operation as in Synthesis Examples 7 and 8 using (1)
And 4 were obtained as a crude product. 2: 1 H NMR (CDCl 3 , 250 MHz) δpp
m: 1.46 (s, 9H), 1.93 (2ddd, J =
(3.9, 9.4, 13.2 Hz, 2H), 2.07
(S, 3H), 2.15 to 2.25 (m, 2H), 2.
67 (s, 1H), 3.34 (2ddd, J = 3.6,
9.7, 13.5 Hz, 2H), 3.72 (m, 2
H).
【0463】2)粗精製である4(1.08g)のEt
2 O溶液(1ml)を氷浴上撹拌し、4N HCl/E
tOAc溶液(4ml)を滴下した。室温でしばらく撹
拌した後、生成物5を濾取した。この粗精製物(890
mg)、BrCH2 CO2 Et(0.61ml、5.5
mmol)およびK2 CO3 (2.2g、15.9mm
ol)をトルエン(10ml)に懸濁させ、70〜80
℃で4時間撹拌した。反応混合物を放冷後、水(40m
l)、EtOAc(40ml)を加え、有機層を分離し
た。水層をEtOAc(15ml)で抽出し、抽出液を
乾燥(Na2 SO4 )、濃縮した。残渣をシリカゲルカ
ラムクロマトグラフィー(ヘキサン:EtOAc=4:
1→1:1)で精製し、目的物であるアセチレン3tを
得た(460mg,1からの収率37%)。2) Et of crude purified 4 (1.08 g)
The 2 O solution (1 ml) was stirred on an ice bath and 4N HCl / E
A tOAc solution (4 ml) was added dropwise. After stirring at room temperature for a while, the product 5 was collected by filtration. The crude product (890)
mg), BrCH 2 CO 2 Et (0.61 ml, 5.5
mmol) and K 2 CO 3 (2.2 g, 15.9 mm
ol) in toluene (10 ml),
Stirred at C for 4 hours. After allowing the reaction mixture to cool, water (40 m
1), EtOAc (40 ml) was added and the organic layer was separated. The aqueous layer was extracted with EtOAc (15 ml), and the extract was dried (Na 2 SO 4 ) and concentrated. The residue was subjected to silica gel column chromatography (hexane: EtOAc = 4:
Purification was carried out by 1: 1: 1) to obtain acetylene 3t (460 mg, yield 37% from 1).
【0464】3t: 1H NMR(CDCl3 ,300
MHz)δppm:1.28(t,J=7.1Hz,3
H),1.93(2ddd,J=3.7,10.6,1
3.5Hz,2H),2.22(m,2H),2.49
(s,1H),2.66(2ddd,J=2.6,1
0.5Hz,2H),2.82(m,2H),3.25
(s,2H),4.19(q,J=7.1Hz,2
H),6.79(m,1H),6.94(m,2H),
7.18(m,2H). 合成例35 アセチレン3u3t: 1 H NMR (CDCl 3 , 300
MHz) δ ppm: 1.28 (t, J = 7.1 Hz, 3
H), 1.93 (2ddd, J = 3.7, 10.6, 1
3.5Hz, 2H), 2.22 (m, 2H), 2.49
(S, 1H), 2.66 (2ddd, J = 2.6, 1
0.5 Hz, 2H), 2.82 (m, 2H), 3.25
(S, 2H), 4.19 (q, J = 7.1 Hz, 2
H), 6.79 (m, 1H), 6.94 (m, 2H),
7.18 (m, 2H). Synthesis Example 35 Acetylene 3u
【0465】[0465]
【化125】 Embedded image
【0466】下記スキームに従い製造した。The compound was produced according to the following scheme.
【0467】[0467]
【化126】 Embedded image
【0468】1)CeCl3 :7H2 O(10.12
g、27.2mmol)を減圧下140℃で4時間撹拌
しながら乾燥した。これに室温でTHF(70ml)を
加え、1時間撹拌した。一方、トリメチルシリルアセチ
レン(3.84ml,27.2mmol)のTHF溶液
(20ml)をドライアイス−EtOH浴で冷却し、
1.6Mのn−BuLiヘキサン溶液(16.9ml、
27.0mmol)を滴下し、ゆっくりと室温まで昇温
した。この溶液を上記の方法で調製し、−65℃に冷却
したCeCl3 THF懸濁液に滴下し、30分間撹拌し
た。この懸濁液にインダノン(3.30g、25.0m
mol)のTHF溶液(9ml)を滴下し、1時間撹拌
後、無水酢酸(3.1ml、32.4mmol)を加え
た。反応液をゆっくりと室温まで昇温し、一晩放置した
後、NH4 Cl水溶液を加え濃縮した。生成物をEtO
Acで抽出し、抽出液を飽和NaHCO3 水溶液で洗浄
し、乾燥(Na2 SO4 )、濃縮した。残渣を短いシリ
カゲルカラムクロマトグラフィー(ヘキサン:EtOA
c=4/1)に付し、2を含む油状物質を得た。これを
THF(20ml)に溶解し、1M n−Bu4 NF
THF溶液(1ml、1.0mmol)を加え、室温で
1時間撹拌した。反応溶液に飽和NH4 Cl水溶液を加
え、生成物をEtOAc(50ml)で抽出した。抽出
液を乾燥(Na2SO4 )、濃縮し、残渣をシリカゲル
カラムクロマトグラフィー(ヘキサン:EtOAc=1
5:1→9:1)で精製し、4を結晶性固体として得た
(1.71g、34%)。1) CeCl 3 : 7H 2 O (10.12)
g, 27.2 mmol) was dried at 140 ° C. under reduced pressure with stirring for 4 hours. To this was added THF (70 ml) at room temperature, and the mixture was stirred for 1 hour. On the other hand, a THF solution (20 ml) of trimethylsilylacetylene (3.84 ml, 27.2 mmol) was cooled in a dry ice-EtOH bath,
1.6 M n-BuLi hexane solution (16.9 ml,
27.0 mmol) was added dropwise, and the temperature was slowly raised to room temperature. This solution was prepared by the method described above, added dropwise to the CeCl 3 THF suspension cooled to -65 ° C, and stirred for 30 minutes. Add this suspension to indanone (3.30 g, 25.0 m
mol) in THF (9 ml) was added dropwise, and after stirring for 1 hour, acetic anhydride (3.1 ml, 32.4 mmol) was added. The reaction solution was slowly warmed to room temperature, left overnight, and then added with an aqueous NH 4 Cl solution and concentrated. The product is treated with EtO
Extract with Ac, wash the extract with saturated aqueous NaHCO 3 , dry (Na 2 SO 4 ) and concentrate. The residue was subjected to short silica gel column chromatography (hexane: EtOA).
c = 4/1) to give an oil containing 2. This was dissolved in THF (20 ml), and 1 M n-Bu 4 NF
A THF solution (1 ml, 1.0 mmol) was added and stirred at room temperature for 1 hour. Saturated aqueous NH 4 Cl was added to the reaction solution and the product was extracted with EtOAc (50 ml). The extract was dried (Na 2 SO 4 ), concentrated, and the residue was subjected to silica gel column chromatography (hexane: EtOAc = 1).
Purification from 5: 1 to 9: 1) afforded 4 as a crystalline solid (1.71 g, 34%).
【0469】4: 1H NMR(CDCl3 ,300M
Hz)δppm:2.02(s,3H),2.57
(s,1H),3.56(2d,J=17.5Hz,2
H),358(2d,J=17.5Hz,2H),7.
21(s,4H). 2)出発物質として4とEthyl 4−piperi
dinecarboxylateを用い合成例8と同様
な操作を行ない目的物3uを白色粉末結晶として得た
(収率20%)。 3u: 1H NMR(CDCl3 ,300MHz)δp
pm:1.26(t,J=7.1Hz,3H),1.7
2−1.90(m,3H),1.94−2.02(m,
2H),2.16(s,1H),2.28−2.48
(m,3H),2.93(m,2H),3.15(d,
J=14.7Hz,2H),3.27(d,J=14.
7Hz,2H),4.15(q,J=7.1Hz,2
H),7.10−7.25(m,4H). 合成例36 アセチレン3v4: 1 H NMR (CDCl 3 , 300M
Hz) δ ppm: 2.02 (s, 3H), 2.57
(S, 1H), 3.56 (2d, J = 17.5 Hz, 2
H), 358 (2d, J = 17.5 Hz, 2H), 7.
21 (s, 4H). 2) 4 and Ethyl 4-piperi as starting materials
The same operation as in Synthesis Example 8 was performed using Dinecarboxylate to obtain the desired product 3u as white powder crystals (yield: 20%). 3u: 1 H NMR (CDCl 3 , 300 MHz) δp
pm: 1.26 (t, J = 7.1 Hz, 3H), 1.7
2-1.90 (m, 3H), 1.94-2.02 (m, 3H)
2H), 2.16 (s, 1H), 2.28-2.48
(M, 3H), 2.93 (m, 2H), 3.15 (d,
J = 14.7 Hz, 2H), 3.27 (d, J = 14.
7 Hz, 2H), 4.15 (q, J = 7.1 Hz, 2
H), 7.10-7.25 (m, 4H). Synthesis Example 36 Acetylene 3v
【0470】[0470]
【化127】 Embedded image
【0471】下記スキームに従い製造した。The compound was produced according to the following scheme.
【化128】 1)Diethyl Benzylmalonate
(1.00g、4.0mmol)のTHF溶液(40m
l)にt−BuOK(494mg、4.4mmol)を
加え室温で30分間撹拌後、氷−メタノール浴で冷却し
た。〔(Trimethylsilyl)ethyny
l〕(phenyl)iodoniumTriflat
e(J.Org.Chem.1991,56,3912
の方法に従い製造)(1.80g、4.0mmol)の
THF溶液(20ml)を加え室温で3時間撹拌した。
水−CH2 Cl2 で分配し、有機層を乾燥(Na2 SO
4)、濃縮し、残渣をシリカゲルカラムクロマトグラフ
ィーに付し、Diethyl benzyl〔(tri
methylsilyl)ethynyl〕malon
ate(2)を得た。Embedded image 1) Diethyl Benzylmalonate
(1.00 g, 4.0 mmol) in THF (40 m
t-BuOK (494 mg, 4.4 mmol) was added to 1), and the mixture was stirred at room temperature for 30 minutes, and then cooled in an ice-methanol bath. [(Trimethylsilyl) ethylny
l] (phenyl) iodoniumTriflat
e (J. Org. Chem. 1991, 56, 3912).
(Prepared according to the method described in (1)) (1.80 g, 4.0 mmol) in THF (20 ml), and the mixture was stirred at room temperature for 3 hours.
Partition with water-CH 2 Cl 2 and dry the organic layer (Na 2 SO
4 ), concentrated, the residue was subjected to silica gel column chromatography, and Diethyl benzyl [(tri
methylsilyl) ethyln] malon
ate (2) was obtained.
【0472】2: 1H NMR(CDCl3 ,300M
Hz)δppm:0.16(s,9H),1.23
(t,J=7.1Hz,6H),3.38(s,2
H),4.21(q,J=7.1Hz,4H),7.1
2−7.36(m,5H). 2)上記2を含水THF(10ml)に溶解し、1Mの
n−Bu4 NF THF溶液(0.1ml、0.1mm
ol)を加え室温で1時間撹拌した。EtOAc(30
ml)と飽和NH4 Cl水溶液(30ml)を加え、有
機層を分離、乾燥(Na2 SO4 )、濃縮し、残渣をシ
リカゲルカラムクロマトグラフィーで精製し、目的とす
る3vを得た(390mg、1より収率32%)。 3v: 1H NMR(CDCl3 ,300MHz)δp
pm:1.25(t,J=7.1Hz,6H),2.5
2(s,1H),3.41(s,2H),4.23
(q,J=7.1Hz,4H),7.16−7.34
(m,5H). 合成例372: 1 H NMR (CDCl 3 , 300M
Hz) δ ppm: 0.16 (s, 9H), 1.23
(T, J = 7.1 Hz, 6H), 3.38 (s, 2
H), 4.21 (q, J = 7.1 Hz, 4H), 7.1
2-7.36 (m, 5H). 2) the 2 was dissolved in water THF (10 ml), 1M of n-Bu 4 NF THF solution (0.1 ml, 0.1 mm
ol) and stirred at room temperature for 1 hour. EtOAc (30
ml) and a saturated aqueous NH 4 Cl solution (30 ml), the organic layer was separated, dried (Na 2 SO 4 ) and concentrated, and the residue was purified by silica gel column chromatography to obtain the desired 3v (390 mg, 1 to 32%). 3v: 1 H NMR (CDCl 3 , 300 MHz) δp
pm: 1.25 (t, J = 7.1 Hz, 6H), 2.5
2 (s, 1H), 3.41 (s, 2H), 4.23
(Q, J = 7.1 Hz, 4H), 7.16-7.34
(M, 5H). Synthesis Example 37
【0473】[0473]
【化129】 Embedded image
【0474】ジベンジルケトン(2.1g、10mmo
l)に0.5MエチニルマグネシウムクロリドTHF溶
液(24ml、12mmol)を加え、撹拌した。塩化
アンモニウム水溶液を注ぎ、酢酸エチルで抽出後、有機
層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し
た。減圧下溶媒を留去し、目的物3w(2.28g、
9.7mmol、97%)を得た。 3w: 1H NMR(CDCl3 ,250MHz)δp
pm:2.49(s,1H),3.02(s,4H),
7.27−7.38(m,10H). 合成例38Dibenzyl ketone (2.1 g, 10 mmol
To l) was added a 0.5 M ethynylmagnesium chloride THF solution (24 ml, 12 mmol) and the mixture was stirred. An aqueous ammonium chloride solution was poured, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the desired product 3w (2.28 g,
9.7 mmol, 97%). 3w: 1 H NMR (CDCl 3 , 250 MHz) δp
pm: 2.49 (s, 1H), 3.02 (s, 4H),
7.27-7.38 (m, 10H). Synthesis Example 38
【0475】[0475]
【化130】 Embedded image
【0476】1−フェニル−2−ブタノン(2.96
g、20mmol)のTHF(3ml)溶液を0.5M
エチニルマグネシウムクロリドTHF溶液(60ml、
30mmol)に滴下した。反応液に塩化アンモニウム
水溶液を加え酢酸エチルで抽出し、有機層を飽和食塩水
で洗浄後、硫酸ナトリウムで乾燥し、減圧下溶媒を留去
した。1-phenyl-2-butanone (2.96)
g, 20 mmol) in THF (3 ml) at 0.5 M
Ethinyl magnesium chloride THF solution (60 ml,
30 mmol). An aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
【0477】目的物3x(3.18g、18.3mmo
l、91%)を得た。1 H NMR(CDCl3 ,250MHz)δppm:
1.11(t,J=7.4Hz,3H),1.74
(q,J=7.4Hz,2H),2.46(s,1
H),2.88(d,J=13.2Hz,1H),3.
00(d,J=13.2Hz,1H),7.25−7.
50(m,5H). 合成例39The target substance 3x (3.18 g, 18.3 mmo
1, 91%). 1 H NMR (CDCl 3 , 250 MHz) δ ppm:
1.11 (t, J = 7.4 Hz, 3H), 1.74
(Q, J = 7.4 Hz, 2H), 2.46 (s, 1
H), 2.88 (d, J = 13.2 Hz, 1H), 3.
00 (d, J = 13.2 Hz, 1H), 7.25-7.
50 (m, 5H). Synthesis Example 39
【0478】[0478]
【化131】 Embedded image
【0479】ベンジルアセトン(7.4g、50mmo
l)のTHF(20ml)溶液を0.5Mエチニルマグ
ネシウムクロライドTHF溶液(110ml、55mm
ol)に滴下した。反応液に1N HClを注ぎ、有機
層を酢酸エチルで抽出後、飽和食塩水で洗浄し、硫酸ナ
トリウムで乾燥後、減圧下溶媒を留去し、プロパルジル
アルコール3Y(8.8g、0.05mol定量的)を
得た。1 H NMR(CDCl3 ,250MHz)δppm:
1.55(s,3H),1.94−2.03(m,2
H),2.51(s,1H),2.83−2.90
(m,2H),7.16−7.32(m,5H). 合成例40Benzyl acetone (7.4 g, 50 mmol
l) in THF (20 ml) was added to a 0.5 M ethynylmagnesium chloride THF solution (110 ml, 55 mm
ol). 1N HCl was poured into the reaction solution, and the organic layer was extracted with ethyl acetate, washed with saturated saline, dried over sodium sulfate, and then the solvent was distilled off under reduced pressure to give propargyl alcohol 3Y (8.8 g, 0.1 g). 05 mol quantitative). 1 H NMR (CDCl 3 , 250 MHz) δ ppm:
1.55 (s, 3H), 1.94-2.03 (m, 2
H), 2.51 (s, 1H), 2.83-2.90
(M, 2H), 7.16-7.32 (m, 5H). Synthesis Example 40
【0480】[0480]
【化132】 Embedded image
【0481】4−フルオロフェニルアセトン(250m
g、1.64mmol)のTHF(3ml)溶液に0.
5MエチニルマグネシウムクロライドTHF溶液(3.
5ml、1.75mmol)を加えた。反応液に塩化ア
ンモニウム水溶液を加え、有機層を酢酸エチルで抽出し
た後、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、
減圧下溶媒を留去し、プロパルジルアルコール3Zと原
料の混合物(215mg、NMR比3:1、57%)を
得た。1 H NMR(CDCl3 ,250MHz)δppm:
1.54(s,3H),2.47(s,1H),2.8
9(d,J=13.4Hz,1H),2.98(d,J
=13.4Hz,1H),6.97−7.06(m,2
H),7.26−7.32(m,2H). 合成例41 以下の方法で2を合成した。4-fluorophenylacetone (250 m
g (1.64 mmol) in THF (3 ml).
5M ethynylmagnesium chloride THF solution (3.
(5 ml, 1.75 mmol). An aqueous ammonium chloride solution was added to the reaction solution, and the organic layer was extracted with ethyl acetate, washed with brine, dried over sodium sulfate,
The solvent was distilled off under reduced pressure to obtain a mixture of propargyl alcohol 3Z and the raw material (215 mg, NMR ratio 3: 1, 57%). 1 H NMR (CDCl 3 , 250 MHz) δ ppm:
1.54 (s, 3H), 2.47 (s, 1H), 2.8
9 (d, J = 13.4 Hz, 1H), 2.98 (d, J
= 13.4 Hz, 1H), 6.97-7.06 (m, 2
H), 7.26-7.32 (m, 2H). Synthesis Example 41 2 was synthesized by the following method.
