JPH01250369A - Production of condensed oxazine - Google Patents
Production of condensed oxazineInfo
- Publication number
- JPH01250369A JPH01250369A JP63330030A JP33003088A JPH01250369A JP H01250369 A JPH01250369 A JP H01250369A JP 63330030 A JP63330030 A JP 63330030A JP 33003088 A JP33003088 A JP 33003088A JP H01250369 A JPH01250369 A JP H01250369A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- reaction
- formula
- solvent
- added
- 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.)
- Granted
Links
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 6
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 121
- -1 propoxybenzene compound Chemical class 0.000 claims abstract description 37
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 11
- 125000005843 halogen group Chemical group 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims description 27
- 239000000126 substance Substances 0.000 claims description 11
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims 4
- 238000006243 chemical reaction Methods 0.000 abstract description 53
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 abstract description 9
- 239000002994 raw material Substances 0.000 abstract description 5
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 abstract description 4
- 229960001699 ofloxacin Drugs 0.000 abstract description 4
- 239000000543 intermediate Substances 0.000 abstract description 3
- 239000003242 anti bacterial agent Substances 0.000 abstract description 2
- 229910052736 halogen Inorganic materials 0.000 abstract 2
- 150000002367 halogens Chemical class 0.000 abstract 2
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 230000002140 halogenating effect Effects 0.000 abstract 1
- 230000026030 halogenation Effects 0.000 abstract 1
- 238000005658 halogenation reaction Methods 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 68
- 239000002904 solvent Substances 0.000 description 50
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 38
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 34
- 239000000203 mixture Substances 0.000 description 34
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 28
- 238000005160 1H NMR spectroscopy Methods 0.000 description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 24
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 238000010898 silica gel chromatography Methods 0.000 description 21
- 238000003756 stirring Methods 0.000 description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 20
- 238000001816 cooling Methods 0.000 description 20
- 239000012044 organic layer Substances 0.000 description 20
- 238000002844 melting Methods 0.000 description 19
- 230000008018 melting Effects 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 12
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
- 235000017557 sodium bicarbonate Nutrition 0.000 description 10
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 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 9
- 229910052751 metal Inorganic materials 0.000 description 9
- 239000002184 metal Substances 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- 235000011181 potassium carbonates Nutrition 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- 238000010531 catalytic reduction reaction Methods 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 238000007363 ring formation reaction Methods 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 150000007530 organic bases Chemical class 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 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 6
- 101150041968 CDC13 gene Proteins 0.000 description 5
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 238000009835 boiling Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 150000007529 inorganic bases Chemical class 0.000 description 5
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 5
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical class C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 4
- DCTOHCCUXLBQMS-UHFFFAOYSA-N 1-undecene Chemical compound CCCCCCCCCC=C DCTOHCCUXLBQMS-UHFFFAOYSA-N 0.000 description 4
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 150000003973 alkyl amines Chemical group 0.000 description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- 239000012280 lithium aluminium hydride Substances 0.000 description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
- 239000002798 polar solvent Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 4
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 4
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical class CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 150000004703 alkoxides Chemical class 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- NDKBVBUGCNGSJJ-UHFFFAOYSA-M benzyltrimethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)CC1=CC=CC=C1 NDKBVBUGCNGSJJ-UHFFFAOYSA-M 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 239000004310 lactic acid Substances 0.000 description 3
- 235000014655 lactic acid Nutrition 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 229910052987 metal hydride Inorganic materials 0.000 description 3
- 150000004681 metal hydrides Chemical class 0.000 description 3
- 239000000178 monomer Substances 0.000 description 3
- LITQLZTWAYBHOB-UHFFFAOYSA-N n,n-diethylaniline;pyridine Chemical compound C1=CC=NC=C1.CCN(CC)C1=CC=CC=C1 LITQLZTWAYBHOB-UHFFFAOYSA-N 0.000 description 3
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 3
- 239000011736 potassium bicarbonate Substances 0.000 description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 3
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 150000008383 propoxybenzenes Chemical class 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 3
- WBQTXTBONIWRGK-UHFFFAOYSA-N sodium;propan-2-olate Chemical compound [Na+].CC(C)[O-] WBQTXTBONIWRGK-UHFFFAOYSA-N 0.000 description 3
- 238000005694 sulfonylation reaction Methods 0.000 description 3
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 2
- SSUJUUNLZQVZMO-UHFFFAOYSA-N 1,2,3,4,8,9,10,10a-octahydropyrimido[1,2-a]azepine Chemical compound C1CCC=CN2CCCNC21 SSUJUUNLZQVZMO-UHFFFAOYSA-N 0.000 description 2
- ARCACZWMYGILNI-UHFFFAOYSA-N 1,2,3-trifluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C(F)=C1F ARCACZWMYGILNI-UHFFFAOYSA-N 0.000 description 2
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000004020 conductor Substances 0.000 description 2
- 150000003983 crown ethers Chemical class 0.000 description 2
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 2
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 2
- LZCLXQDLBQLTDK-UHFFFAOYSA-N ethyl 2-hydroxypropanoate Chemical compound CCOC(=O)C(C)O LZCLXQDLBQLTDK-UHFFFAOYSA-N 0.000 description 2
- 229940116333 ethyl lactate Drugs 0.000 description 2
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 description 2
- 229910000000 metal hydroxide Inorganic materials 0.000 description 2
- 150000004692 metal hydroxides Chemical class 0.000 description 2
- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- DSNYFFJTZPIKFZ-UHFFFAOYSA-N propoxybenzene Chemical compound CCCOC1=CC=CC=C1 DSNYFFJTZPIKFZ-UHFFFAOYSA-N 0.000 description 2
- 230000006340 racemization Effects 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 1
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 1
- KEGOHDCHURMFKX-UHFFFAOYSA-N 2,3-difluoro-6-nitrophenol Chemical compound OC1=C(F)C(F)=CC=C1[N+]([O-])=O KEGOHDCHURMFKX-UHFFFAOYSA-N 0.000 description 1
- MZRIVLOAWMCWBS-PKEIRNPWSA-N 2-[(2r)-1-(2,3-difluoro-6-nitrophenoxy)propan-2-yl]oxyoxane Chemical compound C([C@@H](C)OC1OCCCC1)OC1=C(F)C(F)=CC=C1[N+]([O-])=O MZRIVLOAWMCWBS-PKEIRNPWSA-N 0.000 description 1
- CFLBIADORGSMCX-UHFFFAOYSA-N 2h-1,4-benzoxazine-6-carboxylic acid Chemical compound O1CC=NC2=CC(C(=O)O)=CC=C21 CFLBIADORGSMCX-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- 229930182843 D-Lactic acid Natural products 0.000 description 1
- JVTAAEKCZFNVCJ-UWTATZPHSA-N D-lactic acid Chemical compound C[C@@H](O)C(O)=O JVTAAEKCZFNVCJ-UWTATZPHSA-N 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- ZDQWESQEGGJUCH-UHFFFAOYSA-N Diisopropyl adipate Chemical compound CC(C)OC(=O)CCCCC(=O)OC(C)C ZDQWESQEGGJUCH-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 239000004146 Propane-1,2-diol Substances 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 150000005130 benzoxazines Chemical group 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- ZFTFAPZRGNKQPU-UHFFFAOYSA-N dicarbonic acid Chemical compound OC(=O)OC(O)=O ZFTFAPZRGNKQPU-UHFFFAOYSA-N 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- RHFZTBSULNJWEI-UHFFFAOYSA-N dimethyl 2-(methoxymethylidene)propanedioate Chemical compound COC=C(C(=O)OC)C(=O)OC RHFZTBSULNJWEI-UHFFFAOYSA-N 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- LZCLXQDLBQLTDK-BYPYZUCNSA-N ethyl (2S)-lactate Chemical compound CCOC(=O)[C@H](C)O LZCLXQDLBQLTDK-BYPYZUCNSA-N 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-M hydrosulfide Chemical compound [SH-] RWSOTUBLDIXVET-UHFFFAOYSA-M 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000005905 mesyloxy group Chemical group 0.000 description 1
- 229910001510 metal chloride Inorganic materials 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- LPEKGGXMPWTOCB-GSVOUGTGSA-N methyl (R)-lactate Chemical compound COC(=O)[C@@H](C)O LPEKGGXMPWTOCB-GSVOUGTGSA-N 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- 229940057867 methyl lactate Drugs 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[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
- 229960004063 propylene glycol Drugs 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical class ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical group CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000007070 tosylation reaction Methods 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
Description
【発明の詳細な説明】
〈産業上の技術分野〉
本発明は、抗菌性化合物の製造中間体に関するものであ
る。DETAILED DESCRIPTION OF THE INVENTION <Industrial Technical Field> The present invention relates to an intermediate for producing an antibacterial compound.
〈従来技術〉
オフロキサシン（（±）−９−フルオロ−３−メチルー
１Ｏ−（４−メチル−１−ピペラジニル）−７−オキソ
−２，３−ジヒドロ−７８−ピリド（１，２，３−ｄｅ
ｌ ［１，４］ベンゾオキサジン−６−カルボン酸：特
開昭５７−４６９８６号公報参照）およびその３− （
Ｓ）−異性体（ＥＰ−Ａ−０，２０６，２８３および特
開昭６２−２５２７９０号公報参照）は優れた合成抗菌
剤として知られている。<Prior art> Ofloxacin ((±)-9-fluoro-3-methyl-1O-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-78-pyrido (1,2,3-de
l [1,4]benzoxazine-6-carboxylic acid: see JP-A-57-46986) and its 3- (
The S)-isomer (see EP-A-0,206,283 and JP-A-62-252790) is known as an excellent synthetic antibacterial agent.
本発明者は、オフロキサシンとその光学活性体の製造に
有用な中間体の新しい製造法を見出し本発明を完成した
。The present inventors discovered a new method for producing intermediates useful for producing ofloxacin and its optically active form, and completed the present invention.
１−威
本発明は、式
（式中、Ｒ１は水素原子又は−ＣＯ−Ｃ（Ｃｏｏ−低級
７３＋ル）２を、Ｒ２は水酸基、ハロゲン原子又は置換
スルホニルオキシ基を、Ｘａ、 Ｘｂは各々独立してハ
ロゲン原子を意味する。）で表わされるプロポキシベン
ゼン化合物を閉環することを特徴とする式（式中、Ｒ′
、Ｘａ、 Ｘｂは前記の定義に等しい）の化合物の製法
に関する。1-I The present invention relates to the formula (wherein R1 is a hydrogen atom or -CO-C(Coo-lower 73+)2, R2 is a hydroxyl group, a halogen atom or a substituted sulfonyloxy group, and Xa and Xb are each independently is a halogen atom.) (wherein R' means a halogen atom)
, Xa, Xb are as defined above).
置換スルホニルオキシ基として一般的なものはパラトル
エンスルホニルオキシ基（以下、トシルオキシ基または
ＴｓＯと略する）、メタンスルホニルオキシ基、トリフ
ルオロメタンスルホニルオキシ基等である。Common substituted sulfonyloxy groups include para-toluenesulfonyloxy group (hereinafter abbreviated as tosyloxy group or TsO), methanesulfonyloxy group, trifluoromethanesulfonyloxy group, and the like.
本発明の方法によって得られるベンゾオキサジン化合物
は、前記公報記載の方法でオフロキサシン又はその光学
活性体に導くことができる。The benzoxazine compound obtained by the method of the present invention can be converted into ofloxacin or its optically active form by the method described in the above publication.
次に、本発明の製造法について３ ｆｌ類に分けて説明
する。なお原料合成を含めた反応式の例を最終頁に示す
。Next, the manufacturing method of the present invention will be explained separately for 3 types. An example of a reaction formula including raw material synthesis is shown on the last page.
先ず、置換スルホニルオキシ基を有するプロポキシベン
ゼン化合物（刈または店）は、塩基性条件下に処理して
閉環することができる。この塩基としては無機塩基、有
機塩基の何れでもよく、無機塩基としては水酸化リチウ
ム、水酸化ナトリウム、水酸化カリウム等の金属水酸化
物、炭酸リチウム、炭酸ナトリウム、炭酸カリウム等の
金属炭酸塩類、炭酸水素ナトリウム、炭酸水素カリウム
等の金属炭酸水素塩類を挙げることができる。First, a propoxybenzene compound (Kari or Ten) having a substituted sulfonyloxy group can be treated under basic conditions to undergo ring closure. The base may be either an inorganic base or an organic base, and examples of the inorganic base include metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate; Examples include metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate.
有機塩基としてはトリエチルアミン、トリブチルアミン
、Ｎ、Ｎ−ジイソプロピルエチルアミン等の三級アルキ
ルアミン類、Ｎ、Ｎ−ジメチルアニリン、Ｎ、Ｎ−ジエ
チルアニリン等のジアルキルアニリン類、ピリジン、Ｎ
、ｌ／−ジメチルアミノピリジン、Ｎ−メチルモルホリ
ン等の複素環アミン類、ナトリウムメトキサイド、ナト
リウムエトキサイド、ナトリウムイソプロポキサイド、
カリウム第三級ブトキサイド等の金属アルコキサイド等
、この他１．８−ジアザビシクロ［５，４，０］ ウン
デセン、Ｎ−ベンジルトリメチルアンモニウムハイドロ
キサイド等を例示することができる。Examples of organic bases include tertiary alkylamines such as triethylamine, tributylamine, and N,N-diisopropylethylamine; dialkylanilines such as N,N-dimethylaniline and N,N-diethylaniline; pyridine;
, 1/-dimethylaminopyridine, heterocyclic amines such as N-methylmorpholine, sodium methoxide, sodium ethoxide, sodium isopropoxide,
Other examples include metal alkoxides such as potassium tertiary butoxide, 1,8-diazabicyclo[5,4,0] undecene, N-benzyltrimethylammonium hydroxide, and the like.
反応溶媒としてはメタノール、エタノール、プロパツー
ル類、ブタノール類等の低級アルコール類、ジエチルエ
ーテル、テトラハイドロフラン、ジオキサン、ｌ、２−
ジメトキシエタン、２−メトキシエチルエーテル、エチ
レングリコール・ジエチルエーテル等のエーテル類、
Ｎ、Ｎ−ジメチルホルムアミド、 Ｎ、Ｎ−ジメチルア
セトアミド、Ｎ−メチル−２−ピロリドン等のアミド類
、ジメチルスルホキサイド、スルホラン等の非プロトン
性極性溶媒等を挙げることができる。Reaction solvents include methanol, ethanol, propatools, lower alcohols such as butanols, diethyl ether, tetrahydrofuran, dioxane, l, 2-
Ethers such as dimethoxyethane, 2-methoxyethyl ether, ethylene glycol diethyl ether,
Examples include amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and N-methyl-2-pyrrolidone, and aprotic polar solvents such as dimethylsulfoxide and sulfolane.
反応温度は室温から１５０℃の範囲で実施すればよい。The reaction temperature may be in the range of room temperature to 150°C.
また、この閉環反応では反応促進剤としてヨウ化カリウ
ム、ヨウ化ナトリウム、クラウンエーテル等をプロポキ
シベンゼン化合物に対して１７２０当量またはそれ以上
を加えるのが有効なことがある。Further, in this ring-closing reaction, it may be effective to add potassium iodide, sodium iodide, crown ether, etc. as a reaction accelerator in an amount of 1720 equivalents or more based on the propoxybenzene compound.
置換スルホニルオキシ化合物の置換スルホニルオキシ基
としては、トシルオキシ基を用いるのが一般的であるが
、この他の例えばメタンスルホニルオキシ基（メシルオ
キシ基）を用いると反応時間が短縮される等、操作性が
改善される場合もあり、トシルオキシ基でなくともよい
。As the substituted sulfonyloxy group in substituted sulfonyloxy compounds, tosyloxy group is generally used, but other methods such as methanesulfonyloxy group (mesyloxy group) can shorten the reaction time and improve operability. In some cases, it may be improved, and it does not need to be a tosyloxy group.
化合物Ｘの様に水酸基を有するプロポキシベンゼン化合
物の場合は、塩化チオニル、三塩化リン、三臭化リン等
のハロゲン化剤によって水酸基をハロゲン化した後、先
に述べたのと同様の塩基性条件下に閉環させればよいが
、また、１乃至１．５当量程度のミツノブ試薬（０，Ｍ
ｉｔｓｕｎｏｂｕ、 鉦躬加１旦。In the case of a propoxybenzene compound having a hydroxyl group like Compound The ring may be closed downward, but it is also possible to use approximately 1 to 1.5 equivalents of Mitsunobu reagent (0, M
Itsunobu, 1st day.
１−２８ （１９８１） ’）を用いて閉環させること
もできる。1-28 (1981)') can also be used for ring closure.
ミツノブ試薬はアゾジカルボン酸ジエステル、例えばジ
エチルエステル、ジメチルエステル、ジプロピルエステ
ル、ジイソプロピルエステル、ジベンジルニスエル等と
トリフェニルホスフィンまたはトリアルキルホスフィン
とから調製できる。The Mitsunobu reagent can be prepared from an azodicarboxylic acid diester, such as diethyl ester, dimethyl ester, dipropyl ester, diisopropyl ester, dibenzylnisyl ester, etc., and triphenylphosphine or trialkylphosphine.
