JPH0254331B2 - - Google Patents
Info
- Publication number
- JPH0254331B2 JPH0254331B2 JP57158422A JP15842282A JPH0254331B2 JP H0254331 B2 JPH0254331 B2 JP H0254331B2 JP 57158422 A JP57158422 A JP 57158422A JP 15842282 A JP15842282 A JP 15842282A JP H0254331 B2 JPH0254331 B2 JP H0254331B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- methyl
- added
- compound
- benzyloxycarbonyl
- 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.)
- Expired - Lifetime
Links
- -1 methoxycarbonylethyl group Chemical group 0.000 claims description 31
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 114
- 150000001875 compounds Chemical class 0.000 description 46
- 239000002904 solvent Substances 0.000 description 38
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 34
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- 239000000243 solution Substances 0.000 description 26
- 238000003756 stirring Methods 0.000 description 26
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Natural products OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 25
- 239000000203 mixture Substances 0.000 description 25
- 239000012230 colorless oil Substances 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- 239000003921 oil Substances 0.000 description 21
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 17
- 235000019341 magnesium sulphate Nutrition 0.000 description 17
- 238000000034 method Methods 0.000 description 16
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 13
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- ZCILODAAHLISPY-UHFFFAOYSA-N biphenyl ether Natural products C1=C(CC=C)C(O)=CC(OC=2C(=CC(CC=C)=CC=2)O)=C1 ZCILODAAHLISPY-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 235000011121 sodium hydroxide Nutrition 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 11
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 125000003277 amino group Chemical group 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 7
- 150000003983 crown ethers Chemical class 0.000 description 7
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- 239000011701 zinc Substances 0.000 description 7
- 229910052725 zinc Inorganic materials 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 5
- 238000006887 Ullmann reaction Methods 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 150000002170 ethers Chemical class 0.000 description 5
- 239000007800 oxidant agent Substances 0.000 description 5
- 150000002989 phenols Chemical class 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 4
- NDKBVBUGCNGSJJ-UHFFFAOYSA-M benzyltrimethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)CC1=CC=CC=C1 NDKBVBUGCNGSJJ-UHFFFAOYSA-M 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- IPBVNPXQWQGGJP-UHFFFAOYSA-N phenyl acetate Chemical compound CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- 229960004441 tyrosine Drugs 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- DBJUEJCZPKMDPA-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O DBJUEJCZPKMDPA-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 238000010531 catalytic reduction reaction Methods 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- FYWSTUCDSVYLPV-UHFFFAOYSA-N nitrooxythallium Chemical compound [Tl+].[O-][N+]([O-])=O FYWSTUCDSVYLPV-UHFFFAOYSA-N 0.000 description 3
- 230000009257 reactivity Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 3
- AXDLCFOOGCNDST-VIFPVBQESA-N (2s)-3-(4-hydroxyphenyl)-2-(methylamino)propanoic acid Chemical compound CN[C@H](C(O)=O)CC1=CC=C(O)C=C1 AXDLCFOOGCNDST-VIFPVBQESA-N 0.000 description 2
- HXQQJHHWWNVMJS-UHFFFAOYSA-N 2,4-dimethylpentan-3-yl hydrogen carbonate Chemical compound CC(C)C(C(C)C)OC(O)=O HXQQJHHWWNVMJS-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- 238000010306 acid treatment Methods 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- SLUNEGLMXGHOLY-UHFFFAOYSA-N benzene;hexane Chemical compound CCCCCC.C1=CC=CC=C1 SLUNEGLMXGHOLY-UHFFFAOYSA-N 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- NJAPCAIWQRPQPY-UHFFFAOYSA-N benzyl hydrogen carbonate Chemical compound OC(=O)OCC1=CC=CC=C1 NJAPCAIWQRPQPY-UHFFFAOYSA-N 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 150000002118 epoxides Chemical class 0.000 description 2
- 150000002148 esters Chemical group 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- LHGVFZTZFXWLCP-UHFFFAOYSA-N guaiacol Chemical compound COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- IWDCLRJOBJJRNH-UHFFFAOYSA-N p-cresol Chemical compound CC1=CC=C(O)C=C1 IWDCLRJOBJJRNH-UHFFFAOYSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- 229960002256 spironolactone Drugs 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 229910052716 thallium Inorganic materials 0.000 description 2
- BKVIYDNLLOSFOA-UHFFFAOYSA-N thallium Chemical compound [Tl] BKVIYDNLLOSFOA-UHFFFAOYSA-N 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 2
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 2
- 235000012141 vanillin Nutrition 0.000 description 2
- IKHPYOWXSQSDNF-UHFFFAOYSA-N (1-cyano-2-methylpropan-2-yl) hydrogen carbonate Chemical compound N#CCC(C)(C)OC(O)=O IKHPYOWXSQSDNF-UHFFFAOYSA-N 0.000 description 1
- CMBCAWNOBIGGTE-UHFFFAOYSA-N (2,3,4,5,6-pentamethylphenyl)methanol Chemical compound CC1=C(C)C(C)=C(CO)C(C)=C1C CMBCAWNOBIGGTE-UHFFFAOYSA-N 0.000 description 1
- JPNBVWIRDQVGAC-UHFFFAOYSA-N (2-nitrophenyl) hydrogen carbonate Chemical compound OC(=O)OC1=CC=CC=C1[N+]([O-])=O JPNBVWIRDQVGAC-UHFFFAOYSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- PTHGDVCPCZKZKR-UHFFFAOYSA-N (4-chlorophenyl)methanol Chemical compound OCC1=CC=C(Cl)C=C1 PTHGDVCPCZKZKR-UHFFFAOYSA-N 0.000 description 1
- HZFLPRPFCHEBPQ-UHFFFAOYSA-N (4-methoxyphenyl)methyl hydrogen carbonate Chemical compound COC1=CC=C(COC(O)=O)C=C1 HZFLPRPFCHEBPQ-UHFFFAOYSA-N 0.000 description 1
- JWZMLPVLGNVRKQ-UHFFFAOYSA-N (4-nitrophenyl)methyl hydrogen carbonate Chemical compound OC(=O)OCC1=CC=C([N+]([O-])=O)C=C1 JWZMLPVLGNVRKQ-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- KZEVSDGEBAJOTK-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[5-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CC=1OC(=NN=1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O KZEVSDGEBAJOTK-UHFFFAOYSA-N 0.000 description 1
- NYSXWUPVOCFRSE-UHFFFAOYSA-N 1-phenyl-ethene-1,2-diol Natural products OC=C(O)C1=CC=CC=C1 NYSXWUPVOCFRSE-UHFFFAOYSA-N 0.000 description 1
- ZWVHTXAYIKBMEE-UHFFFAOYSA-N 2-hydroxyacetophenone Chemical compound OCC(=O)C1=CC=CC=C1 ZWVHTXAYIKBMEE-UHFFFAOYSA-N 0.000 description 1
- DZRUNSUYJCQUIG-UHFFFAOYSA-N 2-methylbutan-2-yl hydrogen carbonate Chemical compound CCC(C)(C)OC(O)=O DZRUNSUYJCQUIG-UHFFFAOYSA-N 0.000 description 1
- YNJSNEKCXVFDKW-UHFFFAOYSA-N 3-(5-amino-1h-indol-3-yl)-2-azaniumylpropanoate Chemical compound C1=C(N)C=C2C(CC(N)C(O)=O)=CNC2=C1 YNJSNEKCXVFDKW-UHFFFAOYSA-N 0.000 description 1
- XBIUWALDKXACEA-UHFFFAOYSA-N 3-[bis(2,4-dioxopentan-3-yl)alumanyl]pentane-2,4-dione Chemical compound CC(=O)C(C(C)=O)[Al](C(C(C)=O)C(C)=O)C(C(C)=O)C(C)=O XBIUWALDKXACEA-UHFFFAOYSA-N 0.000 description 1
- XWQVQSXLXAXOPJ-QNGMFEMESA-N 4-[[[6-[5-chloro-2-[[4-[[(2r)-1-methoxypropan-2-yl]amino]cyclohexyl]amino]pyridin-4-yl]pyridin-2-yl]amino]methyl]oxane-4-carbonitrile Chemical compound C1CC(N[C@H](C)COC)CCC1NC1=CC(C=2N=C(NCC3(CCOCC3)C#N)C=CC=2)=C(Cl)C=N1 XWQVQSXLXAXOPJ-QNGMFEMESA-N 0.000 description 1
- WXNZTHHGJRFXKQ-UHFFFAOYSA-N 4-chlorophenol Chemical compound OC1=CC=C(Cl)C=C1 WXNZTHHGJRFXKQ-UHFFFAOYSA-N 0.000 description 1
- JKTYGPATCNUWKN-UHFFFAOYSA-N 4-nitrobenzyl alcohol Chemical compound OCC1=CC=C([N+]([O-])=O)C=C1 JKTYGPATCNUWKN-UHFFFAOYSA-N 0.000 description 1
- JRLTTZUODKEYDH-UHFFFAOYSA-N 8-methylquinoline Chemical group C1=CN=C2C(C)=CC=CC2=C1 JRLTTZUODKEYDH-UHFFFAOYSA-N 0.000 description 1
- LZMCAAGVMFMSKC-UHFFFAOYSA-N Ascamycin Natural products OC1C(O)C(COS(=O)(=O)NC(=O)C(N)C)OC1N1C2=NC(Cl)=NC(N)=C2N=C1 LZMCAAGVMFMSKC-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- RIKQKQZFQWAAFG-UHFFFAOYSA-N CC(C=C1)=CC=C1S(CCOC(O)=O)(=O)=O Chemical class CC(C=C1)=CC=C1S(CCOC(O)=O)(=O)=O RIKQKQZFQWAAFG-UHFFFAOYSA-N 0.000 description 1
- FLRXCRYRYZPGPB-MKICQXMISA-N Codonocarpine Chemical compound C1=C(OC=2C(=CC=C(C=2)\C=C\C(=O)NCCCNCCCCNC(=O)\C=C\2)O)C(OC)=CC/2=C1 FLRXCRYRYZPGPB-MKICQXMISA-N 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- 239000005749 Copper compound Substances 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- MNSGOOCAMMSKGI-UHFFFAOYSA-N N-(hydroxymethyl)phthalimide Chemical compound C1=CC=C2C(=O)N(CO)C(=O)C2=C1 MNSGOOCAMMSKGI-UHFFFAOYSA-N 0.000 description 1
- JYAPBWCAZXNDAR-UHFFFAOYSA-N Oxyacanthine Natural products COc1cc2CCN(C)C3Cc4ccc(Oc5cccc(CC6N(C)CCc7cc(OC)c(OC)c(Oc(c1)c23)c67)c5)c(O)c4 JYAPBWCAZXNDAR-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 1
- 108010081391 Ristocetin Proteins 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- LZMCAAGVMFMSKC-IZKXYQSCSA-N [(2r,3s,4r,5r)-5-(6-amino-2-chloropurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl n-[(2s)-2-aminopropanoyl]sulfamate Chemical compound O[C@@H]1[C@H](O)[C@@H](COS(=O)(=O)NC(=O)[C@@H](N)C)O[C@H]1N1C2=NC(Cl)=NC(N)=C2N=C1 LZMCAAGVMFMSKC-IZKXYQSCSA-N 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- OWAQXCQNWNJICI-UHFFFAOYSA-N benzene;chloroform Chemical compound ClC(Cl)Cl.C1=CC=CC=C1 OWAQXCQNWNJICI-UHFFFAOYSA-N 0.000 description 1
- ZYKHBCUNRIKFPE-UHFFFAOYSA-N benzhydryl hydrogen carbonate Chemical compound C=1C=CC=CC=1C(OC(=O)O)C1=CC=CC=C1 ZYKHBCUNRIKFPE-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 150000003938 benzyl alcohols Chemical class 0.000 description 1
- XDGYHAAUHYNDMA-UHFFFAOYSA-N benzyl hypochlorite Chemical compound ClOCC1=CC=CC=C1 XDGYHAAUHYNDMA-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- YHASWHZGWUONAO-UHFFFAOYSA-N butanoyl butanoate Chemical group CCCC(=O)OC(=O)CCC YHASWHZGWUONAO-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- BGTFCAQCKWKTRL-YDEUACAXSA-N chembl1095986 Chemical compound C1[C@@H](N)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]([C@H]1C(N[C@H](C2=CC(O)=CC(O[C@@H]3[C@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)=C2C=2C(O)=CC=C(C=2)[C@@H](NC(=O)[C@@H]2NC(=O)[C@@H]3C=4C=C(C(=C(O)C=4)C)OC=4C(O)=CC=C(C=4)[C@@H](N)C(=O)N[C@@H](C(=O)N3)[C@H](O)C=3C=CC(O4)=CC=3)C(=O)N1)C(O)=O)=O)C(C=C1)=CC=C1OC1=C(O[C@@H]3[C@H]([C@H](O)[C@@H](O)[C@H](CO[C@@H]5[C@H]([C@@H](O)[C@H](O)[C@@H](C)O5)O)O3)O[C@@H]3[C@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O[C@@H]3[C@H]([C@H](O)[C@@H](CO)O3)O)C4=CC2=C1 BGTFCAQCKWKTRL-YDEUACAXSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- FLRXCRYRYZPGPB-UHFFFAOYSA-N codonocarpine Natural products C1=C(OC=2C(=CC=C(C=2)C=CC(=O)NCCCNCCCCNC(=O)C=C2)O)C(OC)=CC2=C1 FLRXCRYRYZPGPB-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 150000001880 copper compounds Chemical class 0.000 description 1
- XCIXKGXIYUWCLL-UHFFFAOYSA-N cyclopentanol Chemical compound OC1CCCC1 XCIXKGXIYUWCLL-UHFFFAOYSA-N 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- KPUNOVLMCQQCSK-UHFFFAOYSA-N diazomethane;ethoxyethane Chemical compound C=[N+]=[N-].CCOCC KPUNOVLMCQQCSK-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- QILSFLSDHQAZET-UHFFFAOYSA-N diphenylmethanol Chemical compound C=1C=CC=CC=1C(O)C1=CC=CC=C1 QILSFLSDHQAZET-UHFFFAOYSA-N 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N epoxyketone group Chemical class O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000035784 germination Effects 0.000 description 1
- 229960001867 guaiacol Drugs 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 150000002506 iron compounds Chemical class 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 150000004967 organic peroxy acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- HGNHIFJNOKGSKI-WDYNHAJCSA-N oxyacanthine Chemical compound C([C@H]1N(C)CCC=2C=C(C(OC=3C(OC)=C(OC)C=C4CCN(C)[C@H](C=34)CC3=CC=C(C=C3)O3)=CC=21)OC)C1=CC=C(O)C3=C1 HGNHIFJNOKGSKI-WDYNHAJCSA-N 0.000 description 1
- NWVVVBRKAWDGAB-UHFFFAOYSA-N p-methoxyphenol Chemical compound COC1=CC=C(O)C=C1 NWVVVBRKAWDGAB-UHFFFAOYSA-N 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- NIXKBAZVOQAHGC-UHFFFAOYSA-N phenylmethanesulfonic acid Chemical compound OS(=O)(=O)CC1=CC=CC=C1 NIXKBAZVOQAHGC-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- WRYVAAOTYQUHAL-UHFFFAOYSA-N potassium benzene 2-methylpropan-2-olate Chemical compound C1=CC=CC=C1.CC(C)([O-])C.[K+] WRYVAAOTYQUHAL-UHFFFAOYSA-N 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 229950004257 ristocetin Drugs 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- ATHGHQPFGPMSJY-UHFFFAOYSA-N spermidine Chemical class NCCCCNCCCN ATHGHQPFGPMSJY-UHFFFAOYSA-N 0.000 description 1
- 229930003405 spermidine alkaloid Natural products 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- XKXIQBVKMABYQJ-UHFFFAOYSA-N tert-butyl hydrogen carbonate Chemical compound CC(C)(C)OC(O)=O XKXIQBVKMABYQJ-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000003476 thallium compounds Chemical class 0.000 description 1
- LZTRCELOJRDYMQ-UHFFFAOYSA-N triphenylmethanol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(O)C1=CC=CC=C1 LZTRCELOJRDYMQ-UHFFFAOYSA-N 0.000 description 1
Description
【発明の詳細な説明】
本発明は新規ビフエニルエーテル化合物及びそ
れらの新規製造方法に関する。更に詳細には、本
発明はオルソ位に水酸基を有するビフエニルエー
テル化合物及びその製造方法に係り、この方法に
よる目的化合物はその中間化合物を含めて全て文
献未収載の新規な化合物であり、目的化合物を製
造するための方法も新規なものである。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel biphenyl ether compounds and novel methods for their production. More specifically, the present invention relates to a biphenyl ether compound having a hydroxyl group at the ortho position and a method for producing the same, and the target compound obtained by this method, including its intermediate compounds, is a novel compound that has not been described in any literature. The method for manufacturing is also new.