【0482】[0482]
【化133】 Embedded image
【0483】1)3,4−ジクロロフェニル酢酸(2
0.0g、97.5mmol)の1,2−ジクロロエタ
ン(100ml)溶液にチオニルクロリド(11.8
g、99.2mmol)とDMF一滴を加え、3時間加
熱還流したのち減圧下濃縮し油状物質23.3gを得
た。金属マグネシウム(2.56g、107mmo
l)、エタノール(2ml)THF(30ml)混液に
四塩化炭素(0.2ml)を加えた後、マロン酸ジエチ
ルエステル(16.8g、105mmol)のエタノー
ル(10ml)THF(8ml)溶液を加えた。次いで
先に得た油状物質(23.3g)のTHF(10ml)
溶液を氷冷下滴下し、室温で2時間撹拌した。これに氷
冷下、2N硫酸水溶液(50ml)、水(20ml)を
加え、撹拌した後、油層を分離し、水層を酢酸エチルで
抽出後、合わせて飽和食塩水で洗浄し減圧下溶媒を留去
した。これに酢酸(24ml)、水(16ml)、濃硫
酸(3ml)を加え加熱還流(115℃〜145℃、8
時間)した。反応液をエーテルで抽出し、20%水酸化
ナトリウム水溶液で洗浄した後、有機層を無水硫酸ナト
リウムで乾燥後減圧下溶媒を留去した。残渣をシリカゲ
ルカラムクロマトグラフィーで精製し、3,4−ジクロ
ロフェニルアセトン(1)(15.3g、91mmo
l、収率94%)で得た。1) 3,4-Dichlorophenylacetic acid (2
Thionyl chloride (11.8) was added to a solution of 0.0g (97.5 mmol) in 1,2-dichloroethane (100 ml).
g, 99.2 mmol) and one drop of DMF, and the mixture was heated under reflux for 3 hours and concentrated under reduced pressure to obtain 23.3 g of an oily substance. Metallic magnesium (2.56 g, 107 mmo
l), carbon tetrachloride (0.2 ml) was added to a mixed solution of ethanol (2 ml) and THF (30 ml), and then a solution of diethyl malonate (16.8 g, 105 mmol) in ethanol (10 ml) and THF (8 ml) was added. . The oil obtained above (23.3 g) in THF (10 ml) was then obtained.
The solution was added dropwise under ice cooling, and the mixture was stirred at room temperature for 2 hours. Under ice-cooling, a 2N aqueous solution of sulfuric acid (50 ml) and water (20 ml) were added, and the mixture was stirred. The oil layer was separated, and the aqueous layer was extracted with ethyl acetate. Distilled off. Acetic acid (24 ml), water (16 ml) and concentrated sulfuric acid (3 ml) were added thereto, and the mixture was refluxed under heating (115 ° C to 145 ° C, 8 ml).
Time). After the reaction solution was extracted with ether and washed with a 20% aqueous sodium hydroxide solution, the organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, and 3,4-dichlorophenylacetone (1) (15.3 g, 91 mmol) was used.
1, yield 94%).
【0484】2)3,4−ジクロロフェニルアセトン
(1)(1.28g、7.6mmol)に氷冷下、0.
5MエチニルマグネシウムクロライドTHF溶液(16
ml、8mmol)を滴下し、次いで無水酢酸(0.8
2ml、8.6mmol)を滴下した。反応液に塩化ア
ンモニウム水溶液を加え酢酸エチルで抽出した後、有機
層を飽和炭酸水素ナトリウム水溶液、飽和食塩水の順に
洗浄し、減圧下濃縮し油状物質(1.55g)を得た。
上と同様の操作で3,4−ジクロロフェニルアセトン
(7g、41.8mmol)から油状物質8.1gを得
た。2) 0.30 g of 3,4-dichlorophenylacetone (1) (1.28 g, 7.6 mmol) was added under ice cooling.
5M ethynylmagnesium chloride THF solution (16
ml, 8 mmol) was added dropwise, followed by acetic anhydride (0.8
2 ml, 8.6 mmol) were added dropwise. An aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated saline in this order, and concentrated under reduced pressure to obtain an oily substance (1.55 g).
In the same manner as above, 8.1 g of an oily substance was obtained from 3,4-dichlorophenylacetone (7 g, 41.8 mmol).
【0485】この油状物質を合わせ、THF(100m
l)に溶解させ、ジエチルアミン(20ml、193m
mol)、塩化銅(I)(200mg、2mmol)を
加え加熱還流した。反応液を酢酸エチルで抽出し、塩化
アンモニウム水溶液で洗浄後減圧下溶媒を留去した。残
渣をカラムクロマトグラフィーで洗浄し、プロパルジル
アミン3aa(1.74g、6.2mmol、収率12
%)を得た。1 H NMR(CDCl3 ,300MHz)δppm:
1.11(t,J=7.2Hz,6H),1.24
(s,3H),2.32(s,1H),2.71−2.
79(m,5H),2.98(d,J=13.2Hz,
1H),7.15(dd,J=8.4,1.8Hz,1
H),7.39(d,J=8.4Hz,1H),7.4
3(d,J=1.8Hz,1H). 合成例42The oily substances were combined, and THF (100 m
l) and diethylamine (20 ml, 193 m
mol) and copper (I) chloride (200 mg, 2 mmol) were added and the mixture was heated under reflux. The reaction solution was extracted with ethyl acetate, washed with an aqueous ammonium chloride solution, and the solvent was distilled off under reduced pressure. The residue was washed by column chromatography, and propargylamine 3aa (1.74 g, 6.2 mmol, yield 12)
%). 1 H NMR (CDCl 3 , 300 MHz) δ ppm:
1.11 (t, J = 7.2 Hz, 6H), 1.24
(S, 3H), 2.32 (s, 1H), 2.71-2.
79 (m, 5H), 2.98 (d, J = 13.2 Hz,
1H), 7.15 (dd, J = 8.4, 1.8 Hz, 1
H), 7.39 (d, J = 8.4 Hz, 1H), 7.4
3 (d, J = 1.8 Hz, 1H). Synthesis Example 42
【0486】[0486]
【化134】 Embedded image
【0487】上記ルートにしたがって、アミノアセチレ
ン(3ab)を合成した。次に示す。 1)J.Org.Chem.22,939(195
7),C.Osuch,R.Levine,の記述にし
たがって、4−ピリジルアセトン(1)を合成した。す
なわち、4−ピコリン(23.9g、257mmol)
のエーテル(300ml)溶液にメチルリチウム(1.
5M in Et2 O、170ml、255mmol)
を滴下した。これにメチルアセテート(9.5g、12
8mmol)のエーテル(20ml)溶液を滴下し、1
h加熱還流した。反応液に水を加え、エーテル、酢酸エ
チルの順に抽出し、有機層を合わせて飽和食塩水で洗浄
後、無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去し
た。残渣をシリカゲルカラムクロマトグラフィー(クロ
ロホルム→クロロホルム:メタノール=9:1)で分離
精製し、4−ピリジルアセトン(1)(2.7g、20
mmol、15%)を得た。According to the above route, aminoacetylene (3ab) was synthesized. Shown below. 1) J. Org. Chem. 22, 939 (195
7), C.I. Osuch, R .; According to the description of Levine, 4-pyridylacetone (1) was synthesized. That is, 4-picoline (23.9 g, 257 mmol)
To a solution of methyllithium (1.
5M in Et 2 O, 170ml, 255mmol)
Was added dropwise. To this was added methyl acetate (9.5 g, 12
8 mmol) in ether (20 ml) was added dropwise.
Heated to reflux for h. Water was added to the reaction solution, and the mixture was extracted with ether and ethyl acetate in this order. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (chloroform → chloroform: methanol = 9: 1), and 4-pyridylacetone (1) (2.7 g, 20
mmol, 15%).
【0488】1: 1H NMR(CDCl3 ,250M
Hz)δppm:2.22(s,3H),3.73
(s,2H),7.13−7.16(m,2H),8.
55−8.58(m,2H). 2)トリメチルシリルアセチレン(3.65ml、2
5.8mmol)のTHF(20ml)溶液にnBuL
i(1.66M in Hexane 15.6ml、
25.9ml)を−78℃にて滴下した。これを3塩化
セリウム7水和物(10.38g、28mmol)を減
圧下2時間140℃で加熱乾燥したものに−78℃にて
滴下した。この溶液に1(2.69g、20mmol)
を加え、1時間撹拌した後、無水酢酸(2.3ml、2
4mmol)を加えた。反応液に水を加え、酢酸エチル
で抽出した後、有機層を炭酸水素ナトリウム水溶液、次
いで飽和食塩水で洗浄し、減圧下溶媒を留去した。残渣
をシリカゲルカラムクロマトグラフィー(Hexan
e:AcOEt4:1→1:1)にて分離精製して2
(0.9g、3.3mmol、16%)を得た。1: 1 H NMR (CDCl 3 , 250M
Hz) δ ppm: 2.22 (s, 3H), 3.73
(S, 2H), 7.13-7.16 (m, 2H), 8.
55-8.58 (m, 2H). 2) Trimethylsilylacetylene (3.65 ml, 2
NBuL in 5.8 mmol) of THF (20 ml) solution
i (1.66 M in Hexane 15.6 ml,
25.9 ml) was added dropwise at -78 ° C. This was dropped at -78 ° C to cerium trichloride heptahydrate (10.38g, 28mmol) which was dried by heating at 140 ° C for 2 hours under reduced pressure. 1 (2.69 g, 20 mmol) in this solution
After stirring for 1 hour, acetic anhydride (2.3 ml, 2 ml
4 mmol) was added. After water was added to the reaction solution and the mixture was extracted with ethyl acetate, the organic layer was washed with an aqueous sodium hydrogen carbonate solution and then with a saturated saline solution, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (Hexan
e: AcOEt 4: 1 → 1: 1) to separate and purify
(0.9 g, 3.3 mmol, 16%).
【0489】2: 1H NMR(CDCl3 ,250M
Hz)δppm:0.15(s,9H),1.68
(s,3H),2.12(s,3H),3.06(d,
J=13.2Hz,1H),3.29(d,J=13.
2Hz,1H),7.22−7.26(m,2H),
8.51−8.55(m,2H). 3)2(0.9g,3.3mmol)のTHF(10m
l)溶液にnBu4 NF(1M in THF,0.8
ml,0.8mmol)を加え室温で3.5時間撹拌し
た。反応液に水を加え酢酸エチルで抽出後、有機層を無
水硫酸ナトリウムで乾燥後減圧下溶媒を留去し、3を含
む残渣(700mg)を得た。これを精製せずに次の反
応に用いた。2: 1 H NMR (CDCl 3 , 250M
Hz) δ ppm: 0.15 (s, 9H), 1.68
(S, 3H), 2.12 (s, 3H), 3.06 (d,
J = 13.2 Hz, 1H), 3.29 (d, J = 13.
2Hz, 1H), 7.22-7.26 (m, 2H),
8.51-8.55 (m, 2H). 3) 2 (0.9 g, 3.3 mmol) of THF (10 m
l) Add nBu 4 NF (1M in THF, 0.8
ml, 0.8 mmol) and stirred at room temperature for 3.5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue containing 3 (700 mg). This was used for the next reaction without purification.
【0490】3: 1H NMR(CDCl3 ,250M
Hz)δppm:1.69(s,3H),2.04
(s,3H),2.62(s,1H),3.13(d,
J=13.3Hz,1H),3.27(d,J=13.
3Hz,1H),7.24−7.26(m,2H),
8.53−8.56(m,2H). 4)3を含む油状物質(700mg)とジエチルアミン
(2.78ml、27mmol)のTHF(20ml)
溶液に塩化銅(I)(15mg、0.15mmol)を
加え、3時間加熱還流した。反応液を酢酸エチルで抽出
し、塩化アンモニウム水溶液で洗浄後、有機層を無水硫
酸ナトリウムで乾燥し減圧下溶媒を留去した。残渣をシ
リカゲルカラムクロマトグラフィー(ヘキサン:酢酸エ
チル4:1→1:1)で分離精製し、目的物3ab(1
01mg、0.47mmol 2より14%)を得た。3: 1 H NMR (CDCl 3 , 250M
Hz) δ ppm: 1.69 (s, 3H), 2.04
(S, 3H), 2.62 (s, 1H), 3.13 (d,
J = 13.3 Hz, 1H), 3.27 (d, J = 13.3 Hz).
3Hz, 1H), 7.24-7.26 (m, 2H),
8.53-8.56 (m, 2H). 4) An oil containing 3 (700 mg) and diethylamine (2.78 ml, 27 mmol) in THF (20 ml).
Copper (I) chloride (15 mg, 0.15 mmol) was added to the solution, and the mixture was refluxed for 3 hours. The reaction solution was extracted with ethyl acetate, washed with an aqueous ammonium chloride solution, and then the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (hexane: ethyl acetate 4: 1 → 1: 1) to give the desired product 3ab (1
01 mg, 14% from 0.47 mmol 2).
【0491】3ab: 1H NMR(CDCl3 ,25
0MHz)δppm:1.11(t,J=7.4Hz,
3H),1.74(q,J=7.4Hz,2H),2.
46(s,1H),2.88(d,J=13.2Hz,
1H),3.00(d,J=13.2Hz,1H),
7.25−7.50(m,5H). 合成例433ab: 1 H NMR (CDCl 3 , 25
0 MHz) δ ppm: 1.11 (t, J = 7.4 Hz,
3H), 1.74 (q, J = 7.4 Hz, 2H), 2.
46 (s, 1H), 2.88 (d, J = 13.2 Hz,
1H), 3.00 (d, J = 13.2 Hz, 1H),
7.25-7.50 (m, 5H). Synthesis Example 43
【0492】[0492]
【化135】 Embedded image
【0493】上記スキームに従って、3−エチニル−4
−フェニル安息香酸エチル(3ac)を合成した。以下
に示す。 1)4−ブロモ安息香酸エチル(23g、100mmo
l)を、発煙硝酸(28g)、濃硫酸(37g)混液に
液温20℃〜31℃に保ちながら加えた。反応液を氷水
(1リットル)にあけ生じた結晶を濾取し、エタノール
懸洗後、濾取した結晶と懸洗後の濾液を減圧下濃縮した
ものに水を加え濾取した結晶を合わせ、乾燥し、4−ブ
ロモ−3ニトロ安息香酸エチル(1)(26.8g、9
8mmol、98%)を得た。According to the above scheme, 3-ethynyl-4
-Ethyl phenylbenzoate (3ac) was synthesized. It is shown below. 1) Ethyl 4-bromobenzoate (23 g, 100 mmol
l) was added to a mixture of fuming nitric acid (28 g) and concentrated sulfuric acid (37 g) while maintaining the liquid temperature at 20 ° C to 31 ° C. The reaction solution was poured into ice water (1 liter), and the resulting crystals were collected by filtration, washed with ethanol, washed and filtered, and the filtrate after washing was concentrated under reduced pressure. Water was added, and the collected crystals were combined. Dry and dry ethyl 4-bromo-3nitrobenzoate (1) (26.8 g, 9
(8 mmol, 98%).
【0494】1; 1H NMR(CDCl3 ,250M
Hz)δppm:1.42(t,J=7.1Hz,3
H),4.43(q,J=7.1Hz,2H),7.8
4(d,J=8.4Hz,1H),8.08(dd,J
=8.4Hz,1.9Hz,1H),8.46(d,J
=1.9Hz,1H). 2)1(5.0g、18.2mmol)とフェニルホウ
酸(2.67g、21.8mmol)、ビス(トリフェ
ニルホスフィン)−パラジウム(II)クロライド(63
0mg、0.90mmol)、トリエチルアミン(7.
5ml、53mmol)のDMF(50ml)溶液を6
時間加熱還流した。1; 1 H NMR (CDCl 3 , 250M
Hz) δ ppm: 1.42 (t, J = 7.1 Hz, 3
H), 4.43 (q, J = 7.1 Hz, 2H), 7.8
4 (d, J = 8.4 Hz, 1H), 8.08 (dd, J
= 8.4 Hz, 1.9 Hz, 1H), 8.46 (d, J
= 1.9 Hz, 1H). 2) 1 (5.0 g, 18.2 mmol), phenylboric acid (2.67 g, 21.8 mmol), bis (triphenylphosphine) -palladium (II) chloride (63
0 mg, 0.90 mmol), triethylamine (7.
5 ml, 53 mmol) in DMF (50 ml)
Heated to reflux for an hour.
【0495】反応液を減圧下濃縮し、残渣をカラムクロ
マトグラフィー(ヘキサン→ヘキサン:酢酸エチル=
4:1)により精製し、3−ニトロ−4フェニル安息香
酸エチル(2)(3.0g、11mmol、60%)を
得た。 2: 1H NMR(CDCl3 ,250MHz)δpp
m:1.44(t,J=7.2Hz,3H),4.45
(q,J=7.2Hz,2H),7.31−7.36
(m,2H),7.43−7.57(m,3H),7.
54(d,J=8Hz,1H),8.27(dd,J=
8.1,7Hz,1H),8.49(d,J=1.7H
z,1H).The reaction solution was concentrated under reduced pressure, and the residue was subjected to column chromatography (hexane → hexane: ethyl acetate =
4: 1) to give ethyl 3-nitro-4phenylbenzoate (2) (3.0 g, 11 mmol, 60%). 2: 1 H NMR (CDCl 3 , 250 MHz) δpp
m: 1.44 (t, J = 7.2 Hz, 3H), 4.45
(Q, J = 7.2 Hz, 2H), 7.31-7.36
(M, 2H), 7.43-7.57 (m, 3H), 7.
54 (d, J = 8 Hz, 1H), 8.27 (dd, J =
8.1, 7 Hz, 1 H), 8.49 (d, J = 1.7 H)
z, 1H).