ミツノブ試薬は水によって容易に分解される性質がある
ため、使用する直前に無水条件下に調製するのが好まし
い。Since the Mitsunobu reagent has the property of being easily decomposed by water, it is preferably prepared under anhydrous conditions immediately before use.
ミツノブ試薬存在下での閉環反応の溶媒としては、通常
、ジエチルエーテル、テトラハイドロフラン、１．２−
ジメトキシエタン等のエーテル系溶媒を使用する。この
反応温度は水冷下乃至５０℃の範囲でよい。The solvent for the ring-closing reaction in the presence of Mitsunobu reagent is usually diethyl ether, tetrahydrofuran, 1.2-
Use an ether solvent such as dimethoxyethane. The reaction temperature may range from water cooling to 50°C.
プロポキシベンゼン話導体のベンゾオキサジン化合物へ
の閉環反応ではプロポキシ部分の不斉炭素原子での立体
配置が反転する。すなわち、（Ｒ）−体のプロポキシベ
ンゼン説導体からは （Ｓ）一体のベンゾオキサジン化
合物が生成し、（Ｓ）一体のプロポキシベンゼン誘導体
からは （Ｒ）一体のベンゾオキサジン化合物が生成す
る。In the ring-closing reaction of a propoxybenzene conductor to a benzoxazine compound, the configuration at the asymmetric carbon atom of the propoxy moiety is reversed. That is, from the propoxybenzene derivative in the (R)-isomer, an (S)-integrated benzoxazine compound is produced, and from the (S)-integrated propoxybenzene derivative, an (R)-integrated benzoxazine compound is produced.
次に閉環反応の原料となるプロポキシベンゼン話導体の
製法の例について説明する。Next, an example of a method for producing a propoxybenzene conductor, which is a raw material for the ring-closing reaction, will be explained.
先ず、式！
（式中、ＸａおよびＸｂは各々独立にハロゲン原子を、
Ｒｃは水酸基の保護基を意味する）で表わされる３、４
−ジハロゲノ−６−二トロブロボキシベンゼンの合成で
あるが、式１１
％式％
（式中、Ｘａ、 ＸｂおよびＸｃは各々独立にハロゲン
原子を意味する）で表わされる２、３．４−トリハロゲ
ノニトロベンゼンに式■
ＨＯＣ８２ＣＨ（にＨ３）ＯＲＣｍ
（式中、Ｒｅは水酸基の保護基を意味する）で表わされ
る １．２−プロパンジオール誘導体を反応させて実施
するか、あるいは式■
（Ｊｌ−１
（式中、Ｘａ、およびＸｂは前記の定義に同じ）で表わ
される２、３−ジハロゲノ−６−二トロフエノールに前
記の式Ｉ■で表わされる化合物または式ＶＸｄＣＨｘＣ
Ｈ（ＣＨｓ）ＯＲｃ Ｖ（式中、ＲＣは前記の定義
に等しく、Ｘｄはハロゲン原子又は置換スルホニルオキ
シ基を意味する）で表わされる化合物を反応させて実施
される。First, the ceremony! (In the formula, Xa and Xb each independently represent a halogen atom,
Rc means a hydroxyl protecting group) 3,4
-Dihalogeno-6-nitrobroboxybenzene is synthesized using 2,3,4-tritribenzene represented by the formula 11% (wherein, Xa, Xb and Xc each independently represent a halogen atom). This is carried out by reacting halogenonitrobenzene with a 1,2-propanediol derivative represented by the formula ■ HOC82CH(H3)ORCm (wherein Re means a hydroxyl group protecting group), or by reacting the formula ■ (Jl-1 2,3-dihalogeno-6-nitrophenol (wherein Xa and
The reaction is carried out by reacting a compound represented by H(CHs)ORc V (wherein RC is as defined above and Xd means a halogen atom or a substituted sulfonyloxy group).
これらの化合物！！又は■は、欧州特許、審査済登録特
許、 ＥＰ−８−０，０４７，００５あるいは米国特許
第４．３８２，３９８に記載の方法で合成できる。These compounds! ! or ■ can be synthesized by the method described in European Patent, Examined and Registered Patent, EP-8-0,047,005, or US Pat. No. 4,382,398.
化合物ＩＩと化合物ＩＩＩの反応は通常は塩基存在下に
実施する。この塩基は無機塩基、有機塩基のいずれでも
よいが、無機塩基としては水素化ナトリウム、水素化カ
ルシウム等の金属水素化物、水酸化リチウム、水酸化ナ
トリウム、水酸化カリウム等の金属水酸化物、炭酸リチ
ウム、炭酸ナトリウム、炭酸カリウム等の金属炭酸塩類
、炭酸水素ナトリウム、炭酸水素カリウム等の金属炭酸
水素塩類を挙げることができる。The reaction between compound II and compound III is usually carried out in the presence of a base. This base may be either an inorganic base or an organic base, but examples of inorganic bases include metal hydrides such as sodium hydride and calcium hydride, metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide, and carbonic acid. Examples include metal carbonates such as lithium, sodium carbonate, and potassium carbonate, and metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate.
有機塩基としてはトリエチルアミン、トリブチルアミン
、Ｎ、Ｎ−ジイソプロピルエチルアミン等の三級アルキ
ルアミン類、 Ｎ、Ｎ−ジメチルアニリン、Ｎ、Ｎ−ジ
エチルアニリン等のジアルキルアニリン類、ピリジン、
Ｎ、Ｎ−ジメチルアミノピリジン、Ｎ−メチルモルホリ
ン等の複素環アミン類、ナトリウムメトキサイド、ナト
リウムエトキサイド、ナトリウムイソプロポキサイド、
カリウム第三級ブトキサイド等の金属アルコキサイド等
、この他１．８−ジアザビシクロ［５，４，０］ ウン
デセン、Ｎ−ベンジルトリメチルアンモニウムハイドロ
キサイド等を例示することができる。Examples of organic bases include tertiary alkylamines such as triethylamine, tributylamine, and N,N-diisopropylethylamine; dialkylanilines such as N,N-dimethylaniline and N,N-diethylaniline; pyridine;
Heterocyclic amines such as N,N-dimethylaminopyridine and N-methylmorpholine, sodium methoxide, sodium ethoxide, sodium isopropoxide,
Other examples include metal alkoxides such as potassium tertiary butoxide, 1,8-diazabicyclo[5,4,0] undecene, N-benzyltrimethylammonium hydroxide, and the like.
化合物！■と化合物ＩＩＩの反応は、反応に対して不活
性な溶媒の存在下に実施してもよい。この様な溶媒の例
としては、ベンゼン、トルエン、キシレン、ｎ−ヘキサ
ン、サイクロヘキサン、ｎ−ペンタン等の炭化水素類、
メタノール、エタノール、プロパツール類、ブタノール
類等の低級アルコール類、ジエチルエーテル、テトラハ
イドロフラン、ジオキサン、１．２−ジメトキシエタン
等のエーテル類、Ｎ、Ｎ−ジメチルホルムアミド、Ｎ、
Ｎ−ジメチルアセトアミド、Ｎ−メチル−２−ピロリド
ン等のアミド類、ジメチルスルホキサイド、スルホラン
等の非プロトン性極性溶媒等を挙げることができる。Compound! The reaction between (1) and compound III may be carried out in the presence of a solvent inert to the reaction. Examples of such solvents include hydrocarbons such as benzene, toluene, xylene, n-hexane, cyclohexane, and n-pentane;
Lower alcohols such as methanol, ethanol, propatools, butanols, ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,
Amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone; aprotic polar solvents such as dimethyl sulfoxide and sulfolane; and the like.
化合物！■と化合物■！の割合はモル比で１：１からｌ
：３の範囲であれば充分であり、通常は１：１．１程度
でよい。Compound! ■ and compound ■! The molar ratio is from 1:1 to l
:3 is sufficient, and usually about 1:1.1 is sufficient.
化合物！■と化合物ＩＩＩの反応温度は、−７８℃から
１５０℃の範囲でよい、また反応時間は１０分から４日
で完結する。Compound! The reaction temperature between (1) and compound III may be in the range of -78°C to 150°C, and the reaction time is completed within 10 minutes to 4 days.
化合物！■と化合物■の反応において、光学活性な化合
物ＩＩＩを使用すると光学活性な化合物Ｉを合成するこ
とができる。化合物ＩＩと化合物ＩＩＩの反応を塩基性
条件下で実施しても、化合物ＩＩＩにはラセミ化は起こ
らないことが確認されている。すなわち、化合物！！！
はその不斉炭素上の立体配置が変化することなく化合物
ＩＩに置換する。化合物ＩＩの（Ｒ）一体を用いた場合
には化合物■の （Ｒ）一体を、そして （Ｓ）一体を
用いた場合には化合物Ｉの（Ｓ）−体を、各々高い光学
純度で得ることができる。Compound! In the reaction between (1) and compound (2), optically active compound I can be synthesized by using optically active compound III. It has been confirmed that even if the reaction between Compound II and Compound III is carried out under basic conditions, racemization does not occur in Compound III. Namely, compounds! ! !
is substituted into compound II without changing the configuration on the asymmetric carbon. When using the (R) monomer of Compound II, obtain the (R) monomer of Compound II, and when using the (S) monomer, the (S)-isomer of Compound I, each with high optical purity. Can be done.
式■の化合物の第二の合成法として２．３−ジハロゲノ
−６−二トロフエノール＋Ｖを使用する方法がある。す
なわち、化合物■に前記の化合物ＩＩＩもしくはＶを反
応させてもよい。A second method for synthesizing the compound of formula (1) is to use 2,3-dihalogeno-6-nitrophenol +V. That is, compound (1) may be reacted with the above-mentioned compound III or V.
化合物■と化合物ＩＩＩの反応はミツノブ試薬の存在下
で実施することができる。The reaction between compound ① and compound III can be carried out in the presence of Mitsunobu reagent.
、化合物ＩＩＩと化合物■とをミツノブ試薬の存在下に
反応させる際、ジエチルエーテル、テトラハイドロフラ
ン、ジオキサン、１．２−ジメトキシエタン等のエーテ
ル系の溶媒の存在下で実施することもできる。When compound III and compound (1) are reacted in the presence of Mitsunobu's reagent, the reaction can also be carried out in the presence of an ether solvent such as diethyl ether, tetrahydrofuran, dioxane, or 1,2-dimethoxyethane.
また、反応温度は０℃から５０℃の範囲の温度でよい。Further, the reaction temperature may be in the range of 0°C to 50°C.
化合物■を用いる他の合成法として化合物■を反応させ
る方法がある。この反応は塩基存在下に実施すればよく
、この塩基は無機、有機の何れでもよい。無機塩基とし
ては水素化ナトリウム、水素化カルシウム等の金属水素
化物、水酸化リチウム、水酸化ナトリウム、水酸化カリ
ウム等のアルカリ金属水酸化物、炭酸リチウム、炭酸ナ
トリウム、炭酸カリウム等の金属炭酸塩類、炭酸水素ナ
トリウム、炭酸水素カリウム等の金属炭酸水素塩類を挙
げることができる。Another synthetic method using compound (2) is a method in which compound (2) is reacted. This reaction may be carried out in the presence of a base, and this base may be either inorganic or organic. Examples of inorganic bases include metal hydrides such as sodium hydride and calcium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate; Examples include metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate.
有機塩基としてはトリエチルアミン、トリブチルアミン
、Ｎ、Ｎ−ジイソプロピルエチルアミン等の三級アルキ
ルアミン類、 Ｎ、Ｎ−ジメチルアニリン、Ｎ、Ｎ−ジ
エチルアニリン等のジアルキルアニリン類、ピリジン、
Ｎ、Ｎ−ジメチルアミノピリジン、Ｎ−メチルモルホ
リン等の複素環アミン類、ナトリウムメトキサイド、ナ
トリウムエトキサイド、ナトリウムイソプロポキサイド
、カリウム第三級ブトキサイド等の金属アルコキサイド
等、この他１，８−ジアザビシクロ［５，４，０］
ウンデセン、Ｎ−ベンジルトリメチルアンモニウムハイ
ドロキサイド等を例示することができる。Examples of organic bases include tertiary alkylamines such as triethylamine, tributylamine, and N,N-diisopropylethylamine; dialkylanilines such as N,N-dimethylaniline and N,N-diethylaniline; pyridine;
Heterocyclic amines such as N,N-dimethylaminopyridine and N-methylmorpholine, metal alkoxides such as sodium methoxide, sodium ethoxide, sodium isopropoxide, potassium tertiary butoxide, and 1,8-diazabicyclo [5,4,0]
Examples include undecene and N-benzyltrimethylammonium hydroxide.
化合物■と化合物Ｖの反応は、反応に対して不活性な溶
媒の存在下に実施してもよい。この様な溶媒の例として
は、ベンゼン、トルエン、キシレン、ｎ−ヘキサン、サ
イクロヘキサン、ｎ−ペンタン等の炭化水素類、メタノ
ール、エタノール、プロパツール類、ブタノール類等の
低級アルコール類、ジエチルエーテル、テトラハイドロ
フラン、ジオキサン、１．２−ジメトキシエタン等のエ
ーテル類、Ｎ、Ｎ−ジメチルホルムアミド、Ｎ、Ｎ−ジ
メチルアセトアミド、Ｎ−メチル−２−ピロリドン等の
アミド類、ジメチルスルホキサイド、スルホラン等の非
プロトン性極性溶媒等を挙げることができる。The reaction between compound (1) and compound V may be carried out in the presence of a solvent inert to the reaction. Examples of such solvents include hydrocarbons such as benzene, toluene, xylene, n-hexane, cyclohexane, and n-pentane, lower alcohols such as methanol, ethanol, propatools, and butanols, diethyl ether, Ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethylsulfoxide, sulfolane, etc. Examples include aprotic polar solvents and the like.
化合物ＩＶと化合物Ｖの割合はモル比で１＝１から１：
３の範囲であれば充分であり、通常は１：１．ｌ程度で
よい。The molar ratio of compound IV and compound V is from 1=1 to 1:
A range of 3 is sufficient, usually 1:1. About 1 is enough.
反応は室温から使用する溶媒の沸点までの範囲の温度で
実施すればよい。The reaction may be carried out at a temperature ranging from room temperature to the boiling point of the solvent used.
化合物■と化合物Ｖとの縮合反応では、ヨウ化カリウム
、ヨウ化ナトリウム、クラウンエーテル等を化合物■に
対し１７１００〜１当量程度を反応促進剤として加える
のが有効なことがある。In the condensation reaction between compound (1) and compound (V), it may be effective to add about 17,100 to 1 equivalent of potassium iodide, sodium iodide, crown ether, etc. to compound (1) as a reaction accelerator.
１．２−プロパンジオール誘導体ＩＩＩは、例えば、乳
酸もしくはそのエステル体をリチウムアルミニウムハイ
ドライドを用いた還元で得られる他、（参考文献：ザ・
ジャーナル・オブ・アメリカン・ケミカル・ソサイエテ
ィー、１９８４年、第１０６巻、４９１６〜２２頁）、
本発明者はより簡便なメタルハイドライドの水素化ホウ
素ナトリウムを用いる還元によっても合成が可能である
ことを見いだした。1.2-Propanediol derivative III can be obtained, for example, by reducing lactic acid or its ester with lithium aluminum hydride;
Journal of the American Chemical Society, 1984, Vol. 106, pp. 4916-22),
The present inventors have discovered that synthesis is also possible by simpler reduction of metal hydride using sodium borohydride.
この還元に際し、乳酸化合物の水酸基はあらかじめ適当
な保護基で保護しておくのが好ましい。During this reduction, it is preferable to protect the hydroxyl group of the lactic acid compound with an appropriate protecting group in advance.
この様な保護基の例としてはテトラハイドロピラニル基
、メトキシメチル基、ベンジル基、ｐ−メトキシベンジ
ル基、トリフェニルメチル基等を挙げることができる
乳酸もしくはそのエステル体はラセミ体だけでなく、光
学活性体も入手が容易であり、（Ｒ）−乳酸あるいはそ
のエステル体からは、（Ｒ）−１，２−プロパンジオー
ル誘導体を、（Ｓ）−乳酸あるいはそのエステル体から
は （Ｓ）−１，２−プロパンジオール誘導体を容易に
得ることができる。そして既に説明した方法に従うこと
で、光学活性な化合物Ｉの簡便な合成が可能となった。Examples of such protecting groups include tetrahydropyranyl group, methoxymethyl group, benzyl group, p-methoxybenzyl group, triphenylmethyl group, etc. Lactic acid or its ester form is not only racemic, but also Optically active substances are also easily available; (R)-1,2-propanediol derivatives are obtained from (R)-lactic acid or its esters, and (S)- from (S)-lactic acid or its esters. 1,2-propanediol derivatives can be easily obtained. By following the method already explained, it became possible to easily synthesize optically active compound I.