本発明の新規ビフエニルエーテル化合物は次の
一般式：
ただし、R′はパラ位が少なくとも１つのハロ
ゲン原子、ホルミル基、アルキル基、アルコキシ
基または置換アルキル基によつて置換されたフエ
ニル基であり、R″はＨまたは保護されたもしく
は保護されていないアミノ基であつて、低級アル
キル置換されていてもよく、およびＲはＨまた
はエステル残基を示す、で表わされる。 The novel biphenyl ether compound of the present invention has the following general formula: However, R' is a phenyl group substituted at the para position with at least one halogen atom, formyl group, alkyl group, alkoxy group, or substituted alkyl group, and R'' is H or protected or unprotected. It is an amino group, which may be substituted with lower alkyl, and R represents H or an ester residue.
また、本発明による製造工程を略記すれば以下
の通りである。 Further, the manufacturing process according to the present invention is briefly described below.
ここでR1およびR2は夫々前記のR″およびＲ
と同じであり、R3はハロゲン原子、ホルミル基、
アルキル基、アルコキシ基または置換アルキル基
を示し、かつR4は低級アルコキシ基を表わす。 Here, R 1 and R 2 are the above-mentioned R″ and R
is the same as, R 3 is a halogen atom, a formyl group,
It represents an alkyl group, an alkoxy group or a substituted alkyl group, and R 4 represents a lower alkoxy group.
化合物は本発明の出発物質であつて、R1は
水素又は置換されたアミノ基であり、公知物質を
含む。化合物は酸化剤によつてを環化させた
ジエノンスピロラクトン化合物であり、化合物
は化合物をエポキシ化させたのちに、カルボキ
シル保護基R2を作用させたエノンエポキサイド
化合物であり、化合物及び″は化合物にフ
エノール誘導体を化合させて得られるエーテル化
合物であり、また化合物は化合物及び／又は
″を還元して得られるビフエニルエーテル化合
物である。 The compounds are starting materials of the present invention, in which R 1 is hydrogen or a substituted amino group, and include known substances. The compound is a dienone spirolactone compound that has been cyclized with an oxidizing agent, and the compound is an enone epoxide compound that has been epoxidized and then treated with a carboxyl protecting group R2 . It is an ether compound obtained by combining a compound with a phenol derivative, and the compound is a biphenyl ether compound obtained by reducing the compound and/or "."
化合物は酸又はアルカリの存在下における反
応によつて容易に環化して、一般式′：
のエノンスピロラクトンエポキサイド化合物を与
える。 The compound is easily cyclized by reaction in the presence of acid or alkali to give the general formula': of enone spirolactone epoxide compound.
この化合物及び′はフエノール化合物と速
かに反応して、化合物及び／又は″を形成し、
更に還元によつて容易に化合物に転化される。 The compound and/or ' reacts quickly with the phenolic compound to form the compound and/or ',
Furthermore, it is easily converted into a compound by reduction.
化合物を酸化剤によつて環化させる反応にお
いてはカルボキシル基又はその誘導体の存在が不
可欠ではあるが、アミノ基の存在は何ら反応に関
与するものではないので、この位置に単に水素で
置換されている化合物でもよい。ベンゼン環から
カルボキシル基または置換カルボキシル基までの
炭素数は、好ましくは２〜３個であるが、この数
は制限はされず、これらの化合物を更に修飾する
ことによつて種々の化合物を製造することも可能
である。 Although the presence of a carboxyl group or its derivative is essential in the reaction of cyclizing a compound with an oxidizing agent, the presence of an amino group does not participate in the reaction at all, so it is necessary to simply substitute hydrogen at this position. It may be a compound that has The number of carbon atoms from the benzene ring to the carboxyl group or substituted carboxyl group is preferably 2 to 3, but this number is not limited, and various compounds can be produced by further modifying these compounds. It is also possible.
本発明方法を１例を挙げてより詳細に説明す
る。 The method of the present invention will be explained in more detail by giving one example.
カルボベンジルオキシクロライドの如きアミノ
保護剤で保護したチロシン及びこれを更にアルキ
ル化したＮ−ベンジルオキシカルボニル−Ｎ−メ
チル−Ｌ−チロシン又はｐ−ヒドロキシフエニル
プロピオン酸の如きパラ位にアルキルカルボン酸
基を有するフエノール類の化合物を、電解酸化
又は硝酸タリウムの如き酸化剤によつて環化さ
せ、一般式のジエノンラクトン化合物を生成さ
せる。この生成物をまず、過酸化水素の如き酸化
剤と反応させてエポキサイドを形成し、更に遊離
カルボキシル基をジアゾメタンの如きアルキル化
剤又はカルボキシル保護基によつてエステル化
し、一般式のエノンエポキサイド化合物を得
る。化合物はフエノール化合物又はその塩類と
直接反応させることによつて一般式及び／又は
″のエーテル化合物とすることが出来、また、
クラウンエーテルなどの反応促進剤の存在下で反
応させることも可能である。又、化合物に塩基
又は酸を作用させることによつて生成する一般式
′のエノンラクトンエポキサイドに、全く同一
の操作を加えることによつても化合物及び／又
は″を得る事が出来る。 Tyrosine protected with an amino protecting agent such as carbobenzyloxychloride and an alkylcarboxylic acid group at the para position such as N-benzyloxycarbonyl-N-methyl-L-tyrosine or p-hydroxyphenylpropionic acid, which is further alkylated. A phenolic compound having the formula is cyclized by electrolytic oxidation or an oxidizing agent such as thallium nitrate to produce a dienone lactone compound of the general formula. This product is first reacted with an oxidizing agent such as hydrogen peroxide to form the epoxide, and the free carboxyl groups are then esterified with an alkylating agent such as diazomethane or a carboxyl protecting group to form an enone epoxide compound of the general formula. obtain. The compound can be made into an ether compound of the general formula and/or "by directly reacting with a phenol compound or its salt, and
It is also possible to carry out the reaction in the presence of a reaction accelerator such as a crown ether. Furthermore, the compound and/or `` can also be obtained by applying exactly the same operation to the enone lactone epoxide of the general formula ``, which is produced by reacting the compound with a base or an acid.
通常のエポキシケトン化合物の加熱反応に於て
は、エノン化合物の生成が報告されているが、本
発明の化合物又は′の反応においてR1がアミ
ノ基又は置換アミノ基である時は、マススペクト
ロメトリーのデーターによれば、一般式のジエ
ノンエーテル化合物と共に一般式″のエノンエ
ーテル化合物の生成も確認出来た。 It has been reported that enone compounds are produced in the heating reaction of ordinary epoxyketone compounds, but when R 1 is an amino group or a substituted amino group in the reaction of the compound of the present invention or ', mass spectrometry According to the data, it was confirmed that an enone ether compound of the general formula '' was also produced in addition to the dienone ether compound of the general formula.
化合物及び化合物″は亜鉛／酢酸の如き還
元剤によつて容易に一般式のビフエニルエーテ
ル化合物に転化することが出来る。またまず、無
水酢酸の如きアシル化剤で処理して生成する化合
物又は／及び′のアシル化物（′）
R5はアシル残基である。 The compound and the compound "can be easily converted into the biphenyl ether compound of the general formula by using a reducing agent such as zinc/acetic acid. Also, the compound or/and compound" can be converted into the biphenyl ether compound of the general formula by first treating with an acylating agent such as acetic anhydride. and acylated product (′) R 5 is an acyl residue.
を前記と同様の還元剤で処理することにより化合
物とすることも容易である。It is also easy to form a compound by treating with the same reducing agent as mentioned above.
ビフエニルエーテルを合成するための方法とし
ては従来
銅化合物等によるウルマン反応を利用する方
法；
鉄化合物等によるフエノール・オキシデーシ
ヨン法；
が知られており、また最近見い出された方法とし
ては、
タリウム化合物による方法；
電解酸化法；
等がある。 Conventional methods for synthesizing biphenyl ether include a method using Ullmann reaction using copper compounds, etc.; phenol oxidation method using iron compounds, etc.; and a recently discovered method using thallium. There are methods using compounds; electrolytic oxidation methods; etc.
ビフエニルエーテルを合成するため従来より行
われている最も一般的な方法はのウルマン反応
を利用するものであるが、反応条件が苛酷である
ことに基き多数の副生成物の共生が避けられず、
従つて収率も低く、更に精製が難かしいのが一般
的であり、その為に複雑な化合物をつくる際には
適当な合成方法とはいえなかつた。特に、本発明
に係るような複雑な構造を有し、不斉炭素がある
物質の、しかもフエノールのオルソ位にエーテル
結合をつくるような場合は更に困難であり、反応
が進行したとしてもほんの数％にすぎず、多数の
副反応生成物の中から目的物質を単離することは
不可能に近い努力を必要とする。 The most common conventional method for synthesizing biphenyl ether is the Ullmann reaction, but due to the harsh reaction conditions, the co-existence of many by-products is unavoidable. ,
Therefore, the yield is generally low and furthermore, purification is difficult, and for this reason, it cannot be said to be an appropriate synthetic method for producing complex compounds. In particular, it is even more difficult to create an ether bond at the ortho position of the phenol in a substance with a complex structure and asymmetric carbon, as in the present invention, and even if the reaction progresses, only a few %, and it requires almost impossible efforts to isolate the target substance from among the large number of side reaction products.
ウルマン反応をより進めるための改良方法とし
ては、フエノールの水酸基と化合させるべき化合
物のハロゲン原子の反応性を高めることが考えら
れ、その為には、環に電子吸引性基（たとえばニ
トロ基など）を付加することである。その後ウル
マン反応を行えば一般に反応は進行しやすくな
る。 As an improvement method to further advance the Ullmann reaction, it is possible to increase the reactivity of the halogen atom of the compound to be combined with the hydroxyl group of phenol. To do this, it is necessary to add an electron-withdrawing group (such as a nitro group) to the ring. It is to add . If the Ullmann reaction is then performed, the reaction generally progresses more easily.
しかし、この基をその後に脱離するために更に
数工程の反応が必須であることと、本発明の物質
の如く保護基が使用され、不斉炭素が存在する様
な物質にあつては反応の条件、使用する試薬に制
限があり、反応は更に困難となる。 However, in order to remove this group afterwards, several more reaction steps are essential, and in the case of substances such as the substances of the present invention in which a protecting group is used and an asymmetric carbon is present, the reaction is difficult. There are restrictions on the conditions and reagents used, making the reaction even more difficult.
のフエノールを酸化的に結合させるフエノー
ルオキシデーシヨン法は一般的にＣ−Ｃ結合が優
先し、Ｃ−Ｏ−Ｃの結合を生成させることは困難
であり、特に複雑な化合物に応用することはウル
マン反応と同様に不適当である。 The phenol oxidation method, in which the phenols of Like the Ullmann reaction, it is inappropriate.