【0496】3)2(1.0g,3.7mmol)の酢
酸エチル(10.2ml)、酢酸(6.8ml)溶液に
10%パラジウム−炭素(0.1g)を加え、水素雰囲
気下4〜5気圧で8時間撹拌した。反応液を濾過し、水
を加え、酢酸エチルで抽出し、炭酸水素ナトリウム水溶
液、次いで飽和食塩水で洗浄後無水硫酸ナトリウムで乾
燥し、減圧下溶媒を留去した。残渣をシリカゲルカラム
クロマトグラフィー(ヘキサン・酢酸エチル4:1→
2:1)で精製し、3−アミノ−4−フェニル−安息香
酸エチル(3)(787mg、326mmol、88
%)を得た。 3: 1H NMR(CDCl3 ,250MHz)δpp
m:1.40(t,J=7.1Hz,3H),4.37
(q,J=7.1Hz,2H),7.18(d,J=
7.8Hz,1H),7.39〜7.45(m,7
H).3) 10% palladium-carbon (0.1 g) was added to a solution of 2 (1.0 g, 3.7 mmol) in ethyl acetate (10.2 ml) and acetic acid (6.8 ml), and the solution was added under hydrogen atmosphere. Stirred at 5 atm for 8 hours. The reaction solution was filtered, water was added, the mixture was extracted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution and then with a saturated saline solution, and dried over anhydrous sodium sulfate. The residue was subjected to silica gel column chromatography (hexane / ethyl acetate 4: 1 →
2: 1) and ethyl 3-amino-4-phenyl-benzoate (3) (787 mg, 326 mmol, 88
%). 3: 1 H NMR (CDCl 3 , 250 MHz) δpp
m: 1.40 (t, J = 7.1 Hz, 3H), 4.37
(Q, J = 7.1 Hz, 2H), 7.18 (d, J =
7.8 Hz, 1 H), 7.39 to 7.45 (m, 7
H).
【0497】4)3(787mg、3.26mmol)
の24%臭化水素酸混液に70%亜硝酸ナトリウム水溶
液(5ml)、臭化銅(1.15g、8mmol)48
%臭化水素酸(5ml)溶液を加え、60℃で1時間加
熱した。反応液に水を加え酢酸エチルで抽出し、有機層
を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後減
圧下溶媒を留去した。残渣をシリカゲルカラムクロマト
グラフィー(ヘキサン:酢酸エチル 8:1→4:1)
で分離精製し、3−ブロモ−4−フェニル安息香酸エチ
ル(4)(541mg、1.7mmol、53%)を得
た。 4: 1H NMR(CDCl3 ,250MHz)δpp
m:1.42(t,J=7.0Hz,3H),4.41
(q,J=7.0Hz,2H),7.38−7.49
(m,6H),8.19(dd,J=8.1,1.6H
z,1H),8.34(d,J=1.6Hz,1H).4) 3 (787 mg, 3.26 mmol)
A 70% aqueous solution of sodium nitrite (5 ml) was added to a mixture of 24% hydrobromic acid, and copper bromide (1.15 g, 8 mmol) 48
A solution of 5% hydrobromic acid (5 ml) was added and heated at 60 ° C. for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Silica gel column chromatography of the residue (hexane: ethyl acetate 8: 1 → 4: 1)
To give ethyl 3-bromo-4-phenylbenzoate (4) (541 mg, 1.7 mmol, 53%). 4: 1 H NMR (CDCl 3 , 250 MHz) δpp
m: 1.42 (t, J = 7.0 Hz, 3H), 4.41
(Q, J = 7.0 Hz, 2H), 7.38-7.49
(M, 6H), 8.19 (dd, J = 8.1, 1.6H)
z, 1H), 8.34 (d, J = 1.6 Hz, 1H).
【0498】5)4(430mg、1.42mmo
l)、トリエチルシリルアセチレン(0.4ml、2.
8mmol)、ビス−(トリフェニルホスフィン)−パ
ラジウム(II)クロライド(20mg、0.029mm
ol)、トリフェニルホスフィン(10mg、0.03
8mmol)、ヨウ化銅(I)(10mg、0.053
mmol)、トリエチルアミン(1.5ml、10.8
mmol)のDMF(1ml)溶液を100℃で1.5
時間加熱した。反応液を酢酸エチルで抽出し、塩化アン
モニウム水溶液、飽和食塩水の順に洗浄し、減圧下溶媒
を留去した。これに4(541mg、1.77mmo
l)を同様の操作を行い、得た残渣を合わせシリカゲル
パート(ヘキサン→ヘキサン:酢酸エチル18:1)に
より高極性物質を除いたカップリング生成物を含む油状
物質(916mg)を得た。5) 4 (430 mg, 1.42 mmol)
l), triethylsilylacetylene (0.4 ml, 2.
8 mmol), bis- (triphenylphosphine) -palladium (II) chloride (20 mg, 0.029 mm)
ol), triphenylphosphine (10 mg, 0.03
8 mmol), copper (I) iodide (10 mg, 0.053
mmol), triethylamine (1.5 ml, 10.8
mmol) in DMF (1 ml) at 100.degree.
Heated for hours. The reaction solution was extracted with ethyl acetate, washed sequentially with an aqueous ammonium chloride solution and saturated saline, and the solvent was distilled off under reduced pressure. Add 4 (541 mg, 1.77 mmol)
The same operation as in 1) was performed, and the obtained residues were combined to obtain an oily substance (916 mg) containing a coupling product from which a highly polar substance had been removed by a silica gel part (hexane → hexane: ethyl acetate 18: 1).
【0499】これをTHF(10ml)に溶解させ、1
MテトラノルマルブチルアンモニウムフルオライドTH
F溶液(3.1ml、3.1mmol)を加え、30分
撹拌した。反応液に塩化アンモニウム水溶液を加え、酢
酸エチルで抽出後、飽和食塩水で洗浄し、無水硫酸ナト
リウムで乾燥後、減圧下溶媒を留去した。残渣をシリカ
ゲルカラムクロマトグラフィー(ヘキサン→ヘキサン:
酢酸エチル=40:1)にて精製し、3−エチニル−4
−フェニル安息香酸エチル3ac(173mg、0.6
9mmol、22%)を得た。 3ac: 1H NMR(CDCl3 ,250MHz)δ
ppm:1.42(t,J=7.2Hz,3H),3.
09(s,1H),4.41(q,J=7.2Hz,2
H),7.38〜7.50(m,4H),7.59−
7.64(m,2H),8.06(dd,J=8.1,
1.8Hz,1H),8.29(d,J=1.8Hz,
1H). 合成例44This was dissolved in THF (10 ml), and 1
M tetra-n-butylammonium fluoride TH
The F solution (3.1 ml, 3.1 mmol) was added and stirred for 30 minutes. An aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane → hexane:
Ethyl acetate = 40: 1) to give 3-ethynyl-4
-Ethyl phenylbenzoate 3ac (173 mg, 0.6
9 mmol, 22%). 3ac: 1 H NMR (CDCl 3 , 250 MHz) δ
ppm: 1.42 (t, J = 7.2 Hz, 3H);
09 (s, 1H), 4.41 (q, J = 7.2 Hz, 2
H), 7.38 to 7.50 (m, 4H), 7.59-
7.64 (m, 2H), 8.06 (dd, J = 8.1,
1.8 Hz, 1 H), 8.29 (d, J = 1.8 Hz,
1H). Synthesis Example 44
【0500】[0500]
【化136】 Embedded image
【0501】上記ルートに従って2を合成した。次に示
す。 1)エチニルマグネシウム(0.5M in THF、
145ml、72.5mmol)に4−フルオロフェニ
ルアセトン(10g、66mmol)のTHF(10m
l)溶液を滴下し、次いで無水酢酸(7.5ml、79
mmol)を滴下した。反応液に塩化アンモニウム水溶
液を加え、酢酸エチルで抽出した後、有機層を飽和塩化
ナトリウム水溶液で洗浄し、減圧下溶媒を留去した。残
渣をシリカゲル(70g)に通し、(展開溶媒、ヘキサ
ン:酢酸エチル4:1)減圧下溶媒を留去した後、残渣
をエーテルで希釈し、飽和炭酸水素ナトリウム水溶液、
飽和食塩水の順に洗浄し、減圧下溶媒を留去し、1(1
4.6g、66mmol、定量的)を得た。According to the above route, 2 was synthesized. Shown below. 1) Ethinyl magnesium (0.5M in THF,
145 ml, 72.5 mmol) in 4-fluorophenylacetone (10 g, 66 mmol) in THF (10 m
l) The solution was added dropwise and then acetic anhydride (7.5 ml, 79
mmol) was added dropwise. An aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and the solvent was distilled off under reduced pressure. The residue was passed through silica gel (70 g), and the solvent was distilled off under reduced pressure (developing solvent, hexane: ethyl acetate 4: 1). The residue was diluted with ether, and saturated aqueous sodium hydrogen carbonate solution was added.
After washing with saturated saline in order, the solvent was distilled off under reduced pressure, and 1 (1
4.6 g, 66 mmol, quantitative) were obtained.
【0502】1: 1H NMR(CDCl3 ,250M
Hz)δppm:1.64(s,3H),2.03
(s,3H),2.60(s,1H),3.13(d,
J=13.7Hz,1H),3.23(d,J=13.
7Hz,1H),6.95−7.03(m,2H),
7.22−7.29(m,2H). 2)アセテート(1)(7.0g、31.8mmol)
とイソニペコチン酸エチル(12.0g、76.4mm
ol)のTHF(70ml)溶液に塩化銅(I)(22
2mg、2.2mmol)を加え、66℃で2時間、8
6℃で10分間加熱した。減圧下溶媒を留去した。残渣
をエーテル(100ml)で抽出し、アンモニア水溶
液、次いで飽和食塩水で洗浄した。有機層を3N塩酸水
溶液(160ml)で抽出した後、水層に3N水酸化ナ
トリウム水溶液(150ml)、飽和炭酸水素ナトリウ
ム水溶液を加え、ジクロロメタン(300ml)で抽出
した。減圧下溶媒を留去し、残渣をシリカゲルカラムク
ロマトグラフィー(silica50g、ヘキサン:酢
酸エチル=4:1)で精製し、目的物3ad(8.21
g、25.8mmol、81%)を得た。1: 1 H NMR (CDCl 3 , 250M
Hz) δ ppm: 1.64 (s, 3H), 2.03
(S, 3H), 2.60 (s, 1H), 3.13 (d,
J = 13.7 Hz, 1H), 3.23 (d, J = 13.
7Hz, 1H), 6.95-7.03 (m, 2H),
7.22-7.29 (m, 2H). 2) Acetate (1) (7.0 g, 31.8 mmol)
And ethyl isonipecotate (12.0 g, 76.4 mm
ol) in THF (70 ml) solution.
2 mg, 2.2 mmol) and 66 ° C. for 2 hours, 8
Heated at 6 ° C. for 10 minutes. The solvent was distilled off under reduced pressure. The residue was extracted with ether (100 ml), and washed with an aqueous ammonia solution and then with a saturated saline solution. After the organic layer was extracted with a 3N aqueous hydrochloric acid solution (160 ml), a 3N aqueous sodium hydroxide solution (150 ml) and a saturated aqueous sodium hydrogen carbonate solution were added to the aqueous layer, and the mixture was extracted with dichloromethane (300 ml). The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (silica 50 g, hexane: ethyl acetate = 4: 1) to obtain the desired product 3ad (8.21).
g, 25.8 mmol, 81%).
【0503】3ad: 1H NMR(CDCl3 ,25
0MHz)δppm:1.20(s,3H),1.26
(t,J=7.1Hz,3H),1.67−1.88
(m,2H),1.89−2.05(m,2H),2.
20−2.38(m,3H),2.38(s,1H),
2.81(d,J=13.4Hz,1H),2.97−
3.19(m,1H),3.02(d,J=13.4H
z,1H),3.20−3.31(m,1H),4.1
4(q,J=7.1Hz,2H),6.90−7.0
(m,2H),7.22−7.29(m,2H). 合成例453ad: 1 H NMR (CDCl 3 , 25
0 MHz) δ ppm: 1.20 (s, 3H), 1.26
(T, J = 7.1 Hz, 3H), 1.67-1.88.
(M, 2H), 1.89-2.05 (m, 2H), 2.
20-2.38 (m, 3H), 2.38 (s, 1H),
2.81 (d, J = 13.4 Hz, 1H), 2.97 −
3.19 (m, 1H), 3.02 (d, J = 13.4H)
z, 1H), 3.20-3.31 (m, 1H), 4.1
4 (q, J = 7.1 Hz, 2H), 6.90-7.0
(M, 2H), 7.22-7.29 (m, 2H). Synthesis Example 45
【0504】[0504]
【化137】 Embedded image
【0505】フェニルアセトン(4g、29.8mmo
l)のTHF(10ml)溶液に0.5Mエチニルマグ
ネシウムクロライドTHF溶液(71ml、37mmo
l)を加え、1時間撹拌した。反応液に、0.5N塩酸
水溶液を加え、酢酸エチルで抽出した。有機層を飽和食
塩水で洗浄後、硫酸マグネシウムで乾燥、減圧下溶媒を
留去し、プロパルジルアルコール3ae(4.36g,
27.2mmol,91%)を得た。Phenylacetone (4 g, 29.8 mmol)
l) in THF (10 ml) was added to a 0.5 M ethynylmagnesium chloride THF solution (71 ml, 37 mmo).
l) was added and stirred for 1 hour. A 0.5N hydrochloric acid aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and propargyl alcohol 3ae (4.36 g,
27.2 mmol, 91%).
【0506】3ae: 1H NMR(CDCl3 ,25
0MHz)δppm:1.56(s,3H),2.47
(s,1H),2.93(d,J=13.2Hz,1
H),3.01(d,J=13.2Hz,1H),7.
27−7.35(m,5H). 合成例463ae: 1 H NMR (CDCl 3 , 25
0 MHz) δ ppm: 1.56 (s, 3H), 2.47
(S, 1H), 2.93 (d, J = 13.2 Hz, 1
H), 3.01 (d, J = 13.2 Hz, 1H), 7.
27-7.35 (m, 5H). Synthesis Example 46
【0507】[0507]
【化138】 Embedded image
【0508】4−メチルフェノール(1.08g、10
mmol)、プロパルジルアルコール(840mg、1
0mmol)、トリフェニルホスフィン(2.62g、
10mmol)のTHF(10ml)溶液に氷水溶下か
きまぜながらジエチルアゾジカルボキシレート(1.5
8ml、10mmol)を滴下した後、室温で一昼夜放
置した。溶媒を留去し、残渣をシリカゲルカラムクロマ
トで精製(展開液,n−ヘキサン:酢酸エチル15:
1)し、目的とするエーテル体3af(260mg、
1.5mmol、収率15%)を得た。 3af: 1H NMR(CDCl3 ,300MHz)δ
ppm:1.62(s,6H),2.30(s,3
H),2.52(s,1H),7.05−7.15
(m,4H). 合成例47 以下の方法で3agを合成した。4-methylphenol (1.08 g, 10
mmol), propargyl alcohol (840 mg, 1
0 mmol), triphenylphosphine (2.62 g,
10 mmol) in a THF (10 ml) solution while stirring under an aqueous solution of ice with diethyl azodicarboxylate (1.5 ml).
(8 ml, 10 mmol) was added dropwise and left at room temperature for 24 hours. The solvent was distilled off, and the residue was purified by silica gel column chromatography (developing solution, n-hexane: ethyl acetate 15:
1) Then, the desired ether compound 3af (260 mg,
1.5 mmol, 15% yield). 3af: 1 H NMR (CDCl 3 , 300 MHz) δ
ppm: 1.62 (s, 6H), 2.30 (s, 3
H), 2.52 (s, 1H), 7.05-7.15.
(M, 4H). Synthesis Example 47 3ag was synthesized by the following method.
【0509】[0509]
【化139】 Embedded image
【0510】1)2−フェニルプロピオンアルデヒド
(6.7g、50mmol)のジクロロメタン(450
ml)溶液にトリフェニルホスフィン(52g、200
mmol)、四臭化炭素(33.2g、100mmo
l)を0℃にて加え撹拌した。反応液を濾過後、減圧下
濃縮し残渣をカラムクロマトグラフィーにて精製し、1
(11.2g、39mmol、77%)を得た。 2)1(11.2g、39mmol)に40%トリトン
Bメタノール溶液(73ml)、ジエチルアミン(55
ml、540mmol)を加え撹拌した。反応液に水を
加え、ジクロロメタンで抽出し、有機層を減圧下濃縮し
た。残渣をシリカゲルカラムクロマトグラフィーで精製
し、3ag(2.7g、13.4mmol、35%)を
得た。1) 2-Phenylpropionaldehyde (6.7 g, 50 mmol) in dichloromethane (450
ml) solution into triphenylphosphine (52 g, 200 g).
mmol), carbon tetrabromide (33.2 g, 100 mmol
l) was added at 0 ° C and stirred. The reaction mixture was filtered, concentrated under reduced pressure, and the residue was purified by column chromatography.
(11.2 g, 39 mmol, 77%) were obtained. 2) 1 (11.2 g, 39 mmol) in 40% triton B methanol solution (73 ml), diethylamine (55
ml, 540 mmol) and stirred. Water was added to the reaction solution, extracted with dichloromethane, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3ag (2.7 g, 13.4 mmol, 35%).
【0511】3ag: 1H NMR(CDCl3 ,30
0MHz)δppm:1.04(t,J=7.2Hz,
6H),1.58(s,3H),2.24(s,1
H),2.43(dt,J=7.2,13.8Hz,1
H),2.45(dt,J=7.2,13.8Hz,1
H),2.67(dt,J=7.2,13.8Hz,1
H),2.69(dt,J=7.2,13.8Hz,1
H),7.22−7.33(m,5H),7.71−
7.74(m,1H). 合成例48 以下の方法で3ahを合成した。3ag: 1 H NMR (CDCl 3 , 30
0 MHz) δ ppm: 1.04 (t, J = 7.2 Hz,
6H), 1.58 (s, 3H), 2.24 (s, 1
H), 2.43 (dt, J = 7.2, 13.8 Hz, 1
H), 2.45 (dt, J = 7.2, 13.8 Hz, 1
H), 2.67 (dt, J = 7.2, 13.8 Hz, 1
H), 2.69 (dt, J = 7.2, 13.8 Hz, 1
H), 7.22-7.33 (m, 5H), 7.71-
7.74 (m, 1H). Synthesis Example 48 3ah was synthesized by the following method.