この化合物Ｉに、ａ）ニトロ基の還元反応、ｂ）メチレ
ンマロネート化反応、Ｃ）保護基の除去反応（例えば、
脱ＴＨＰ反応）、ｄ）スルホニル化反応等を組合せて種
々のプロポキシベンゼン説導体を製造することができ、
ｅ）閉環反応の原料とすることができる。This compound I is subjected to a) nitro group reduction reaction, b) methylene malonation reaction, C) protecting group removal reaction (e.g.
Various propoxybenzene derivatives can be produced by combining THP removal reaction), d) sulfonylation reaction, etc.
e) It can be used as a raw material for ring-closing reaction.
各工程の生成物は一般的な方法で単離、精製することが
できる６例えば、抽出、再結晶、シリカゲル等を担体と
するクロマトグラフィーまたはそれらの組合せ等である
。The products of each step can be isolated and purified by conventional methods, such as extraction, recrystallization, chromatography using silica gel as a carrier, or a combination thereof.
以下にこれらの反応について述べる。These reactions will be described below.
ａ）のニトロ基の還元反応は、ラネイニッケル、パラジ
ウム−炭素、白金等の触媒を用いる接触還元（常圧乃至
５０ｋｇ／ｃｍ２）や、ハイドロサルファイドによる還
元、水素化ホウ素ナトリウムと金属塩化物の組合せによ
る還元等で実施できる。The reduction reaction of the nitro group in a) can be carried out by catalytic reduction (normal pressure to 50 kg/cm2) using a catalyst such as Raney nickel, palladium-carbon, platinum, etc., reduction with hydrosulfide, or a combination of sodium borohydride and metal chloride. This can be done through reduction etc.
ニトロ基を還元して生成するアミノ基には適当な保護基
を導入してもよい０例えば、アセチルクロライド、無水
酢酸等によりアセチル基を、トリチルクロライドにより
トリフェニルメチル基を、ジ第三級ブチル・ジカーボネ
ートにより第三級ブトキシカルボニル基を、ベンジルオ
キシカルボニルクロライドによりベンジルオキシカルボ
ニル基を導入できる。これらの保護基は各々に対応する
一般的な方法で除去してアミノ基に戻すことができる。An appropriate protecting group may be introduced into the amino group generated by reducing the nitro group. For example, acetyl chloride, acetic anhydride, etc. may be used to protect the acetyl group, trityl chloride may be used to protect the triphenylmethyl group, ditertiary butyl - A tertiary butoxycarbonyl group can be introduced using dicarbonate, and a benzyloxycarbonyl group can be introduced using benzyloxycarbonyl chloride. These protecting groups can be removed and returned to amino groups by the corresponding common methods.
ｂ）のメチレンマロネート化反応は、その原料のアミノ
化合物、例えば化合物■、■、刈等に対して好ましくは
等モル以上の化合物ＸＶＩＹ−ＣＨ−Ｃ（ＣＯＯ−イ氏
級フルキル）、 ＸＶＩ（Ｙは低級ア
ルコキシル基、ハロゲン原子、ジ低級アルキルアミノ基
等を意味する）を用い、無溶媒で両者を１００〜１８０
℃程度に加熱攪拌するか、適当な溶媒中で加熱還流する
ことによって実施できる。In the methylene malonation reaction b), the compound XVIY-CH-C (COO-I-class fulkyl), XVIY ( (Y means a lower alkoxyl group, a halogen atom, a di-lower alkylamino group, etc.), and both are 100 to 180
This can be carried out by heating and stirring at about 0.degree. C. or heating and refluxing in an appropriate solvent.
この際の溶媒としては、反応に対して不活性ならば特に
限定されず、例えばベンゼン、トルエン、キシレン、ｎ
−ヘキサン、サイクロヘキサン、ｎ−ペンタン等の炭化
水素類、メタノール、エタノール、プロパツール類、ブ
タノール類等の低級アルコール類、ジエチルエーテル、
テトラハイドロフラン、ジオキサン、１．２−ジメトキ
シエタン等のエーテル類、Ｎ、Ｎ−ジメチルホルムアミ
ド、Ｎ、Ｎ−ジメチルアセトアミド、Ｎ−メチル−２−
ピロリドン等のアミド類、ジメチルスルホキサイド、ス
ルホラン等の非プロトン性極性溶媒等を挙げることがで
きる。The solvent at this time is not particularly limited as long as it is inert to the reaction, such as benzene, toluene, xylene, n
- Hydrocarbons such as hexane, cyclohexane, n-pentane, lower alcohols such as methanol, ethanol, propatools, butanols, diethyl ether,
Ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-
Examples include amides such as pyrrolidone, aprotic polar solvents such as dimethyl sulfoxide, and sulfolane.
溶媒を使用する場合には、反応は溶媒の沸点以下の温度
で実施すればよい。When a solvent is used, the reaction may be carried out at a temperature below the boiling point of the solvent.
Ｃ）の脱保護反応は使用している保護基の一般的脱離反
応に従って実施すればよいが、例えば脱ＴＨＰ反応の場
合は酸性条件下で室温乃至１００℃で処理することによ
って行うことができる。この酸性条件としては例えば、
アルコール系溶媒またはカルボン酸系溶媒中で塩化水素
、臭化水°素、または硫酸で処理する方法、また、プロ
トン系溶媒中ピリジニウム・パラトルエンスルホネート
で処理する方法等を挙げることができる。The deprotection reaction in C) may be carried out according to the general elimination reaction of the protecting group used, but for example, in the case of THP removal reaction, it can be carried out by treatment under acidic conditions at room temperature to 100°C. . Examples of this acidic condition include:
Examples include a method of treatment with hydrogen chloride, hydrogen bromide, or sulfuric acid in an alcoholic solvent or a carboxylic acid solvent, and a method of treatment with pyridinium paratoluenesulfonate in a protic solvent.
ｄ）のスルホニル化反応は、塩基の存在下でバラトルエ
ンスルホニルクロライド（トシルクロライド）、メタン
スルホニルクロライド等の置換スルホニル塩化物あるい
は、無水トリフルオロメタンスルホン酸と、脱保護した
化合物とをＯ乃至１００℃程度の温度で処理すればよい
。In the sulfonylation reaction of d), a substituted sulfonyl chloride such as valatoluenesulfonyl chloride (tosyl chloride) or methanesulfonyl chloride or trifluoromethanesulfonic anhydride and the deprotected compound are heated at 0 to 100°C in the presence of a base. It should be treated at a certain temperature.
このスルホニル化で使用する塩基としては、有機塩基の
トリエチルアミン、トリブチルアミン、Ｎ、Ｎ−ジイソ
プロピルエチルアミン等の三級アルキルアミン類、Ｎ、
Ｎ−ジメチルアニリン、 Ｎ、Ｎ−ジエチルアニリン等
のジアルキルアニリン類、ピリジン、Ｎ、Ｎ−ジメチル
アミノピリジン、Ｎ−メチルモルホリン等の複素環アミ
ン類等、この他１．８−ジアザビシクロ［５，４，Ｏｌ
ウンデセン等を例示することができる。The base used in this sulfonylation includes organic bases such as triethylamine, tributylamine, tertiary alkylamines such as N,N-diisopropylethylamine, N,
Dialkylanilines such as N-dimethylaniline and N,N-diethylaniline, heterocyclic amines such as pyridine, N,N-dimethylaminopyridine, and N-methylmorpholine, and 1,8-diazabicyclo[5,4 ,Ol
Undecene etc. can be exemplified.
溶媒を使用する場合は、非プロトン系の溶媒が望ましく
、ジエチルエーテル、テトラハイドロフラン、ジオキサ
ン、１．２−ジメトキシエタン等のエーテル類、 Ｎ、
Ｎ−ジメチルホルムアミド、Ｎ、Ｎ−ジメチルアセトア
ミド、Ｎ−メチル−２−ピロリドン等のアミド類、ジク
ロロメタン、クロロホルム、１．２−ジクロロエタン等
を例示することができる。When using a solvent, it is preferable to use an aprotic solvent, such as ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, N,
Examples include amides such as N-dimethylformamide, N,N-dimethylacetamide, and N-methyl-2-pyrrolidone, dichloromethane, chloroform, and 1,2-dichloroethane.
次に参考例と実施例により本発明を説明するが本発明は
この実施例に限定されるものではない。Next, the present invention will be explained using reference examples and examples, but the present invention is not limited to these examples.
なお、公開された文献及び特許においては、ベンゾオキ
サジン骨格が、ｒ２．３−ジヒドロ−４Ｈ−［１，４］
−ベンゾオキサジン、Ｉと表現されたものもあるが、本
件では「３．４−ジヒドロ−２Ｈ−［１，４］ベンゾオ
キサジン」と統一することとする。In addition, in published literature and patents, the benzoxazine skeleton is r2.3-dihydro-4H-[1,4]
Although it is sometimes expressed as -benzoxazine, I, in this case it will be unified as "3,4-dihydro-2H-[1,4]benzoxazine."
’ ＩＩ−ＮＭＲスペクトルは、日本電子ＦＸ−９０Ｑ
を用いて測定した。'II-NMR spectrum is JEOL FX-90Q
Measured using
艶＊ １１Ｌ二二二
ｄｉ−乳酸エチル２９．５３ｇ、２．３−ジヒドロビラ
ン２５．２４ｇおよびｄｌ−カンファー１０−スルホン
酸２．９ｇを水冷下で無水ジエチルエーテル１２５ｍ１
に溶解し、室温で一夜攪拌した。反応後、ジエチルエー
テル約１５０ｍ１を加え、エーテル層を飽和重曹水、水
、飽和塩化ナトリウム水の順に洗い、無水硫酸マグネシ
ウムにて乾燥後、溶媒を減圧留去して、標記の化合物を
定量的に得た。Gloss* 11L 29.53 g of 222 di-ethyl lactate, 25.24 g of 2.3-dihydrobilane and 2.9 g of dl-camphor 10-sulfonic acid were mixed with 125 ml of anhydrous diethyl ether under water cooling.
and stirred at room temperature overnight. After the reaction, about 150 ml of diethyl ether was added, and the ether layer was washed successively with saturated sodium bicarbonate solution, water, and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to quantitatively obtain the title compound. Obtained.
無水ジエチルエーテル５００ｍ１にリチウムアルミニウ
ムハイドライド １０．０４ｇを懸濁させ、水冷攪拌し
ながらこれに、Ａ−１，１で得たエステル５２ｇを無水
ジエチルエーテル１５０＋ｎｌに溶解した溶液を滴下し
、室温で２０分、加熱速流しながら２時間、さらに室温
で一夜攪拌した。次いで反応混合物を氷冷し、攪拌下に
水１０．０４ｍ１１１５％Ｆ水酸化ナトリウム水溶液１
０．０４ｍ１及び水３０．１２ｍ１をこの順に加え、し
ばらく攪拌した後不溶物を濾去した。エーテルをほぼ半
量まで濃縮して無水硫酸マグネシウムで脱水し、エーテ
ルを減圧留去して標記の化合物を定量的に得た。さらに
減圧蒸留して次の反応に用いた。10.04 g of lithium aluminum hydride was suspended in 500 ml of anhydrous diethyl ether, and a solution prepared by dissolving 52 g of the ester obtained in A-1, 1 in 150+ nl of anhydrous diethyl ether was added dropwise to this while stirring under water cooling, and the mixture was stirred at room temperature for 20 minutes. The mixture was stirred for 2 hours with rapid heating and then overnight at room temperature. The reaction mixture was then cooled on ice, and while stirring, 10.04 ml of water and 1 15% F sodium hydroxide aqueous solution were added.
0.04 ml and 30.12 ml of water were added in this order, and after stirring for a while, insoluble matter was filtered off. The ether was concentrated to approximately half its volume, dried over anhydrous magnesium sulfate, and the ether was distilled off under reduced pressure to quantitatively obtain the title compound. It was further distilled under reduced pressure and used in the next reaction.
沸点： １０８〜１１４℃（ｔ４ｍａｕｇ）’Ｈ−ＮＭ
Ｒ（ＣＤＣＩｓ ）δ：
１．１３．１．２２（ｔｏｔａｌ ３Ｈ，ｅａｃｈ ｄ
、 Ｊ＝６．５）１ｘ）。Boiling point: 108-114℃ (t4maug)'H-NM
R (CDCIs) δ: 1.13.1.22 (total 3H, each d
, J=6.5)1x).
１．３０−１．９４（６１（、ｍｌ、 ２．２８（ｌ）
ｌ、 ｄｄ、 Ｊ−５，５，７Ｈｚ）。1.30-1.94(61(, ml, 2.28(l)
l, dd, J-5,5,7Hz).
３．２６−４．１０（５Ｈ，ｍ）、 ４．４８−４．７
８（１）１． ｍ ）以上はＪ、 Ａｍ、 Ｃｈｅｍ、
Ｓａｃ、、 １０８．４９１８−４９２２（１９８４
）に記載の方法に準じて合成した。3.26-4.10 (5H, m), 4.48-4.7
8(1)1. m) The above is J, Am, Chem,
Sac, 108.4918-4922 (1984
It was synthesized according to the method described in ).
トリフェニルホスフィン２．０４ｇを無水ＴＨＦ １０
ｍ１に溶解し、氷冷攪拌下にアゾジカルボン酸ジエチル
１．３６ｇを滴下し、同温で３０分間攪拌した。次いで
２．３−ジフルオロ−６−二トロフエノール（ＩＶ。2.04g of triphenylphosphine in anhydrous THF 10
1.36 g of diethyl azodicarboxylate was added dropwise to the solution under ice-cooling and stirring, and the mixture was stirred at the same temperature for 30 minutes. Then 2,3-difluoro-6-nitrophenol (IV.
Ｘａ＝Ｘｂ−Ｆ）、１．０５ｇおよび参考例Ａ−１．２
テ得た２−〇−（テトラヒドロピラン−２−イル）プロ
パン−１，２−ジオール（ＩＩＩ、 Ｒｅ−ＴＨＰ）、
１．０１ｇを無水ＴＨＦ、 ５ｍｌに溶解した溶液を滴
下し、室温で一夜攪拌した。Xa=Xb-F), 1.05g and Reference Example A-1.2
The obtained 2-0-(tetrahydropyran-2-yl)propane-1,2-diol (III, Re-THP),
A solution of 1.01 g dissolved in 5 ml of anhydrous THF was added dropwise, and the mixture was stirred at room temperature overnight.
反応後、溶媒を減圧留去し、ベンゼンと飽和重曹水を加
えて振盪後、有機層を分離し、有機層を水、飽和塩化ナ
トリウム水の順に洗った。無水硫酸マグネシウムで乾燥
後溶媒を減圧留去した。残渣をシリカゲルカラムクロマ
トグラフィーに付して、標記の化合物１．８５ｇを油状
物質として得た。After the reaction, the solvent was distilled off under reduced pressure, benzene and saturated aqueous sodium bicarbonate were added, and after shaking, the organic layer was separated, and the organic layer was washed successively with water and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.85 g of the title compound as an oily substance.
生成物はジアステレオマーの混合物であり、薄層クロマ
トグラフィーにて２個のスポット状に観察される。その
うちの主たるスポットの生成物の’ Ｈ−ＮＭＲは以下
の通りであり、もう一方の生成物の’ Ｈ−ＮＭＲもほ
とんど同一であった。The product is a mixture of diastereomers and is observed as two spots on thin layer chromatography. The 'H-NMR of the product in the main spot was as follows, and the 'H-NMR of the other product was almost the same.
’Ｈ−ＮＭＲ（ＣＤＣＩｓ ）δ：
１．１８−１．８４（９Ｈ，ｍ）、 ３．２３−４．２
８（５Ｈ，Ｉ）。'H-NMR (CDCIs) δ: 1.18-1.84 (9H, m), 3.23-4.2
8 (5H, I).
４．７４（ＩＨ，ｂｒ ｓ）、 ６．９４（ＩＨ，ｄｄ
ｄ、 Ｊ−５，７，５ａｎｄ９Ｈｚ）、 ７．６５（Ｉ
Ｈ，ｄｄｄ、 Ｊ＝２．５．５．５ ａｎｄ ９）１ｚ
）施仔２：２．３−ジフルオロ−６−アミノ−２−（テ
実施例１で得た化合物１．８２ｇをエタノール５０ｍ１
に溶解し、詰パラジウムー炭素、５００ｍｇを添加し、
常圧で接触還元に付した（１時間）。反応後、触媒を濾
去し、溶媒を留去して標記の化合物を得た。4.74 (IH, br s), 6.94 (IH, dd
d, J-5,7,5and9Hz), 7.65(I
H, ddd, J=2.5.5.5 and 9) 1z
) Shizai 2: 2.3-difluoro-6-amino-2-(te) 1.82 g of the compound obtained in Example 1 was added to 50 ml of ethanol.
and added 500 mg of packed palladium-carbon,
It was subjected to catalytic reduction at normal pressure (1 hour). After the reaction, the catalyst was filtered off and the solvent was distilled off to obtain the title compound.
これを精製すること無く次の反応に用いた。This was used in the next reaction without purification.