のタリウムによる方法は同一分子間でエーテ
ルを合成する反応には有用であるが、本発明によ
る化合物の如く異つたフエノール間でエーテルを
合成する手法としては不適当である。 Although the method using thallium is useful for the reaction of synthesizing ethers between the same molecules, it is inappropriate as a method for synthesizing ethers between different phenols, such as the compound according to the present invention.
の電解による方法もと同様に考えられ、特
に複雑なビフエニールエーテル化合物を製造する
ための満足のゆく方法は開発途上の段階であつ
た。 Electrolytic methods for the production of particularly complex biphenyl ether compounds were also considered, and a satisfactory method for producing particularly complex biphenyl ether compounds was still in the development stage.
本発明による化合物に属する２−〔ｐ−
2′（Ｓ）−（Ｎ−ｔ−ブトキシカルボニル−Ｎ−メ
チルアミノ）−2′−ベンジルオキシカルボニル−
エチル−フエノキシ〕−４−〔2′（Ｓ）−（Ｎ−ベン
ジルオキシカルボニル−Ｎ−メチルアミノ）−
2′−メトキシカルボニル−エチル〕フエノール
をアセチル化し、接触還元によりアミノ保護基
のベンジルオキシカルボニル、カルボキシル保護
基のベンジル基を除き、次いでカルボキシル基
をメチルエステル化し、アミノ基をアセチル化
−１し、続いてトリフルオロ酢酸でアミノ保護基
のｔ−ブトキシカルボニルを除き−２、次いで
遊離状態となつたアミノ基をアセチル化した２−
〔ｐ−2′（Ｓ）−（Ｎ−アセチル−Ｎ−メチルアミノ
−2′−メトキシカルボニル−エチル−フエノキ
シ〕−４−〔2′（Ｓ）−（Ｎ−アセチル−Ｎ−メチル
アミノ）−2′−メトキシカルボニル−エチル〕フ
エノールアセテート：
は、先に出願した特願昭56−117968に関る発明中
におけるTPC−Ｃを加水分解したのち、無水酢
酸／苛性ソーダ、ジアゾメタンを順次作用させた
ビフエニルエーテル化合物と、薄層クロマトグラ
フイー、逆層を用いた薄層クロマトグラフイー及
び赤外線吸収スペクトラム（IR）において完全
に一致した。 2-[p-
2'(S)-(N-t-butoxycarbonyl-N-methylamino)-2'-benzyloxycarbonyl-
Ethyl-phenoxy]-4-[2'(S)-(N-benzyloxycarbonyl-N-methylamino)-
2'-Methoxycarbonyl-ethyl]phenol is acetylated, the amino-protecting group benzyloxycarbonyl and the carboxyl-protecting group benzyl group are removed by catalytic reduction, the carboxyl group is methyl esterified, the amino group is acetylated-1, Subsequently, the amino protecting group t-butoxycarbonyl was removed with trifluoroacetic acid, and the free amino group was then acetylated to give 2-.
[p-2'(S)-(N-acetyl-N-methylamino-2'-methoxycarbonyl-ethyl-phenoxy]-4-[2'(S)-(N-acetyl-N-methylamino)- 2'-Methoxycarbonyl-ethyl]phenol acetate: is a biphenyl ether compound obtained by hydrolyzing TPC-C in the invention related to the previously filed patent application 117968/1982, and then reacting with acetic anhydride/caustic soda and diazomethane in sequence, and thin layer chromatography. There was complete agreement in thin layer chromatography using reversed layers and infrared absorption spectra (IR).
従つて、本発明に係る化合物は前記発明に係る
TPC類の化合物を製造するための中間体として
重要な位置を占め、有用である。また現在、天然
物中に存在するアルカロイドの中だけでもオキシ
アカンチン、インスラリン、セフアランチンの如
くフエノールのオルソ位にＣ−Ｏ−Ｃ結合を有す
る化合物は数多く発見されており、リストセチ
ン、バスタジンの如き特異な骨格を有する化合物
の合成においても、本発明の方法は広範囲の応用
が可能である。即ち、本発明によるビフエニルエ
ーテル化反応は従来の方法に比し、穏和な条件
で、速やかにかつ効率よく進行し、オルソ位に水
酸基を有し、側鎖に光学活性基を有する化合物の
製法に適当であると共に通常のビフエニルエーテ
ルの製法にも応用出来る。 Therefore, the compound according to the present invention is a compound according to the above-mentioned invention.
It occupies an important position and is useful as an intermediate for producing TPC compounds. Furthermore, among the alkaloids present in natural products, many compounds have been discovered that have a C-O-C bond at the ortho position of phenol, such as oxyacanthine, insulin, and cephalanthine, and compounds such as ristocetin and vastadine. The method of the present invention can be widely applied to the synthesis of compounds having unique skeletons. That is, the biphenyl etherification reaction according to the present invention proceeds quickly and efficiently under mild conditions compared to conventional methods, and is a method for producing a compound having a hydroxyl group in the ortho position and an optically active group in the side chain. It is suitable for use in conventional biphenyl ether production methods.
又、本発明により合成された２−（ｏ−メトキ
シ−ｐ−ホルミルフエノキシ）−４−（2′−メトキ
シカルボニルエチル）フエノールは既知の方法で
ホルミル基をアルキルカルボン酸エステルに転化
したのち、又は２−〔ｏ−メトキシ−ｐ−（2′−メ
トキシカルボニルエチル）−フエノキシ〕−４−
〔2′（Ｓ）−（Ｎ−ベンジルオキシカルボニル−Ｎ−
メチルアミノ）−2′−メトキシカルボニルエチル〕
−フエノールのアミノ基をメタクロル過安息香
酸で酸化的に脱離した２−メトキシ−2′−アシル
オキシ−４−（メチル−β−プロピオネート）−
5′−（メチル−β−アクリレート）−ビフエニルエ
ーテルをアミン化合物で閉環させることによつ
て、スペルミジンアルカロイドの１種であるコド
ノカルピン及びそのテトラヒドロ体を合成するた
めに使用することが出来る。 Furthermore, 2-(o-methoxy-p-formylphenoxy)-4-(2'-methoxycarbonylethyl)phenol synthesized according to the present invention is obtained by converting the formyl group into an alkylcarboxylic acid ester by a known method. , or 2-[o-methoxy-p-(2'-methoxycarbonylethyl)-phenoxy]-4-
[2'(S)-(N-benzyloxycarbonyl-N-
methylamino)-2'-methoxycarbonylethyl]
-2-methoxy-2'-acyloxy-4-(methyl-β-propionate) obtained by oxidatively removing the amino group of phenol with methachloroperbenzoic acid.
By ring-closing 5'-(methyl-β-acrylate)-biphenyl ether with an amine compound, it can be used to synthesize codonocarpine, a type of spermidine alkaloid, and its tetrahydro derivative.
一般式及び′で表わされるエポキサイド化
合物は植物の罹病組織、ストレプトコツカス属な
どの細菌類などから分離される。これらの中に
は、単なる植物毒としてのみならず、抗癌性をは
じめ抗菌性、発芽抑制作用を有する化合物が多い
ことから、これらの化合物に含まれるひずみのか
かつたエポキサイドと生物活性との間には何らか
の相関が規定されて来ており、特に近年、エポキ
サイドを有するアミノ酸は例えばアスカマイシン
の如く抗菌性物質としての効能が注目され、ハイ
ドロキシエポキサイドエノン及び不飽和ラクトン
は抗癌作用発現基として位置づけられ、各々の分
野でその機構の解明が進められている。 Epoxide compounds represented by the general formula and ' are isolated from diseased tissues of plants, bacteria such as Streptococcus genus, and the like. Among these compounds, there are many compounds that not only act as simple plant poisons but also have anticancer, antibacterial, and germination inhibitory effects. In particular, in recent years, amino acids with epoxides have attracted attention for their efficacy as antibacterial substances, such as ascamycin, and hydroxyepoxide enones and unsaturated lactones have been positioned as groups expressing anticancer effects. The mechanism has been elucidated in various fields.
本発明に用いるカルボキシル保護基としては一
般的に用いられている保護基が普通に使用出来る
が、保護物質のその後の反応条件によつて反応中
に切断されないものが好ましい。例えば、接触還
元によつて除去出来るものとしてはベンジルアル
コール、フエナシルアルコール、ｐ−クロロベン
ジルアルコール、ｐ−ニトロベンジルアルコー
ル、ｏ−シアノベンジルアルコールの如きベンジ
ルアルコール類及びピコリルアルコール及びこれ
らの反応性エステル化誘導体を、酸処理で除去し
得るものとしては、ｔ−ブチルアルコール、ジフ
エニルメチルアルコール、トリチルアルコール、
トリメチルベンジルアルコール、ペンタメチルベ
ンジルアルコールなど及びこれらの反応性エステ
ル化誘導体を、またアルカリ処理で除去し得るも
のとしてはメチルアルコール、β−メチルチオエ
チルアルコール、フタルイミドメチルアルコー
ル、シクロペンチルアルコールなど及びこれらの
反応性エステル化誘導体を主として用いることが
できる。 As the carboxyl protecting group used in the present invention, commonly used protecting groups can be used, but it is preferable to use one that will not be cleaved during the reaction depending on the subsequent reaction conditions of the protecting substance. For example, those that can be removed by catalytic reduction include benzyl alcohols such as benzyl alcohol, phenacyl alcohol, p-chlorobenzyl alcohol, p-nitrobenzyl alcohol, o-cyanobenzyl alcohol, picolyl alcohol, and their reactivity. Esterified derivatives that can be removed by acid treatment include t-butyl alcohol, diphenylmethyl alcohol, trityl alcohol,
Trimethylbenzyl alcohol, pentamethylbenzyl alcohol, etc., and their reactive esterified derivatives, and those that can be removed by alkali treatment include methyl alcohol, β-methylthioethyl alcohol, phthalimidomethyl alcohol, cyclopentyl alcohol, etc., and their reactivity. Esterified derivatives can primarily be used.
一方、アミノ保護基としては、カルボキシル保
護基と同様にその後の反応に適当なものが選択さ
れ、接触還元で除去出来るものとしてはベンジル
オキシカルボン酸、ｐ−ニトロベンジルオキシカ
ルボン酸、ジイソプロピルメチロキシカルボン
酸、ベンツヒドリルオキシカルボン酸、ベンジル
スルホン酸及びそれらの反応性誘導体を、酸処理
で除去出来るものとしてはｔ−ブトキシカルボン
酸、ｔ−アミロキシカルボン酸、ベンジルオキシ
カルボン酸、ｐ−メトキシベンジルオキシカルボ
ン酸、ｐ−ビフエニルイソプロピルオキシカルボ
ン酸及びそれらの反応性誘導体を、またアルカリ
処理で除去出来るものとしてはトリフルオロ酢
酸、ｐ−メチルフエニルチオエトキシカルボン
酸、ｏ−ニトロフエノキシカルボン酸、２−シア
ノ−１，１−ジメチルエトキシカルボン酸、ｐ−
トルエンスルフオニルエトキシカルボン酸及びそ
れらの反応性誘導体を主として利用することがで
きる。 On the other hand, as the amino protecting group, like the carboxyl protecting group, one suitable for the subsequent reaction is selected, and those that can be removed by catalytic reduction include benzyloxycarboxylic acid, p-nitrobenzyloxycarboxylic acid, diisopropylmethyloxycarboxylic acid, and diisopropylmethyloxycarboxylic acid. Acid, benzhydryloxycarboxylic acid, benzylsulfonic acid, and their reactive derivatives can be removed by acid treatment such as t-butoxycarboxylic acid, t-amyloxycarboxylic acid, benzyloxycarboxylic acid, p-methoxybenzyl Oxycarboxylic acid, p-biphenylisopropyloxycarboxylic acid, and their reactive derivatives can be removed by alkali treatment, such as trifluoroacetic acid, p-methylphenylthioethoxycarboxylic acid, and o-nitrophenoxycarboxylic acid. acid, 2-cyano-1,1-dimethylethoxycarboxylic acid, p-
Toluenesulfonyl ethoxycarboxylic acids and their reactive derivatives can primarily be utilized.
更に酸化剤としてはタリウム化合物の他過安息
香酸の如き有機過酸、過酸化水素の他フエリシア
ン化カリ、酸化銀、過クロル鉄、フレミー塩、フ
エチゾン試薬などの使用が可能であり、また還元
剤としては亜鉛／酢酸が好ましいが、その他ソヂ
ウムボロハイドライド、ジンクボロハイドライド
などの使用が可能である。 Further, as oxidizing agents, in addition to thallium compounds, organic peracids such as perbenzoic acid, hydrogen peroxide, potassium ferricyanide, silver oxide, iron perchloride, Flemy's salt, fethizone reagent, etc. can be used, and reducing agents. Zinc/acetic acid is preferred, but other materials such as sodium borohydride and zinc borohydride can also be used.
以下、本発明を実施例によつて説明するが、本
発明はこれらに限定されるものではない。 EXAMPLES The present invention will be explained below with reference to Examples, but the present invention is not limited thereto.
参考例 １
Ｎ−メチル−Ｌ−チロシン（−１）1.95ｇを
２規定苛性ソーダ10mlに溶解し、12.5％リン酸水
素二カリウム33ml、アセトン10mlを加えたのち、
反応液のPHを２規定苛然ソーダで10に調節しなが
らカルボベンジルオキシクロライド3.75ｇを注意
深く滴下した。滴下後、撹拌を継続し反応終了の
のち６規定塩酸でPHを3.0に調節し、酢酸エチル
で抽出した。抽出液を飽和食塩水で洗浄したの
ち、硫酸マグネシウムで乾燥し、減圧下に溶媒を
留去し、ｎ−ヘキサンを加えて過剰のカルボベン
ジルオキシクロライドを除去して薄茶色のオイル
（−１）3.51ｇを得た。Reference example 1 Dissolve 1.95 g of N-methyl-L-tyrosine (-1) in 10 ml of 2N caustic soda, add 33 ml of 12.5% dipotassium hydrogen phosphate, and 10 ml of acetone.