【0512】[0512]
【化140】 Embedded image
【0513】1)2−ブロモ−ビフェニル(1g、4.
29mmol)のTHF(40ml)溶液に1.7Mノ
ルマルブチルリチウムヘキサン溶液(3ml、5.15
mmol)を−78℃にて滴下した。30分撹拌後、ジ
メチルホルムアミド(0.5ml、6.45mmol)
を加え室温とした後、塩化アンモニウム水溶液を注い
だ。酢酸エチルで抽出し、有機層を無水硫酸ナトリウム
で乾燥後、減圧下濃縮した。残渣をカラムクロマトグラ
フィー(ヘキサン:酢酸エチル=10:1)で分離精製
し1(748mg、4.1mmol、96%)を得た。 2)1(748mg、4.1mmol)のジクロロメタ
ン(40ml)溶液に0℃にてトリフェニルホスフィン
(4.3g、16.4mmol)、四臭化炭素(2.7
2g、8.2mmol)を加え、30分撹拌した。これ
にペンタン(160ml)を加え濾過した濾液を減圧下
濃縮した。残渣をカラムクロマトグラフィー(ヘキサ
ン)で精製し、2(1.21g、3.57mmol、8
7%)を得た。1) 2-bromo-biphenyl (1 g, 4.
29 mmol) in THF (40 ml) was dissolved in a 1.7 M solution of n-butyllithium in hexane (3 ml, 5.15).
mmol) was added dropwise at -78 ° C. After stirring for 30 minutes, dimethylformamide (0.5 ml, 6.45 mmol)
Was added to room temperature, and then an aqueous ammonium chloride solution was poured. After extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (hexane: ethyl acetate = 10: 1) to obtain 1 (748 mg, 4.1 mmol, 96%). 2) Triphenylphosphine (4.3 g, 16.4 mmol), carbon tetrabromide (2.7) in a dichloromethane (40 ml) solution of 1 (748 mg, 4.1 mmol) at 0 ° C.
2 g, 8.2 mmol) and stirred for 30 minutes. To this, pentane (160 ml) was added, and the filtrate was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (hexane) to give 2 (1.21 g, 3.57 mmol, 8
7%).
【0514】3)2(2.29g、6.77mmol)
のTHF(20ml)溶液に−78℃にて、1.7Mノ
ルマルブチルリチウムヘキサン溶液(3.98ml、
6.77mmol)を加え室温とした。反応液に水を加
え、有機層を減圧下濃縮した。残渣をカラムクロマトグ
ラフィー(ヘキサン)にて精製し、3ah(796m
g、4.47mmol、66%)を得た。 3ah: 1H NMR(CDCl3 ,300MHz)δ
ppm:3.03(s,1H),7.30−7.43
(m,6H),7.57−7.60(m,3H). 合成例493) 2 (2.29 g, 6.77 mmol)
In THF (20 ml) at −78 ° C. at 1.7 M n-butyllithium in hexane (3.98 ml,
(6.77 mmol) was added to room temperature. Water was added to the reaction solution, and the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (hexane) and 3ah (796 m
g, 4.47 mmol, 66%). 3ah: 1 H NMR (CDCl 3 , 300 MHz) δ
ppm: 3.03 (s, 1H), 7.30-7.43
(M, 6H), 7.57-7.60 (m, 3H). Synthesis Example 49
【0515】[0515]
【化141】 Embedded image
【0516】アセテート体(1)(1.0g、4.54
mmol)、ジエチルアミン(1.02ml,9.86
mmol)、塩化銅(I)(30.7mg、0.31m
mol)のTHF(20ml)溶液を30分加熱還流し
た。減圧下溶媒を留去し、エーテルで希釈したのち希塩
酸水溶液で抽出した。水層を水酸化ナトリウム水溶液で
アルカリ性とし、ジクロロメタンで抽出した。有機層を
減圧下濃縮し3ai(296mg、1.35mmol)
を得た。 3ai: 1H NMR(CDCl3 ,300MHz)δ
ppm:1.11(t,J=7.1Hz,6H),1.
23(s,3H),2.29(s,1H),2.74
(d,J=13.2Hz,1H),2.77(q,J=
7.1Hz,4H),3.04(d,J=13.2H
z,1H),6.80−6.83(m,2H),7.2
2−7.26(m,2H). 合成例50Acetate (1) (1.0 g, 4.54
mmol), diethylamine (1.02 ml, 9.86)
mmol), copper (I) chloride (30.7 mg, 0.31 m
mol) in THF (20 ml) was heated to reflux for 30 minutes. The solvent was distilled off under reduced pressure, diluted with ether, and extracted with a dilute aqueous hydrochloric acid solution. The aqueous layer was made alkaline with an aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was concentrated under reduced pressure and 3ai (296 mg, 1.35 mmol)
I got 3ai: 1 H NMR (CDCl 3 , 300 MHz) δ
ppm: 1.11 (t, J = 7.1 Hz, 6H), 1.
23 (s, 3H), 2.29 (s, 1H), 2.74
(D, J = 13.2 Hz, 1H), 2.77 (q, J =
7.1 Hz, 4H), 3.04 (d, J = 13.2H)
z, 1H), 6.80-6.83 (m, 2H), 7.2
2-7.26 (m, 2H). Synthesis Example 50
【0517】[0517]
【化142】 Embedded image
【0518】1)シクロヘキシルアセトン(2g、1
4.3mmol)のTHF溶液に、0.5Mエチニルマ
グネシウムクロライドTHF溶液(86ml、43mm
ol)を滴下し、3時間加熱還流した。反応液に氷冷下
無水酢酸(4.75ml、50.1mmol)を加え撹
拌した。反応液にエーテルを加え、塩化アンモニウム水
溶液、炭酸水素ナトリウム水溶液、飽和食塩水の順に洗
浄した。無水硫酸ナトリウムで乾燥後、減圧下溶媒を留
去した。残渣をシリカゲルカラムクロマトグラフィー
(ヘキサン:酢酸エチル=16:1)にて分離精製し、
1(1.95g、9.36mmol、65%)を得た。1) Cyclohexylacetone (2 g, 1
4.3 mmol) in a 0.5 M ethynylmagnesium chloride THF solution (86 ml, 43 mm).
ol) was added dropwise, and the mixture was heated under reflux for 3 hours. Acetic anhydride (4.75 ml, 50.1 mmol) was added to the reaction solution under ice cooling, and the mixture was stirred. Ether was added to the reaction solution, and the mixture was washed successively with an aqueous solution of ammonium chloride, an aqueous solution of sodium hydrogen carbonate, and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 16: 1),
1 (1.95 g, 9.36 mmol, 65%) was obtained.
【0519】2)1(1.95g、9.36mmo
l)、ジエチルアミン(2.1ml、20.3mmo
l)、塩化銅(I)(63mg、0.64mmol)の
THF(40ml)溶液を30分加熱還流した。減圧下
溶媒を留去し、エーテルで希釈したのち、希塩酸水溶液
で抽出した。水層を水酸化ナトリウム水溶液でアルカリ
性とし、ジクロロメタンで抽出後、有機層を減圧下濃縮
し、残渣をシリカゲルカラムクロマトグラフィー(ヘキ
サン:酢酸エチル=5:1)にて分離精製し3aj(8
99mg、4.06mmol、43%)を得た。 3aj: 1H NMR(CDCl3 ,300MHz)δ
ppm:1.06(t,J=7.1Hz,6H),1.
12−1.68(m,11H),1.35(s,3
H),1.74−1.78(m,1H),1.88−
1.92(m,1H),2.20(s,1H),2.6
4(q,J=7.1Hz,4H). 合成例5 以下の方法で3akを合成した。2) 1 (1.95 g, 9.36 mmol)
l), diethylamine (2.1 ml, 20.3 mmol)
l), a solution of copper (I) chloride (63 mg, 0.64 mmol) in THF (40 ml) was heated to reflux for 30 minutes. The solvent was distilled off under reduced pressure, diluted with ether, and extracted with a dilute aqueous hydrochloric acid solution. The aqueous layer was made alkaline with an aqueous sodium hydroxide solution, extracted with dichloromethane, the organic layer was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give 3aj (8
99 mg, 4.06 mmol, 43%). 3aj: 1 H NMR (CDCl 3 , 300 MHz) δ
ppm: 1.06 (t, J = 7.1 Hz, 6H), 1.
12-1.68 (m, 11H), 1.35 (s, 3
H), 1.74-1.78 (m, 1H), 1.88-
1.92 (m, 1H), 2.20 (s, 1H), 2.6
4 (q, J = 7.1 Hz, 4H). Synthesis Example 5 3ak was synthesized by the following method.
【0520】[0520]
【化143】 Embedded image
【0521】1)2,2−ジメチル−3−フェニル−1
−プロパノール(1.64g、10mmol)のジクロ
ロメタン(150ml)溶液にピリジニウムクロロクロ
メート(3.23g、15mmol)を加え撹拌した。
反応液をセライトを用い濾過し、濾液を減圧下濃縮し得
られた残渣をカラムクロマトグラフィー(ヘキサン:酢
酸エチル=1:1)で精製し1(1.61g、9.96
mmol、99.6%)を得た。1) 2,2-dimethyl-3-phenyl-1
Pyridinium chlorochromate (3.23 g, 15 mmol) was added to a dichloromethane (150 ml) solution of -propanol (1.64 g, 10 mmol) and stirred.
The reaction solution was filtered using celite, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate = 1: 1) to give 1 (1.61 g, 9.96).
mmol, 99.6%).
【0522】2)2,2−ジメチル−3−フェニル−1
−プロパノール(1)(1.94g、12mmol)の
ジクロロメタン(50ml)溶液にトリフェニルホスフ
ィン(12.6g、48mmol)、四臭化炭素(8.
0g、24mmol)を加え撹拌した。反応液を減圧下
濃縮し残渣をシリカゲルカラムクロマトグラフィー(ヘ
キサン→ヘキサン:酢酸エチル=5:1)で精製し2
(2.26g、7.11mmol、59%)を得た。2) 2,2-dimethyl-3-phenyl-1
-To a solution of propanol (1) (1.94 g, 12 mmol) in dichloromethane (50 ml) was added triphenylphosphine (12.6 g, 48 mmol) and carbon tetrabromide (8.9 g).
(0 g, 24 mmol). The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane → hexane: ethyl acetate = 5: 1) to give a residue.
(2.26 g, 7.11 mmol, 59%) was obtained.
【0523】3)(2.26g、7.11mmol)の
THF(50ml)溶液に−78℃にて1.6Mノルマ
ルブチルリチウムヘキサン溶液(9.8ml、15.6
mmol)を滴下した。反応液を室温とし、水を加え反
応を停止し、エーテルで抽出した。有機層を飽和食塩水
で洗浄後、無水硫酸ナトリウムで乾燥し、減圧下溶媒を
留去した。残渣をシリカゲルカラムクロマトグラフィー
(ヘキサン)で洗浄し、3ak(1.02g、6.45
mmol、91%)を得た。 3ak: 1H NMR(CDCl3 ,300MHz)δ
ppm:1.22(s,6H),2.14(s,1
H),2.72(s,2H),7.26−7.27
(m,5H). 合成例52 以下のスキームに従って、4を合成した。3) A 1.6 M solution of normal butyllithium in hexane (9.8 ml, 15.6) was added to a solution of (2.26 g, 7.11 mmol) in THF (50 ml) at -78 ° C.
mmol) was added dropwise. The reaction solution was brought to room temperature, water was added to stop the reaction, and the mixture was extracted with ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was washed with silica gel column chromatography (hexane) and washed with 3ak (1.02g, 6.45).
mmol, 91%). 3ak: 1 H NMR (CDCl 3 , 300 MHz) δ
ppm: 1.22 (s, 6H), 2.14 (s, 1
H), 2.72 (s, 2H), 7.26-7.27
(M, 5H). Synthesis Example 52 Compound 4 was synthesized according to the following scheme.
【0524】[0524]
【化144】 Embedded image
【0525】1)4−メトキシフェニルアセトン(3.
28g、20mmol)を合成例35の2の合成法と同
様の方法で反応を行い1(7.17g、17.9mmo
l、90%)を得た。1(7.17g、17.9mmo
l)のTHF(100ml)溶液に1Mテトラノルマル
ブチルアンモニウムフルオライドTHF溶液(18m
l、18mmol)を滴下し撹拌した。反応液に水を加
え、酢酸エチルで抽出後減圧下溶媒を留去した。残渣を
カラムクロマトグラフィー(ヘキサン:酢酸エチル=
4:1)で精製し、2(3.71g、19.5mmo
l、98%)を得た。1) 4-methoxyphenylacetone (3.
28 g (20 mmol) was reacted in the same manner as in the synthesis method of Synthesis Example 35-2 to give 1 (7.17 g, 17.9 mmol).
1, 90%). 1 (7.17 g, 17.9 mmo
l) in a THF (100 ml) solution was added to a 1M tetra-n-butylammonium fluoride THF solution (18 m
1, 18 mmol) was added dropwise and stirred. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography (hexane: ethyl acetate =
4: 1) and 2 (3.71 g, 19.5 mmol)
1, 98%).
【0526】2)2(3.71g、19.5mmol)
のTHF(20ml)溶液に−78℃にて1Mナトリウ
ムヘキサメチルジシラジドTHF溶液(21.5ml、
21.5mmol)を滴下し次いで0℃にて無水酢酸
(2.19g、21.5mmol)を加えた。反応液に
炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し
た。有機層を飽和塩化ナトリウム水溶液で洗浄後無水硫
酸ナトリウムで乾燥し、減圧下溶媒を留去した。残渣を
カラムクロマトグラフィー(ヘキサン:酢酸エチル=
5:1)で精製し、3(2.08g、8.95mmo
l、46%)を得た。2) 2 (3.71 g, 19.5 mmol)
1M sodium hexamethyldisilazide in THF (20 ml) at −78 ° C. (21.5 ml,
Acetic anhydride (2.19 g, 21.5 mmol) was added at 0 ° C. An aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography (hexane: ethyl acetate =
5: 1) and 3 (2.08 g, 8.95 mmol)
1, 46%).
【0527】3)3(2.08g、8.95mmol)
のTHF(10ml)溶液にジエチルアミン(2m
l)、塩化銅(60mg、0.61mmol)を加え加
熱還流した。反応液を減圧下濃縮し、残渣をカラムクロ
マトグラフィー(ヘキサン:酢酸エチル=10:1)で
精製し、3al(559mg、2.28mmol、25
%)を得た。 3al: 1H NMR(CDCl3 ,300MHz)δ
ppm:1.20(t,J=7.1Hz,6H),1.
24(s,3H),2.28(s,1H),2.70
(d,J=13.2Hz,1H),2.77(q,J=
7.1Hz,2H),2.78(q,J=7.1Hz,
2H),3.03(d,J=13.2Hz,1H),
3.59(s,3H),6.80−6.83(m,2
H),7.22−7.26(m,2H). 合成例533) 3 (2.08 g, 8.95 mmol)
In a THF (10 ml) solution was added diethylamine (2 m
l) and copper chloride (60 mg, 0.61 mmol) were added and the mixture was heated under reflux. The reaction solution was concentrated under reduced pressure, the residue was purified by column chromatography (hexane: ethyl acetate = 10: 1), and 3al (559 mg, 2.28 mmol, 25
%). 3al: 1 H NMR (CDCl 3 , 300 MHz) δ
ppm: 1.20 (t, J = 7.1 Hz, 6H), 1.
24 (s, 3H), 2.28 (s, 1H), 2.70
(D, J = 13.2 Hz, 1H), 2.77 (q, J =
7.1 Hz, 2H), 2.78 (q, J = 7.1 Hz,
2H), 3.03 (d, J = 13.2 Hz, 1H),
3.59 (s, 3H), 6.80-6.83 (m, 2
H), 7.22-7.26 (m, 2H). Synthesis Example 53
【0528】[0528]
【化145】 Embedded image
【0529】上記ルートに従ってピリミジン誘導体2
p、2qを合成した。 1)4,6−ジクロロ−5−ニトロピリミジン(9.3
g、48mmol)をJ,Chem.Soc.99,
(1951)、W.R.Boon,W.C.M.Jon
es and G.R.Ramageの方法で反応を行
い、4−アミノ−6−クロロ−5−ニトロピリミジン
(2p)(4.4g、25mmol、52%)を得た。Following the above route, pyrimidine derivative 2
p and 2q were synthesized. 1) 4,6-dichloro-5-nitropyrimidine (9.3
g, 48 mmol), according to J. Chem. Soc. 99,
(1951); R. Boon, W.C. C. M. Jon
es and G. R. The reaction was carried out according to the method of Ramage to obtain 4-amino-6-chloro-5-nitropyrimidine (2p) (4.4 g, 25 mmol, 52%).
【0530】2)4−アミノ−6−クロロ−5−ニトロ
ピリミジン2p(5.0g、28mmol)をJ.A
m.Chem.Soc.75,263(1953)、
R.K.Robins,らの方法で反応を行い、4,5
−ジアミノ−6−クロロピリミジン(1)(2.5g、
17mmol、60%)を得た。 3)4,5−ジアミノ−6−クロロピリミジン(1)
(1.9g、13mmol)をJ.Am.Chem.S
oc.,78,225(1956)J.W.Dalyら
の方法で反応を行い、4−クロロ−6,7−ジメチルプ
テリジン(2q)(1.9g、9.8mmol、75
%)を得た。 合成例542) 4-Amino-6-chloro-5-nitropyrimidine 2p (5.0 g, 28 mmol) was obtained according to J. Am. A
m. Chem. Soc. 75 , 263 (1953),
R. K. The reaction was carried out by the method of Robins, et al.
-Diamino-6-chloropyrimidine (1) (2.5 g,
17 mmol, 60%). 3) 4,5-diamino-6-chloropyrimidine (1)
(1.9 g, 13 mmol). Am. Chem. S
oc. , 78, 225 (1956); W. The reaction was carried out according to the method of Dally et al., And 4-chloro-6,7-dimethylpteridine (2q) (1.9 g, 9.8 mmol, 75
%). Synthesis Example 54
【0531】[0531]
【化146】 Embedded image
【0532】発煙硝酸(7.5ml)と濃硫酸(38m
l)混液に、30〜35℃にて2,4−ジアミノ−6−
クロロピリミジン(7.2g、0.05mol)を少量
ずつ加え、30分撹拌した。反応液を氷(250g)に
注ぎアンモニア水溶液でpH9とした後、結晶を濾取
し、減圧下乾燥させ、2,4−ジアミノ−5−ニトロ−
6−クロロピリミジン(2r)(4.6g、0.026
2mol、52%)を得た。 合成例55Fuming nitric acid (7.5 ml) and concentrated sulfuric acid (38 m
1) Add 2,4-diamino-6- to the mixture at 30-35 ° C.