実施例２で得た化合物およびジエチル・エトキシメチレ
ンマロネー） （ＸＶＩ、 Ｙ−ＥｔＯ１低級フルキル
−Ｅｔ、以下、ＥＭＭＥと略す） １．２４ｇを無溶媒
で１４５〜１５０℃に加熱しながら混合、攪拌した。
１．５時間後、減圧とし、発生するエタノールを除去し
ながらさらに３０分間攪拌した。反応混合物を放冷後、
シリカゲルカラムクロマトグラフィにて精製し、テトラ
ヒドロピラニル基が脱離した標記の化合物１．３３ｇを
得た。1.24 g of the compound obtained in Example 2 and diethyl ethoxymethylene maloney (XVI, Y-EtO1 lower fulkyl-Et, hereinafter abbreviated as EMME) were mixed and stirred without solvent while heating to 145 to 150°C. did.
After 1.5 hours, the pressure was reduced and the mixture was stirred for an additional 30 minutes while removing generated ethanol. After cooling the reaction mixture,
Purification was performed by silica gel column chromatography to obtain 1.33 g of the title compound from which the tetrahydropyranyl group was removed.
さらにＴＩ（Ｐ基が残った化合物も５８０ａ＋ｇ得られ
たが、ピリジニウムトシレートで処理してＴ）ＩＰ基を
除去し、標記の化合物に話導した。Furthermore, 580a+g of a compound in which the TI(P group remained) was obtained, but the T)IP group was removed by treatment with pyridinium tosylate, leading to the title compound.
融点：５２〜５５℃、 ＭＳ； ｍ／ｅ−３７３（Ｍ
”）ＮＭＲ（ＣＤＣＩｓ）δ：
１．２２−１．４６（９Ｈ，ｎ＋）、 ３．５５（ＩＨ
，ｄ、 Ｊ−４，５８Ｚ）。Melting point: 52-55°C, MS; m/e-373 (M
”) NMR (CDCIs) δ: 1.22-1.46 (9H, n+), 3.55 (IH
, d, J-4, 58Z).
３．８８−４．４３（７Ｈ，ｍｌ、 ６．７５−７．０
８（２Ｈ，ｍ）。3.88-4.43 (7H, ml, 6.75-7.0
8 (2H, m).
８．４８（１）１． ｄ、 Ｊ−１４，５Ｈｚ）トリフ
ェニルホスフィン３４１１Ｉ１ｇを無水ＴＨＦ、５ｍｌ
に溶解し、アゾジカルボン酸ジエチル２２６ｍｇを加え
、水冷下２０分間攪拌した。次いで、実施例３で得た化
合物を無水ＴＨＦ、３ａ＋１に溶解して加え、室温で一
夜攪拌した。8.48(1)1. d, J-14,5Hz) 1 g of triphenylphosphine 3411I in anhydrous THF, 5 ml
226 mg of diethyl azodicarboxylate was added thereto, and the mixture was stirred for 20 minutes under water cooling. Then, the compound obtained in Example 3 was added dissolved in anhydrous THF, 3a+1, and stirred overnight at room temperature.
反応後、溶媒を減圧留去し、残漬をシリカゲルカラムク
ロマトグラフィーに付し、標記の化合物をほぼ定量的に
得た。物理定数は標品と一致した（特開昭６０−１２８
１９０号公報）。After the reaction, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain the title compound almost quantitatively. The physical constants were consistent with the standard (Japanese Patent Application Laid-open No. 128-1983)
Publication No. 190).
融点二６８℃
’Ｈ−ＮＭＲ（ＣＤＣＩ、） δ ：１．２０−１．
４１（９Ｈ，ａ＋）、３．９０−４．４４（７Ｈ，ｍ）
。Melting point: 268°C 'H-NMR (CDCI,) δ: 1.20-1.
41 (9H, a+), 3.90-4.44 (7H, m)
.
６．７１−６．８５（２８，ｉｔ）、７．７６（１Ｂ、
Ｓ）す≦１エに１吐
実施例３で得た化合物７４７ｔａｇをピリジン２ｍｌに
溶解し、トシルクロライド７１０ｍｇを加え、水冷下２
４時間、室温で４時間攪拌した。反応後、酢酸エチルと
１規定塩酸を加えて振盪後、有機層を分離し、有機層を
さらに水洗して、無水硫酸マグネシウムで乾燥後濃縮乾
固した。残漬をシリカゲルカラムクロマトグラフィに付
して精製し、標記の化合物１．０ｇを得た。6.71-6.85 (28, it), 7.76 (1B,
S) Dissolve compound 747tag obtained in Example 3 in 2 ml of pyridine, add 710 mg of tosyl chloride, and add 710 mg of tosyl chloride.
The mixture was stirred for 4 hours and at room temperature for 4 hours. After the reaction, ethyl acetate and 1N hydrochloric acid were added, and after shaking, the organic layer was separated, further washed with water, dried over anhydrous magnesium sulfate, and concentrated to dryness. The residue was purified by silica gel column chromatography to obtain 1.0 g of the title compound.
融点：６１〜６２℃
’）ｌ−ＮＭＲ（ＣＤＣ１３） δ：１．３４．１．
３６（ｅａｃｈ ３Ｈ，ｅａｃｈ ｔ、 Ｊ−７Ｈｚ）
。Melting point: 61-62°C') l-NMR (CDC13) δ: 1.34.1.
36 (each 3H, each t, J-7Hz)
.
１．５０（３Ｈ，ｄ、 Ｊ＝７Ｈｚ）、 ２．４０（３
Ｈ，ｓ）。1.50 (3H, d, J=7Hz), 2.40 (3
H,s).
４．１２−４．４０（６Ｈ，ｍ）、 ４．９４（１）
１． ５ｉｘｔｅｔ−１ｉｋｅ）。4.12-4.40 (6H, m), 4.94 (1)
1. 5ixtet-1ike).
６．８３−６．９７（２Ｈ，ｍｌ、 ７．２６． ７
．７６（ｅａｃｈ ２）！。6.83-6.97 (2H, ml, 7.26.7
．． 76 (each 2)! .
ｅａｃｈ ｄ、 Ｊ＝９Ｈｚ）、 ８．３４（ＩＨ
，ｄ、 Ｊ＝１４）１ｚ）実施例５で得た化合物７９
１ｍｇを無水り閘Ｆ、５ｍｌに溶解し、炭酸カリウム２
０７ｍｇ及び触媒量の１８−クラウン−６−エーテルを
加え、８０℃で８．５時間攪拌した。反応後、酢酸エチ
ルと水を加えて振盪後、有機層を分離し、有機層を水洗
した。無水硫酸マグネシウムで乾燥後濃縮して得た残漬
をシリカゲルカラムクロマトグラフィーに付し、標記の
化合物の結晶をほぼ定量的に得た。物理定数は標品と一
致した（特開昭６０−１２６１９０号公報）。each d, J=9Hz), 8.34(IH
,d, J=14)1z) Compound 79 obtained in Example 5
Dissolve 1 mg in 5 ml of anhydrous lock F, add 2 ml of potassium carbonate
07 mg and a catalytic amount of 18-crown-6-ether were added and stirred at 80°C for 8.5 hours. After the reaction, ethyl acetate and water were added and shaken, and then the organic layer was separated and washed with water. The residue obtained by drying over anhydrous magnesium sulfate and concentration was subjected to silica gel column chromatography to obtain crystals of the title compound almost quantitatively. The physical constants matched those of the standard product (Japanese Unexamined Patent Publication No. 126190/1983).
ひ１吐
２．３−ジフルオロ−６−ニトロ−［［２−（テトラヒ
ドロビラン−２−イル）オキシプロピル］オキシ］ベン
ゼン（１，Ｘａ−Ｘｂ−Ｆ、 Ｒｃ−ＴＨＰ）、６．３
５ｇを無水エタノール６０ｍ１に溶解し、ピリジニウム
・トシレート６４０＋ａｇを加えて室温で一夜攪拌した
後、１時間加熱還流した０反応後エタノールを留去し、
残漬に酢酸エチルと１規定塩酸を加えて振盪後、有機層
を分離した。有機層を飽和重曹水および水で洗い、無水
硫酸マグネシウムで乾燥した。溶媒を減圧留去して、油
状の標記の化合物の枢体を得、精製することなく次の反
応に用いた。2.3-Difluoro-6-nitro-[[2-(tetrahydrobilan-2-yl)oxypropyl]oxy]benzene (1,Xa-Xb-F, Rc-THP), 6.3
Dissolve 5 g in 60 ml of absolute ethanol, add pyridinium tosylate 640+ag, stir overnight at room temperature, heat under reflux for 1 hour, and then distill off the ethanol.
Ethyl acetate and 1N hydrochloric acid were added to the residue, and after shaking, the organic layer was separated. The organic layer was washed with saturated aqueous sodium bicarbonate and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain an oily central compound of the title compound, which was used in the next reaction without purification.
’Ｈ−ＮＭＲ（ＣＤＣＩｓ ）δ：
１．２５（３Ｈ，ｄ、 Ｊ＝６Ｈｚ）、 ３．００（Ｉ
Ｈ，ｂｒ ｄ、Ｊ−２，５Ｈｚ）。'H-NMR (CDCIs) δ: 1.25 (3H, d, J=6Hz), 3.00 (I
H, br d, J-2,5Hz).
３．９９−４．４３ （３Ｈ，ｍ） 。3.99-4.43 (3H, m).
７．０３（ＩＨ，ｄｄｄ、 Ｊ＝７．９ ａｎｄ ９．
５８Ｚ）。7.03 (IH, ddd, J=7.9 and 9.
58Z).
７．７４（ＩＨ，ｄｄｄ、 Ｊ＝２．５．５．５ ａｎ
ｄ ７Ｈｚ）実施例７で得た化合物３．１７ｇをエタノ
ール４５ｍ１に溶解し、５零パラジウム−炭素、７８０
ｍｇを加え、常温常圧下で接触還元した。反応終了後、
触媒を濾去して溶媒を減圧留去し、残漬にジメチル・メ
トキシメチレンマロネート ２．４４ｇ （ＸＶＩ、
Ｙ−ＯＭｅ。7.74 (IH, ddd, J=2.5.5.5 an
d 7Hz) 3.17g of the compound obtained in Example 7 was dissolved in 45ml of ethanol, and 50% palladium-carbon, 780
mg was added, and catalytic reduction was carried out at room temperature and normal pressure. After the reaction is complete,
The catalyst was filtered off, the solvent was distilled off under reduced pressure, and 2.44 g of dimethyl methoxymethylene malonate (XVI,
Y-OMe.
低級フルキル−Ｍｅ）を加え１４０℃で常圧で１時間、
減圧下で１時間、再度常圧で１時間加熱攪拌した。放冷
後、反応混合物をシリカゲルクロマトグラフィーに付し
、標題化合物４．０ｇを得た。Add lower furkyl-Me) and heat at 140°C for 1 hour at normal pressure.
The mixture was heated and stirred for 1 hour under reduced pressure and again for 1 hour at normal pressure. After cooling, the reaction mixture was subjected to silica gel chromatography to obtain 4.0 g of the title compound.
融点＝１０７〜１０８℃
’）Ｉ−ＮＭＲ（ＣＤＣｌ２ ）δ：
１．２９（３）１． ｄ、 Ｊ−６，５８Ｚ）、 ３．
４５（ＬＨ，ｄ、 Ｊ−４，５Ｈｚ）。Melting point = 107-108°C') I-NMR (CDCl2) δ: 1.29 (3) 1. d, J-6,58Z), 3.
45 (LH, d, J-4,5Hz).
３．８０．３．８８（ｅａｃｈ ３８． ｅａｃｈ ｓ
）。3.80.3.88 (each 38. each s
).
８．７６−７．１２（２Ｈ，ｍ）、 ８．５３（ＩＨ，
ｄ、 Ｊ−１４，５）１ｚ）Ｒｄ＝Ｔｓ、 Ｒ＝Ｍｅ）
実施例８で得た化合物２．０７ｇをピリジン４．２ａ＋
１に溶解し、トシルクロライド １．４９ｇを加え、５
℃前後の外温で３日間攪拌した。反応後、酢酸エチルを
加え、１規定塩酸、飽和重曹水、水で洗浄し、無水硫酸
マグネシウムで乾燥した。溶媒を減圧留去して得た残渣
をシリカゲルカラムクロマトグラフィに付し、標記の化
合物２．７６ｇを得た。8.76-7.12 (2H, m), 8.53 (IH,
d, J-14,5) 1z) Rd=Ts, R=Me) 2.07 g of the compound obtained in Example 8 was added to 4.2a+ of pyridine.
Dissolve in 1, add 1.49g of tosyl chloride,
The mixture was stirred for 3 days at an external temperature of around °C. After the reaction, ethyl acetate was added, and the mixture was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and water, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography to obtain 2.76 g of the title compound.
融点二８９〜９０℃
’Ｈ−ＮＭＲ（ＣＤＣＩｓ ）δ：
１．５０（３Ｈ，ｄ、 ＪＪ、５Ｈｚ）、 ２．４０（
３）１． ｓ）。Melting point 289-90℃'H-NMR (CDCIs) δ: 1.50 (3H, d, JJ, 5Hz), 2.40 (
3)1. s).
３．８０．３．８５（ｅａｃｈ ３Ｈ，ｅａｃｈ ｓ）
。3.80.3.85 (each 3H, each s)
.
４．０４−４．４２（２Ｈ，ｍ）、 ４．８０−５．１
４（ＩＨ，ｍ）。4.04-4.42 (2H, m), 4.80-5.1
4 (IH, m).
６．７６−７．１２（Ｈｌ、 ｍ）、 ７．２８．７．
８０（ｅａｃｈ ２Ｈ。6.76-7.12 (Hl, m), 7.28.7.
80 (each 2H.
ｅａｃｈ ｄ、 Ｊ＝８Ｈｘ）、 ８．４１１Ｈ，ｄ、
Ｊ”１４Ｈｚ）実施例９で得た化合物７４９ｍｇを無
水ＤＭＦ、５ＩＩ１１に溶解し、炭酸カリウム２０７Ｂ
を加え、８０℃で８時間攪拌した６反応後、酢酸エチル
で希釈し、希釈液を水洗して無水硫酸マグネシウムで乾
燥した。each d, J=8Hx), 8.411H,d,
J''14Hz) 749 mg of the compound obtained in Example 9 was dissolved in anhydrous DMF, 5II11, and potassium carbonate 207B
After six reactions, the mixture was stirred at 80° C. for 8 hours, diluted with ethyl acetate, the diluted solution was washed with water, and dried over anhydrous magnesium sulfate.
溶媒を減圧留去して得た残漬をシリカゲルカラムクロマ
トグラフィーに付し、標記の化合物４５５ｍｇを得た。The residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography to obtain 455 mg of the title compound.
融点：１４６〜１４７℃
’Ｈ−ＮＭＲ（ＣＤＣＩｓ ）δ ：１．３２（３Ｈ
，ｄ、 Ｊ−７Ｈ２）、 ３．８１． ３．８５（
ｅａｃｈ ３Ｈ。Melting point: 146-147°C 'H-NMR (CDCIs) δ: 1.32 (3H
, d, J-7H2), 3.81. 3.85 (
each 3H.
ｅａｃｈ ｓ）、 ３．９４−４．６３（３Ｈ，ｍ）
。each s), 3.94-4.63 (3H, m)
.
４．８０−５．１４（ＩＨ，ｍ）、 ６．８０（２Ｈ
，ｑ−１１ｋｅ）。4.80-5.14 (IH, m), 6.80 (2H
, q-11ke).
７．８２（ＩＨ，Ｓ）
Ｆ、Ｒｄ−Ｔｓ）
実施例７と同様にして得た化合物４．５ｇをピリジン８
．６ｍｌに溶解し、トシルクロライド６ｇを加え、水冷
下４時間、室温で４時間攪拌した。反応後、酢酸エチル
と１規定塩酸を加えて振盪後、有機層を分離し、有機層
を水洗して無水硫酸マグネシウムで乾燥した。溶媒を減
圧留去して得た残漬をシリカゲルカラムクロマトグラフ
ィに付して精製し、標記の化合物６．５２ｇを得た。7.82(IH,S)F,Rd-Ts) 4.5g of the compound obtained in the same manner as in Example 7 was dissolved in pyridine 8
．． 6 ml of the solution was added, and 6 g of tosyl chloride was added thereto, followed by stirring for 4 hours under water cooling and for 4 hours at room temperature. After the reaction, ethyl acetate and 1N hydrochloric acid were added, and after shaking, the organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography to obtain 6.52 g of the title compound.
融点：６７〜６９℃
’Ｈ−ＮＭＲ（ＣＤＣＩｓ ）δ：
１．４４（３）１． ｄ、 Ｊ−６Ｈ２）、 ２．４１
（３Ｈ，Ｓ）。Melting point: 67-69°C 'H-NMR (CDCIs) δ: 1.44 (3) 1. d, J-6H2), 2.41
(3H, S).
４．０８−４．４０（２Ｈ，ｍ）、 ４．７６−５．０
８（１）１． ｍ）。4.08-4.40 (2H, m), 4.76-5.0
8(1)1. m).
７．３０（１）１，５ｉｘｔｅｔ−１ｉｋｅ）。7.30(1)1,5ixtet-1ike).
７．８７（ＩＨ，ｄｄｄ、Ｊ＝２．５，５．５，８．５
Ｈｚ）。7.87 (IH, ddd, J=2.5, 5.5, 8.5
Hz).