3.75 g of carbobenzyloxychloride was carefully added dropwise while adjusting the pH of the reaction solution to 10 with 2N caustic soda. After the dropwise addition, stirring was continued, and after the reaction was completed, the pH was adjusted to 3.0 with 6N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and n-hexane was added to remove excess carbobenzyloxychloride to obtain a light brown oil (-1). 3.51g was obtained.
IRνKBr naxcm-1；1200、1210、1230、1260、1700、
1750
NMR（CDCl3）δ：2.8（3H、ｓ）；5.1、5.2
（各々2H、ｓ）；7.1（4H、bs）；7.3、7.4
（各々5H、ｓ）
参考例 ２
Ｏ，Ｎ−ジベンジルオキシカルボニル−Ｎ−メ
チル−Ｌ−チロシン（−１）1.7ｇをメタノー
ル200mlに溶解し、１規定苛性ソーダ8.5mlを加
え、室温で１時間撹拌した。６規定塩酸でPHを５
に調節し、減圧下で濃縮して更にPHを３に調節し
たのち酸酢エチルで抽出した。抽出液を飽和食塩
水で洗浄したのち、重曹水で抽出した。抽出液を
酢酸エチルで洗浄したのち６規定塩酸でPHを３に
調節し、再び酢酸エチルで抽出し、飽和食塩水で
洗浄したのち、硫酸マグネシウムで乾燥し、減圧
下に溶媒を留去して無色のオイル（−２）1.2
ｇを得た。 IRν KBr nax cm -1 ; 1200, 1210, 1230, 1260, 1700,
1750 NMR (CDCl 3 ) δ: 2.8 (3H, s); 5.1, 5.2
(2H, s each); 7.1 (4H, bs); 7.3, 7.4
(5H, s each) Reference example 2 1.7 g of O,N-dibenzyloxycarbonyl-N-methyl-L-tyrosine (-1) was dissolved in 200 ml of methanol, 8.5 ml of 1N caustic soda was added, and the mixture was stirred at room temperature for 1 hour. Adjust the pH to 5 with 6N hydrochloric acid.
The pH was adjusted to 3, concentrated under reduced pressure, and the pH was adjusted to 3, followed by extraction with ethyl acetate. The extract was washed with saturated brine, and then extracted with aqueous sodium bicarbonate. The extract was washed with ethyl acetate, adjusted to pH 3 with 6N hydrochloric acid, extracted again with ethyl acetate, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Colorless oil (-2) 1.2
I got g.
IRνKBr naxcm-1；1140、1220、1330、1400、1450、
1515、1670、1710
NMR（CDCl3）δ：2.8（3H、ｓ）；3.05（2H、
ｄ、Ｊ＝５Hz）；4.2（1H、ｔ、Ｊ＝５
Hz）；5.2（2H、ｓ）；7.1（4H、ｓ）；7.3
（5H、ｓ）
参考例 ３
Ｌ−チロシン（）90.5ｇを２規定苛性ソーダ
500mlに溶解し、10％リン酸水素二カリウム１
を加え、ベンジルオキシカルボニルクロライド85
ｇのアセトン0.5溶液と２規定苛性ソーダ0.25
を交互に加えたのち、更に１時間撹拌を継続し
た。６規定塩酸でPHを２として酢酸エチルで抽出
し、抽出液を乾燥してジアゾメタンのエーテル溶
液で処理し、硫酸マグネシウムで乾燥したのち、
減圧下で溶媒を留去して200ｇの白色結晶（＊）
を得た。この結晶をベンゼン−ヘキサンから再結
晶すると無色針状晶を得られた。融点108〜110
℃。得られた結晶23ｇをジメチルホルムアミド
200mlに溶解し、−25℃で水素化ナトリウム（50％
オイル）3.6ｇ、ヨウ化メチル10mlを加え−20℃
〜−25℃で３時間撹拌した。飽和クエン酸50ml、
水300mlを順次加え、酢酸エチルで抽出し、抽出
液を水洗、乾燥したのち減圧下に濃縮した。残渣
をアセトニトリル100ml、メタノール100mlの混液
に溶解し、２規定の苛性ソーダ75mlを加え一夜放
置した。溶液のPHを６規定塩酸で２に調節し、有
機溶媒を減圧下に留去したのち酢酸エチルで抽出
し、更に抽出液を重炭酸カリウムで抽出した。抽
出液のPHを６規定塩酸で２に調節したのち酢酸エ
チルで抽出し、水洗、乾燥後、減圧下で濃縮して
無色のオイル（−２）13.4ｇを得た。 IRν KBr nax cm -1 ; 1140, 1220, 1330, 1400, 1450,
1515, 1670, 1710 NMR (CDCl 3 ) δ: 2.8 (3H, s); 3.05 (2H,
d, J = 5Hz); 4.2 (1H, t, J = 5
Hz); 5.2 (2H, s); 7.1 (4H, s); 7.3
(5H, s) Reference example 3 90.5g of L-tyrosine () in 2N caustic soda
10% dipotassium hydrogen phosphate dissolved in 500ml
and benzyloxycarbonyl chloride 85
0.5 g of acetone solution and 2N caustic soda 0.25
were added alternately, and stirring was continued for an additional hour. Adjust the pH to 2 with 6N hydrochloric acid, extract with ethyl acetate, dry the extract, treat with an ethereal solution of diazomethane, and dry with magnesium sulfate.
Distill the solvent under reduced pressure to obtain 200g of white crystals (*)
I got it. This crystal was recrystallized from benzene-hexane to obtain colorless needle crystals. Melting point 108~110
℃. 23g of the obtained crystals were dissolved in dimethylformamide.
Dissolve in 200 ml of sodium hydride (50%
Add 3.6g of oil) and 10ml of methyl iodide at -20℃
Stirred at ~-25°C for 3 hours. 50ml saturated citric acid,
300 ml of water was successively added, extracted with ethyl acetate, the extract was washed with water, dried, and concentrated under reduced pressure. The residue was dissolved in a mixture of 100 ml of acetonitrile and 100 ml of methanol, 75 ml of 2N caustic soda was added, and the mixture was left overnight. The pH of the solution was adjusted to 2 with 6N hydrochloric acid, and the organic solvent was distilled off under reduced pressure, followed by extraction with ethyl acetate, and the extract was further extracted with potassium bicarbonate. The pH of the extract was adjusted to 2 with 6N hydrochloric acid, extracted with ethyl acetate, washed with water, dried, and concentrated under reduced pressure to obtain 13.4 g of colorless oil (-2).
実施例２のオイルと1R、NMRにおいて一致し
た。 It matched the oil of Example 2 in 1R and NMR.
参考例 ４
12.5％リン酸水素二カリウム水溶液1600mlにＬ
−チロシン（）85ｇを加え、撹拌下に２規定苛
性ソーダ700ml、アセトン300mlを加えてPHを11.5
付近に調節した後、13〜17℃の間でベンジルオキ
シクロライド200ｇのアセトン200ml溶液を２規定
の苛性ソーダでPHを10付近に調節しながら滴下し
た。撹拌を30分継続したのち６規定塩酸でPHを２
〜３付近に調節し、酢酸エチルで抽出し、飽和食
塩水で洗浄し、硫酸マグネシウムで乾燥し、減圧
下に溶媒を留去して190ｇの微黄色オイルを得た。
得られたオイル８ｇをジメチルホルムアミド120
mlに溶解し、−25℃でヨウ化メチル10ml、水素化
ナトリウム（50％オイル）3.7ｇを順次加えたの
ち、徐々に−15℃付近迄昇温し、撹拌を90分間継
続した。温度を−30℃付近に迄下げて飽和クエン
酸を加え、酢酸エチルで抽出したのち飽和食塩水
で洗浄し、硫酸マグネシウムで乾燥し、減圧下に
溶媒を留去して7.2ｇの微黄色のオイル（＊＊）
を得た。得られたオイル7.2ｇを氷浴中にてメタ
ノール、アセトニトリル（１：１）混液60mlに溶
解し、２規定苛性ソーダ20mlを加え、10分後室温
にもどし、４時間撹拌を継続した。反応終了後、
６規定塩酸でPHを３付近に調節し、酢酸エチルで
抽出したのち飽和食塩水で洗浄し、飽和重炭酸カ
リウムで抽出した。抽出液を酢酸エチルで洗浄
し、６規定塩酸でPHを３付近に調節したのち酢酸
エチルで抽出した。抽出液を飽和食塩水で洗浄
し、硫酸マグネシウムで乾燥し、減圧下に溶媒を
留去して無色のオイル（−２）4.2ｇを得た。Reference example 4 12.5% dipotassium hydrogen phosphate aqueous solution 1600ml
-Add 85g of tyrosine (), add 700ml of 2N caustic soda and 300ml of acetone while stirring to bring the pH to 11.5.
After adjusting the pH to around 10, a solution of 200 g of benzyloxychloride in 200 ml of acetone was added dropwise at a temperature of 13 to 17° C. while adjusting the pH to around 10 with 2N caustic soda. After stirring for 30 minutes, the pH was adjusted to 2 with 6N hydrochloric acid.
-3, extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 190 g of slightly yellow oil.
8 g of the obtained oil was mixed with 120 g of dimethylformamide.
10 ml of methyl iodide and 3.7 g of sodium hydride (50% oil) were sequentially added at -25°C, and then the temperature was gradually raised to around -15°C and stirring was continued for 90 minutes. The temperature was lowered to around -30°C, saturated citric acid was added, extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give 7.2 g of a slightly yellow color. oil(**)
I got it. 7.2 g of the obtained oil was dissolved in 60 ml of a mixture of methanol and acetonitrile (1:1) in an ice bath, 20 ml of 2N caustic soda was added, the temperature was returned to room temperature after 10 minutes, and stirring was continued for 4 hours. After the reaction is complete,
The pH was adjusted to around 3 with 6N hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, and extracted with saturated potassium bicarbonate. The extract was washed with ethyl acetate, the pH was adjusted to around 3 with 6N hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 4.2 g of colorless oil (-2).
実施例２および３のオイルと1R、NMRにおい
て一致した。 It matched the oils of Examples 2 and 3 in 1R and NMR.
参考例 ５
実施例２で得られたＮ−ベンジルオキシカルボ
ニル−Ｎ−メチル−Ｌ−チロシン−（−２）
19.4ｇをジクロロメタン400ml、１，２−ジメト
キシエタン130mlの混合溶媒に溶解し、０℃で撹
拌しつつ硝酸第二タリウム63ｇを少量づつ加え
た。15分後室温にもどし、一夜撹拌を続けた。析
出した結晶様物質を別し、減圧下に溶媒を留去
し、得られた残渣を酢酸エチルに溶解し、飽和水
塩水で洗浄したのち、硫酸マグネシウムで乾燥
し、減圧下に溶媒を留去してシリカゲルクロマト
に付した。クロロホルム−ベンゼン（１：１）溶
媒で溶出する画分を集め、溶媒を留去したのちベ
ンゼン：ｎ−ヘキサン（１：１）溶媒から再結晶
して無色針状晶（）12.6ｇを得た。融点97.5〜
100℃
IRνKBr naxcm-1；1200、1630、1670、1770
NMR（CDCl3）δ：2.53（2H、ｄ、Ｊ＝10Hz）、
3.03（3H、ｓ）；4.7（1H、ｔ、Ｊ＝10Hz）；
5.13（2H、ｓ）；6.2 6.83（各2H、ｄ、Ｊ＝
10Hz）；7.33（5H、ｓ）
参考例 ６
2′，5′−シクロヘキサノジエノ−4′−オキソ−
1′−スピロ−２−〔４（ｓ）−（Ｎ−ベンジルオキシ
カルボキニル−Ｎ−メチルアミノ）−５−オキソ〕
−テトラヒドロフラン（）840mgをエタノール
30ml、クロロホルム12mlの混合溶媒に溶解し、約
−８℃に冷却し、撹拌下に30％過酸化水素１ml、
トリトンＢ（トリメチルベンジルアンモニウムハ
イドロオキサイド）−40％メタノール溶液１ｇを
順次加え、４時間、同温度で撹拌反応させた。10
％亜硫酸水素ナトリウム水溶液を加えたのち、減
圧下に溶媒を留去した。水を加え重曹水でPHを８
に調節し、酢酸エチルで洗浄したのち６規定塩酸
でPHを３に調節し、酢酸エチルで更に抽出した。
抽出液を飽和水塩水で洗浄したのち、硫酸マグネ
シウムで乾燥し、減圧下に溶媒を留去してジアゾ
メタンで短時間処理すると無色のオイル（）
750mgが得られた。Reference example 5 N-benzyloxycarbonyl-N-methyl-L-tyrosine-(-2) obtained in Example 2
19.4 g was dissolved in a mixed solvent of 400 ml of dichloromethane and 130 ml of 1,2-dimethoxyethane, and 63 g of thallium nitrate was added little by little while stirring at 0°C. After 15 minutes, the temperature was returned to room temperature, and stirring was continued overnight. Separate the precipitated crystal-like substance and evaporate the solvent under reduced pressure, dissolve the resulting residue in ethyl acetate, wash with saturated brine, dry over magnesium sulfate, and evaporate the solvent under reduced pressure. It was then subjected to silica gel chromatography. Fractions eluted with chloroform-benzene (1:1) solvent were collected, the solvent was distilled off, and recrystallized from benzene:n-hexane (1:1) solvent to obtain 12.6 g of colorless needles (). . Melting point 97.5~
100℃ IRν KBr nax cm -1 ; 1200, 1630, 1670, 1770 NMR (CDCl 3 ) δ: 2.53 (2H, d, J = 10Hz),
3.03 (3H, s); 4.7 (1H, t, J=10Hz);
5.13 (2H, s); 6.2 6.83 (each 2H, d, J =
10Hz); 7.33 (5H, s) Reference example 6 2′,5′-cyclohexanodieno-4′-oxo-
1'-Spiro-2-[4(s)-(N-benzyloxycarboxinyl-N-methylamino)-5-oxo]
-Tetrahydrofuran () 840mg to ethanol
Dissolve in a mixed solvent of 30 ml and 12 ml of chloroform, cool to about -8℃, and add 1 ml of 30% hydrogen peroxide and 1 ml of 30% hydrogen peroxide while stirring.