Chloropyrimidine (7.2 g, 0.05 mol) was added little by little and stirred for 30 minutes. After the reaction solution was poured into ice (250 g) and the pH was adjusted to 9 with an aqueous ammonia solution, the crystals were collected by filtration, dried under reduced pressure, and 2,4-diamino-5-nitro-
6-chloropyrimidine (2r) (4.6 g, 0.026
2 mol, 52%). Synthesis Example 55
【0533】[0533]
【化147】 Embedded image
【0534】55〜58%ヨウ化水素酸(50ml)に
氷冷下クロロキナゾリン(5.0g、22.3mmo
l)を少量づつ加え2時間撹拌した。水(50ml)を
注ぎ、黄色結晶を濾取した後、クロロホルム(300m
l)に溶解させ、5%アンモニア水溶液、水の順に洗浄
し、Na2 SO4 で乾燥後、溶媒を留去(6.0g、1
8.9mmol、収率85%)でヨードキナゾリン(2
s)を得た。 2s: 1H NMR(DMSO−d6 ,250MHz)
δppm:4.0(s,3H),4.01(s,3
H),7.14(s,1H),7.35(s,1H),
8.69(s,1H). EI−MASS 316(M+ ),189(M−I) 合成例56Chloroquinazoline (5.0 g, 22.3 mmol) was added to 55-58% hydroiodic acid (50 ml) under ice-cooling.
l) was added little by little and stirred for 2 hours. Water (50 ml) was poured, and yellow crystals were collected by filtration.
1), washed with a 5% aqueous ammonia solution and water in that order, dried over Na 2 SO 4 , and the solvent was distilled off (6.0 g, 1 g).
8.9 mmol (yield 85%) with iodoquinazoline (2
s) was obtained. 2s: 1 H NMR (DMSO-d 6 , 250 MHz)
δ ppm: 4.0 (s, 3H), 4.01 (s, 3
H), 7.14 (s, 1H), 7.35 (s, 1H),
8.69 (s, 1H). EI-MASS 316 (M + ), 189 (MI) Synthesis Example 56
【0535】[0535]
【化148】 Embedded image
【0536】上記ルートに従い6−ヨード−9−メチル
プリン(2t)を合成した。次に示す。 1)水素化ナトリウム(60%油性、77mg、1.9
mmol)のTHF(2ml)混液に6−クロロプリン
(251mg、1.6mmol)のTHF(2ml)、
DMF(2ml)溶液を加えた。次いでヨウ化メチル
(0.12ml、1.9mmol)を加えた後水を注
ぎ、ジクロロメタンで抽出した。有機層を飽和食塩水で
洗浄し、無水硫酸ナトリウムで乾燥後減圧下溶媒を留去
した。残渣をシリカゲルカラムクロマトグラフィー(C
HCl3 :MeOH=10:1)で分離精製し、6−ク
ロロ−9−メチルプリン(1)(167mg、1.08
mmol、61%)、6−クロロ−7−メチルプリン
(69mg、0.41mmol、25%)を得た。According to the above route, 6-iodo-9-methylpurine (2t) was synthesized. Shown below. 1) Sodium hydride (60% oily, 77 mg, 1.9)
mmol) in THF (2 ml), and 6-chloropurine (251 mg, 1.6 mmol) in THF (2 ml).
DMF (2 ml) solution was added. Then, after adding methyl iodide (0.12 ml, 1.9 mmol), water was poured, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (C
HCl 3 : MeOH = 10: 1) and purified by purification. 6-Chloro-9-methylpurine (1) (167 mg, 1.08)
mmol, 61%), 6-chloro-7-methylpurine (69 mg, 0.41 mmol, 25%).
【0537】1: 1H NMR(CDCl3 ,250M
Hz)δppm:3.95(s,3H),8.12
(s,1H),8.78(s,1H). 2)ヨウ化水素酸(55%、2ml)に氷冷下6−クロ
ロ−9−メチルプリン(1)(175mg、1.0mm
ol)を加え1.5時間撹拌した。反応液にアンモニア
水溶液を注ぎ、酢酸エチル、クロロホルムの順に抽出し
た。有機層を無水硫酸ナトリウムで乾燥後、減圧下溶媒
を留去し、6−ヨード−9−メチルプリン(2t)(2
33mg、0.89mmol、89%)を得た。 2t; 1H NMR(CDCl3 ,250MHz)δp
pm:3.93(s,3H),8.13(s,1H),
8.65(s,1H). 実施例1281: 1 H NMR (CDCl 3 , 250M
Hz) δ ppm: 3.95 (s, 3H), 8.12
(S, 1H), 8.78 (s, 1H). 2) 6-chloro-9-methylpurine (1) (175 mg, 1.0 mm) was added to hydroiodic acid (55%, 2 ml) under ice-cooling.
ol) and stirred for 1.5 hours. An aqueous ammonia solution was poured into the reaction solution, and ethyl acetate and chloroform were extracted in this order. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give 6-iodo-9-methylpurine (2t) (2t).
33 mg, 0.89 mmol, 89%). 2t; 1 H NMR (CDCl 3 , 250 MHz) δp
pm: 3.93 (s, 3H), 8.13 (s, 1H),
8.65 (s, 1H). Example 128
【0538】[0538]
【化149】 Embedded image
【0539】プロパルジルアミン3am(1.00g、
3.2mmol)とクロロキナゾリン2j(835m
g、3.2mmol)を実施例7と同様に反応を行い、
目的物(1.37g、2.74mmol、86%)を赤
褐色油状物質として得た。1 H NMR(CDCl3 ,300MHz)δppm:
1.25(t,J=7.0Hz,3H),1.50
(t,J=7.0Hz,3H),1.56(t,J=
7.0Hz,3H),1.61(s,3H),1.75
−1.90(m,2H),1.93−2.08(m,2
H),2.13−2.50(m,5H),2.81−
2.92(m,2H),3.13−3.39(m,2
H),4.14(q,J=7.0Hz,2H),4.1
7(q,J=7.0Hz,2H),4.28(q,J=
7.0Hz,2H),7.16−7.32(m,6
H),7.46(s,1H),9.06(s,1H). 実施例129Propardylamine 3am (1.00 g,
3.2 mmol) and chloroquinazoline 2j (835 m
g, 3.2 mmol) in the same manner as in Example 7.
The desired product (1.37 g, 2.74 mmol, 86%) was obtained as a reddish brown oily substance. 1 H NMR (CDCl 3 , 300 MHz) δ ppm:
1.25 (t, J = 7.0 Hz, 3H), 1.50
(T, J = 7.0 Hz, 3H), 1.56 (t, J =
7.0 Hz, 3H), 1.61 (s, 3H), 1.75
-1.90 (m, 2H), 1.93-2.08 (m, 2
H), 2.13-2.50 (m, 5H), 2.81-
2.92 (m, 2H), 3.13-3.39 (m, 2
H), 4.14 (q, J = 7.0 Hz, 2H), 4.1.
7 (q, J = 7.0 Hz, 2H), 4.28 (q, J =
7.0 Hz, 2H), 7.16-7.32 (m, 6
H), 7.46 (s, 1H), 9.06 (s, 1H). Example 129
【0540】[0540]
【化150】 Embedded image
【0541】実施例128で得たエステル体(1.20
g、2.26mmol)を実施例8と同様に反応を行
い、目的物(1.00g、1.99mmol、88%)
を得た。 白色結晶 IR(KBr)νcm-1:3422,2984,293
7,2808,2214,1718,1612,157
7,1500,1469,1396,1369,123
6,1043,939,852,825,748,70
0,632.1 H NMR(DMSO−d6 ,250MHz)δpp
m:1.35(t,J=6.9Hz,3H),1.41
(t,J=6.9Hz,3H),1.55(s,3
H),1.57−1.72(m,2H),1.80−
1.95(m,2H),2.04−2.40(m,4
H),2.42−2.50(m,1H),2.70−
2.82(m,2H),3.01−3.24(m,2
H),4.14(q,J=6.9Hz,2H),4.2
5(q,J=6.9Hz,2H),7.12−7.30
(m,5H),7.33(s,1H),7.39(s,
1H),8.98(s,1H). 実施例130The ester obtained in Example 128 (1.20
g, 2.26 mmol) was reacted in the same manner as in Example 8 to give the desired product (1.00 g, 1.99 mmol, 88%).
I got White crystal IR (KBr) νcm -1 : 3422,2984,293
7, 2808, 2214, 1718, 1612, 157
7,1500,1469,1396,1369,123
6,1043,939,852,825,748,70
0,632. 1 H NMR (DMSO-d 6 , 250 MHz) δpp
m: 1.35 (t, J = 6.9 Hz, 3H), 1.41
(T, J = 6.9 Hz, 3H), 1.55 (s, 3
H), 1.57-1.72 (m, 2H), 1.80-
1.95 (m, 2H), 2.04-2.40 (m, 4
H), 2.42-2.50 (m, 1H), 2.70-
2.82 (m, 2H), 3.01-3.24 (m, 2
H), 4.14 (q, J = 6.9 Hz, 2H), 4.2
5 (q, J = 6.9 Hz, 2H), 7.12-7.30
(M, 5H), 7.33 (s, 1H), 7.39 (s,
1H), 8.98 (s, 1H). Example 130
【0542】[0542]
【化151】 Embedded image
【0543】プロパルジルアミン3i(385mg、
1.29mmol)と4−クロロ−6−ニトロキナゾリ
ン2u(270mg、1.29mmol)を、実施例7
と同様に反応を行い、目的物(578mg、1.22m
mol、95%)を赤茶色油状物質として得た。 IR(neat)νcm-1:3379,2932,28
10,2208,1728,1622,1577,15
27,1485,1439,1412,1356,13
40,1263,1178,1045,962,85
2,806,744,702.Propardylamine 3i (385 mg,
1.29 mmol) and 4-chloro-6-nitroquinazoline 2u (270 mg, 1.29 mmol) were prepared in Example 7
The reaction was carried out in the same manner as described above, and the desired product (578 mg, 1.22 m
mol, 95%) as a red-brown oil. IR (neat) νcm -1 : 3379,2932,28
10, 2208, 1728, 1622, 1577, 15
27, 1485, 1439, 1412, 1356, 13
40,1263,1178,1045,962,85
2,806,744,702.
【0544】1H NMR(CDCl3 ,300MH
z)δppm:1.26(t,J=6.9Hz,3
H),1.56(s,3H),1.75−1.95
(m,2H),2.00−2.13(m,2H),2.
27−2.62(m,3H),3.11(d,J=1
3.2Hz,1H),3.26−3.32(m,1
H),3.29(d,J=13.2Hz,1H),3.
45−3.55(m,1H),4.15(d,J=6.
9Hz,2H),7.21−7.33(m,3H),
7.35−7.38(m,2H),8.19(d,J=
9.2Hz,1H),8.66(dd,J=9.2,
2.4Hz,1H),9.09(d,J=2.4Hz,
1H),9.42(s,1H). 実施例131 1 H NMR (CDCl 3 , 300 MH
z) δ ppm: 1.26 (t, J = 6.9 Hz, 3
H), 1.56 (s, 3H), 1.75-1.95.
(M, 2H), 2.00-2.13 (m, 2H), 2.
27-2.62 (m, 3H), 3.11 (d, J = 1
3.2 Hz, 1 H), 3.26-3.32 (m, 1
H), 3.29 (d, J = 13.2 Hz, 1H);
45-3.55 (m, 1H), 4.15 (d, J = 6.
9Hz, 2H), 7.21-7.33 (m, 3H),
7.35-7.38 (m, 2H), 8.19 (d, J =
9.2 Hz, 1H), 8.66 (dd, J = 9.2,
2.4 Hz, 1 H), 9.09 (d, J = 2.4 Hz,
1H), 9.42 (s, 1H). Example 131
【0545】[0545]
【化152】 Embedded image
【0546】3an(1.0g、3.3mmol)とク
ロロキナゾリン(830mg、3.14mmol)を、
実施例7と同様に反応を行い、目的物(870mg、
1.62mmol、52%)を得た。1 H NMR(CDCl3 ,250MHz)δppm:
1.34(t,J=7.0Hz,3H),1.54
(t,J=7.0Hz,3H),2.44(s,3
H),3.63(q,J=7.0Hz,2H),4.2
5(q,J=7.0Hz,2H),7.15(s,1
H),7.24−7.46(m,7H),7.68−
7.71(m,1H),7.70(d,J=8.3H
z,2H),7.85(d,J=8.3Hz,2H),
9.07(s,1H). 実施例1323an (1.0 g, 3.3 mmol) and chloroquinazoline (830 mg, 3.14 mmol) were obtained.
The reaction was carried out in the same manner as in Example 7, and the target product (870 mg,
(1.62 mmol, 52%). 1 H NMR (CDCl 3 , 250 MHz) δ ppm:
1.34 (t, J = 7.0 Hz, 3H), 1.54
(T, J = 7.0 Hz, 3H), 2.44 (s, 3
H), 3.63 (q, J = 7.0 Hz, 2H), 4.2
5 (q, J = 7.0 Hz, 2H), 7.15 (s, 1
H), 7.24-7.46 (m, 7H), 7.68-
7.71 (m, 1H), 7.70 (d, J = 8.3H)
z, 2H), 7.85 (d, J = 8.3 Hz, 2H),
9.07 (s, 1H). Example 132
【0547】[0547]
【化153】 Embedded image
【0548】実施例131でトシル体(140mg、
0.26mmol)のエタノール(4ml)、THF
(2ml)、混合溶液に1規定水酸化ナトリウム水溶液
(0.5ml、0.5mmol)を加え、4.5時間撹
拌した。反応液に1規定塩酸水溶液(1ml)を加えジ
クロロメタンで抽出後、有機層を飽和食塩水で洗浄し、
無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。
残渣をシリカゲルカラムクロマトグラフィー(クロロホ
ルム→クロロホルム:メタノール 30:1)にて精製
し、目的物(68mg、0.18mmol、68%)を
得た。The tosyl form (140 mg,
0.26 mmol) of ethanol (4 ml), THF
(2 ml), a 1 N aqueous solution of sodium hydroxide (0.5 ml, 0.5 mmol) was added to the mixed solution, and the mixture was stirred for 4.5 hours. A 1N aqueous hydrochloric acid solution (1 ml) was added to the reaction solution, and the mixture was extracted with dichloromethane.
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
The residue was purified by silica gel column chromatography (chloroform → chloroform: methanol 30: 1) to obtain the desired product (68 mg, 0.18 mmol, 68%).
【0549】淡黄色結晶 m.p.201−204℃ IR(KBr)νcm-1:3412,3155,298
4,2910,2361,2341,2183,161
2,1572,1531,1502,1458,142
9,1344,1332,1234,1201,114
9,1037,935,852,837,783,75
2,698,630,617,605.1 H NMR(CDCl3 ,250MHz)δppm:
1.34(t,J=7.0Hz,3H),1.55
(t,J=7.0Hz,3H),3.64(q,J=
7.0Hz,2H),4.26(q,J=7.0Hz,
2H),6.98−7.02(m,1H),7.24−
7.32(m,3H),7.34−7.43(m,3
H),7.75−7.79(m,2H),8.90−
9.10(m,1H),9.06(s,1H). TOF−MS m/z;384(M+H). 実施例133Light yellow crystals m. p. 201-204 ° C IR (KBr) νcm -1 : 3412,3155,298
4,2910,2361,2341,183,161
2,1572,1531,1502,1458,142
9,1344,1332,1234,1201,114
9,1037,935,852,837,783,75
2,698,630,617,605. 1 H NMR (CDCl 3 , 250 MHz) δ ppm:
1.34 (t, J = 7.0 Hz, 3H), 1.55
(T, J = 7.0 Hz, 3H), 3.64 (q, J =
7.0 Hz, 2H), 4.26 (q, J = 7.0 Hz,
2H), 6.98-7.02 (m, 1H), 7.24-
7.32 (m, 3H), 7.34-7.43 (m, 3
H), 7.75-7.79 (m, 2H), 8.90-
9.10 (m, 1H), 9.06 (s, 1H). TOF-MS m / z; 384 (M + H). Example 133
【0550】[0550]
【化154】 Embedded image
【0551】実施例132で得た物質(50mg、0.
13mmol)のDMF(2ml)溶液に60%水素化
ナトリウム(6.2g、0.16mmol)を加え次い
でヨウ化メチル(8.9μl、0.143mmol)を
加えた。反応液に水を加え、クロロホルムで抽出した。
有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾
燥後、減圧下溶媒を留去した。残渣をシリカゲルカラム
クロマトグラフィー(クロロホルム→クロロホルム:メ
タノール=40:1)で精製し、得られた結晶をエーテ
ルで洗浄し、目的物質(21mg、0.053mmo
l、41%)を得た。The substance obtained in Example 132 (50 mg, 0.1 mg) was obtained.
To a solution of 13 mmol) in DMF (2 ml) was added 60% sodium hydride (6.2 g, 0.16 mmol) followed by methyl iodide (8.9 μl, 0.143 mmol). Water was added to the reaction solution, and extracted with chloroform.
The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform → chloroform: methanol = 40: 1), and the obtained crystals were washed with ether to give the desired substance (21 mg, 0.053 mmol).
1, 41%).