７．３２，７．８０（ｅａｃｈ ２Ｈ，ｅａｃｈ
ｄ、Ｊ＝８Ｈｘ）実施例１１で得た化合物２．３２ｇを
エタノール５０ｍ１に溶解し、繋パラジウムー炭素、Ｉ
ｇを加え、常温常圧で接触還元した（約１時間）。触媒
を濾去し、エタノールを減圧留去して標記の化合物を得
た。7.32, 7.80 (each 2H, each
d, J=8Hx) 2.32 g of the compound obtained in Example 11 was dissolved in 50 ml of ethanol, and the compound palladium-carbon, I
g was added thereto, and catalytic reduction was carried out at room temperature and normal pressure (about 1 hour). The catalyst was filtered off and ethanol was distilled off under reduced pressure to obtain the title compound.
これをそのまま次の反応に用いた。This was used as it was in the next reaction.
Ｒｄ＝Ｔｓ、 Ｒ−Ｅｔ）
実施例１２で得た化合物にＥＭＭＥ、 １．３０ｇを加
え１４５〜１５０℃で常圧下１時間、減圧下１時間加熱
攪拌した。次いで、反応混合物をシリカゲルカラムクロ
マトグラフィに付して標記の化合物１．６４ｇを得た。Rd=Ts, R-Et) 1.30 g of EMME was added to the compound obtained in Example 12, and the mixture was heated and stirred at 145 to 150°C for 1 hour under normal pressure and 1 hour under reduced pressure. The reaction mixture was then subjected to silica gel column chromatography to obtain 1.64 g of the title compound.
この化合物は先に実施例５で得た化合物と一致した。This compound was identical to the compound obtained previously in Example 5.
■
実施例１２と同様にして得た化合物７２０ｍｇを無水Ｄ
ＭＦ ５ｍｌに溶解し、炭酸カリウム２７６ｍｇおよび
触媒量の１８−クラウン−６−エーテルを加え、８０℃
で一夜加熱攪拌した。反応後、酢酸エチルと水を加えて
振盪後、有機層を分離し、有機層をさらに水洗した。無
水硫酸マグネシウムで乾燥後、溶媒を濃縮乾固して得た
残漬をシリカゲルカラムクロマトグラフィに付し、標記
の化合物２８７ｍｇを得た。■ 720 mg of the compound obtained in the same manner as in Example 12 was added to anhydrous D
Dissolved in 5 ml of MF, added 276 mg of potassium carbonate and a catalytic amount of 18-crown-6-ether, and heated to 80°C.
The mixture was heated and stirred overnight. After the reaction, ethyl acetate and water were added, and after shaking, the organic layer was separated, and the organic layer was further washed with water. After drying over anhydrous magnesium sulfate, the solvent was concentrated to dryness and the resulting residue was subjected to silica gel column chromatography to obtain 287 mg of the title compound.
物理定数は標品のそれと一致した（日本特許第１．４４
４．０４３号、米国特許第４，３８２，８９２号）。The physical constants matched those of the standard (Japanese Patent No. 1.44)
No. 4.043, U.S. Pat. No. 4,382,892).
融点：５２℃
（Ｓ） −（−）−乳酸エチル５９．０６ｇ、２．３−
ジヒドロビラン５０．４８ｇ及びカンファー１０−スル
ホン酸５．８ｇを無水ジエチルエーテル２５０ａ＋１に
溶解し、水冷下３０分、室温で一夜攪拌した。反応後、
ジエチルエーテル３００ＩＩｌｌを加え、飽和重曹水お
よび飽和塩化ナトリウム水で洗い、無水硫酸マグネシウ
ムで乾燥後濃縮乾固して、標記の化合物を定量的に得た
。Melting point: 52°C (S) -(-)-Ethyl lactate 59.06g, 2.3-
50.48 g of dihydrobilane and 5.8 g of camphor 10-sulfonic acid were dissolved in 250a+1 of anhydrous diethyl ether, and stirred under water cooling for 30 minutes and overnight at room temperature. After the reaction,
300 IIll of diethyl ether was added, washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated to dryness to quantitatively obtain the title compound.
無水ジエチルエーテル１ｊ２にリチウムアルミニウムハ
イドライド２０．１ｇを懸濁させ、水冷、攪拌下に先に
得た０−（テトラヒドロビラン−２−イル）−（Ｓ）−
乳酸エチルを無水ジエチルエーテル２００ＬＩｌｌに溶
解して滴下した。次いで室温で１時間攪拌し、さらに２
時間加熱還流した。−夜室温で静置後氷冷し、水２０．
１ｍｌ、１５零水酸化ナトリウム水溶液２０．１ｍｌ、
水６１．５ｍｌの順に加えた。不溶物を濾去し、濾液を
無水硫酸マグネシウムで乾燥後濃縮した。得られた残渣
を減圧蒸留し、標記の化合物をジアステレオマーの混合
物として得た。20.1 g of lithium aluminum hydride was suspended in anhydrous diethyl ether 1j2, and the previously obtained 0-(tetrahydrobilan-2-yl)-(S)- was cooled with water and stirred.
Ethyl lactate was dissolved in 200 LIll of anhydrous diethyl ether and added dropwise. It was then stirred at room temperature for 1 hour, and then stirred for an additional 2 hours.
The mixture was heated to reflux for an hour. - Leave to stand at room temperature overnight, cool on ice, and water 20.
1 ml, 20.1 ml of 15 zero sodium hydroxide aqueous solution,
61.5 ml of water was then added. Insoluble materials were removed by filtration, and the filtrate was dried over anhydrous magnesium sulfate and concentrated. The obtained residue was distilled under reduced pressure to obtain the title compound as a mixture of diastereomers.
未習；沸点：８８〜９３℃（５ｍｍＨｇ） ６３．１３
ｇ、初後留：１０．５３ｇ、 ’ｌ（−ＮＭＲは未習、
初後留ともほぼ同じであった。Unlearned; Boiling point: 88-93℃ (5mmHg) 63.13
g, first goru: 10.53g, 'l (-NMR not learned,
It was almost the same as Hatsugoru.
’）Ｉ−ＮＭＲ（ＣＤＣ１３）δ：
１．１３．１．２２（ｔｏｔａｌ ３Ｈ，ｅａｃｈ ｄ
、 Ｊ＝６．５）１ｘ）。') I-NMR (CDC13) δ: 1.13.1.22 (total 3H, each d
, J=6.5)1x).
１．３６−１．９６（６Ｈ，ｆｆ１）、 ３．３０−４
．１２（５Ｈ，ＩＩＩ）。1.36-1.96 (6H, ff1), 3.30-4
．． 12 (5H, III).
４．５０−４．６０．４．６８−４．８０（１）１．
ｍ）実施例１に準じ、２．３−ジフルオロ−６−ニトロ
フエ／−ル（ＴＶ、 Ｘａ−Ｘｂ−Ｆ）、１２．２６ｇ
、 ２−０−ｆｆトラヒドロビラン−２−イル） −（
Ｓ）−プロパン−１，２−ジオール（ＩＩＩ−５，Ｒｃ
−ＴＨＰ）、１１．７８ｇおよびフェノールに対し １
．３当量のミツノブ試薬より、油状の標記化合物２０．
４ｇをジアステレオマーの混合物として得た。4.50-4.60.4.68-4.80(1)1.
m) According to Example 1, 2,3-difluoro-6-nitropher/-ol (TV, Xa-Xb-F), 12.26 g
, 2-0-ff trahydrobilan-2-yl) -(
S)-propane-1,2-diol (III-5, Rc
-THP), 11.78g and phenol 1
．． From 3 equivalents of Mitsunobu reagent, the oily title compound 20.
4 g were obtained as a mixture of diastereomers.
’）Ｉ−ＮＭＲ（ＣＤＧＩｓ ）δ：
１．２８．１．３２（ｔｏｔａｌ ３１１． ｅａｃｈ
ｄ、 Ｊ−６Ｈｚ）。') I-NMR (CDGIs) δ: 1.28.1.32 (total 311. each
d, J-6Hz).
１．４０−１．８６（６８，１１，３，３６−４，４２
（５Ｈ，ｌ）。1.40-1.86 (68, 11, 3, 36-4, 42
(5H, l).
４．６８−４．８６（ＩＨ，ｍ）、７．００（Ｉｌｌ、
ｄｄｄ、Ｊ−７，９ａｎｄ９．５Ｈｚ）、 ７．６８
（ＩＨ，ｄｄｄ、 Ｊ−２，５，５，５ａｎｄ ７Ｈ
２）実施例１５で得た化合物６．３５ｇおよびピリジニ
ウム・トシレート６４０ｍｇを用いて、実施例７の方法
に準じ脱ＴＨＰ化し標記の化合物を得た。油状物質（未
精製）。4.68-4.86 (IH, m), 7.00 (Ill,
ddd, J-7,9and9.5Hz), 7.68
(IH, ddd, J-2, 5, 5, 5 and 7H
2) Using 6.35 g of the compound obtained in Example 15 and 640 mg of pyridinium tosylate, THP was removed according to the method of Example 7 to obtain the title compound. Oily substance (unrefined).
’Ｈ−ＮＭＲ（ＣＤＣｈ ）δ：
１．２８（３Ｈ，ｄ、 ＪＪＨｚ）、 ２．８８（ＩＨ
，ｄ、 Ｊ−２，５Ｈｚ）。'H-NMR (CDCh) δ: 1.28 (3H, d, JJHz), 2.88 (IH
, d, J-2,5Hz).
３．９６−４．４４（３）１． ｍ）、 ７．０３（Ｉ
Ｈ，ｄｄｄ、 Ｊ−７，９ａｎｄ９．５Ｈｚ）、 ７．
７５（Ｉｌｌ、 ｄｄｄ、 Ｊ−２，５，５，５ａｎｄ
７Ｈｚ）実施例１６で得た化合物４．３５ｇを実施例
１１の方法に準じて、ピリジン８ｍｌおよびトシルクロ
ライド４．２７ｇでトシル化し、標記の化合物６．９８
ｇを得た。3.96-4.44(3)1. m), 7.03(I
H,ddd, J-7,9and9.5Hz), 7.
75 (Ill, ddd, J-2, 5, 5, 5 and
7Hz) According to the method of Example 11, 4.35 g of the compound obtained in Example 16 was tosylated with 8 ml of pyridine and 4.27 g of tosyl chloride to obtain 6.98 g of the title compound.
I got g.
融点二６８〜６９．５℃
’Ｈ−ＮＭＲ（ＣＤＣ１＊） δ ：１．４４（３Ｈ
，ｄ、Ｊ−６Ｈｚ）、２．４２（３Ｈ，Ｓ）。Melting point 268-69.5℃ 'H-NMR (CDC1*) δ: 1.44 (3H
, d, J-6Hz), 2.42 (3H,S).
４．０８−４．４０（２Ｂ、ｍ）、４．７６−５．０８
（ＩＨ，ｍｌ。4.08-4.40 (2B, m), 4.76-5.08
(IH, ml.
７．０３（ＬＨ，ｄｄｄ、Ｊ＠７．９ ａｎｄ ９
．５Ｈｚ）。7.03 (LH, ddd, J@7.9 and 9
．． 5Hz).
７．６８（ＩＨ，ｄｄｄ、Ｊ＝２．５，５．５ ａｎ
ｄ ７Ｈ２）実施例１２および実施例１４に準じ、２
．３−ジフルオロ−６−ニトロ−［［（５１２−トシル
オキシプロピル］−オキシ］ベンゼン（ＸＩ−５，Ｘａ
＝Ｘｂ−Ｆ、 Ｒｄ＝Ｔｓ） ７７５ａ＋ｇより標記の
化合物を２８０ｍｇ得た。機器データは標品と一致（＾
ｒｉｃ、 Ｂｉｏｌ、 Ｃｈｅｍ、、 ５１． （５）
、 １２６５−１２７０ （１９Ｂ？））。7.68 (IH, ddd, J=2.5, 5.5 an
d 7H2) According to Example 12 and Example 14, 2
．． 3-difluoro-6-nitro-[[(512-tosyloxypropyl]-oxy]benzene (XI-5, Xa
=Xb-F, Rd=Ts) 280 mg of the title compound was obtained from 775a+g. The device data matches the standard (^
ric, Biol, Chem, 51. (5)
, 1265-1270 (19B?)).
（Ｒ）−（÷）−乳酸メチル（ダイセル株式会社製）３
１．２３ｇ、 ２．３−ジヒドロピラン３０．２８ｇお
よびカンファーｌロースルホン酸３．４８ｇを無水ジエ
チルエーテル１５０ｍ１に溶解し、水冷下３０分、室温
で一夜攪拌した０反応後、ジエチルエーテル１８０ｍ１
を加え、飽和重曹水、水、飽和塩化ナトリウム水の順に
洗い、無水硫酸マグネシウムで乾燥後溶媒を減圧留去し
て、標記の化合物を定量的に得た。油状物質。(R)-(÷)-methyl lactate (manufactured by Daicel Corporation) 3
1.23 g, 30.28 g of 2,3-dihydropyran, and 3.48 g of camphorulose sulfonic acid were dissolved in 150 ml of anhydrous diethyl ether, and stirred under water cooling for 30 minutes and at room temperature overnight. After the reaction, 180 ml of diethyl ether was dissolved.
The mixture was washed with saturated sodium bicarbonate solution, water, and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to quantitatively obtain the title compound. oily substance.
’Ｈ−ＮＭＲ（ＣＤＣＩｓ ）δ：
１．２０．１．２６（ｔｏｔａｌ ３Ｈ，ｄ、 Ｊ＝６
．５Ｈｚ）。'H-NMR (CDCIs) δ: 1.20.1.26 (total 3H, d, J=6
．． 5Hz).
１．３６−２．０２（８Ｈ，ｍ）、 ３．７４（３Ｈ，
ｓ）。1.36-2.02 (8H, m), 3.74 (3H,
s).
３．３２−４．０２（２Ｈ，ｍ）、 ４．２２．４．４
４（ｔｏｔａｌ ＩＨ。3.32-4.02 (2H, m), 4.22.4.4
4 (total IH.
ｅａｃｈ ｑ、 Ｊ＝７Ｈｘ）、 ４．６４−４．７８
．４．９０−５．０２（ｔｏｔａｌ ＩＨ，ｍ）
無水ジエチルエーテル８００ｍ１にリチウムアルミニウ
ムハイドライド２５．７ｇを懸濁させ、氷冷攪拌下に、
Ａ−３、１で得た化合物５７．０９ｇを無水ジエチルエ
ーテル２００ｍ１に溶解した溶液を滴下した０次いで室
温で１時間攪拌し、さらに２時間加熱還流した。室温で
一夜静置後、再度氷冷し、水２５．７ｍｌ、１銚水酸化
ナトリウム水溶液２５．７ｍｌ、水７７．１ｍｌの順に
加えた。不溶物を濾去し、濾液を無水硫酸マグネシウム
で乾燥後、溶媒を減圧留去して得た残渣を減圧蒸留し、
標記の化合物をジアステレオマーの混合物として得た。each q, J=7Hx), 4.64-4.78
．． 4.90-5.02 (total IH, m) 25.7 g of lithium aluminum hydride was suspended in 800 ml of anhydrous diethyl ether and stirred under ice cooling.
A solution of 57.09 g of the compound obtained in A-3, 1 dissolved in 200 ml of anhydrous diethyl ether was added dropwise.Then, the mixture was stirred at room temperature for 1 hour, and further heated under reflux for 2 hours. After standing overnight at room temperature, the mixture was cooled on ice again, and 25.7 ml of water, 25.7 ml of a 1-part aqueous solution of sodium hydroxide, and 77.1 ml of water were added in this order. Insoluble matters were removed by filtration, the filtrate was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was distilled under reduced pressure.
The title compound was obtained as a mixture of diastereomers.
未習；沸点：８６〜９０．５℃（４，５〜５ｍｍＨｇ）
４０．２１ｇ 。Unlearned; Boiling point: 86-90.5℃ (4.5-5mmHg)
40.21g.
初後留４．４５ｇ。The initial amount is 4.45g.
’Ｈ−ＮＭＲ（ＣＤＣＩ、 ）δ：
１．１３．１．２２（ｔｏｔａｌ ３Ｈ，ｄ、 Ｊ＝６
．５８ｘ）。'H-NMR (CDCI, ) δ: 1.13.1.22 (total 3H, d, J=6
．． 58x).
１．３３−１．９７（６Ｈ，ａ＋）、 ２．２１１Ｈ，
ｔ−１１ｋｅ。1.33-1.97 (6H, a+), 2.211H,
t-11ke.
Ｊ”５．５Ｈｚ）、 ３．２８−４．１３（５Ｈ，Ｌｌ
ｌ）。J"5.5Hz), 3.28-4.13(5H, Ll
l).