1 g of a 40% methanol solution of Triton B (trimethylbenzylammonium hydroxide) was successively added, and the mixture was stirred and reacted at the same temperature for 4 hours. Ten
% aqueous sodium bisulfite solution was added, and the solvent was distilled off under reduced pressure. Add water and adjust the pH to 8 with baking soda water.
After washing with ethyl acetate, the pH was adjusted to 3 with 6N hydrochloric acid and further extracted with ethyl acetate.
The extract was washed with saturated brine, dried over magnesium sulfate, evaporated under reduced pressure, and treated briefly with diazomethane to yield a colorless oil ().
750mg was obtained.
IRνKBr naxcm-1；1150、1330、1400、1685、1740
NMR（CDCl3）δ：2.1〜2.6（2H、complex）；
2.93（3H、ｓ）；3.34 3.5（各1H、
complex）；3.7（3H、bs）；5.13（2H、
ｓ）；5.8、6.4（各1H、bd、Ｊ＝10Hz）；
7.23（10H、ｓ）
参考例 ７
５，６−エポキシ−４−〔2′（Ｓ）−（Ｎ−ベンジ
ルオキシカルボニル−Ｎ−メチルアミノ）−2′−
メトキシカルボニル−エチル〕−４−ハイドロキ
シ−２−シクロヘキセン−１−オン（）1.22ｇ
をアセトニトリル30mlに溶解し、アルミニウムア
セチルアセトネート１ｇを加えて50℃で４時間撹
拌を続けた。減圧下に溶媒を留去し、シリカゲル
クロマトに付した。ｎ−ヘキサン−酢酸エチル
（10：２〜10：３）の溶出部分を集め、溶媒を留
去して無色のオイル（）1.1ｇを得た。 IRν KBr nax cm -1 ; 1150, 1330, 1400, 1685, 1740 NMR ( CDCl3 ) δ: 2.1-2.6 (2H, complex);
2.93 (3H, s); 3.34 3.5 (1H each,
complex); 3.7 (3H, bs); 5.13 (2H,
s); 5.8, 6.4 (each 1H, bd, J = 10Hz);
7.23 (10H, s) Reference example 7 5,6-epoxy-4-[2'(S)-(N-benzyloxycarbonyl-N-methylamino)-2'-
Methoxycarbonyl-ethyl]-4-hydroxy-2-cyclohexen-1-one () 1.22 g
was dissolved in 30 ml of acetonitrile, 1 g of aluminum acetylacetonate was added, and stirring was continued at 50°C for 4 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography. The eluate of n-hexane-ethyl acetate (10:2 to 10:3) was collected, and the solvent was distilled off to obtain 1.1 g of a colorless oil.
IRνCHCl3 naxcm-1；1690、1790
NMR（CDCl3）δ：2.3〜3.0（2H、ｍ）；3.03
（3H、ｓ）；3.52、3.68（各1H、
complex）；4.68（1H、ｔ、Ｊ＝10Hz）；
5.12（2H、ｓ）；7.31（5H、ｓ）
参考例 ８
Ｎ−メチル−Ｌ−チロシン（−１）1.95ｇを
２規定苛性ソーダ10mlに溶解し、ｔ−ブタノール
５ml、ジメチルホルムアミド３mlを加え室温で撹
拌下にジ−ｔ−ブチルジカルボネート（第三酪酸
無水物）2.6ｇの２mlｔ−ブタノール溶液を滴下
し、１時間撹拌を継続後６規定酢酸でPHを３に調
節し、酢酸エチルで抽出した。抽出液を飽和水塩
水で洗浄したのち、硫酸マグネシウムで乾燥し、
溶媒を減圧下に留去すると2.3ｇの微黄色のオイ
ルが得られた。得られたオイルをエタノール20ml
に溶解し、水２ml、ヒドラジンヒドラート200ml
を加え、55℃で約５時間加熱撹拌し、減圧下に溶
媒を留去したのち、水約10mlを加え、飽和クエン
酸溶液により酸性として酢酸エチルで抽出した。
抽出液を水洗したのち飽和重曹水で抽出した。抽
出液を酢酸エチルで洗浄したのち再度クエン酸々
性となし、飽和食塩水で洗浄し、硫酸マグネシウ
ムで乾燥して減圧下に溶媒を留去して2.06ｇの無
色のオイル（）を得た。 IRν CHCl3 nax cm -1 ; 1690, 1790 NMR (CDCl 3 ) δ: 2.3-3.0 (2H, m); 3.03
(3H, s); 3.52, 3.68 (1H each,
complex); 4.68 (1H, t, J=10Hz);
5.12 (2H, s); 7.31 (5H, s) Reference example 8 Dissolve 1.95 g of N-methyl-L-tyrosine (-1) in 10 ml of 2N caustic soda, add 5 ml of t-butanol and 3 ml of dimethylformamide, and stir at room temperature to dissolve di-t-butyl dicarbonate (tertiary butyric anhydride). ) 2.6 g of 2 ml t-butanol solution was added dropwise, stirring was continued for 1 hour, the pH was adjusted to 3 with 6N acetic acid, and the mixture was extracted with ethyl acetate. After washing the extract with saturated brine, drying with magnesium sulfate,
The solvent was distilled off under reduced pressure to obtain 2.3 g of a slightly yellow oil. Add the obtained oil to 20ml of ethanol.
Dissolve in 2 ml of water and 200 ml of hydrazine hydrate.
After heating and stirring at 55°C for about 5 hours, the solvent was distilled off under reduced pressure, about 10 ml of water was added, the mixture was acidified with saturated citric acid solution, and extracted with ethyl acetate.
The extract was washed with water and then extracted with saturated aqueous sodium bicarbonate. The extract was washed with ethyl acetate, then citric acidified again, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 2.06 g of a colorless oil (). .
IRνKBr naxcm-1；1155、1240、1260、1400、1440、
1515、1615、1660、1720
NMR（d6DMSO）δ：1.3（9H、ｓ）；2.65（3H、
ｓ）；4.2〜4.8（1H、ｍ）；6.6、6.93（各
2HABq、Ｊ＝９Hz）
参考例 ９
Ｎ−ｔ−ブトキシカルボニル−Ｎ−メチル−Ｌ
−チロシン（）5.44ｇをジメチルホルムアミド
30mlに溶解し、ジイソプロピルアミン2.0ｇを加
えて０℃以下でベンジルブロマイド3.22ｇの10ml
ジメチルホルムアミド溶液を滴下した。その後室
温で一夜撹拌を継続したのち水を加え、６規定の
塩酸でPHを４に調節し、酢酸エチルで抽出した。
抽出液を飽和重曹水、飽和食塩水で順次洗浄し、
減圧下に溶媒を留去して5.31ｇの無色のオイル状
外観を呈するベンジル−Ｎ−ｔ−ブトキシカルボ
ニル−Ｎ−メチル−Ｌ−チロシネート（）を得
た。 IRν KBr nax cm -1 ; 1155, 1240, 1260, 1400, 1440,
1515, 1615, 1660, 1720 NMR (d 6 DMSO) δ: 1.3 (9H, s); 2.65 (3H,
s); 4.2-4.8 (1H, m); 6.6, 6.93 (each
2HABq, J=9Hz) Reference example 9 N-t-butoxycarbonyl-N-methyl-L
-5.44g of tyrosine () in dimethylformamide
Dissolve 3.22 g of benzyl bromide in 10 ml of 3.22 g of benzyl bromide at below 0℃ by adding 2.0 g of diisopropylamine.
Dimethylformamide solution was added dropwise. After that, stirring was continued at room temperature overnight, water was added, the pH was adjusted to 4 with 6N hydrochloric acid, and the mixture was extracted with ethyl acetate.
The extract was washed sequentially with saturated sodium bicarbonate solution and saturated saline solution,
The solvent was distilled off under reduced pressure to obtain 5.31 g of benzyl-Nt-butoxycarbonyl-N-methyl-L-tyrosinate () exhibiting the appearance of a colorless oil.
IRνKBr naxcm-1；1175、1225、1370、1520、1675、
1750
NMR（CDCl3）δ：1.5（9H、ｓ）；2.9（3H、
ｓ）；5.3（2H、ｓ）；6.86、7.15（各2H、
ABq、Ｊ＝９Hz）；7.5（5H、ｓ）
参考例 10
ベンジルＮ−ｔ−ブトキシカルボニル−Ｎ−メ
チル−Ｌ−チロシネート（）577mgを無水テト
ラヒドロフラン44mlに溶解しカリウム−ｔ−ブト
キサイド125mgを加え、室温で85分間撹拌の後、
５，６−エポキシ−４−〔2′（Ｓ）−（Ｎ−ベンジル
オキシカルボニル−Ｎ−メチルアミノ）−2′−メ
トキシカルボニル−エチル〕−４−ハイドロキシ
−２−シクロヘキセン−１−オン（）410mgを
加えて90分間室温で反応させた。溶媒を留去した
のち飽和重曹水を加えて酢酸エチルで抽出した。
抽出液を飽和クエン酸で酸性とし、飽和食塩水で
洗浄したのち硫酸マグネシウムで乾燥し、過し
た。液を減圧下に濃縮してジアゾメタンのエー
テル溶液で短時間処理した後、シリカゲルの湿式
クロマトに付した。ベンゼン：酢酸エチル（10：
２）の溶出部分を除去したのち、同溶媒（10：
４）で溶出する画分を集め、減圧下で溶媒を留去
して515mgの無色のオイル（）を得た。 IRν KBr nax cm -1 ; 1175, 1225, 1370, 1520, 1675,
1750 NMR ( CDCl3 ) δ: 1.5 (9H, s); 2.9 (3H,
s); 5.3 (2H, s); 6.86, 7.15 (2H each,
ABq, J=9Hz); 7.5 (5H, s) Reference example 10 577 mg of benzyl N-t-butoxycarbonyl-N-methyl-L-tyrosinate () was dissolved in 44 ml of anhydrous tetrahydrofuran, 125 mg of potassium t-butoxide was added, and after stirring at room temperature for 85 minutes,
5,6-Epoxy-4-[2'(S)-(N-benzyloxycarbonyl-N-methylamino)-2'-methoxycarbonyl-ethyl]-4-hydroxy-2-cyclohexen-1-one () 410 mg was added and reacted for 90 minutes at room temperature. After the solvent was distilled off, saturated aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate.
The extract was made acidic with saturated citric acid, washed with saturated brine, dried over magnesium sulfate, and filtered. The solution was concentrated under reduced pressure and briefly treated with an ethereal solution of diazomethane, followed by wet chromatography on silica gel. Benzene: Ethyl acetate (10:
After removing the eluted portion of 2), the same solvent (10:
The fractions eluted in step 4) were collected, and the solvent was distilled off under reduced pressure to obtain 515 mg of a colorless oil ().
IRνKBr naxcm-1；1170、1215、1320、1390、1450、
1680、1735
NMR（CDCl3）δ：1.37（9H、ｓ）；2.7（3H、
ｓ）；2.8（3H、ｓ）；3.7（3H、bs）；5.1
（4H、ｓ）；5.7〜6.2（2H、complex）；6.85
〜7.1（5H、complex）；7.3（10H、ｓ）
参考例 11
5′，6′−エポキシ−4′−オキソ−2′−シクロヘ
キセン−1′−スピロ−２〔４（Ｓ）−（Ｎ−ベンジル
オキシカルボニル−Ｎ−メチルアミノ）−５−オ
キソ〕−テトラヒドロフラン（）343mgについて
も実施例10と同一操作を施して520mgの無色のオ
イル（）を得た。 IRν KBr nax cm -1 ; 1170, 1215, 1320, 1390, 1450,
1680, 1735 NMR ( CDCl3 ) δ: 1.37 (9H, s); 2.7 (3H,
s); 2.8 (3H, s); 3.7 (3H, bs); 5.1
(4H, s); 5.7~6.2 (2H, complex); 6.85
~7.1 (5H, complex); 7.3 (10H, s) Reference example 11 5',6'-Epoxy-4'-oxo-2'-cyclohexene-1'-spiro-2[4(S)-(N-benzyloxycarbonyl-N-methylamino)-5-oxo]-tetrahydrofuran ( ) was subjected to the same operation as in Example 10 to obtain 520 mg of colorless oil ().
得られたオイルのIR値、NMR値共に実施例10
で得られた物性と一致した。 Both the IR value and NMR value of the obtained oil are Example 10
The physical properties were consistent with those obtained in .
参考例 11
２−〔ｐ−2′（Ｓ）−（Ｎ−ｔ−プトキシカルボニ
ル−Ｎ−メチルアミノ）−2′−（ベンジルオキシカ
ルボニルエチルフエノキシ〕−４−〔2′（Ｓ）−（Ｎ
−ベンジルオキシカルボニル−Ｎ−メチルアミ
ノ）2′−メトキシカルボニルエチル〕−４−ヒド
ロキシ−２，５−シクロヘキサジエノ−１−オン
（）90mgを無水ピリジン１mlに溶解し、無水酢
酸0.5mlを加えて室温下に一夜放置後、50〜60℃
で約３時間加熱撹拌した。反応終了後、減圧下に
溶媒を留去し、シリカゲルの湿式クロマトグラフ
イーに付し、クロロホルムによる溶出部分を集
め、溶媒を減圧下に留去して無色のオイル（′）
60.1mgを得た。Reference example 11 2-[p-2′(S)-(N-t-ptoxycarbonyl-N-methylamino)-2′-(benzyloxycarbonylethylphenoxy]-4-[2′(S)-(N
Dissolve 90 mg of -benzyloxycarbonyl-N-methylamino)2'-methoxycarbonylethyl]-4-hydroxy-2,5-cyclohexadien-1-one () in 1 ml of anhydrous pyridine, and add 0.5 ml of acetic anhydride. After leaving it at room temperature overnight, leave it at 50-60℃.