【0552】黄色結晶 m.p.136−137.5℃ IR(KBr)νcm-1:3427,2982,293
4,2361,2341,2189,1612,157
0,1502,1452,1417,1400,135
9,1342,1232,1201,1155,103
7,900,829,775,742,698,65
3,605,5841 H NMR(CDCl3 ,250MHz)δppm:
1.33(t,J=7.0Hz,3H),1.55
(t,J=7.0Hz,3H),3.61(q,J=
7.0Hz,2H),3.75(s,3H),4.26
(q,J=7.0Hz,2H),6.79(d,J=
2.3Hz,1H),7.17(d,J=2.3Hz,
1H),7.23−7.40(m,5H),7.71−
7.75(m,2H),9.05(s,1H). TOF−MS m/z;398(M+H) 実施例134Yellow crystals m.p. p. 136-137.5 ° C IR (KBr) νcm -1 : 3427,2982,293
4,2361,2341,189,1612,157
0, 1502, 1452, 1417, 1400, 135
9,1342,1232,1201,1155,103
7,900,829,775,742,698,65
3,605,584 1 H NMR (CDCl 3 , 250 MHz) δ ppm:
1.33 (t, J = 7.0 Hz, 3H), 1.55
(T, J = 7.0 Hz, 3H), 3.61 (q, J =
7.0 Hz, 2H), 3.75 (s, 3H), 4.26
(Q, J = 7.0 Hz, 2H), 6.79 (d, J =
2.3 Hz, 1 H), 7.17 (d, J = 2.3 Hz,
1H), 7.23-7.40 (m, 5H), 7.71-
7.75 (m, 2H), 9.05 (s, 1H). TOF-MS m / z; 398 (M + H) Example 134
【0553】[0553]
【化155】 Embedded image
【0554】実施例132で得た物質(100mg、
0.26mmol)と、ブロモ酢酸エチルエステル(6
5mg、0.39mmol)を実施例132と同様に反
応を行い、目的物(68mg、0.145mmol、5
5%)を得た。 白色結晶 mp.174−175℃ IR(KBr)νcm-1:3425,2982,295
3,2363,2202,1739,1614,157
0,1500,1458,1444,1363,131
3,1232,1205,1161,1035,102
4,850,825,777,740,700,62
8,607,592.The substance obtained in Example 132 (100 mg,
0.26 mmol) and bromoacetic acid ethyl ester (6
5 mg, 0.39 mmol) was reacted in the same manner as in Example 132 to give the desired product (68 mg, 0.145 mmol, 5
5%). White crystals mp. 174-175 ° C IR (KBr) νcm -1 : 3425,2982,295
3,2363,2202,1739,1614,157
0, 1500, 1458, 1444, 1363, 131
3,1232,1205,1161,1035,102
4,850,825,777,740,700,62
8,607,592.
【0555】1H NMR(CDCl3 ,300MH
z)δppm:1.32(t,J=7.0Hz,3
H),1.33(t,J=7.0Hz,3H),1.5
4(t,J=7.0Hz,3H),3.63(q,J=
7.0Hz,2H),4.25(q,J=7.0Hz,
2H),4.28(q,J=7.0Hz,2H),4.
68(s,2H),6.84−6.85(m,1H),
7.22−7.29(m,4H),7.33−7.39
(m,2H),7.73−7.77(m,2H),9.
05(s,1H). TOF−MS m/z;470(M+H) 実施例135 1 H NMR (CDCl 3 , 300 MH
z) δ ppm: 1.32 (t, J = 7.0 Hz, 3
H), 1.33 (t, J = 7.0 Hz, 3H), 1.5
4 (t, J = 7.0 Hz, 3H), 3.63 (q, J =
7.0 Hz, 2H), 4.25 (q, J = 7.0 Hz,
3H), 4.28 (q, J = 7.0 Hz, 2H), 4.
68 (s, 2H), 6.84-6.85 (m, 1H),
7.22-7.29 (m, 4H), 7.33-7.39
(M, 2H), 7.73-7.77 (m, 2H), 9.
05 (s, 1H). TOF-MS m / z; 470 (M + H) Example 135
【0556】[0556]
【化156】 Embedded image
【0557】実施例134で得たエチルエステル体(3
5mg、0.0745mmol)を実施例8と同様に加
水分解反応を行い、目的物(30mg、0.068mm
ol、91%)を得た。 黄色結晶 230〜244℃ 熱分解 IR(KBr)νcm-1:3427,3123,298
6,2941,2490,2364,2195,195
7,1720,1612,1574,1531,150
0,1450,1400,1363,1315,124
2,1159,1035,931,898,785,7
46,698,6111 H NMR(DMSO−d6 ,300MHz)δpp
m:1.30(t,J=6.9Hz,3H),1.42
(t,J=6.9Hz,3H),3.78(q,J=
6.9Hz,2H),4.26(q,J=6.9Hz,
2H),4.89(s,2H),7.24(d,J=
2.1Hz,1H),7.26−7.32(m,3
H),7.38−7.44(m,2H),7.59
(d,J=2.1Hz,1H),7.72−7.73
(m,1H),7.74−7.75(m,1H),8.
99(s,1H),12.9−13.4(m,1H). TOF−MS m/z;442(M+H)The ethyl ester obtained in Example 134 (3
5 mg, 0.0745 mmol) was subjected to a hydrolysis reaction in the same manner as in Example 8 to give the desired product (30 mg, 0.068 mm).
ol, 91%). Yellow crystal 230-244 ° C Thermal decomposition IR (KBr) νcm -1 : 3427,3123,298
6,2941,2490,2364,2195,195
7, 1720, 1612, 1574, 1531, 150
0, 1450, 1400, 1363, 1315, 124
2,1159,1035,931,898,785,7
46,698,611 1 H NMR (DMSO-d 6 , 300 MHz) δpp
m: 1.30 (t, J = 6.9 Hz, 3H), 1.42
(T, J = 6.9 Hz, 3H), 3.78 (q, J =
6.9 Hz, 2H), 4.26 (q, J = 6.9 Hz,
2H), 4.89 (s, 2H), 7.24 (d, J =
2.1Hz, 1H), 7.26-7.32 (m, 3
H), 7.38-7.44 (m, 2H), 7.59.
(D, J = 2.1 Hz, 1H), 7.72-7.73
(M, 1H), 7.74-7.75 (m, 1H), 8.
99 (s, 1H), 12.9-13.4 (m, 1H). TOF-MS m / z; 442 (M + H)
【0558】[0558]
【表174】 [Table 174]
【0559】[0559]
【表175】 [Table 175]
【0560】[0560]
【表176】 [Table 176]
【0561】[0561]
【表177】 [Table 177]
【0562】[0562]
【表178】 [Table 178]
【0563】[0563]
【表179】 [Table 179]
【0564】[0564]
【表180】 [Table 180]
【0565】[0565]
【表181】 [Table 181]
【0566】[0566]
【表182】 [Table 182]
【0567】[0567]
【表183】 [Table 183]
【0568】合成例57 以下のルートに従って3amを合成した。Synthesis Example 57 3am was synthesized according to the following route.
【0569】[0569]
【化157】 Embedded image
【0570】1)0.5Mエチニルマグネシウムクロリ
ドTHF溶液(104ml、52mmol)に、ベンジ
ルアセトン(7g、47.2mmol)を滴下した。次
いで、反応液に無水酢酸(5.36ml、56.5mm
ol)を滴下した。反応液に1N HCl水溶液(60
ml)を加え、酢酸エチルで抽出した。有機層を飽和食
塩水、炭酸水素ナトリウム水溶液、飽和食塩水の順に洗
浄し、無水硫酸ナトリウムで乾燥後減圧下溶媒を留去し
た。残渣をシリカゲルカラムクロマトグラフィー(ヘキ
サン→ヘキサン:酢酸エチル=8:1)で精製し、1
(9.5g、44mmol、93%)を得た。 1: 1H NMR(CDCl3 ,250MHz)δpp
m:1.74(s,3H),2.03(s,3H),
2.09−2.31(m,2H),2.62(s,1
H),2.75−2.90(m,2H),7.16−
7.35(m,5H).1) Benzyl acetone (7 g, 47.2 mmol) was added dropwise to a 0.5 M ethynylmagnesium chloride THF solution (104 ml, 52 mmol). Next, acetic anhydride (5.36 ml, 56.5 mm) was added to the reaction solution.
ol) was added dropwise. A 1N HCl aqueous solution (60
ml) and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, an aqueous sodium hydrogen carbonate solution and a saturated saline solution in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane → hexane: ethyl acetate = 8: 1) to give 1
(9.5 g, 44 mmol, 93%). 1: 1 H NMR (CDCl 3 , 250 MHz) δpp
m: 1.74 (s, 3H), 2.03 (s, 3H),
2.09-2.31 (m, 2H), 2.62 (s, 1
H), 2.75-2.90 (m, 2H), 7.16-
7.35 (m, 5H).
【0571】2)アセテート(1)(5g、23mmo
l)のTHF(50ml)溶液に塩化銅(I)(161
mg、1.6mmol)、イソニペコチン酸エチル
(8.71g、55.4mmol)を加え、3時間加熱
還流した。反応液を室温とし、減圧下濃縮した後、エー
テルで抽出した。これを、塩化アンモニウム水溶液、飽
和食塩水の順に洗浄した後、3N HCl水溶液で抽出
した。この水層をエーテルで洗浄後、2N NaOH水
溶液および炭酸水素ナトリウム水溶液を加え、ジクロロ
メタンで抽出した。有機層を飽和食塩水で洗浄後、無水
硫酸ナトリウムで乾燥させ、減圧下濃縮した。残渣をシ
リカゲルカラムクロマトグラフィー(ヘキサン→ヘキサ
ン:酢酸エチル=4:1)で精製し、3am(5.02
g、16mmol、69%)を得た。2) Acetate (1) (5 g, 23 mmol)
l) in THF (50 ml) was added to copper (I) chloride (161).
mg, 1.6 mmol) and ethyl isonipecotate (8.71 g, 55.4 mmol), and the mixture was heated under reflux for 3 hours. The reaction solution was brought to room temperature, concentrated under reduced pressure, and extracted with ether. This was washed with an aqueous ammonium chloride solution and a saturated saline solution in this order, and then extracted with a 3N aqueous HCl solution. After washing the aqueous layer with ether, a 2N aqueous solution of NaOH and an aqueous solution of sodium hydrogen carbonate were added, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane → hexane: ethyl acetate = 4: 1) to give 3am (5.02).
g, 16 mmol, 69%).
【0572】3am; 1H NMR(CDCl3 ,25
0MHz)δppm:1.25(t,J=7.0Hz,
3H),1.40(s,3H),1.75−1.85
(m,2H),1.90−2.00(m,4H),2.
20−2.30(m,3H),2.33(s,1H),
2.70−2.78(m,2H),3.00−3.21
(m,2H),4.13(q,J=7.0Hz,2
H),7.17−7.21(m,2H),7.25−
7.32(m,3H). 合成例58 以下のルートに従って3anを合成した。3am; 1 H NMR (CDCl 3 , 25
0 MHz) δ ppm: 1.25 (t, J = 7.0 Hz,
3H), 1.40 (s, 3H), 1.75-1.85
(M, 2H), 1.90-2.00 (m, 4H), 2.
20-2.30 (m, 3H), 2.33 (s, 1H),
2.70-2.78 (m, 2H), 3.00-3.21
(M, 2H), 4.13 (q, J = 7.0 Hz, 2
H), 7.17-7.21 (m, 2H), 7.25-
7.32 (m, 3H). Synthesis Example 58 3an was synthesized according to the following route.
【0573】[0573]
【化158】 Embedded image
【0574】1)ケイ酸ベンジルエステル(1.2g、
5mmol)と、p−トルエンスルホニルメチルイソシ
アニド(976mg、5mmol)のエーテル(10m
l)、DMSO(5ml)混合溶液をNaH(60%、
240mg、6mmol)のエーテル(10ml)懸濁
液に滴下し、15分撹拌した。反応液に水を注ぎ、酢酸
エチルで抽出した。有機層を飽和食塩水で洗浄後、無水
硫酸ナトリウムで乾燥させ、減圧下溶媒を留去した。得
られた結晶をエーテルで洗浄し、1(864mg、3.
12mmol、62%)を得た。1) Benzyl silicate (1.2 g,
5 mmol) and ether of p-toluenesulfonylmethyl isocyanide (976 mg, 5 mmol) (10 m
1) DMSO (5 ml) mixed solution with NaH (60%,
(240 mg, 6 mmol) in ether (10 ml) was added dropwise and stirred for 15 minutes. Water was poured into the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crystals were washed with ether, and 1 (864 mg, 3.
12 mmol, 62%).
【0575】1H NMR(CDCl3 ,250MH
z)δppm:5.22(s,2H),6.76−6.
79(m,1H),7.23−7.37(m,8H),
7.44−7.54(m,3H),8.40−8.60
(m,1H). 2)1(864mg、3.12mmol)のTHF(1
0ml)溶液にトリエチルアミン(650μl、4.6
6mmol)、ジメチルアミノピリジン(189mg、
1.55mmol)、p−トルエンスルホニルクロリド
(711mg、3.73mmol)を加え、3.5時間
撹拌した。反応液に塩化アンモニウム水溶液を注ぎ、酢
酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無
水硫酸ナトリウムで乾燥させ、減圧下溶媒を留去した。
残渣をシリカゲルカラムクロマトグラフィー(ヘキサ
ン:酢酸エチル4:1)にて精製し、2(1.29g、
3.0mmol、96%)を得た。 1 H NMR (CDCl 3 , 250 MH
z) δ ppm: 5.22 (s, 2H), 6.76-6.
79 (m, 1H), 7.23-7.37 (m, 8H),
7.44-7.54 (m, 3H), 8.40-8.60
(M, 1H). 2) 1 (864 mg, 3.12 mmol) of THF (1
0 ml) solution in triethylamine (650 μl, 4.6
6 mmol), dimethylaminopyridine (189 mg,
1.55 mmol) and p-toluenesulfonyl chloride (711 mg, 3.73 mmol) were added, and the mixture was stirred for 3.5 hours. An aqueous ammonium chloride solution was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
The residue was purified by silica gel column chromatography (hexane: ethyl acetate 4: 1) to give 2 (1.29 g,
(3.0 mmol, 96%).
【0576】1H NMR(CDCl3 ,250MH
z)δppm:2.43(s,3H),5.18(s,
2H),7.12(d,J=2.7Hz,1H),7.
23−7.41(m,12H),7.80−7.84
(m,2H),7.85(d,J=2.7Hz,1
H). 3)2(2.76g、6.4mmol)のTHF(70
ml)溶液にリチウムアルミニウムヒドリド(291m
g、7.7mmol)を加え、40分撹拌した。反応液
に水(0.3ml)3規定水酸化ナトリウム水溶液
(0.3ml)、水(0.9ml)の順に加え上清を濾
取した後、減圧下溶媒を留去した。残渣をシリカゲルカ
ラムクロマトグラフィー(ヘキサン:酢酸エチル=4:
1→酢酸エチル)にて精製し、3(1.94g、5.9
mmol、92%)を無色油状物質として得た。 1 H NMR (CDCl 3 , 250 MH
z) δ ppm: 2.43 (s, 3H), 5.18 (s,
2H), 7.12 (d, J = 2.7 Hz, 1H), 7.
23-7.41 (m, 12H), 7.80-7.84
(M, 2H), 7.85 (d, J = 2.7 Hz, 1
H). 3) 2 (2.76 g, 6.4 mmol) of THF (70
ml) solution with lithium aluminum hydride (291 m
g, 7.7 mmol) and stirred for 40 minutes. Water (0.3 ml), 3N aqueous sodium hydroxide solution (0.3 ml) and water (0.9 ml) were added to the reaction solution in that order, and the supernatant was collected by filtration. The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 4:
1 → ethyl acetate) to purify 3 (1.94 g, 5.9)
mmol, 92%) as a colorless oil.
【0577】1H NMR(CDCl3 ,250MH
z)δppm:2.41(s,3H),4.59(s,
1H),4.61(s,1H),7.23−7.40
(m,7H),7.43−7.48(m,2H),7.
80(d,J=8.4Hz,2H). 4)3(1.94g、5.9mmol)のジクロロメタ
ン(100ml)溶液に二酸化マンガン(7.8g)を
加え、7時間撹拌した。反応液をセライト−シリカゲル
を用い濾過し、濾液を減圧下濃縮し、4(1.66g、
5.1mmol、86%)を得た。 1 H NMR (CDCl 3 , 250 MH
z) δ ppm: 2.41 (s, 3H), 4.59 (s,
1H), 4.61 (s, 1H), 7.23-7.40.
(M, 7H), 7.43-7.48 (m, 2H), 7.
80 (d, J = 8.4 Hz, 2H). 4) To a solution of 3 (1.94 g, 5.9 mmol) in dichloromethane (100 ml) was added manganese dioxide (7.8 g), and the mixture was stirred for 7 hours. The reaction solution was filtered using Celite-silica gel, and the filtrate was concentrated under reduced pressure to give 4 (1.66 g,
5.1 mmol, 86%).
【0578】1H NMR(CDCl3 ,250MH
z)δppm:2.44(s,3H),7.23(d.
J=2.4Hz,1H),7.33−7.45(m,7
H),7.85(d,J=8.5Hz,2H),7.8
6(d,J=2.4Hz,1H),9.89(s,1
H). 5)4(1.66g、5.1mmol)のジクロロメタ
ン(50ml)溶液にトリフェニルホスフィン(2.6
8g、10.2mmol)を加え、氷冷下、四臭化炭素
(1.86g、5.6mmol)のジクロロメタン(1
5ml)溶液を滴下し、40分撹拌した。炭酸水素ナト
リウム水溶液を加え、ジクロロメタンで抽出後、有機層
を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥
させ、シリカ(10g)を加え、減圧下溶媒を留去し
た。残渣をシリカゲルクロマトグラフィー(ヘキサン:
酢酸エチル=9:1→ジクロロメタン)にて精製し、5
(2.33g、4.85mmol、95%)を白色結晶
として得た。 1 H NMR (CDCl 3 , 250 MH
z) δ ppm: 2.44 (s, 3H), 7.23 (d.
J = 2.4 Hz, 1H), 7.33-7.45 (m, 7
H), 7.85 (d, J = 8.5 Hz, 2H), 7.8
6 (d, J = 2.4 Hz, 1H), 9.89 (s, 1
H). 5) Triphenylphosphine (2.6) was added to a solution of 4 (1.66 g, 5.1 mmol) in dichloromethane (50 ml).