４．４８−４．８１ （１）１． ｎ＋）実施例１に準
じ、２．３−ジフルオロ−６−ニトロフエツー／ｌ／
（ＩＶ、 Ｘａ−Ｘｂ＝Ｆ）、１２．２１ｇ、 ２−０
−（テトラヒドロピラン−２−イル） −（Ｒ）−プロ
パン−１，２−ジオール（ＩＩＩ−Ｒ，Ｒｃ−ＴＨＰ）
、１１．７８ｇおよびフェノールに対し１．３当量のミ
ツノブ試薬より ２０．４９ｇの標記化合物を得た。油
状物質。4.48-4.81 (1)1. n+) According to Example 1, 2,3-difluoro-6-nitrofetu/l/
(IV, Xa-Xb=F), 12.21g, 2-0
-(tetrahydropyran-2-yl) -(R)-propane-1,2-diol (III-R,Rc-THP)
, 11.78 g and 1.3 equivalents of Mitsunobu reagent based on phenol, 20.49 g of the title compound was obtained. oily substance.
’Ｈ−ＮＭＲ（ＣＤＣ１ａ ）δ ：
１．２８． １．３２（ｔｏｔａｌ ３Ｈ，ｄ、
Ｊ−６Ｈｚ）。'H-NMR (CDC1a) δ: 1.28. 1.32 (total 3H, d,
J-6Hz).
１．４０−１．９４（６Ｈ，ｆｆ１）、 ３．３４−
４．４４（５Ｈ，り。1.40-1.94 (6H, ff1), 3.34-
4.44 (5H, Ri.
４．８８−４．８６（ＩＨ，ｍ）、 ７．００（ＩＨ
，ｄｄｄ、 Ｊ−７，９ａｎｄ９．５Ｈｚ）、 ７．
６８（ＬＨ，ｄｄｄ、 Ｊ−２，５，５，５ａｎｄ ７
Ｈ２）実施例２０で得た化合物６．３５ｇから、実施例
７の方法に準じて標記の化合物４．８２ｇを得た。油状
物質。4.88-4.86 (IH, m), 7.00 (IH
, ddd, J-7,9and9.5Hz), 7.
68 (LH, ddd, J-2, 5, 5, 5 and 7
H2) From 6.35 g of the compound obtained in Example 20, 4.82 g of the title compound was obtained according to the method of Example 7. oily substance.
’Ｈ−ＮＭＲ（ＣＤＣＩｓ ）δ：
１．２６（３Ｈ，ｄ、 Ｊ−６Ｈｚ）、 ２．８９（Ｉ
Ｈ，ｄ、 Ｊ−２，５）１ｚ）。'H-NMR (CDCIs) δ: 1.26 (3H, d, J-6Hz), 2.89 (I
H, d, J-2, 5) 1z).
３．９５−４．４６（３Ｈ，ａ＋）、 ７．０３（ＩＨ
，ｄｄｄ、 Ｊ−７，９ａｎｄ９．５Ｈｚ）、 ７．７
５（ＩＨ，ｄｄｄ、 Ｊ＝２．５．５．５ ａｎｄ ７
Ｈｚ）実施例２１で得た化合物４．８２ｇを実施例１１
の方法に準じて、ピリジン１２ｍ１中トシルクロライド
４．５３ｇを用いてトシル化し、標記化合物６．７４ｇ
を得た。3.95-4.46 (3H, a+), 7.03 (IH
,ddd, J-7,9and9.5Hz), 7.7
5 (IH, ddd, J=2.5.5.5 and 7
Hz) 4.82 g of the compound obtained in Example 21 was added to Example 11.
Tosylation was carried out using 4.53 g of tosyl chloride in 12 ml of pyridine according to the method of
I got it.
融点： ８７．５〜６８℃
’Ｈ−ＮＭＲ（ＣＤＣＩｓ ）δ：
１．４３（３）１． ｄ、 Ｊ−６Ｈｚ）、 ２．４１
（３Ｈ，Ｓ）。Melting point: 87.5-68°C 'H-NMR (CDCIs) δ: 1.43 (3) 1. d, J-6Hz), 2.41
(3H, S).
４．０８−４．４０（２Ｈ，ｆｆ１）、 ４．７６−
５．０８（ＩＨ，■）。4.08-4.40 (2H, ff1), 4.76-
5.08 (IH, ■).
７．０４（ＬＨ，ｄｄｄ、 Ｊ−７，９ａｎｄ ９．５
Ｈｚ）。7.04 (LH, ddd, J-7, 9 and 9.5
Hz).
７．３２．７．８０（ｅａｃｈ ２Ｈ，ｅａｃｈ ｄ、
Ｊ−８，５Ｈｚ）実施例２２で得た化合物５８１ｍｇ
をエタノール２０■ｌに溶解し、５零パラジウム−炭素
、２００ｍｇを加え、常温常圧で接触還元した。理論量
の水素の吸収を確認した後、触媒を濾去し溶媒を減圧留
去した。7.32.7.80 (each 2H, each d,
J-8,5Hz) 581 mg of the compound obtained in Example 22
was dissolved in 20 μl of ethanol, 200 mg of 5-zero palladium on carbon was added, and catalytic reduction was carried out at room temperature and pressure. After confirming that the theoretical amount of hydrogen had been absorbed, the catalyst was filtered off and the solvent was distilled off under reduced pressure.
得られた残渣をシリカゲルカラムクロマトグラフィに付
し、標記の化合物５２０ｍｇを得た。The obtained residue was subjected to silica gel column chromatography to obtain 520 mg of the title compound.
融点：３７〜３８℃
’Ｈ−ＮＭＲ（ＣＤＣＩｓ ）δ：
１．３４（３Ｈ，ｄ、 Ｊ＝６．５Ｈｚ）、 ２．４４
（３）１． ｓ）。Melting point: 37-38°C 'H-NMR (CDCIs) δ: 1.34 (3H, d, J=6.5Hz), 2.44
(3)1. s).
３．５０（２Ｈ，ｂｒ ｓ）、 ４．０２−４．１４
（２Ｈ，ｍ）。3.50 (2H, br s), 4.02-4.14
(2H, m).
４．０２−４．１４（２Ｈ，ｍ）、 ４．８０−５．
１４（ＩＨ，ｍ）。4.02-4.14 (2H, m), 4.80-5.
14 (IH, m).
８．３８（ＩＨ，ｄｄｄ、 Ｊ＝２．５． ５．５
ａｎｄ ７Ｈｚ）。8.38 (IH, ddd, J=2.5. 5.5
and 7Hz).
６．７１（１８，ｄｄｄ、Ｊ−１，９ａｎｄ ９．５
Ｈｚ）。6.71 (18, ddd, J-1, 9 and 9.5
Hz).
７．３５． ７．８５（ｅａｃｈ ２Ｈ，ｅａｃｈ ｄ
、 Ｊ−８，５Ｈｚ）実施例２３及び実施例１４の方
法に従い、７７５ＩＩ１ｇの２．３−ジフルオロ−６−
ニトロ−［［（Ｒ）−（２−パラトルエンスルホニルオ
キシプロビル）］オキシ］ベンゼン（ＸＩ−Ｒ，Ｘａ−
Ｘｂ−Ｆ、 Ｒｄ−Ｔｓ）から標記の化合物２８２ｍｇ
を得た。物理定数は標品のそれと一致した。7.35. 7.85 (each 2H, each d
, J-8,5Hz) According to the method of Example 23 and Example 14, 1 g of 775II 2,3-difluoro-6-
Nitro-[[(R)-(2-paratoluenesulfonyloxyprobyl)]oxy]benzene (XI-R, Xa-
282 mg of the title compound from Xb-F, Rd-Ts)
I got it. The physical constants were consistent with those of the standard product.
（Ａ ｒｉｃ、 Ｂｉｏｌ、 Ｃｈｅｍ、、 ５１．（
５）、 １２６５−１２７０（１９８７）、ＥＰ−＾−
０．２０６．２８３）
２．３−ジフルオロ−６−二トロー［［（Ｒ）−２−（
テトラヒドロピラン−２−イル）オキシプロピル］オキ
シ】−ベンゼン（１−Ｒ，Ｘａ＝Ｘｂ−Ｆ、 Ｒｃ−Ｔ
ＨＰ）、４７６ｍｇをエタノール２０ｍ１に溶解し、情
パラジウムー炭素２００ｍｇを添加し、常温常圧で接触
還元した。理論量の水素の吸収を確認した後、触媒を濾
去し、溶媒を減圧留去して得た残漬をシリカゲルカラム
クロマトグラフィで精製して標記の化合物３８５ｒｎｇ
をジアステレオマーの混合物として得た。油状物質。(Aric, Biol, Chem,, 51.(
5), 1265-1270 (1987), EP-^-
0.206.283) 2.3-difluoro-6-nitro[[(R)-2-(
Tetrahydropyran-2-yl)oxypropyl]oxy]-benzene (1-R, Xa=Xb-F, Rc-T
HP), 476 mg was dissolved in 20 ml of ethanol, 200 mg of palladium on carbon was added, and catalytic reduction was carried out at room temperature and pressure. After confirming the absorption of the theoretical amount of hydrogen, the catalyst was filtered off, and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography to obtain 385rng of the title compound.
was obtained as a mixture of diastereomers. oily substance.
’ ）ｌ−ＮＭＲ（ＣＤＣＩｊ）δ二
１．２３．１．３３（ｔｏｔａｌ ３Ｈ，ｅａｃｈ ｄ
、 Ｊ−６Ｈｚ）。) l-NMR (CDCIj) δ2 1.23.1.33 (total 3H, each d
, J-6Hz).
１．３６−１．９８（６Ｈ，ｍ）、 ３．３６−４．３
２（５）１． ｍ）。1.36-1.98 (6H, m), 3.36-4.3
2(5)1. m).
４．７０−４．！１Ｇ（２）１． ｍ）、 ８．３９（
２）１． ｄｄｄ、 Ｊ−２，５゜５．５ ａｎｄ ７
Ｈｚ）、 ６．７２（ＩＨ，ｄｄｄ、 Ｊ＝７．９ ａ
ｎｄ９．５）１ｚ）
Ｒ−Ｅｔ）
実施例２５と同様に処理して６．３５ｇの２．３−ジフ
ルオロ−６−二トロー［［（Ｒ）−２−（テトラハイド
ロピラン−２−イル）プロピル］オキシ］ベンゼン（Ｉ
−Ｒ。4.70-4. ! 1G(2)1. m), 8.39(
2)1. ddd, J-2, 5゜5.5 and 7
Hz), 6.72 (IH, ddd, J=7.9 a
nd9.5) 1z) R-Et) Treated as in Example 25 to obtain 6.35 g of 2,3-difluoro-6-nitro[[(R)-2-(tetrahydropyran-2-yl) propyl]oxy]benzene (I
-R.
Ｘａ＝Ｘｂ−Ｆ、 Ｒｅ−ＴＨＰ）から得た２、３−ジ
フルオロ−６−アミノ−［［（Ｒ）−２−（テトラハイ
ドロビラン−２−イル）プロピル］オキシ］ベンゼン（
ＶＩ−Ｒ，Ｘａ−Ｘｂ−Ｆ。2,3-difluoro-6-amino-[[(R)-2-(tetrahydrobyran-2-yl)propyl]oxy]benzene (Xa = Xb-F, Re-THP)
VI-R, Xa-Xb-F.
Ｒｃ＝ＴＨＰ）を精製せずに用い、これに ＥＭＭＥ、
４．３７ｇを加え、常圧で１５０℃に加熱しながら
１．５時間攪拌した。さらに減圧下同温で３０分加熱し
た後、無水エタノール６０ｍ１及びピリジニウム・トシ
レート６４０ｍｇを加えて室温で一夜攪拌した。エタノ
ールを留去し残漬を酢酸エチルに溶解して、１規定塩酸
、飽和重曹水、及び飽和塩化ナトリウム水の順に洗った
。有機層を無水硫酸マグネシウムで乾燥後、濃縮乾固し
て得た残漬をシリカゲルカラムクロマトグラフィに付し
、標記の化合物５．５６ｇを得た。Rc=THP) was used without purification, and this was treated with EMME,
Add 4.37g and heat to 150℃ under normal pressure.
Stirred for 1.5 hours. After further heating at the same temperature under reduced pressure for 30 minutes, 60 ml of absolute ethanol and 640 mg of pyridinium tosylate were added and stirred overnight at room temperature. The ethanol was distilled off, the residue was dissolved in ethyl acetate, and the solution was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride in this order. The organic layer was dried over anhydrous magnesium sulfate, concentrated to dryness, and the resulting residue was subjected to silica gel column chromatography to obtain 5.56 g of the title compound.
融点二８８〜９０℃
’Ｈ−ＮＭＲ（ＣＤＣＩｓ ）δ：
１．２５−１．４５（９）１． ｍ）、 ３．５４（Ｉ
Ｈ，ｄ、 Ｊ−４，５Ｈｚ）。Melting point: 288-90°C 'H-NMR (CDCIs) δ: 1.25-1.45 (9) 1. m), 3.54(I
H, d, J-4,5Hz).
３、＆６−４．４６（７Ｈ，ｌ）、 ６．７６−７．１
０（２Ｈ，ａｔ）。3, &6-4.46 (7H, l), 6.76-7.1
0(2H, at).
８．４９（ＩＨ，ｄ、 Ｊ−１４，５Ｈｚ）施例２７：
（Ｓ）−ジエチル （７，８−ジフルオロ−Ｘｂ−
Ｆ、 Ｒ−Ｅｔ）
実施例２６で得た化合物５８０ｍｇを、実施例４の方法
に準じ、 １．３当量のミツノブ試薬を用いて閉環反応
に付し、標記の化合物をほぼ定量的に得た。8.49 (IH, d, J-14, 5Hz) Example 27:
(S)-diethyl (7,8-difluoro-Xb-
F, R-Et) 580 mg of the compound obtained in Example 26 was subjected to a ring-closing reaction using 1.3 equivalents of Mitsunobu reagent according to the method of Example 4, and the title compound was obtained almost quantitatively. .
’）ｌ−ＮＭＲ（ＣＤＣｈ ）δ：
１．２２−１．４２（９Ｈ，ｍ）、 ３．９０−４．４
４（７Ｈ，ｍ）。') l-NMR (CDCh) δ: 1.22-1.42 (9H, m), 3.90-4.4
4 (7H, m).
６．７４−６．８８（２Ｈ，ｍ）、 ７．７８（ＩＨ，
ｓ）実施例２６で得た化合物２．４３ｇを実施例５の方
法に準じ、ピリジン４．５ＩＩｌに溶解して、トシルク
ロライド １．４９ｇを用いてトシル化し、標記の化合
物３．２６ｇを得た。6.74-6.88 (2H, m), 7.78 (IH,
s) According to the method of Example 5, 2.43 g of the compound obtained in Example 26 was dissolved in 4.5 IIl of pyridine and tosylated using 1.49 g of tosyl chloride to obtain 3.26 g of the title compound. .
融点：６８〜６９℃
’Ｈ−ＮＭＲ（ＣＤＣＩｓ ）δ ；１．３３，１．
３８（ｅａｃｈ ３Ｈ，ｅａｃｈ ｔ、Ｊ−７Ｈｚ
）。Melting point: 68-69°C 'H-NMR (CDCIs) δ; 1.33, 1.
38 (each 3H, each t, J-7Hz
).
１．５０（３Ｈ，ｄ、Ｊ−ＨＩｚ）、２．４０（３）１
．ｓ）。1.50 (3H, d, J-HIz), 2.40 (3) 1
．． s).
４．０２−４．４２（６１，ｍｌ 、４．９６（１８，
５Ｉｘｔｅｔ−目ｋｅ）。4.02-4.42 (61, ml, 4.96 (18,
5Ixtet-th ke).
６．８５−７．００（２Ｈ，ｍ）、７．２８，７．７９
（ｅａｃｈ ２Ｈ。6.85-7.00 (2H, m), 7.28, 7.79
(each 2H.
ｅａｃｈ ｄ、Ｊ＝８．５Ｈｚ）、８．３７（ＩＨ，
ｄ、Ｊ−１４，５Ｈｚ）Ｘｂ−Ｆ、Ｒ−Ｅｔ）
実施例２８で得た化合物７９１ｍｇを炭酸カリウム２０
７ｍｇ及び触媒量の１８−クラウン−６−エーテルを用
いて実施例６に準じた方法で閉環反応に付し、標記の化
合物を定量的に得た。油状物質。each d, J=8.5Hz), 8.37(IH,
d, J-14,5Hz) Xb-F, R-Et) 791 mg of the compound obtained in Example 28 was added with 20
A ring-closing reaction was carried out using 7 mg and a catalytic amount of 18-crown-6-ether in the same manner as in Example 6 to quantitatively obtain the title compound. oily substance.
Ｘａ＝Ｘｂ−Ｆ）
２．３−ジフルオロ−６−二トロー［［（Ｒ）−２−ヒ
ドロキシプロピル］オキシ］ベンゼン（ＶＩＩＩ−Ｒ，
Ｘａ−Ｘｂ−Ｆ）、３．１ｇをエタノール５０ｍ１に溶
解し、５９６パラジラム−炭素５００ｍｇを添加し、常
温常圧で接触還元した。反応終了後、触媒を濾去し溶媒
を減圧留去して得た残漬をシリカゲルカラムクロマトグ
ラフィで精製し、標記の化合物２．４７ｇを得た。Xa=Xb-F) 2.3-difluoro-6-nitro[[(R)-2-hydroxypropyl]oxy]benzene (VIII-R,
Xa-Xb-F), 3.1 g was dissolved in 50 ml of ethanol, 500 mg of 596 palladylam-carbon was added, and catalytic reduction was carried out at room temperature and pressure. After the reaction was completed, the catalyst was filtered off and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography to obtain 2.47 g of the title compound.