The mixture was heated and stirred for about 3 hours. After the reaction, the solvent was distilled off under reduced pressure, subjected to wet chromatography on silica gel, the chloroform eluate was collected, and the solvent was distilled off under reduced pressure to obtain a colorless oil (').
60.1 mg was obtained.
IRνCHCl3 naxcm-1；1640、1680、1730
NMR（CDCl3）δ：1.36（9H、ｓ）；1.93（3H、
ｓ）；2.7（3H、ｓ）；2.8（3H、ｓ）；3.7
（3H、bs）；4.5〜５（2H、complex）；5.13
（4H、ｓ）5.7〜6.4（2H、complex）；6.7〜
7.2（5H、complex）；7.3（10H、ｓ）
実施例 １
２−〔ｐ−2′（Ｓ）−（Ｎ−ｔ−ブトキシカルボニ
ル−Ｎ−メチルアミノ）−2′−（ベンジルオキシカ
ルボニルエチルフエノキシ〕−４−〔2′（Ｓ）−（Ｎ
−ベンジルオキシカルボニル−Ｎ−メチルアミ
ノ）2′−メトキシカルボニルエチル〕−４−アセ
トキシ−２，５−シクロヘキサジエノ−１−オン
（′）55mgを90％酢酸３mlに溶解し、室温で撹拌
下に亜鉛70mgを加えて15分撹拌後、過し、減圧
下に溶媒を留去し、残渣を酢酸エチルに溶解し、
飽和食塩水で洗浄したのち硫酸マグネシウムで乾
燥し、溶媒を留去して単一な無色のオイル（）
50mgを得た。 IRν CHCl3 nax cm -1 ; 1640, 1680, 1730 NMR (CDCl 3 ) δ: 1.36 (9H, s); 1.93 (3H,
s); 2.7 (3H, s); 2.8 (3H, s); 3.7
(3H, bs); 4.5-5 (2H, complex); 5.13
(4H, s) 5.7~6.4 (2H, complex); 6.7~
7.2 (5H, complex); 7.3 (10H, s) Example 1 2-[p-2′(S)-(N-t-butoxycarbonyl-N-methylamino)-2′-(benzyloxycarbonylethylphenoxy]-4-[2′(S)-(N
55 mg of -benzyloxycarbonyl-N-methylamino)2'-methoxycarbonylethyl]-4-acetoxy-2,5-cyclohexadien-1-one (') was dissolved in 3 ml of 90% acetic acid, and the mixture was stirred at room temperature. 70 mg of zinc was added to the solution, stirred for 15 minutes, filtered, the solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate.
After washing with saturated saline and drying with magnesium sulfate, the solvent was distilled off to form a single colorless oil ().
Got 50mg.
IRνCHCl3 naxcm-1；1680、1730
NMR（CDCl3）δ：1.36（9H、ｓ）；2.7（3H、
ｓ）；2.8（3H、ｓ）；3.0〜3.3（4H、
complex）；3.7（3H、bs）；4.5〜5.0（2H、
complex）；6.5〜7.2（7H、complex）；7.3
（10H、ｓ）
実施例 ２
→
２−〔ｐ−2′（Ｓ）−（Ｎ−ｔ−ブトキシカルボニ
ル−Ｎ−メチルアミノ）−2′−（ベンジルオキシカ
ルボニルエチルフエノキシ〕−４−〔2′（Ｓ）−（Ｎ
−ベンジルオキシカルボニル−Ｎ−メチルアミ
ノ）2′−メトキシカルボニルエチル〕−４−ヒド
ロキシ−２，５−シクロヘキサジエノ−１−オン
（）についても前項と同一操作を施し、化合物
190mgから170mgの単一の無色のオイル（）を
得た。 IRν CHCl3 nax cm -1 ; 1680, 1730 NMR (CDCl 3 ) δ: 1.36 (9H, s); 2.7 (3H,
s); 2.8 (3H, s); 3.0~3.3 (4H,
complex); 3.7 (3H, bs); 4.5-5.0 (2H,
complex); 6.5-7.2 (7H, complex); 7.3
(10H, s) Example 2 → 2-[p-2'(S)-(N-t-butoxycarbonyl-N-methylamino)-2'-(benzyloxycarbonylethylphenoxy]-4-[ 2'(S)-(N
-Benzyloxycarbonyl-N-methylamino)2'-methoxycarbonylethyl]-4-hydroxy-2,5-cyclohexadien-1-one () was subjected to the same operation as in the previous section, and the compound
A single colorless oil (170 mg) was obtained from 190 mg.
得られたオイルのIR値、NMR値は共に実施例
13で得られた物質の値と一致した。 The IR value and NMR value of the obtained oil are both in the example.
The value of the substance was consistent with that obtained in 13.
参考例 13
ｐ−クレゾール324mgを乾燥ベンゼン10mlに溶
解し、カリウム−ｔ−ブトキサイド300mgを加え
て室温下に30分撹拌の後、クラウンエーテル18−
６ 140mgを加え澄明な希黄色溶液を得た。この
溶液に5′，6′−エポキシ−4′−オキソ−2′−シク
ロヘキセン−1′−スピロ−２−〔４（Ｓ）−（Ｎ−ベ
ンジルオキシカルボニル−Ｎ−メチルアミノ）−
５−オキソ〕−テトラヒドロフラン（）340mgの
乾燥ベンゼン５ml溶液を加え、70℃で５時間加熱
撹拌した。溶媒を留去したのち、１規定塩酸でPH
を３に調節し、酢酸エチルで抽出した。抽出液を
飽和食塩水で洗浄したのち硫酸マグネシウムで乾
燥し、減圧下に濃縮してジアゾメタンで処理し、
次いでシリカゲルクロマトに付した。ベンゼン：
酢酸エチル（10：２）で溶出する部分を集め、減
圧下に溶媒を留去して410mgの無色のオイル（）
を得た。Reference example 13 324 mg of p-cresol was dissolved in 10 ml of dry benzene, 300 mg of potassium t-butoxide was added, and after stirring at room temperature for 30 minutes, crown ether 18-
6 was added to obtain a clear dilute yellow solution. Add 5',6'-epoxy-4'-oxo-2'-cyclohexene-1'-spiro-2-[4(S)-(N-benzyloxycarbonyl-N-methylamino)-
A solution of 340 mg of 5-oxo]-tetrahydrofuran () in 5 ml of dry benzene was added, and the mixture was heated and stirred at 70°C for 5 hours. After distilling off the solvent, pH was adjusted with 1N hydrochloric acid.
3 and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, concentrated under reduced pressure, and treated with diazomethane.
Then, it was subjected to silica gel chromatography. benzene:
The eluted portion was collected with ethyl acetate (10:2) and the solvent was evaporated under reduced pressure to yield 410 mg of a colorless oil ().
I got it.
IRνKBr naxcm-1：1220、1505、1605、1645、1680、
1740
NMR（CDCl3）δ：2.31（3H、ｓ）；2.77（3H、
ｓ）；3.65（3H、bs）；5.10（2H、ｓ）；5.6
〜6.25（2H、complex）；6.52〜7.2（5H、
ｍ）；7.2（5H、ｓ）
得られたオイルの１部をマススペクトロメトリ
ーにて測定したところ以下のピークが得られた。 IRν KBr nax cm -1 : 1220, 1505, 1605, 1645, 1680,
1740 NMR ( CDCl3 ) δ: 2.31 (3H, s); 2.77 (3H,
s); 3.65 (3H, bs); 5.10 (2H, s); 5.6
~6.25 (2H, complex); 6.52 ~ 7.2 (5H,
m); 7.2 (5H, s) When a part of the obtained oil was measured by mass spectrometry, the following peaks were obtained.
Mass（EI）ｍ／ｅ：483（M+）
Mass（CIアンモニア）ｍ／ｅ：483
参考例 14
→
５，６−エポキシ−４−〔2′（Ｓ）−（Ｎ−ベンジ
ルオキシカルボニル−Ｎ−メチルアミノ）−2′−
メトキシカルボニル−エチル〕−４−ハイドロキ
シ−２−シクロヘキセン−１−オン（）につい
ても実施例15と同一操作を施し、化合物300mg
から310mgの無色のオイル（）を得た。 Mass (EI) m/e: 483 (M + ) Mass (CI ammonia) m/e: 483 Reference example 14 → 5,6-epoxy-4-[2'(S)-(N-benzyloxycarbonyl-N -methylamino)-2'-
The same operation as in Example 15 was performed for methoxycarbonyl-ethyl]-4-hydroxy-2-cyclohexen-1-one (), and 300 mg of the compound
310 mg of colorless oil () was obtained from
得られたオイルのIR値、NMR値は共に実施例
15で得られたオイルの値と一致した。 The IR value and NMR value of the obtained oil are both in the example.
It was consistent with the oil value obtained in 15.
参考例 15
２−（ｐ−メチル−フエノキシ）−４−〔2′（Ｓ）
−（Ｎ−ベンジルオキシカルボニル−Ｎ−メチル
アミノ）2′−メトキシカルボニルエチル〕−４−
ヒドロキシ−２，５−シクロヘキサジエノ−１−
オン（）80mgを実施例12と同様に処理して無色
のオイル（′）54mgを得た。Reference example 15 2-(p-methyl-phenoxy)-4-[2'(S)
-(N-benzyloxycarbonyl-N-methylamino)2'-methoxycarbonylethyl]-4-
Hydroxy-2,5-cyclohexadieno-1-
80 mg of On () was treated in the same manner as in Example 12 to obtain 54 mg of colorless oil (').
IRνCHCl3 naxcm-1；1675、1690、1740
NMR（CDCl3）δ：1.95（3H、bs）；2.32（3H、
ｓ）；2.78（3H、ｓ）；3.69（3H、bs）；5.14
（2H、ｓ）；5.80〜6.40（2H、complex）；
6.67〜7.5（5H、ｍ）；7.3（5H、ｓ）
実施例 ３
２−（ｐ−メチル−フエノキシ）−４−〔2′（Ｓ）
−（Ｎ−ベンジルオキシカルボニル−Ｎ−メチル
アミノ）2′−メトキシカルボニルエチル〕−４−
ヒドロキシ−２，５−シクロヘキサジエノ−１−
オン（）50mgを実施例13と同様に処理して無色
のオイル（）44mgを得た。 IRν CHCl3 nax cm -1 ; 1675, 1690, 1740 NMR (CDCl 3 ) δ: 1.95 (3H, bs); 2.32 (3H,
s); 2.78 (3H, s); 3.69 (3H, bs); 5.14
(2H, s); 5.80-6.40 (2H, complex);
6.67-7.5 (5H, m); 7.3 (5H, s) Example 3 2-(p-methyl-phenoxy)-4-[2'(S)
-(N-benzyloxycarbonyl-N-methylamino)2'-methoxycarbonylethyl]-4-
Hydroxy-2,5-cyclohexadieno-1-
50 mg of On () was treated in the same manner as in Example 13 to obtain 44 mg of colorless oil ().
IRνCHCl3 naxcm-1；1690、1735
NMR（CDCl3）δ：2.28（3H、ｓ）；2.73（3H、
ｓ）；3.65（3H、bs）；5.02（3H、ｓ）；6.6
〜7.2（7H、ｍ）；7.23（5H、ｓ）；
実施例 ４
′ →
２−（ｐ−メチル−フエノキシ）−４−〔2′（Ｓ）
−（Ｎ−ベンジルオキシカルボニル−Ｎ−メチル
アミノ）2′−メトキシカルボニルエチル〕−４−
アセトキシ−２，５−シクロヘキサジエノ−１−
オン（′）50mgを実施例13と同様に処理して無
色のオイル（）41.6mgを得た。 IRν CHCl3 nax cm -1 ; 1690, 1735 NMR (CDCl 3 ) δ: 2.28 (3H, s); 2.73 (3H,
s); 3.65 (3H, bs); 5.02 (3H, s); 6.6
~7.2 (7H, m); 7.23 (5H, s); Example 4' → 2-(p-methyl-phenoxy)-4-[2'(S)
-(N-benzyloxycarbonyl-N-methylamino)2'-methoxycarbonylethyl]-4-
Acetoxy-2,5-cyclohexadieno-1-
50 mg of On (') was treated in the same manner as in Example 13 to obtain 41.6 mg of colorless oil ().
得られたオイルのIR値、NMR値は共に実施例
18で得られた物質の値と一致した。 The IR value and NMR value of the obtained oil are both in the example.
The value of the substance was consistent with that obtained in 18.
実施例 ５
２−（ｐ−メチル−フエノキシ）−４−〔2′（Ｓ）
−（Ｎ−ベンジルオキシカルボニル−Ｎ−メチル
アミノ）−2′−メトキシカルボニル−エチル−〕−
フエノール（）45mgをピリジン１mlに溶解し、
無水酢酸0.5mlを加えて室温下で一夜放置した後、
減圧下に溶媒を留去し、シリカゲルカラムクロマ
トグラフイーに付し、酢酸エチルで溶出し、溶媒
を減圧下に留去すると47mgの無色を呈するオイル
として２−（ｐ−メチルフエノキシ）−４−
〔2′（Ｓ）−（Ｎ−ベンジルオキシカルボニル−Ｎ−
メチル−アミノ）−2′−メトキシカルボニル−エ
チル〕−フエノールアセテート（）を得た。Example 5 2-(p-methyl-phenoxy)-4-[2'(S)
-(N-benzyloxycarbonyl-N-methylamino)-2'-methoxycarbonyl-ethyl-]-
Dissolve 45 mg of phenol () in 1 ml of pyridine,
After adding 0.5 ml of acetic anhydride and leaving it at room temperature overnight,
The solvent was distilled off under reduced pressure and subjected to silica gel column chromatography, eluted with ethyl acetate. When the solvent was distilled off under reduced pressure, 47 mg of 2-(p-methylphenoxy)-4- was obtained as a colorless oil.