8g, 10.2 mmol), and carbon tetrabromide (1.86 g, 5.6 mmol) in dichloromethane (1
5 ml) solution was added dropwise and stirred for 40 minutes. An aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, silica (10 g) was added, and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel (hexane:
(Ethyl acetate = 9: 1 → dichloromethane)
(2.33 g, 4.85 mmol, 95%) as white crystals.
【0579】1H NMR(CDCl3 ,250MH
z)δppm:2.43(s,3H),7.16−7.
17(m,2H),7.26−7.43(m,7H),
7.85(d,J=8.3Hz,2H),7.90−
7.91(m,1H). 2)5(616mg、1.28mmol)のTHF(1
3ml)溶液に、−78℃にて、1.59Mノルマルブ
チルリチウムヘキサン溶液(2.78ml、4.42m
mol)を滴下した。反応液に塩化アンモニウム水溶液
を加え、室温とし、酢酸エチルで抽出した。有機層を飽
和食塩水で洗浄後、無水硫酸ナトリウムで乾燥させ、減
圧下溶媒を留去した。残渣をシリカゲルカラムクロマト
グラフィー(ヘキサン→ヘキサン:酢酸エチル9:1)
で精製し、3an(163mg、0.51mmol、4
0%)を得た。 1 H NMR (CDCl 3 , 250 MH
z) δ ppm: 2.43 (s, 3H), 7.16-7.
17 (m, 2H), 7.26-7.43 (m, 7H),
7.85 (d, J = 8.3 Hz, 2H), 7.90 −
7.91 (m, 1H). 2) 5 (616 mg, 1.28 mmol) in THF (1
Solution at -78 ° C at 1.78 M in normal butyllithium hexane solution (2.78 ml, 4.42 m).
mol) was added dropwise. An aqueous ammonium chloride solution was added to the reaction solution, the mixture was brought to room temperature, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue is subjected to silica gel column chromatography (hexane → hexane: ethyl acetate 9: 1)
And purified by 3an (163 mg, 0.51 mmol, 4
0%).
【0580】1H NMR(CDCl3 ,250MH
z)δppm:2.42(s,3H),3.10(s,
1H),7.25(d,J=2.4Hz,1H),7.
26−7.38(m,5H),7.45(d,J=2.
4Hz,1H),7.65(d,J=8.4Hz,2
H),7.80(d,J=8.4Hz,2H). 合成例59 1 H NMR (CDCl 3 , 250 MH
z) δ ppm: 2.42 (s, 3H), 3.10 (s,
1H), 7.25 (d, J = 2.4 Hz, 1H), 7.
26-7.38 (m, 5H), 7.45 (d, J = 2.
4 Hz, 1 H), 7.65 (d, J = 8.4 Hz, 2
H), 7.80 (d, J = 8.4 Hz, 2H). Synthesis Example 59
【0581】[0581]
【化159】 Embedded image
【0582】上記の様に特開平6−73025号公報の
記述に従って、4−クロロ−6−ニトロキナゾリン2u
を5−ニトロ−アントラニス酸より合成した。 試験例1 <本発明のチロシンキナーゼ阻害剤の評価>本発明のチ
ロシンキナーゼ阻害剤について、チロシンキナーゼ阻害
活性および癌細胞増殖阻害作用について評価するため、
部分的に精製されたヒトEGF(上皮性細胞増殖因子)
受容体チロシンキナーゼ活性測定系およびヒト癌細胞を
用いた細胞培養系において試験を行った。さらに、阻害
活性の強さを比較、評価するために、特許あるいは文献
で開示されている既存のチロシンキナーゼ阻害剤のう
ち、比較的活性の高いものを同時に試験を行った。According to the description of JP-A-6-73025, 4-chloro-6-nitroquinazoline 2u
Was synthesized from 5-nitro-anthranisic acid. Test Example 1 <Evaluation of tyrosine kinase inhibitor of the present invention> In order to evaluate the tyrosine kinase inhibitory activity and cancer cell growth inhibitory activity of the tyrosine kinase inhibitor of the present invention,
Partially purified human EGF (epidermal growth factor)
The test was performed in a receptor tyrosine kinase activity measurement system and a cell culture system using human cancer cells. Furthermore, in order to compare and evaluate the strength of the inhibitory activity, among the existing tyrosine kinase inhibitors disclosed in patents or literature, those having relatively high activity were simultaneously tested.
【0583】(1)チロシンキナーゼ活性阻害作用 (測定方法)チロシンキナーゼ活性阻害作用は、ヒト偏
平上皮癌由来のA431細胞株より部分的に精製された
EGF受容体を用い、Linda J.PikeらのP
roceedings of the Nationa
l Academy ofSciences of t
he U.S.A.79,1433(1982)記載の
チロシンキナーゼ活性測定方法を改良して行った。(1) Tyrosine kinase activity inhibitory action (Measurement method) Tyrosine kinase activity inhibitory action was determined by using an EGF receptor partially purified from a human squamous cell carcinoma-derived A431 cell line according to Linda J. et al. Pike et al.'S P
rosedings of the Nationa
l Academy of Sciences of t
he U.S. S. A. 79, 1433 (1982).
【0584】詳しい方法は以下の通りである。A431
細胞を牛胎児血清(FBS)10%を含むダルベッコ変
法イーグル培地中(DMEM)で37℃、5%炭酸ガス
下で培養し、この細胞を10mM N−2−ハイドロキ
シエチルピペラジノ−N′−2−エタンスルホン酸(H
epes)緩衝液(pH7.4)、0.25Mサッカロ
ース、0.1mM EDTAを含む溶液中でホモジネー
ト後、3000gで5分間遠心分離し、更にその上清を
100,000×gで30分間遠心分離を行いA431
細胞膜画分を得、これを酵素源である部分精製EGF受
容体として測定に供した。The detailed method is as follows. A431
The cells are cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum (FBS) at 37 ° C. under 5% carbon dioxide, and the cells are cultured at 10 mM N-2-hydroxyethylpiperazino-N ′. -2-ethanesulfonic acid (H
epes) After homogenizing in a solution containing a buffer solution (pH 7.4), 0.25 M saccharose, and 0.1 mM EDTA, centrifuging at 3000 g for 5 minutes, and further centrifuging the supernatant at 100,000 × g for 30 minutes. A431
A cell membrane fraction was obtained, and this was subjected to measurement as a partially purified EGF receptor as an enzyme source.
【0585】上記のA431細胞膜画分(10〜15μ
g)、30mM Hepes緩衝液(pH7.7)、2
mM MnCl2 、100μM Na3 VO4 、および
ジメチルスルホキシド(DMSO)に溶解した被検物質
(終濃度1% DMSO)の反応混液に、100ngの
EGFを加えた後、合成基質RR−SRCペプチド(A
rg−Arg−Leu−Ile−Glu−Asp−Al
a−Glu−Tyr−Ala−Ala−Arg−Gl
y)75μg、10μM γ−32P−アデノシン三リン
酸(37Kbp)を加えて反応を開始した。このときの
容量は60μlである。尚、RR−SRCペプチドは、
EGF受容体のチロシンキナーゼの基質となる合成基質
となるものであり、srcの遺伝子産物中リン酸化され
るチロシン残基を含むアミノ酸配列を有する。The A431 cell membrane fraction (10 to 15 μm)
g), 30 mM Hepes buffer (pH 7.7), 2
100 ng of EGF was added to a reaction mixture of a test substance (final concentration 1% DMSO) dissolved in mM MnCl 2 , 100 μM Na 3 VO 4 , and dimethyl sulfoxide (DMSO), and then the synthetic substrate RR-SRC peptide (A
rg-Arg-Leu-Ile-Glu-Asp-Al
a-Glu-Tyr-Ala-Ala-Arg-Gl
y) The reaction was started by adding 75 μg, 10 μM γ- 32 P-adenosine triphosphate (37 Kbp). The volume at this time is 60 μl. In addition, the RR-SRC peptide is
It is a synthetic substrate that serves as a substrate for the tyrosine kinase of the EGF receptor, and has an amino acid sequence containing a tyrosine residue that is phosphorylated in the src gene product.
【0586】反応は氷中にて30分間行い、10mg/
ml牛血清アルブミンを6μlと20%トリクロロ酢酸
を25μl加えて反応を停止し、そのまま氷中に30分
間放置した。次に5000×gで2分間遠心した後、上
清を40μlサンプリングしてP81ホスホセルロース
ペーパーに吸着させた。これを30%酢酸水に15分間
浸して固定し、15%酢酸水に15分間浸して洗浄し
(洗浄は4回繰り返し行った)、液体シンチレーション
カウンターでP81ホスホセルロースペーパーに付着し
た32Pのカウントを測定し、この値をAとした。同時に
被検物質を添加しない反応、被検物質およびEGF共に
添加しない反応のカウントも測定し、各々B、Cとし
た。これらの値から、チロシンキナーゼ阻害率は、下記
の式により求められる。The reaction was carried out in ice for 30 minutes and 10 mg /
The reaction was stopped by adding 6 μl of ml bovine serum albumin and 25 μl of 20% trichloroacetic acid, and left on ice for 30 minutes. Next, after centrifugation at 5000 × g for 2 minutes, 40 μl of the supernatant was sampled and adsorbed on P81 phosphocellulose paper. This was fixed by immersing it in 30% acetic acid water for 15 minutes, washed by immersing it in 15% acetic acid water for 15 minutes (washing was repeated 4 times), and counted 32 P attached to P81 phosphocellulose paper by a liquid scintillation counter. Was measured, and this value was designated as A. At the same time, the counts of the reaction without the addition of the test substance and the reaction without the addition of both the test substance and EGF were also measured, and were designated as B and C, respectively. From these values, the tyrosine kinase inhibition rate is determined by the following equation.
【0587】[0587]
【数1】阻害率(%)=100−{(A−C)/(B−
C)}×100## EQU1 ## Inhibition rate (%) = 100−Δ (AC) / (B−)
C)} × 100
【0588】被検物質の添加濃度を変化させて得られた
阻害率よりIC50値(50%阻害濃度)を算出した。 (2)癌細胞増殖阻害作用 (測定方法)ヒト鼻咽喉癌であるKB細胞は、その細胞
表面上にEGF受容体を過剰に保有している。このKB
細胞を用いて、培養癌細胞の増殖に対する被検物質の効
果の検討を以下の方法で行った。The IC 50 value (50% inhibitory concentration) was calculated from the inhibition rate obtained by changing the concentration of the test substance. (2) Cancer cell growth inhibitory effect (Measurement method) KB cells, which are human nasopharyngeal carcinomas, have an excess of EGF receptor on the cell surface. This KB
Using the cells, the effect of the test substance on the growth of cultured cancer cells was examined by the following method.
【0589】96well dish上に、KB細胞を
2.5×103 cell/wellに播種し、10%F
BS,50U/mlペニシリン及び50μg/mlスト
レプトマイシン含有DMEM:F12(1:1)培地中
で、37℃、5%炭酸ガス条件下で1日培養後、DMS
Oに溶解した被検物質を培地中に添加し(DMSO終濃
度<0.1%)、上記条件下で3日間培養した。なお被
検物質は24時間おきに培地と共に交換した。[0589] KB cells were seeded on a 96-well dish at 2.5 x 10 3 cells / well, and 10% F
After culturing for 1 day in a DMEM: F12 (1: 1) medium containing BS, 50 U / ml penicillin and 50 μg / ml streptomycin at 37 ° C. and 5% carbon dioxide, DMS was added.
A test substance dissolved in O was added to the medium (final DMSO concentration <0.1%), and the cells were cultured under the above conditions for 3 days. The test substance was replaced together with the medium every 24 hours.
【0590】生細胞数のカウントは、Michael
C.AlleyらのCancerReserch 4
8,589(1988)記載の測定法を参考に、MTT
(3−〔4,5−Dimethylthiazol−2
−yl〕−2,5−diphenytetrazoli
um bromide)試薬を用い540nmと660
nmの2波長の比色定量より求め、その値をaとした。
同時に被検物質を加えない時の生細胞数のカウントも測
定し、その値をbとした。細胞増殖阻害率は、下記の式
により求められる。The count of the number of living cells was determined by
C. Alley et al. CancerResearch 4
8,589 (1988) with reference to the MTT method.
(3- [4,5-Dimethylthiazol-2
-Yl] -2,5-diphenetetrazoli
um bromide) reagent at 540 nm and 660
It was determined by colorimetry at two wavelengths of nm, and the value was defined as a.
At the same time, the count of the number of living cells when no test substance was added was also measured, and the value was defined as b. The cell growth inhibition rate is determined by the following equation.
【0591】[0591]
【数2】阻害率(%)={(b−a)/b}×100## EQU2 ## Inhibition rate (%) = {(ba) / b} × 100
【0592】被検物質の添加濃度を変化させて得られた
阻害率よりIC50値(50%阻害濃度)を算出した。以
上の結果を表に示す。表中、Enzは、チロシンキナー
ゼ阻害率を、Cellは、細胞増殖阻害率を表わす。The IC 50 value (50% inhibitory concentration) was calculated from the inhibition rate obtained by changing the concentration of the test substance. The above results are shown in the table. In the table, Enz represents the tyrosine kinase inhibition rate, and Cell represents the cell growth inhibition rate.
【0593】[0593]
【表184】 [Table 184]
【0594】[0594]
【表185】 [Table 185]
【0595】[0595]
【表186】 [Table 186]
【0596】[0596]
【表187】 [Table 187]
【0597】[0597]
【表188】 [Table 188]
【0598】[0598]
【表189】 [Table 189]
【0599】[0599]
【表190】 [Table 190]
【0600】[0600]
【表191】 [Table 191]
【0601】[0601]
【表192】 [Table 192]
【0602】[0602]
【表193】 [Table 193]
【0603】[0603]
【表194】 [Table 194]
【0604】[0604]
【表195】 [Table 195]
【0605】[0605]
【表196】 [Table 196]
【0606】[0606]
【表197】 [Table 197]
【0607】[0607]
【表198】 [Table 198]
【0608】[0608]
【表199】 [Table 199]
【0609】[0609]
【表200】 [Table 200]
【0610】[0610]
【表201】 [Table 201]
【0611】[0611]
【表202】 [Table 202]
【0612】[0612]
【表203】 [Table 203]
【0613】[0613]
【表204】 [Table 204]
【0614】[0614]
【表205】 [Table 205]
【0615】[0615]
【表206】 [Table 206]
【0616】[0616]
【発明の効果】本発明のエチニルピリミジン誘導体は、
強力なチロシンキナーゼ阻害活性及び癌細胞増殖抑制作
用を有するので、制癌剤、免疫抑制剤、血小板凝集阻害
剤、動脈硬化治療薬、抗炎症剤、または癌細胞増殖抑制
薬として有用である。The ethynylpyrimidine derivative of the present invention is
Since it has strong tyrosine kinase inhibitory activity and cancer cell growth inhibitory activity, it is useful as an anticancer agent, an immunosuppressant, a platelet aggregation inhibitor, a therapeutic agent for arteriosclerosis, an anti-inflammatory agent, or a cancer cell growth inhibitor.