融点＝４７〜４８℃
’ Ｈ−ＮＭＲ（ＣＤＣｌ２ ）δ：
１．２１（３Ｈ，ｄ、 ＪＪ、５Ｈｘ）、 ３．２５−
４．３０（６Ｈ，ｍ）。Melting point = 47-48°C' H-NMR (CDCl2) δ: 1.21 (3H, d, JJ, 5Hx), 3.25-
4.30 (6H, m).
６．４３（ＩＨ，ｄｄｄ、 Ｊ−２，５，５，５ａｎｄ
７Ｈｚ）。6.43 (IH, ddd, J-2, 5, 5, 5 and
7Hz).
７．７６（１Ｂ、 ｄｄｄ、 Ｊ＝７．９ ａｎｄ ９
．５Ｈｚ）七呈吐
実施例２１の方法で得た化合物９．３０ｇより実施例８
の方法に準じて、標題化合物１１．９２ｇを得た。7.76 (1B, ddd, J=7.9 and 9
．． Example 8 from 9.30 g of the compound obtained by the method of Example 21
According to the method of 11.92 g of the title compound was obtained.
融点：１０４〜１０５℃
’Ｈ−ＮＭＲ（ＣＤＣＩｓ ）δ：
１．２８（３Ｍ、 ｄ、 Ｊ−６，５８Ｚ）、 ３．４
４（ＩＨ，ｄ、Ｊ−４，５Ｈ２）。Melting point: 104-105°C 'H-NMR (CDCIs) δ: 1.28 (3M, d, J-6,58Z), 3.4
4 (IH, d, J-4, 5H2).
３．７９．３．８７（ｅａｃｈ ３Ｈ，ｅａｃｈ ｓ）
。3.79.3.87 (each 3H, each s)
.
６．７６−７．１１（２）１． ｍ）、 ８．５２（Ｉ
Ｈ，ｄ、 Ｊ−１４，５８Ｚ）例３２： ２，３−ジ
フルオロ−６−（２，２−ジメトキシ実施例３１で得た
化合物１０．３６ｇより、実施例５に準じた方法によっ
て、標記の化合物１３．５２ｇを得た。6.76-7.11 (2) 1. m), 8.52(I
H, d, J-14,58Z) Example 32: 2,3-difluoro-6-(2,2-dimethoxy) From 10.36 g of the compound obtained in Example 31, the title compound was obtained by a method according to Example 5. 13.52 g of compound was obtained.
融点：９２〜９３℃
’Ｈ−ＮＭＲ（ＣＤＣＩｓ ）δ：
１．５１（３）１． ｄ、 Ｊ−６，５Ｈ１）、 ２．
４１（３１（、Ｓ）。Melting point: 92-93°C 'H-NMR (CDCIs) δ: 1.51 (3) 1. d, J-6,5H1), 2.
41(31(,S).
３．８２．３．８８（ｅａｃｈ ３）１． ｅａｃｈ
ｓ）。3.82.3.88 (each 3)1. each
s).
４．０７−４．４４（２Ｈ，ｍ）、 ４．８３−５．１
６（ＩＨ，ｍ）。4.07-4.44 (2H, m), 4.83-5.1
6 (IH, m).
６．８０−７．１５（２）１． ｍ）、 ？、３２．７
．８５（ｅａｃｈ ２）１゜ｅａｃｈ ｄ、 Ｊ＝８Ｈ
ｚ）、 ８．４６（ＬＨ，ｄ、 Ｊ−１４Ｈｚ）■ご工
１士畦
実施例３２で得た化合物４．９９ｇより実施例６の方法
に準じて、標記の化合物を３．１２ｇ得た。6.80-7.15(2)1. m), ? , 32.7
．． 85 (each 2) 1゜each d, J=8H
z), 8.46 (LH, d, J-14Hz) ■Product 1st grade From 4.99 g of the compound obtained in Example 32, 3.12 g of the title compound was obtained according to the method of Example 6. .
融点：１０８〜１０９℃
’Ｈ−ＮＭＲ（ＣＤＣ１３）δ ：
１．３２（３Ｈ，ｄ、 Ｊ−７）１ｚ）、 ３．８１
． ３．８５（ｅａｃｈ ３）１゜ｅａｃｈ ｓ）、
３．９４−４．６３（３Ｍ、 ｍ）。Melting point: 108-109°C 'H-NMR (CDC13) δ: 1.32 (3H, d, J-7) 1z), 3.81
．． 3.85 (each 3) 1゜each s),
3.94-4.63 (3M, m).
６．８０（２）１． ｑ−１ｉｋｅ） 、 ７．８２
（ＬＨ，ｓ）独５吐
水素化ナトリウム（８峙） ２０７ｍｇを脱脂して無水
トルエン４ｍｌに懸濁し、水冷攪拌下にこの懸濁液に２
−〇−テトラヒドロピラニルプロパン−１，２−ジオー
ル（ＩＩＩ、 Ｒｃ＝Ｔ）ＩＰ） ７９３ｍｇを無水ト
ルエン３ｍｌに溶解した溶液を滴下し、同温度にて３０
分間攪拌した０次いで、２，３．４−トリフルオロニト
ロベンゼン（Ｉｌ、 Ｘａ＝Ｘｂ−Ｘｃ−Ｆ） ７９３
ｍｇを無水トルエン３ｍｌに溶解した溶液を水冷攪拌下
に滴下し、約５℃の外温で２４時間攪拌した。反応後、
氷水と酢酸エチルを加えて振盪し有機層を分離した。有
機層を無水硫酸マグネシウムにて乾燥して溶媒を減圧留
去し、２．３−ジフルオロ−６−ニトロ−［［２−（テ
トラヒドロビラン−２−イル）オキシプロピル］オキシ
コベンゼン（Ｉ、 Ｘａ−Ｘｂ−Ｆ、 Ｒｃ＝ＴＨＰ）
の組体を定量的に得た。これは精製すること無く、無水
エタノール１３．５ｍｌに溶解し、ピリジニウムトシレ
ート １４５ｍｇを加え室温で２４時間攪拌した後、１
時間加熱還流した。反応後、エタノールを留去し、残留
物を酢酸エチルに溶解して１規定塩酸、５零重曹水およ
び水で洗浄した。有機層を無水硫酸マグネシウムで乾燥
し、溶媒を減圧留去して得た残留物をシリカゲルカラム
クロマトグラフィーにて精製し、標題化合物９０２ｍｇ
を油状物質として得た。6.80(2)1. q-1ike), 7.82
(LH,s) 207 mg of German sodium hydride (8 parts) was defatted and suspended in 4 ml of anhydrous toluene, and added to this suspension under water cooling and stirring.
-〇-Tetrahydropyranylpropane-1,2-diol (III, Rc = T)
0 then 2,3.4-trifluoronitrobenzene (Il, Xa=Xb-Xc-F) 793
A solution prepared by dissolving 1.0 mg in 3 ml of anhydrous toluene was added dropwise while stirring under water cooling, and the mixture was stirred at an external temperature of about 5° C. for 24 hours. After the reaction,
Ice water and ethyl acetate were added and shaken to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and 2,3-difluoro-6-nitro-[[2-(tetrahydrobilan-2-yl)oxypropyl]oxycobenzene (I, Xa -Xb-F, Rc=THP)
were obtained quantitatively. This was dissolved in 13.5 ml of absolute ethanol without purification, 145 mg of pyridinium tosylate was added, and the mixture was stirred at room temperature for 24 hours.
The mixture was heated to reflux for an hour. After the reaction, ethanol was distilled off, and the residue was dissolved in ethyl acetate and washed with 1N hydrochloric acid, 50% sodium bicarbonate solution, and water. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 902 mg of the title compound.
was obtained as an oil.
’Ｈ−ＮＭＲ（ＣＤＣＩｓ） δ：
１．２５（３Ｈ，ｄ、 ＪＪＨｚ）、 ３．００（ＩＨ
，ｂｒ ｄ。'H-NMR (CDCIs) δ: 1.25 (3H, d, JJHz), 3.00 (IH
,br d.
Ｊ＝２．５）ｌｚ） 、 ３．９９−４．４３ （３Ｈ
，ｍ） 。J=2.5)lz), 3.99-4.43 (3H
, m).
７．０３（ＩＨ，ｄｄｄ、 Ｊ＝７．９ ａｎｄ ９．
５Ｈｚ）。7.03 (IH, ddd, J=7.9 and 9.
5Hz).
７．７４（ＩＨ，ｄｄｄ、 Ｊ＝２．５．５．５ ａｎ
ｄ ７Ｈｚ）Ｘａ＝Ｘｂ−Ｆ）
水素化ナトリウム７２０ａ＋ｇを無水トルエン１２ｍｌ
に懸濁し、この懸濁液に２−〇−テトラヒドロピラニル
ー（Ｒ）−プロパン−１，２−ジオール（ＩＩＩ−Ｒ，
Ｒｃ−ＴＨＰ）、２．８８ｇを無水トルエン １２ｍ１
に溶解した溶液を水冷攪拌下に滴下し、水冷下で３０
分間、室温で１０分間攪拌した。この溶液を、２，３．
４−トリフルオロニトロベンゼン（ＩＩ、 Ｘａ−Ｘｂ
−Ｘｃ−Ｆ）、２．８６ｇを無水トルエン１２ａ＋１に
溶解した溶液中に水冷下で攪拌しながら滴下し、約５℃
で一夜攪拌した。反応後、氷水とベンゼンを加え振盪後
有機層を分離した。有機層を無水硫酸マグネシウムにて
乾燥し、溶媒を減圧留去して、２，３−ジフルオロ −
６−ニトロ−［［（Ｒ）−２−（テトラヒドロピラン−
２−イル）オキシプロピル］オキシ］ベンゼン（Ｉ−Ｒ
，Ｘａ＝Ｘｂ−Ｆ、 Ｒｃ−ＴＨＰ）の枢体を定量的に
得た。これは精製すること無く、無水エタノール３８ｍ
１に溶解し、ピリジニウムトシレート ４５０ｍｇを加
え１時間加熱還流した。7.74 (IH, ddd, J=2.5.5.5 an
d 7Hz) Xa=Xb-F) 720a+g of sodium hydride in 12ml of anhydrous toluene
2-0-tetrahydropyranyl(R)-propane-1,2-diol (III-R,
Rc-THP), 2.88g in anhydrous toluene 12ml
was added dropwise with stirring under water cooling, and the solution was added dropwise under stirring under water cooling.
and stirred at room temperature for 10 minutes. Add this solution to 2, 3.
4-Trifluoronitrobenzene (II, Xa-Xb
-Xc-F), was added dropwise to a solution of 2.86 g dissolved in anhydrous toluene 12a+1 while stirring under water cooling, and the mixture was added dropwise to about 5°C.
The mixture was stirred overnight. After the reaction, ice water and benzene were added and the organic layer was separated after shaking. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and 2,3-difluoro-
6-nitro-[[(R)-2-(tetrahydropyran-
2-yl)oxypropyl]oxy]benzene (I-R
, Xa=Xb-F, Rc-THP) were quantitatively obtained. This is 38ml of absolute ethanol without being purified.
1, 450 mg of pyridinium tosylate was added thereto, and the mixture was heated under reflux for 1 hour.
反応後、エタノールを減圧留去し、残留物を酢酸エチル
に溶解し、１規定塩酸、５零重曹水および水で洗浄した
。これを無水硫酸マグネシウムにて乾燥後溶媒を減圧留
去して得た残留物をシリカゲルカラムクロマトグラフィ
ーにて精製し、油状物質の標題化合物３．２０ｇを得た
。After the reaction, ethanol was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate and washed with 1N hydrochloric acid, 50% sodium bicarbonate solution, and water. This was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 3.20 g of the title compound as an oil.
’Ｈ−ＮＭＲ（ＣＤＣｈ） δ；
１．２６（３）１． ｄ、 Ｊ−６Ｈｚ）、 ２．８９
（１８，ｂｒ ｄ、 Ｊ−２，５）１ｚ）。'H-NMR (CDCh) δ; 1.26 (3) 1. d, J-6Hz), 2.89
(18,br d, J-2,5)1z).
３．９５−４．４６（３Ｌ ｍ）、 ７．０３（ＩＨ，
ｄｄｄ、 Ｊ−７，９ａｎｄ９．５Ｈｚ）、 ７．７５
（１１（、ｄｄｄ、 Ｊ・２．５．５．５ ａｎｄ ７
Ｈｚ）Ｘａ＝Ｘｂ−Ｆ）
実施例３５の方法に準じて２−０−テトラヒドロピラニ
ル−（Ｓ）−プロパン−１，２−ジオール（ＩＩＩ−５
，Ｒｃ−ＴＨＰ）、２．８８ｇ及び２，３．４−トリフ
ルオロニトロベンゼン（ＩＩ、 Ｘａ−Ｘｂ＝Ｘｃ＝Ｆ
）、２．６６ｇとから油状の標題化合物３．０３ｇを得
た。3.95-4.46 (3L m), 7.03 (IH,
ddd, J-7,9and9.5Hz), 7.75
(11(, ddd, J・2.5.5.5 and 7
Hz)Xa=Xb-F) 2-0-tetrahydropyranyl-(S)-propane-1,2-diol (III-5
, Rc-THP), 2.88 g and 2,3.4-trifluoronitrobenzene (II, Xa-Xb=Xc=F
), 3.03 g of the oily title compound was obtained from 2.66 g.
’Ｈ−ＮＭＲ（ＣＤＣ１３） δ：
１．２６（３Ｈ，ｄ、 Ｊ＝６Ｈｚ）、 ２．８８（Ｉ
Ｈ，ｄ、 Ｊ−２，５Ｈｚ）。'H-NMR (CDC13) δ: 1.26 (3H, d, J=6Hz), 2.88 (I
H, d, J-2,5Hz).
３．９６−４．４４（３Ｈ，ｍｌ、 ７．０３（１１（
、ｄｄｄ、 Ｊ−７，９ａｎｄ９．５Ｈｚ）、 ７．
７５（ＩＨ，ｄｄｄ、 Ｊ＝２．５． ５．５ ａ
ｎｄ ７Ｈｚ）なお、実施例３５及び３６で得た化合
物についてはピリジン中で３．５−ジニトロベンゾイル
化後、ダイセル社のキラルセル・ＯＤ・カラムを使用し
、エタノールを溶出溶媒とする高速液体カラムクロマト
グラフィーにて各々が単一ピークとして観測され、ラセ
ミ化していないことを確認した。3.96-4.44(3H, ml, 7.03(11(
, ddd, J-7,9and9.5Hz), 7.
75 (IH, ddd, J=2.5. 5.5 a
The compounds obtained in Examples 35 and 36 were subjected to 3,5-dinitrobenzoylation in pyridine, followed by high performance liquid column chromatography using Daicel's Chiralcel OD column and ethanol as the eluent. Each was observed as a single peak in the graph, and it was confirmed that there was no racemization.
（Ｒ） −（＋）−乳酸メチル（ダイセル株式会社製）
、１５６．１５ｇ、 ２．３−ジヒドロビラン１５１．
４２ｇおよびカンファー１０−スルホン酸１７．４２ｇ
を無水１．２−ジクロロエタン７５０１に氷冷下に溶解
し、同温度で一夜攪拌した６反応後、１．２−ジクロロ
エタン９０ｈｌを加え、飽和重曹水、水、飽和塩化ナト
リウム水の順に洗い、無水硫酸マグネシウムで乾燥した
。(R) -(+)-Methyl lactate (manufactured by Daicel Corporation)
, 156.15g, 2,3-dihydrobilane 151.
42g and camphor 10-sulfonic acid 17.42g
was dissolved in anhydrous 1,2-dichloroethane 7501 under ice-cooling, and stirred overnight at the same temperature. After 6 reactions, 90 hl of 1,2-dichloroethane was added, and the mixture was washed with saturated sodium bicarbonate solution, water, and saturated sodium chloride solution in this order. Dry with magnesium sulfate.
溶媒を減圧留去して、標記の化合物を定量的に得た。油
状物質。The solvent was distilled off under reduced pressure to quantitatively obtain the title compound. oily substance.
無水１．２−ジクロロエタン７５０１に水素化ホウ素ナ
トリウム８５．１２ｇを懸濁させ、攪拌下に、＾−４，
１で得た化合物をメタノール２４３ｍ１に溶解した溶液
を内温を３０℃以下に保って滴下した。次いで同温度で
メタノール１２２ｍ１を滴下した。室温で１時間攪拌し
、反応液に水２２００ｍ１を加えしばらく攪拌後、有機
層を分離した。水層を１．２−ジクロロエタンで抽出し
て、有機層を合した。有機層を飽和塩化ナトリウム水溶
液で洗浄し、無水硫酸マグネシウムにて乾燥した。溶媒
を減圧留去して、残渣を減圧蒸留して標記の化合物１７
４ｇを得た。85.12 g of sodium borohydride was suspended in 7501 anhydrous 1,2-dichloroethane, and while stirring, ^-4,
A solution prepared by dissolving the compound obtained in 1 in 243 ml of methanol was added dropwise while keeping the internal temperature below 30°C. Next, 122 ml of methanol was added dropwise at the same temperature. After stirring at room temperature for 1 hour, 2200 ml of water was added to the reaction solution, and after stirring for a while, the organic layer was separated. The aqueous layer was extracted with 1,2-dichloroethane, and the organic layers were combined. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was distilled under reduced pressure to obtain the title compound 17.