[2'(S)-(N-benzyloxycarbonyl-N-
Methyl-amino)-2'-methoxycarbonyl-ethyl]-phenol acetate () was obtained.
IRνKBr naxcm-1；1190、1210、1260、1500、1698、
1740、1765
NMR（CDCl3）δ：2.17（3H、ｓ）；2.30（3H、
ｓ）；2.78（3H、ｓ）；3.58（3H、bs）；5.05
（2H、ｓ）；6.7〜7.17（7H、ｍ）；7.28（5H、
ｓ）
実施例 ６
２−〔ｐ−2′（Ｓ）−（Ｎ−ｔ−ブトキシカルボニ
ル−Ｎ−メチルアミノ）−2′−ベンジルオキシカ
ルボニル−エチル−フエノキシ〕−４−〔2′（Ｓ）−
（Ｎ−ベンジルオキシカルボニル−Ｎ−メチルア
ミノ）−2′−メトキシカルボニル−エチル〕−フエ
ノール（）70mgに実施例20と同一操作を施し、
73mgの無色のオイル状を呈する２−〔ｐ−2′（Ｓ）
−（Ｎ−ｔ−ブトキシカルボニル−Ｎ−メチルア
ミノ）−2′−ベンジルオキシカルボニル−エチル
−フエノキシ〕−４−〔2′（Ｓ）−（Ｎ−ベンジルオ
キシカルボニル−Ｎ−メチルアミノ）−2′−メト
キシカルボニル−エチル〕フエノールアセテート
を得た。 IRν KBr nax cm -1 ; 1190, 1210, 1260, 1500, 1698,
1740, 1765 NMR ( CDCl3 ) δ: 2.17 (3H, s); 2.30 (3H,
s); 2.78 (3H, s); 3.58 (3H, bs); 5.05
(2H, s); 6.7-7.17 (7H, m); 7.28 (5H,
s) Example 6 2-[p-2'(S)-(N-t-butoxycarbonyl-N-methylamino)-2'-benzyloxycarbonyl-ethyl-phenoxy]-4-[2'(S)-
70 mg of (N-benzyloxycarbonyl-N-methylamino)-2'-methoxycarbonyl-ethyl]-phenol () was subjected to the same operation as in Example 20,
73mg of 2-[p-2'(S) as a colorless oil.
-(N-t-butoxycarbonyl-N-methylamino)-2'-benzyloxycarbonyl-ethyl-phenoxy]-4-[2'(S)-(N-benzyloxycarbonyl-N-methylamino)-2 '-Methoxycarbonyl-ethyl]phenol acetate was obtained.
IRνCHCl3 naxcm-1；1690、1730、1760
NMR（CDCl3）δ：1.36（9H、ｓ）；2.15（3H、
ｓ）；2.7、2.8（各3H、ｓ）；3.15（4H、
complex）；3.7（3H、bs）；5.07、5.16（4H、
ｓ）；6.7〜7.1（7H、ｍ）；7.3（10H、ｍ）
参考例 16
ｐ−ハイドロキシフエニルプロピオン酸（）
3.2ｇをジクロロメタン320mlと１，２−ジメトキ
シエタン80mlを混合溶媒に溶解し、氷浴中で撹拌
下に硝酸第二タリウム17.76ｇを少量ずつ加え、
溶解させ、室温に戻し一夜撹拌を継続した。析出
した沈澱を別したのち、溶液に飽和重曹水を加
えて撹拌し、不溶物を別し、分液した。得られ
た有機層を飽和食塩水で洗浄し、硫酸マグネシウ
ムで乾燥し、減圧下溶媒を留去して微黄色のオイ
ル2.33ｇを得た。放置するとオイルは結晶化しベ
ンゼン−ｎ−ヘキサンより再結晶すると微黄色の
砂状晶が得られた（融点97〜100℃）。 IRν CHCl3 nax cm -1 ; 1690, 1730, 1760 NMR (CDCl 3 ) δ: 1.36 (9H, s); 2.15 (3H,
s); 2.7, 2.8 (3H each, s); 3.15 (4H,
complex); 3.7 (3H, bs); 5.07, 5.16 (4H,
s); 6.7-7.1 (7H, m); 7.3 (10H, m) Reference example 16 p-hydroxyphenylpropionic acid ()
3.2g was dissolved in a mixed solvent of 320ml of dichloromethane and 80ml of 1,2-dimethoxyethane, and 17.76g of thallium nitrate was added little by little while stirring in an ice bath.
The mixture was allowed to dissolve, returned to room temperature, and continued stirring overnight. After separating the deposited precipitate, saturated aqueous sodium bicarbonate was added to the solution and the mixture was stirred to separate insoluble matter and separate the mixture. The obtained organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 2.33 g of a slightly yellow oil. When left to stand, the oil crystallized and recrystallized from benzene-n-hexane to give slightly yellow sand-like crystals (melting point 97-100°C).
IRνKBr naxcm-1；860、1190、1630、1670、1770
NMR（CDCl3）δ：2.4、2.8（各2H、ｔ、Ｊ＝
6.8Hz）；6.23、6.9（各2H、ABq、Ｊ＝10
Hz）
参考例 17
2′，5′−シクロヘキサノジエノ−4′−オキソ−
1′−スピロ−２−（５−オキソ）−テトラヒドロフ
ラン（）218mgをエタノール２ml、ジオキサン
2.5mlの混合溶媒に溶解し、約−８℃に冷却し、
撹拌下に30％過酸化水素0.5ml、トリトンＢ（トリ
メチルベンジルアンモニウムハイドロオキサイ
ド）0.5ｇのメタノール２ml溶液を順次加え、氷
冷下に４時間半撹拌を継続した。反応液に飽和亜
硫酸水素ナトリウム水溶液を加え、減圧下に溶媒
を留去し、水を加えて重曹水でPHを８に調節し、
酢酸エチルで洗浄したのち６規定塩酸でPHを３に
調節してから酢酸エチルで抽出した。抽出液を飽
和食塩水で洗浄し、硫酸マグネシウムで乾燥し、
減圧下で濃縮したのちジアゾメタンで短時間処理
して無色のオイル（）91mgを得た。 IRν KBr nax cm -1 ; 860, 1190, 1630, 1670, 1770 NMR (CDCl 3 ) δ: 2.4, 2.8 (2H, t, J =
6.8Hz); 6.23, 6.9 (each 2H, ABq, J=10
Hz) Reference example 17 2′,5′-cyclohexanodieno-4′-oxo-
Add 218 mg of 1'-spiro-2-(5-oxo)-tetrahydrofuran () to 2 ml of ethanol and dioxane.
Dissolve in 2.5 ml of mixed solvent, cool to about -8℃,
While stirring, a solution of 0.5 ml of 30% hydrogen peroxide and 0.5 g of Triton B (trimethylbenzylammonium hydroxide) in 2 ml of methanol was successively added, and stirring was continued for 4.5 hours under ice cooling. A saturated aqueous sodium bisulfite solution was added to the reaction solution, the solvent was distilled off under reduced pressure, water was added, and the pH was adjusted to 8 with aqueous sodium bicarbonate.
After washing with ethyl acetate, the pH was adjusted to 3 with 6N hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate,
Concentration under reduced pressure and brief treatment with diazomethane gave 91 mg of a colorless oil.
IRνKBr naxcm-1；825、1090、1210、1440、1685、
1725
NMR（CDCl3）δ：2.15、2.65（各2H、ｔ、Ｊ
＝６Hz）；3.3〜3.7（2H、complex）；3.71
（3H、ｓ）；5.9、6.5（各1Hd、ｄ、Ｊ＝10、
２Hz）
参考例 18
バニリン114mgを無水ベンゼン５mlに溶解し、
カリウム−ｔ−ブトキサイド81mgを加えて室温で
30分撹拌した。クラウンエーテル（18−６）を加
えて澄明な溶液とし、５，６−エポキシ−４−
（2′−メトキシカルボニルエチル）−４−ヒドロキ
シ−２−シクロヘキセン−１−オン（）53mgを
加えて、50℃の水浴上で2.5時間加熱撹拌した。
ベンゼンを減圧下に留去し、水を加えて飽和クエ
ン酸水溶液で酸性とし、酢酸エチルで抽出した。
飽和食塩水で洗浄後、硫酸マグネシウムで乾燥
し、溶媒を減圧下に留去し、ジアゾメタンのエー
テル溶液を加えて短時間処理したのち、展開溶媒
としてｎ−ヘキサン：酢酸エチル（１：1.5）を
用いるプレパラテイブ薄層クロマトグラフイーに
付し、43mgの無色のオイル（）を得た。 IRν KBr nax cm -1 ; 825, 1090, 1210, 1440, 1685,
1725 NMR (CDCl 3 ) δ: 2.15, 2.65 (2H, t, J
= 6Hz); 3.3-3.7 (2H, complex); 3.71
(3H, s); 5.9, 6.5 (each 1Hd, d, J=10,
2Hz) Reference example 18 Dissolve 114 mg of vanillin in 5 ml of anhydrous benzene,
Add 81 mg of potassium t-butoxide and stir at room temperature.
Stirred for 30 minutes. Crown ether (18-6) was added to make a clear solution, and 5,6-epoxy-4-
53 mg of (2'-methoxycarbonylethyl)-4-hydroxy-2-cyclohexen-1-one () was added, and the mixture was heated and stirred on a 50°C water bath for 2.5 hours.
Benzene was distilled off under reduced pressure, water was added, the mixture was made acidic with a saturated aqueous citric acid solution, and the mixture was extracted with ethyl acetate.
After washing with saturated brine, drying over magnesium sulfate, distilling off the solvent under reduced pressure, and adding an ether solution of diazomethane for a short treatment, n-hexane:ethyl acetate (1:1.5) was added as a developing solvent. Preparative thin layer chromatography was performed to obtain 43 mg of colorless oil.
IRνKBr naxcm-1：1025、1155、1270、1500、1590、
1645、1675、1730
NMR（CDCl3）δ：2.07、2.33（各2H、ｔ、Ｊ
＝６Hz）；3.6（3H、ｓ）；3.8（3H、ｓ）；
5.8（1H、ｄ、Ｊ＝３Hz）；6.2（1H、ｄ、Ｊ
＝10Hz）；6.8（1H、dd、Ｊ＝10Hz、３
Hz）；7.13（1H、ｄ、Ｊ＝７Hz）；7.4（1H、
ｄ、Ｊ＝７Hz）；7.43（1H、ｓ）；9.85（1H、
ｓ）
実施例 ７
２−（ｏ−メトキシ−Ｐ−ホルミル−フエノキ
シ）−４−（2′−メトキシカルボニルエチル）−４
−ヒドロキシ−２，５−シクロヘキサジエノ−１
−オン（）36.4mgを90％酢酸２mlに溶解し、氷
浴上で撹拌下に亜鉛100mgを加え、10分撹拌した
のち室温で40分撹拌した。酢酸エチルを加えて
過し、減圧下に溶媒を留去すると無色のオイルを
呈する２−（ｏ−メトキシ−ｐ−ホルミルフエノ
キシ）−４−（2′.メトキシカルボニル−エチル）
フエノール（）35mgが得られた。 IRν KBr nax cm -1 : 1025, 1155, 1270, 1500, 1590,
1645, 1675, 1730 NMR (CDCl 3 ) δ: 2.07, 2.33 (2H, t, J
=6Hz); 3.6 (3H, s); 3.8 (3H, s);
5.8 (1H, d, J = 3Hz); 6.2 (1H, d, J
= 10Hz); 6.8 (1H, dd, J = 10Hz, 3
Hz); 7.13 (1H, d, J = 7Hz); 7.4 (1H,
d, J=7Hz); 7.43 (1H, s); 9.85 (1H,
s) Example 7 2-(o-methoxy-P-formyl-phenoxy)-4-(2'-methoxycarbonylethyl)-4
-Hydroxy-2,5-cyclohexadieno-1
36.4 mg of -one () was dissolved in 2 ml of 90% acetic acid, 100 mg of zinc was added while stirring on an ice bath, the mixture was stirred for 10 minutes, and then stirred at room temperature for 40 minutes. After adding ethyl acetate and filtering, the solvent was distilled off under reduced pressure to give a colorless oil, 2-(o-methoxy-p-formylphenoxy)-4-(2'.methoxycarbonyl-ethyl).
35 mg of phenol () was obtained.