【表207】 [Table 207]
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 FI A61K 31/52 ACB A61K 31/52 ACB 31/535 ABC 31/535 ABC C07D 239/42 C07D 239/42 Z 239/62 239/62 239/78 239/78 401/06 239 401/06 239 403/06 207 403/06 207 405/12 239 405/12 239 405/14 211 405/14 211 417/06 239 417/06 239 471/04 108 471/04 108Z 117 117Z 473/00 473/00 475/00 475/00 487/04 144 487/04 144 148 148 491/048 491/048 491/056 491/056 (72)発明者 鈴木 毅 神奈川県横浜市青葉区鴨志田町1000番地 三菱化学株式会社横浜総合研究所内 (72)発明者 大矢 淳 神奈川県横浜市青葉区鴨志田町1000番地 三菱化学株式会社横浜総合研究所内 (72)発明者 原 啓人 東京都千代田区丸の内二丁目5番2号 三 菱化学株式会社医薬カンパニー内──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. 6 Identification code FI A61K 31/52 ACB A61K 31/52 ACB 31/535 ABC 31/535 ABC C07D 239/42 C07D 239/42 Z 239/62 239 / 62 239/78 239/78 401/06 239 401/06 239 403/06 207 403/06 207 405/12 239 405/12 239 405/14 211 405/14 211 417/06 239 417/06 239 471/04 108 471/04 108Z 117 117Z 473/00 473/00 475/00 475/00 487/04 144 487/04 144 148 148 491/048 491/048 491/056 491/056 (72) Inventor Takeshi Suzuki Kanagawa Prefecture 1000, Kamoshida-cho, Aoba-ku, Yokohama-shi Mitsubishi Chemical Corporation Yokohama Research Laboratory (72) Inventor Jun Atsushi Oya 1000, Kamoshida-cho, Aoba-ku, Yokohama-shi, Kanagawa Prefecture Mitsubishi Chemical Yokohama Research Laboratory (72) Inventor Hiroto Hara 2-5-2-2 Marunouchi, Chiyoda-ku, Tokyo Mitsubishi Chemical Corporation Pharmaceutical Company
Claims (5)
て(1)ニトロ基;(2)−(CH2 )n' NR3 R4
(式中、n′は0または1を表し、R3 、R4 はそれぞ
れ独立して(a)水素原子;または(b)カルボキシル
基もしくはC1 〜C5 のアルコキシカルボニル基で置換
されていてもよいC1 〜C5 のアルキル基を表す);ま
たはA、Bが一緒になって環を形成し、(3) 【化2】 〔式中、X1 〜X4 はそれぞれ独立して(a)水素原
子、(b)ハロゲン原子、(c)ニトロ基、(d)−O
R′(式中、R′は(i)酸素原子を1個含んでいても
よいC3 〜C8 のシクロアルキル基、または(ii)C1
〜C5 のアルコキシ基、アミノ基もしくはモルホリノ基
で置換されていてもよいC1 〜C5 のアルキル基を表
す)、(e)C1 〜C5 のアルキル基で置換されていて
もよいアミノ基を表すか、または(f)隣接する置換基
が一緒になって環を形成し、C1 〜C5のオキシアルキ
レン基を表す);(4) 【化3】 (式中、X5 〜X7 はそれぞれ独立して水素原子、ハロ
ゲン原子、C1 〜C5 アルコキシ基またはC1 〜C5 の
アルキル基で置換されていてもよいアミノ基を表す);
(5) 【化4】 (式中、X8 〜X10はそれぞれ独立して水素原子、ハロ
ゲン原子、C1 〜C5 のアルコキシ基、またはC1 〜C
5 のアルキル基で置換されていてもよいアミノ基を表
す);(6) 【化5】 (式中、X11およびX12は水素原子;もしくはC1 〜C
5 のアルキル基を表す);(7) 【化6】 〔式中、Wは窒素原子またはC−X15(式中、X15は水
素原子またはC1 〜C5のアルキル基を表す)を表し、
X13およびX14は水素原子またはC1 〜C5 のアルキル
基を表す〕;(8) 【化7】 (式中、X16およびX17は水素原子またはC1 〜C5 の
アルキル基を表す)を表し、 R1 は(1)水素原子;(2)ハロゲン原子;(3)ハ
ロゲン原子で置換されていてもよいフェニル基;(4)
フェニル基で置換されていてもよいC1 〜C5のアルキ
ル基;(5)カルボキシル基もしくはC1 〜C5 のアル
コキシカルボニル基で置換されていてもよいC1 〜C5
のアルコキシ基;(6)ヒドロキシル基;または(7)
C1 〜C5 のアルキル基もしくはC1 〜C5 のアルカノ
イル基で置換されていてもよいアミノ基を表し、 R2 は(1) 【化8】 <式中、R3 、R4 はそれぞれ独立して、(a)水素原
子;(b)ハロゲン原子、ピリジル基、ピリダジニル
基、もしくはC3 〜C8 のシクロアルキル基で置換され
ていてもよいC1 〜C5 のアルキル基;(c)−COR
6 (式中、R6 は(i)ヒドロキシル基;(ii)C1 〜
C5 のアルコキシ基;(iii)C1 〜C5 のアルキル基で
置換されていてもよいアミノ基;または(iv)ハロゲン
原子もしくはC1 〜C5 のアルコキシ基で置換されてい
てもよいフェニル基を表す);(d) 【化9】 (式中、jは0、1、2または3を表し、Z1 、Z2 、
Z3 はそれぞれ独立して、(i)水素原子;(ii)ハロ
ゲン原子;(iii)ヒドロキシル基;(iv)C1 〜C5 の
アルコキシ基;または(v)C1 〜C5 のアルコキシカ
ルボニル基を表す);または、R3 、R4 が互いに環を
形成し、(e)(i)C1 〜C5 のアルキル基、または
(ii)−(CH2 )n ″R20(式中、n″は0、1また
は2を表し、R20はカルボキシル基を表すか、またはカ
ルボキシル基もしくはC1 〜C5 のアルコキシカルボニ
ル基で置換されていてもよいC3 〜C8 のシクロアルキ
ル基を表す)で置換されていてもよいアミノ基;(f) 【化10】 (式中、R21はカルボキシル基またはC1 〜C5 のアル
コキシカルボニル基を表す);(g) 【化11】 (式中、kは1、2、3または4を表し、R7 は(i)
ヒドロキシル基;(ii)ヒドロキシル基もしくはC1 〜
C5 アルキル基で置換されていてもよいアミノ基;また
は(iii)C1 〜C5 のアルコキシ基を表す);(h) 【化12】 (i) 【化13】 (j) 【化14】 ;または(k) 【化15】 を表す。R5 は(a)ヒドロキシル基;(b)C1 〜C
5 のアルキル基;(c)C1 〜C5 のアルコキシカルボ
ニル基;(d)C1 〜C5 のアルカノイルオキシ基;
(e)カルボキシル基;(f) 【化16】 〔式中、mは0または1を表し、nは0、1、2または
3を表し、Eは(i)酸素原子;(ii)−NHSO
2 −;(iii)−NHCO−;または(iv)−NR7 −
(式中、R7 は1)水素原子;2)C1 〜C5 のアルキ
ル基;もしくは3)ヒドロキシル基、カルボキシル基、
もしくはC1 〜C5 のアルコキシカルボニル基で置換さ
れていてもよいC1 〜C5 のアルキル基を表す)を表
し、Y1 、Y2 、Y3 はそれぞれ独立して、(i)水素
原子;(ii)ハロゲン原子;(iii)ヒドロキシル基;
(iv)C1 〜C5 のアルキル基;または(v)C1 〜C
5 のアルコキシ基を表す〕;(g)−O−(CO)p −
G−COR8 〔式中、pは0または1を表し、Gは
(i)ヒドロキシル基もしくはアセトキシ基で置換され
ていてもよいC1 〜C5 のアルキレン基;または(ii) 【化17】 を表し、R8 は(i)ヒドロキシル基;(ii)C1 〜C
5 のアルコキシ基;または(iii)C1 〜C5 のアルキル
基で置換されていてもよいアミノ基を表す〕;(h)−
NR9 R10{式中、R9 、R10はそれぞれ独立して、
(i)水素原子;(ii)C1 〜C5 のアルキル基;(ii
i)C1 〜C5 のアルコキシカルボニル基で置換されてい
てもよいC3 〜C8 のシクロアルキル基;または(iv)
−(CO)q−L−(CO)r R11〔式中、qおよびr
は0または1を表し、Lは1)ヒドロキシル基もしくは
アセトキシ基で置換されていてもよく、酸素原子を介し
ていてもよいC1 〜C5 のアルキレン基;または2)C
3 〜C8 のシクロアルキレン基を表し、R11は1)ヒド
ロキシル基;2)C1 〜C20のアルコキシ基;3)ピバ
ロイルオキシメトキシ基;または4)−NR12R13(式
中、R12はa)水素原子;b)ヒドロキシル基;または
c)C1 〜C5 のアルキル基を表し、R13はa)水素原
子;b)フェニル基、カルボキシル基もしくはヒドロキ
シル基で置換されていてもよいC1 〜C5 のアルキル
基;c)C1 〜C7 のアルコキシカルボニル基;d)シ
アノ基;e)フェニル基もしくはC1 〜C5 のアルキル
基で置換されていてもよいカルバモイル基;f)フェニ
ル基もしくはC1 〜C5 のアルキル基で置換されていて
もよいスルホニル基;またはg)C1 〜C5 のアルカノ
イル基を表す)〕を表すか、またはR9 、R10が一緒に
なって環を形成し、(v) 【化18】 〔式中、tおよびuは0、1または2を表し、R14は
1)ヒドロキシル基;2)C1 〜C20のアルコキシ基;
3)ピバロイルオキシメトキシ基;4)−NR15R
16(式中、R15はa)水素原子;b)ヒドロキシル基;
またはc)C1 〜C5 のアルキル基を表し、R16はa)
水素原子;b)フェニル基、カルボキシル基および/ま
たはヒドロキシル基で置換されていてもよいC1 〜C5
のアルキル基;またはc)シアノ基を表す)〕;(vi) 【化19】 〔式中、sは0、1、または2を表し、R17は1)ヒド
ロキシル基;2)C1 〜C20のアルコキシ基;3)ピバ
ロイルオキシメトキシ基;または4)ヒドロキシル基も
しくはC1 〜C5 のアルキル基で置換されていてもよい
アミノ基を表す〕を表す}を表す>を表すか、または、
(2) 【化20】 (式中、CyAはベンゼン環、ピリジン環、またはピロ
ール環を表し、Qはハロゲン原子で置換されていてもよ
いフェニル基を表し、Vは(1)水素原子、(2)C1
〜C5 のアルコキシカルボニル基、(3)カルボキシル
基、または(4)C1 〜C5 のアルコキシカルボニル基
もしくはカルボキシル基で置換されていてもよいC1 〜
C5 のアルキル基を表す)を表す〕で表されるエチニル
ピリミジン誘導体並びにそれらの水和物、薬理学的に許
容される塩、光学活性形、ラセミ体およびジアステレオ
マー混合物。1. A compound represented by the following general formula (I) [However, in the above general formula (I), A and B are each independently a (1) nitro group; (2)-(CH 2 ) n ′ NR 3 R 4
(In the formula, n ′ represents 0 or 1, and R 3 and R 4 each independently represent (a) a hydrogen atom; or (b) a carboxyl group or a C 1 -C 5 alkoxycarbonyl group. also represents an alkyl group optionally C 1 -C 5); or a, B together form a ring, (3) ## STR2 ## [Wherein, X 1 to X 4 each independently represent (a) a hydrogen atom, (b) a halogen atom, (c) a nitro group, (d) —O
R '(wherein, R' is (cycloalkyl group i) an oxygen atom optionally one comprise C 3 -C 8 or (ii) C 1,
Alkoxy group -C 5, amino optionally substituted by a group or a morpholino group represents an alkyl group which may C 1 ~C 5), (e ) C 1 ~C 5 alkyl amino which may be substituted with a group Or (f) adjacent substituents together form a ring and represent a C 1 -C 5 oxyalkylene group); (Wherein, X 5 to X 7 each independently represent a hydrogen atom, a halogen atom, a C 1 -C 5 alkoxy group or an amino group optionally substituted with a C 1 -C 5 alkyl group);
(5) (Wherein X 8 to X 10 are each independently a hydrogen atom, a halogen atom, a C 1 -C 5 alkoxy group, or a C 1 -C 5
5 represents an amino group which may be substituted by an alkyl group); (6) (Wherein X 11 and X 12 are hydrogen atoms; or C 1 -C
5 represents an alkyl group); (7) [Wherein, W represents a nitrogen atom or C—X 15 (in the formula, X 15 represents a hydrogen atom or a C 1 -C 5 alkyl group);
X 13 and X 14 represent a hydrogen atom or a C 1 -C 5 alkyl group]; (8) (Wherein X 16 and X 17 represent a hydrogen atom or a C 1 -C 5 alkyl group), and R 1 is (1) a hydrogen atom; (2) a halogen atom; An optionally substituted phenyl group; (4)
Alkyl group optionally C 1 -C 5 substituted phenyl group; (5) a carboxyl group or a C 1 -C 5 alkoxycarbonyl C 1 -C optionally substituted with a group 5
(6) hydroxyl group; or (7)
C 1 -C alkyl group or a C 1 -C 5 alkanoyl group which may be substituted an amino group of 5, R 2 is (1) embedded image Wherein R 3 and R 4 are each independently substituted with (a) a hydrogen atom; (b) a halogen atom, a pyridyl group, a pyridazinyl group, or a C 3 to C 8 cycloalkyl group. alkyl C 1 ~C 5; (c) -COR
6 wherein R 6 is (i) a hydroxyl group; (ii) C 1-
An alkoxy group having C 5; (iii) C 1 ~C 5 amino group which may be substituted by an alkyl group; or (iv) a halogen atom or a C 1 -C 5 phenyl which may be substituted with an alkoxy group (D) represents the group: (In the formula, j represents 0, 1 , 2 or 3, and Z 1 , Z 2 ,
Z 3 is each independently: (i) a hydrogen atom; (ii) a halogen atom; (iii) a hydroxyl group; (iv) a C 1 -C 5 alkoxy group; or (v) a C 1 -C 5 alkoxycarbonyl Or (e) (i) a C 1 -C 5 alkyl group, or (ii) — (CH 2 ) n ″ R 20 (wherein R 3 and R 4 form a ring with each other). , N ″ represents 0, 1 or 2, and R 20 represents a carboxyl group, or a C 3 -C 8 cycloalkyl group optionally substituted with a carboxyl group or a C 1 -C 5 alkoxycarbonyl group. An amino group optionally substituted with: (f) (Wherein R 21 represents a carboxyl group or a C 1 -C 5 alkoxycarbonyl group); (g) (Where k represents 1, 2, 3 or 4; R 7 represents (i)
Hydroxyl group; (ii) hydroxyl group or C 1-
(H) an amino group optionally substituted with a C 5 alkyl group; or (iii) a C 1 -C 5 alkoxy group); (I) (J) Or (k) Represents R 5 is (a) a hydroxyl group; (b) C 1 -C
Alkoxycarbonyl group (c) C 1 ~C 5; ; 5 alkyl group (d) alkanoyloxy group C 1 -C 5;
(E) carboxyl group; (f) [Wherein, m represents 0 or 1, n represents 0, 1, 2, or 3, E represents (i) an oxygen atom; (ii) -NHSO
2 -; (iii) -NHCO-; or (iv) -NR 7 -
(Wherein R 7 is 1) a hydrogen atom; 2) a C 1 -C 5 alkyl group; or 3) a hydroxyl group, a carboxyl group,
Or a C 1 -C 5 alkyl group which may be substituted with a C 1 -C 5 alkoxycarbonyl group), wherein Y 1 , Y 2 and Y 3 each independently represent (i) a hydrogen atom (Ii) a halogen atom; (iii) a hydroxyl group;
(Iv) an alkyl group of C 1 -C 5; or (v) C 1 ~C
5 represents an alkoxy group]; (g) —O— (CO) p −
G-COR 8 wherein p represents 0 or 1, and G represents (i) a C 1 -C 5 alkylene group optionally substituted with a hydroxyl group or an acetoxy group; or (ii) Wherein R 8 is (i) a hydroxyl group; (ii) C 1 -C
5 alkoxy group; or (iii) represents a C 1 -C 5 alkyl amino group which may be substituted with a group of]; (h) -
NR 9 R 10 } wherein R 9 and R 10 are each independently
Alkyl group (ii) C 1 ~C 5; ; (i) a hydrogen atom (ii
i) a cycloalkyl group of C 1 -C 5 alkoxy optionally substituted by a carbonyl group C 3 -C 8; or (iv)
-(CO) q -L- (CO) r R 11 [wherein q and r
Represents 0 or 1, L represents 1) a C 1 -C 5 alkylene group which may be substituted by a hydroxyl group or an acetoxy group and may be via an oxygen atom;
Represents a cycloalkylene group 3 ~C 8, R 11 is 1) hydroxyl groups; 2) alkoxy C 1 -C 20; 3) pivaloyloxymethoxy group; or 4) -NR 12 R 13 (wherein , R 12 is a) a hydrogen atom; an alkyl group or c) C 1 ~C 5, R 13 is a) a hydrogen atom;; b) hydroxyl groups b) a phenyl group, substituted with a carboxyl group or hydroxyl group alkyl group which may C 1 -C 5 and; c) an alkoxycarbonyl group having C 1 ~C 7; d) cyano group; e) phenyl or C 1 -C 5 alkyl carbamoyl optionally substituted by group F) a phenyl group or a sulfonyl group optionally substituted with a C 1 -C 5 alkyl group; or g) a C 1 -C 5 alkanoyl group)] or R 9 , R 10 Together form a ring, (v [Of 18] [Wherein, t and u represent 0, 1 or 2, and R 14 represents 1) a hydroxyl group; 2) a C 1 -C 20 alkoxy group;
3) pivaloyloxymethoxy group; 4) —NR 15 R
16 wherein R 15 is a) a hydrogen atom; b) a hydroxyl group;
Or c) represents a C 1 -C 5 alkyl group, wherein R 16 is a)
Hydrogen atoms; b) phenyl group, a carboxyl group and / or hydroxyl groups C 1 may be substituted with -C 5
(Vi) a cyano group)]; (vi) Wherein s represents 0, 1, or 2, and R 17 represents 1) a hydroxyl group; 2) a C 1 -C 20 alkoxy group; 3) a pivaloyloxymethoxy group; 1 -C be substituted by 5 alkyl groups representing also represents an amino group] represents a} or represents>, or,
(2) (In the formula, CyA represents a benzene ring, a pyridine ring, or a pyrrole ring, Q represents a phenyl group optionally substituted with a halogen atom, V is (1) a hydrogen atom, (2) C 1
Alkoxycarbonyl group -C 5, (3) a carboxyl group, or (4) C 1 ~C 5 alkoxycarbonyl groups or optionally C 1 ~ optionally substituted by carboxyl group
Ethynyl pyrimidine derivatives and their hydrates represented by representing the representative) an alkyl group having C 5], pharmacologically acceptable salts, optically active forms, racemates and diastereomeric mixtures.
環を形成していることを特徴とする請求項1記載のエチ
ニルピリミジン誘導体、並びに、それらの水和物、薬理
学的に許容される塩、光学活性体、ラセミ体、及びジア
ステレオマー混合物。2. The ethynylpyrimidine derivative according to claim 1, wherein A and B together form a ring in the general formula [I], and hydrates and pharmacology thereof. Salts, optically active isomers, racemates, and diastereomeric mixtures.
薬理学的に許容される担体を含んでなる医薬組成物。3. A pharmaceutical composition comprising the compound according to claim 1 and a pharmacologically acceptable carrier.
る疾患に対する予防及び/又は治療剤として使用される
請求項3記載の医薬組成物。4. The pharmaceutical composition according to claim 3, which is used as a prophylactic and / or therapeutic agent for a disease caused by enhanced tyrosine kinase activity.
剤、動脈硬化治療薬、抗炎症剤または癌細胞増殖抑制薬
として使用される請求項3記載の医薬組成物。5. The pharmaceutical composition according to claim 3, which is used as an anticancer agent, an immunosuppressant, a platelet aggregation inhibitor, a therapeutic agent for arteriosclerosis, an anti-inflammatory agent, or a cancer cell growth inhibitor.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP9251348A JPH1180131A (en) | 1997-09-01 | 1997-09-01 | Ethynylpyrimidine derivative |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP9251348A JPH1180131A (en) | 1997-09-01 | 1997-09-01 | Ethynylpyrimidine derivative |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH1180131A true JPH1180131A (en) | 1999-03-26 |
Family
ID=17221499
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP9251348A Pending JPH1180131A (en) | 1997-09-01 | 1997-09-01 | Ethynylpyrimidine derivative |
Country Status (1)
Country | Link |
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JP (1) | JPH1180131A (en) |
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US9422282B2 (en) | 2010-04-01 | 2016-08-23 | Critical Outcome Technologies Inc. | Compounds and method for treatment of HIV |
US9624220B2 (en) | 2010-04-01 | 2017-04-18 | Critical Outcome Technologies Inc. | Compounds and method for treatment of HIV |
US20120142733A1 (en) * | 2010-12-01 | 2012-06-07 | Lanter James C | 4-substituted-cyclohexylamino-4-piperidinyl-acetamide antagonists of ccr2 |
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