4g was obtained.
いずれも、各種機器データは参考例Ａ−３にて得られた
ものに一致した。In all cases, various device data matched those obtained in Reference Example A-3.
実施例２６と同様にして得た化合物（Ｘ−Ｒ，Ｘａ−Ｘ
ｂ−Ｆ、 Ｒ−Ｅｔ）、３．００ｇをピリジン１５ａ＋
１に溶解し、水冷攪拌下にメタンスルホニルクロライド
１．０１ｇヲ加え、室温で２時間攪拌した。溶媒を減
圧留去し、残留物を１．２−ジクロロエタンにて抽出し
た。抽出液を、ＩＮ塩酸、繋炭酸水素ナトリウム水溶液
、水で洗浄し、無水硫酸マグネシウムで乾燥した。Compound obtained in the same manner as Example 26 (X-R, Xa-X
b-F, R-Et), 3.00 g to pyridine 15a+
1, and 1.01 g of methanesulfonyl chloride was added thereto while stirring while cooling with water, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was extracted with 1,2-dichloroethane. The extract was washed with IN hydrochloric acid, aqueous sodium bicarbonate solution, and water, and dried over anhydrous magnesium sulfate.
乾燥した有機層にシリカゲル１．５ｇを加え、３０分攪
拌した後、不溶物を濾去した。溶媒を減圧留去し、残留
物をジイソプロピルエーテルで結晶化させた後集めた。1.5 g of silica gel was added to the dried organic layer, and after stirring for 30 minutes, insoluble matter was filtered off. The solvent was removed under reduced pressure and the residue was collected after crystallization from diisopropyl ether.
標記の化合物３．２１ｇを得た。3.21 g of the title compound was obtained.
融点ニア７〜８０℃
Ｊ−ＮＭＲ（ＣＤＣ１３） δ：
１．２２−１．４７（６Ｈ，ｍ）、 １．５８（３１（
、ｄ、 Ｊ−７）１ｚ）。Melting point near 7-80℃ J-NMR (CDC13) δ: 1.22-1.47 (6H, m), 1.58 (31 (
, d, J-7) 1z).
１．５０（３Ｈ，ｄ、 Ｊ−７Ｈ１）、 ３．１２（３
１（、Ｓ）。1.50 (3H, d, J-7H1), 3.12 (3
1(,S).
３．９８−４．８０ （６）１． ｍ） 、 ４．９５
−５．３５ （１）１． ｍ） 。3.98-4.80 (6)1. m), 4.95
-5.35 (1)1. m).
６．７９−７．１４（２）１． ｍｌ、 ８．４１（Ｌ
Ｈ，ｄ、 Ｊ＝１３．５Ｈ２）元素分析（％） ’
Ｃｌ８）１２３ＮＯ６５Ｆ２ として計算値 Ｃ４７
，８９８５，１３Ｎ ３．１０測定値 Ｃ４７，８４
８４，９７Ｎ ３．０２施例３８： ２，３−ジフ
ルオロ−６−（２，２−ジェトキシ実施例２６と同様に
して得た化合物（Ｘ−Ｒ，Ｘａ−Ｘｂ・Ｆ、 Ｒ−Ｅｔ
）、３．０Ｈｇを１．２−ジクロロエタン３０ｍ１に溶
解し、水冷攪拌下にトリエチルアミン０．９８ｇを加え
、さらに同温度でメタンスルホニルクロライド １．０
１ｇを攪拌下に加えた。室温で２時間攪拌して不溶物を
濾去した。濾液を１．２−ジクロロエタンにて希釈し水
洗後無水硫酸マグネシウムで乾燥した。乾燥した有機層
にシリカゲル１．５ｇを加え、３０分攪拌した後、不溶
物を濾去した。溶媒を減圧留去し、残漬をジイソプロピ
ルエーテルより結晶化後濾取した。標記の化合物３．２
７ｇを得た。融点、’Ｈ−ＮＭＲのデータは実施例３７
のそれと一致した。6.79-7.14 (2) 1. ml, 8.41 (L
H, d, J=13.5H2) Elemental analysis (%)'
Calculated value as Cl8)123NO65F2 C47
,8985,13N 3.10 measurement value C47,84
84,97N 3.02 Example 38: 2,3-difluoro-6-(2,2-jethoxy Compound obtained in the same manner as Example 26 (X-R, Xa-Xb・F, R-Et
), 3.0 Hg was dissolved in 30 ml of 1.2-dichloroethane, 0.98 g of triethylamine was added while stirring while cooling with water, and at the same temperature, 1.0 Hg of methanesulfonyl chloride was dissolved.
1 g was added under stirring. The mixture was stirred at room temperature for 2 hours and insoluble matter was filtered off. The filtrate was diluted with 1,2-dichloroethane, washed with water, and then dried over anhydrous magnesium sulfate. 1.5 g of silica gel was added to the dried organic layer, and after stirring for 30 minutes, insoluble matter was filtered off. The solvent was distilled off under reduced pressure, and the residue was crystallized from diisopropyl ether and collected by filtration. Title compound 3.2
7g was obtained. Melting point and 'H-NMR data are from Example 37.
It matched that of .
層側３９： （Ｓ）−ジエチル （７，８−ジフルオ
ロ−３−Ｆ、 Ｒ−Ｅｔ）
実施例３７と同様にして得た化合物３．００ｇを無水Ｏ
ＭＦ、 １５ｍ１ に溶解し、炭酸カリウム ０．９２
ｇを加え、８０℃で２時間攪拌した。溶媒を減圧留去し
、残渣を酢酸エチルで抽出し、抽出液を水洗して無水硫
酸マグネシウムで乾燥した。溶媒を減圧留去して得た残
漬をシリカゲルカラムクロマトグラフィーに付し、標記
の化合物２．１４ｇを得た。機器データは標品のそれと
一致した。Layer side 39: (S)-diethyl (7,8-difluoro-3-F, R-Et) 3.00 g of the compound obtained in the same manner as in Example 37 was added to anhydrous O
MF, dissolved in 15 ml, potassium carbonate 0.92
g was added thereto, and the mixture was stirred at 80°C for 2 hours. The solvent was distilled off under reduced pressure, the residue was extracted with ethyl acetate, the extract was washed with water and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography to obtain 2.14 g of the title compound. The instrument data matched that of the standard specimen.
Ｆ、 Ｒ−Ｅｔ）
実施例３７と同様にして得た化合物３．０９ｇ、イソプ
ロパツール３０ｍ１、 炭酸カリウム０．９５ｇの混合
物を４時間加熱還流した。溶媒を減圧留去し、残渣を１
．２−ジクロロエタンで抽出し、抽出液を水洗して無水
硫酸マグネシウムで乾燥した。溶媒を減圧留去して得た
残漬をシリカゲルカラムクロマトグラフィーに付し、標
記の化合物２．１７ｇを得た。F, R-Et) A mixture of 3.09 g of the compound obtained in the same manner as in Example 37, 30 ml of isopropanol, and 0.95 g of potassium carbonate was heated under reflux for 4 hours. The solvent was distilled off under reduced pressure, and the residue was
．． Extraction was performed with 2-dichloroethane, and the extract was washed with water and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography to obtain 2.17 g of the title compound.
機器データは標品のそれと一致した。The instrument data matched that of the standard specimen.
２．３−ジフルオロ−６−二トロー［［（Ｒ）−２−ヒ
ドロキシプロピル］オキシ］ベンゼン（ＶＩＩＩ−Ｒ，
Ｘａ−Ｘｂ−Ｆ）、１０．００ｇをピリジン２７ｍ１に
溶解し、水冷攪拌下にメタンスルホニルクロライド５．
４１ｇを４分で滴下し、同温で２分攪拌後、室温で７０
分攪拌した。2.3-difluoro-6-nitro[[(R)-2-hydroxypropyl]oxy]benzene (VIII-R,
Xa-Xb-F), 10.00 g was dissolved in 27 ml of pyridine, and 5.0 g of methanesulfonyl chloride was dissolved under stirring while cooling with water.
41g was added dropwise over 4 minutes, stirred at the same temperature for 2 minutes, and then heated to 70% at room temperature.
The mixture was stirred for a minute.
溶媒を減圧留去し、残漬を１．２−ジクロロエタン（１
８０ｍｌ）にて抽出した。抽出液を、希塩酸、飽和炭酸
水素ナトリウム水溶液、水（いずれも９０ ａｌｌで、
各々２回宛）で洗浄し、無水硫酸マグネシウムで乾燥し
た。溶媒を減圧留去して得られた残漬をシリカゲルカラ
ムクロマトグラフィに付して精製し、油状の標記の化合
物１２．４ｇを得た。The solvent was distilled off under reduced pressure, and the residue was dissolved in 1,2-dichloroethane (1
80 ml). The extract was mixed with dilute hydrochloric acid, saturated aqueous sodium bicarbonate solution, and water (90 all in each case,
and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography to obtain 12.4 g of the title compound as an oil.
’Ｈ−ＮＭＲ（ＣＤＣｈ ）δ ：
１．５０（３Ｈ，ｄ、Ｊ＝６．４Ｈｚ）、３．００（３
Ｈ，ｓ）。'H-NMR (CDCh) δ: 1.50 (3H, d, J = 6.4Hz), 3.00 (3
H,s).
４．３５（２Ｈ，ｍ）、５．１０（ＩＨ，ｍ）。4.35 (2H, m), 5.10 (IH, m).
７．０５（ＩＨ，ｄｄｄ、Ｊ・７．０，９．０ ａｎ
ｄ ９．３）ＩＺ）。7.05 (IH, ddd, J・7.0, 9.0 an
d9.3)IZ).
７．７０（１）１． ｄｄｄ、 Ｊ−２，４，５，
４，９，３８Ｚ）実施例４１で得た化合物１．５８ｇを
イソプロピルアルコールと酢酸エチルの１＝１の混合溶
媒３０ｍ１に溶解し、５零パラジウム−炭素５２０Ｂを
添加し、常温常圧で接触還元した０反応終了後、触媒を
濾去し溶媒を減圧留去して、２．３−ジフルオロ−６−
アミノ−［（Ｒ１２−メタンスルホニルオキシプロピル
］−オキシベンゼンの枢体を得る。このものをジメチル
アセトアミド １５ｍ１に溶解し、炭酸カリウム６９０
＋ａｇを加え８０℃で４８時間攪拌した。溶媒を減圧留
去し、残渣を酢酸エチル（１００ｍｌ）で抽出し、抽出
液を水洗して（３０ｍｌで３回）無水硫酸マグネシウム
で乾燥した。溶媒を減圧留去して得た残漬をシリカゲル
カラムクロマトグラフィーに付し、標記の化合物７５９
Ｂを得た。機器データは標品のそれと一致した。7.70(1)1. ddd, J-2, 4, 5,
4,9,38Z) Dissolve 1.58 g of the compound obtained in Example 41 in 30 ml of a 1=1 mixed solvent of isopropyl alcohol and ethyl acetate, add 50 palladium-carbon 520B, and perform catalytic reduction at room temperature and pressure. After the completion of the reaction, the catalyst was filtered off and the solvent was distilled off under reduced pressure to give 2,3-difluoro-6-
The cardinal of amino-[(R12-methanesulfonyloxypropyl]-oxybenzene is obtained. This is dissolved in 15 ml of dimethylacetamide, and 690 ml of potassium carbonate is added.
+ag was added and stirred at 80°C for 48 hours. The solvent was evaporated under reduced pressure, the residue was extracted with ethyl acetate (100 ml), the extract was washed with water (3 times with 30 ml), and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography to obtain the title compound 759.
I got a B. The instrument data matched that of the standard specimen.
Claims (7)
級アルキル）＿２を、Ｒ＾２は水酸基、ハロゲン原子又
は置換スルホニルオキシ基を、Ｘａ、Ｘｂは各々独立し
てハロゲン原子を意味する。）で表わされるプロポキシ
ベンゼン化合物を閉環することを特徴とする式Ｂ ▲数式、化学式、表等があります▼Ｂ （式中、Ｒ＾１、Ｘａ、Ｘｂは前記の定義に同じ）で表
わされる化合物の製法(1) Formula A ▲There are mathematical formulas, chemical formulas, tables, etc.▼A (In the formula, R^1 is a hydrogen atom or -CH=C(COO-lower alkyl)_2, and R^2 is a hydroxyl group, a halogen atom, or a substituted Formula B is characterized by ring-closing a propoxybenzene compound represented by a sulfonyloxy group, Xa and Xb each independently mean a halogen atom. ▲There are mathematical formulas, chemical formulas, tables, etc.▼B , R^1, Xa, and Xb are the same as defined above)
請求項１記載の製法(2) The method according to claim 1, wherein the compound of formula B is a racemate or an optically active compound.
法(3) The production method according to claim 2, wherein the optically active form is the (S)-form.
で、Ｒ＾２がパラトルエンスルホニルオキシ基で、Ｘａ
およびＸｂがフッ素原子である請求項１、２または３記
載の製法(4) R^1 is -CH=C(COOC_2H_5)_2
So, R^2 is a para-toluenesulfonyloxy group, and Xa
The method according to claim 1, 2 or 3, wherein and Xb is a fluorine atom.
Ｒ＾２がパラトルエンスルホニルオキシ基で、Ｘａおよ
びＸｂがフッ素原子である請求項１、２または３記載の
製法(5) R^1 is -CH=C(COOCH_3)_2,
The method according to claim 1, 2 or 3, wherein R^2 is a para-toluenesulfonyloxy group and Xa and Xb are fluorine atoms.
で、Ｒ＾２が水酸基で、ＸａおよびＸｂがフッ素原子で
ある請求項１、２または３記載の製法(6) R^1 is -CH=C(COOC_2H_5)_2
The method according to claim 1, 2 or 3, wherein R^2 is a hydroxyl group and Xa and Xb are fluorine atoms.
Ｒ＾２が水酸基で、ＸａおよびＸｂがフッ素原子である
請求項１、２または３記載の製法(7) R^1 is -CH=C(COOCH_3)_2,
The method according to claim 1, 2 or 3, wherein R^2 is a hydroxyl group and Xa and Xb are fluorine atoms.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63330030A JP2769174B2 (en) | 1987-12-28 | 1988-12-27 | Production method of condensed oxazine |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP33648987 | 1987-12-28 | ||
| JP62-336489 | 1987-12-28 | ||
| JP63330030A JP2769174B2 (en) | 1987-12-28 | 1988-12-27 | Production method of condensed oxazine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01250369A true JPH01250369A (en) | 1989-10-05 |
| JP2769174B2 JP2769174B2 (en) | 1998-06-25 |
Family
ID=26573405
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63330030A Expired - Lifetime JP2769174B2 (en) | 1987-12-28 | 1988-12-27 | Production method of condensed oxazine |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2769174B2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002284757A (en) * | 2001-03-28 | 2002-10-03 | Dai Ichi Seiyaku Co Ltd | Method for manufacturing optically active propoxynitrobenzene derivative |
| JP2009221209A (en) * | 1999-09-08 | 2009-10-01 | Daiichi Sankyo Co Ltd | Method for producing benzoxazine derivative and production intermediate thereof |
| WO2015141765A1 (en) * | 2014-03-20 | 2015-09-24 | 富士フイルム株式会社 | Compounds useful in production of salacinol and method for producing same, method for producing salacinol, methods for protecting and deprotecting diol group, and diol group protective agent |
-
1988
- 1988-12-27 JP JP63330030A patent/JP2769174B2/en not_active Expired - Lifetime
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009221209A (en) * | 1999-09-08 | 2009-10-01 | Daiichi Sankyo Co Ltd | Method for producing benzoxazine derivative and production intermediate thereof |
| JP2009235077A (en) * | 1999-09-08 | 2009-10-15 | Daiichi Sankyo Co Ltd | Method and intermediate for producing benzoxazine derivative |
| JP2002284757A (en) * | 2001-03-28 | 2002-10-03 | Dai Ichi Seiyaku Co Ltd | Method for manufacturing optically active propoxynitrobenzene derivative |
| WO2015141765A1 (en) * | 2014-03-20 | 2015-09-24 | 富士フイルム株式会社 | Compounds useful in production of salacinol and method for producing same, method for producing salacinol, methods for protecting and deprotecting diol group, and diol group protective agent |
| JP2015182956A (en) * | 2014-03-20 | 2015-10-22 | 富士フイルム株式会社 | Compounds useful in production of salacinol and method for producing the same, method for producing salacinol, method for protecting and deprotecting diol group, and diol group protective agent |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2769174B2 (en) | 1998-06-25 |
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