IRνKBr naxcm-1：1160、1270、1505、1590、1685、
1730
NMR（CDCl3）δ：2.8、2.9（各1H、ｔ、Ｊ＝
６Hz）；3.63（3H、ｓ）；3.93（3H、ｓ）；
6.5〜7.6（6H、complex）；9.85（1H、ｓ）
実施例 ８
ヒドロフエルラ酸メチル624mgを無水ベンゼン
24mlに溶解し、カリウム−ｔ−ブトキサイド320
mgを加えて室温下、１時間撹拌した。クラウンエ
ーテル（18−６）を加えて溶解し、50℃油浴中、
撹拌下に5′，6′−エポキシ−4′−オキソ−2′−シ
クロヘキセン−1′−スピロ−２−〔４（Ｓ）−（Ｎ−
ベンジルオキシカルボニル−Ｎ−メチルアミノ）
−５−オキソ〕−テトラヒドロフラン（）341mg
を一度に加え、付着物を少量のベンゼンで溶解し
加えた。同温度で３時間撹拌を続けたのち、溶媒
を減圧下に留去し、氷クエン酸を加えて酢酸エチ
ルで抽出した。抽出液を飽和食塩水で洗浄のの
ち、ジアゾメタンのエーテル溶液で処理して、シ
リカゲルクロマトグラフイーに付し、クロロホル
ム：酢酸エチル（80：20）で溶出して目的物326
mgを得た。 IRν KBr nax cm -1 : 1160, 1270, 1505, 1590, 1685,
1730 NMR (CDCl 3 ) δ: 2.8, 2.9 (each 1H, t, J =
6Hz); 3.63 (3H, s); 3.93 (3H, s);
6.5-7.6 (6H, complex); 9.85 (1H, s) Example 8 Methyl hydroferulate 624mg in anhydrous benzene
Potassium-t-butoxide dissolved in 24ml 320ml
mg was added and stirred at room temperature for 1 hour. Add crown ether (18-6) and dissolve, in a 50℃ oil bath.
5′,6′-epoxy-4′-oxo-2′-cyclohexene-1′-spiro-2-[4(S)-(N-
benzyloxycarbonyl-N-methylamino)
-5-oxo]-tetrahydrofuran () 341mg
was added all at once, and the deposits were dissolved with a small amount of benzene and added. After continued stirring at the same temperature for 3 hours, the solvent was distilled off under reduced pressure, glacial citric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, treated with an ethereal solution of diazomethane, and subjected to silica gel chromatography, eluting with chloroform:ethyl acetate (80:20) to obtain the desired product, 326
I got mg.
次いで、無水酢酸1.5ml、ピリジン３mlに生成
物を溶解し、60℃の油浴中４時間撹拌し、トルエ
ンを加えて溶液中の無水酢酸、ピリジンを除去し
たのち、90％酢酸10mlに亜鉛710mgを加えて室温
下、20分撹拌を続けた。酢酸エチルを加えて不溶
物を別し、減圧下に溶媒を留去してシリカゲル
クロマトグラフイーに付し、ベンゼン：酢酸エチ
ル（５：１）で溶出して無色オイル状の２−〔ｏ
−メトキシ−ｐ−（2′−メトキシカルボニルエチ
ル）フエノキシ〕−４−〔2′（Ｓ）−（Ｎ−ベンジル
オキカルボニル−Ｎ−メチルアミノ）−2′−メト
キシカルボニルエチル〕フエノール260mgを得た。 Next, the product was dissolved in 1.5 ml of acetic anhydride and 3 ml of pyridine, stirred for 4 hours in an oil bath at 60°C, and toluene was added to remove acetic anhydride and pyridine from the solution. Then, 710 mg of zinc was dissolved in 10 ml of 90% acetic acid. was added and stirring was continued for 20 minutes at room temperature. Ethyl acetate was added to separate insoluble matter, the solvent was distilled off under reduced pressure, and the mixture was subjected to silica gel chromatography, eluting with benzene:ethyl acetate (5:1) to give a colorless oil of 2-[o
-Methoxy-p-(2'-methoxycarbonylethyl)phenoxy]-4-[2'(S)-(N-benzyloxycarbonyl-N-methylamino)-2'-methoxycarbonylethyl]phenol 260 mg was obtained. .
IRνKBr naxcm-1：1700、1735
NMR（CDCl3）δ：2.77（3H、ｓ）；2.7〜3.4
（6H、complex）；3.67、3.7（計9H、各々
ｓ）；4.5〜4.9（1H、complex）；5.03（2H、
bs）；6.1（1H、ｓ）；6.8（6H、complex）
7.23（5H、bs）
実施例 ９
グアヤコール130.2mgを無水ベンゼン3.5mlに溶
解し、カリウム−ｔ−ブトキサイド105mgを加え
室温下撹拌して、析出した塩をクラウンエーテル
（18−６）の添加によつて溶解した。50℃の温浴
上で撹拌下に5′，6′−エポキシ−4′−オキソ−
2′−シクロヘキセン−1′−スピロ−２−〔４（Ｓ）
−（Ｎ−ベンジルオキシカルボニル−Ｎ−メチル
アミノ）−５−オキソ〕−テトラヒドロフラン
（）119mgを一度に加え、その後３時間同温度で
撹拌を続けたのち、減圧下で溶媒を留去し、氷ク
エン酸を加えて酸性となし、酢酸エチルで抽出し
た。抽出液を飽和食塩水で洗浄し、ジアゾメタン
のエーテル溶液で処理したのち、過剰のジアゾメ
タン−エーテルを留去して、90％酢酸水溶液４ml
を加えて溶解し、亜鉛150mgを加え、30分室温下
に撹拌を続けた。酢酸エチル、次いで硫酸マグネ
シウムを加え、不溶物を別したのち溶媒を減圧
下に留去し、シリカゲルクロマトグラフイーに付
した。ベンゼン：酢酸エチル（90：10）で溶出す
る画分より無色油状を呈する２−（ｏ−メトキシ
−フエノキシ）−４−〔2′（Ｓ）−（Ｎ−ベンジルオ
キシカルボニル−Ｎ−メチルアミノ）−2′−メト
キシカルボニルエチル〕フエノール91mgを得た。 IRν KBr nax cm -1 : 1700, 1735 NMR (CDCl 3 ) δ: 2.77 (3H, s); 2.7 to 3.4
(6H, complex); 3.67, 3.7 (total 9H, each s); 4.5-4.9 (1H, complex); 5.03 (2H,
bs); 6.1 (1H, s); 6.8 (6H, complex)
7.23 (5H, bs) Example 9 130.2 mg of guaiacol was dissolved in 3.5 ml of anhydrous benzene, 105 mg of potassium t-butoxide was added, and the mixture was stirred at room temperature, and the precipitated salt was dissolved by adding crown ether (18-6). 5′,6′-epoxy-4′-oxo-
2'-cyclohexene-1'-spiro-2-[4(S)
119 mg of -(N-benzyloxycarbonyl-N-methylamino)-5-oxo]-tetrahydrofuran () was added at once, and stirring was continued at the same temperature for 3 hours. The solvent was distilled off under reduced pressure and iced. The mixture was made acidic by adding citric acid and extracted with ethyl acetate. The extract was washed with saturated brine and treated with an ether solution of diazomethane, and then the excess diazomethane-ether was distilled off and 4 ml of a 90% acetic acid aqueous solution was added.
was added and dissolved, 150 mg of zinc was added, and stirring was continued for 30 minutes at room temperature. Ethyl acetate and then magnesium sulfate were added, and after separating insoluble matter, the solvent was distilled off under reduced pressure, and the mixture was subjected to silica gel chromatography. 2-(o-methoxy-phenoxy)-4-[2'(S)-(N-benzyloxycarbonyl-N-methylamino)] appears as a colorless oil in the fraction eluted with benzene:ethyl acetate (90:10). 91 mg of -2'-methoxycarbonylethyl]phenol was obtained.
IRνKBr naxcm-1：1700、1730
NMR（CDCl3）δ：2.74（3H、ｓ）；2.8〜3.2
（2H、complex）；3.56、3.66（計3H、各
ｓ）；3.78（3H、ｓ）；4.46〜4.92（1H、
complex）；4.96、5.04（計2H、各ｓ）；
6.28（1H、ｓ）、6.5〜7.2（7H、complex）、
7.24（5H、ｓ）
実施例 10
ワニリン319mg、カリウム−ｔ−ブトキサイド
210mg、5′，6′−エポキシ−4′−オキソ−2′−シク
ロヘキセン−1′−スピロ−２−〔４（Ｓ）−（Ｎ−ベ
ンジルオキシカルボニル−Ｎ−メチルアミノ）−
５−オキソ〕−テトラヒドロフラン（）238mgを
実施例27と同様に縮合させ、次いで亜鉛−酢酸を
加えて５℃にて10分間処理したのち、プレパラテ
イブTLC（シリカゲル）によつて油状を呈する２
−（Ｏ−メトキシ−Ｐ−ホルミルフエノキシ）−４
〔2′（Ｓ）−（Ｎ−ベンジルオキシカルボニル−Ｎ−
メチルアミノ）−2′−メトキシカルボニルエチル〕
−フエノール75mgを得た。 IRν KBr nax cm -1 : 1700, 1730 NMR (CDCl 3 ) δ: 2.74 (3H, s); 2.8 to 3.2
(2H, complex); 3.56, 3.66 (total 3H, each s); 3.78 (3H, s); 4.46-4.92 (1H,
complex); 4.96, 5.04 (total 2H, each s);
6.28 (1H, s), 6.5-7.2 (7H, complex),
7.24 (5H, s) Example 10 Vanillin 319mg, potassium t-butoxide
210 mg, 5',6'-epoxy-4'-oxo-2'-cyclohexene-1'-spiro-2-[4(S)-(N-benzyloxycarbonyl-N-methylamino)-
238 mg of 5-oxo]-tetrahydrofuran () was condensed in the same manner as in Example 27, and then zinc-acetic acid was added and treated at 5°C for 10 minutes.
-(O-methoxy-P-formylphenoxy)-4
[2'(S)-(N-benzyloxycarbonyl-N-
methylamino)-2'-methoxycarbonylethyl]
- 75 mg of phenol was obtained.
IRνKBr naxcm-1：1690、1740
NMR（CDCl3）δ：2.8（3H、ｓ）；2.8〜3.3
（2H、ｍ）、3.68、3.74（計3H、各ｓ）、
3.95（3H、ｓ）、5.03、5.07（計2H、各ｓ）、
6.0（1H、ｓ）、6.6〜7.0（3H、ｍ）、7.1〜
7.6（8H、complex）、9.85（1H、bs）
実施例 11
ｐ−クロルフエノール265.7mg、カリウム−ｔ
−ブトキサイド210mg、5′，6′−エポキシ−4′−オ
キソ−2′−シクロヘキセン−1′−スピロ−２−
〔４（Ｓ）−（Ｎ−ベンジルオキシカルボニル−Ｎ−
メチルアミノ）−５−オキソ〕−テトラヒドロフラ
ン（）238mgを実施例27と同様に縮合させ、次
いで亜鉛−酢酸を加えて５℃にて10分間処理した
のち、プレパラテイブTLC（シリカゲル）によつ
て油状を呈する２−（ｐ−クロル−フエノキシ）−
４−〔2′（Ｓ）−（Ｎ−ベンジルオキシカルボニル−
Ｎ−メチルアミノ）−2′−メトキシカルボニルエ
チル〕−フエノール91mgを得た。 IRν KBr nax cm -1 : 1690, 1740 NMR (CDCl 3 ) δ: 2.8 (3H, s); 2.8 to 3.3
(2H, m), 3.68, 3.74 (total 3H, each s),
3.95 (3H, s), 5.03, 5.07 (total 2H, each s),
6.0 (1H, s), 6.6~7.0 (3H, m), 7.1~
7.6 (8H, complex), 9.85 (1H, bs) Example 11 p-chlorophenol 265.7mg, potassium-t
-butoxide 210 mg, 5',6'-epoxy-4'-oxo-2'-cyclohexene-1'-spiro-2-
[4(S)-(N-benzyloxycarbonyl-N-
238 mg of methylamino)-5-oxo]-tetrahydrofuran () was condensed in the same manner as in Example 27, and then zinc-acetic acid was added and treated at 5°C for 10 minutes. 2-(p-chloro-phenoxy)-
4-[2'(S)-(N-benzyloxycarbonyl-
91 mg of N-methylamino)-2'-methoxycarbonylethyl]-phenol was obtained.
IRνKBr naxcm-1：1690、1740
NMR（CDCl3）δ：2.78（3H、ｓ）、2.78〜3.5
（2H、complex）、3.7（3H、bs）、4.5〜５
（1H、complex）、5.04、5.08（計2H、各
ｓ）、5.84（1H、bs）、6.6〜７（5H、
cnmplex）、7.1〜7.5（7H、complex）
実施例 12
ｐ−メトキシフエノール260.4mg、カリウム−
ｔ−ブトキサイド210mg、5′，6′−エポキシ−4′−
オキソ−2′−シクロヘキセン−1′−スピロ−２−
〔４（Ｓ）−（Ｎ−ベンジルオキシカルボニル−Ｎ−
メチルアミノ）−５−オキソ〕−テトラヒドロフラ
ン（）238mgを実施例27と同様に縮合させ、次
いで亜鉛−酢酸を加えて５℃にて10分間処理した
のち、プレパラテイブTLC（シリカゲル）によつ
て油状を呈する２−（ｐ−メトキシ−フエノキシ）
−４−〔2′（Ｓ）−（Ｎ−ベンジルオキシカルボニル
−Ｎ−メチルアミノ）−2′−メトキシカルボニル
エチル〕−フエノール107mgを得た。 IRν KBr nax cm -1 : 1690, 1740 NMR (CDCl 3 ) δ: 2.78 (3H, s), 2.78-3.5
(2H, complex), 3.7 (3H, bs), 4.5~5
(1H, complex), 5.04, 5.08 (total 2H, each s), 5.84 (1H, bs), 6.6~7 (5H,
cnmplex), 7.1 to 7.5 (7H, complex) Example 12 p-methoxyphenol 260.4mg, potassium
t-butoxide 210mg, 5',6'-epoxy-4'-
Oxo-2'-cyclohexene-1'-spiro-2-
[4(S)-(N-benzyloxycarbonyl-N-
238 mg of methylamino)-5-oxo]-tetrahydrofuran () was condensed in the same manner as in Example 27, and then zinc-acetic acid was added and treated at 5°C for 10 minutes. 2-(p-methoxy-phenoxy)
107 mg of -4-[2'(S)-(N-benzyloxycarbonyl-N-methylamino)-2'-methoxycarbonylethyl]-phenol was obtained.
IRνKBr naxcm-1：1700、1740
NMR（CDCl3）δ：2.78（3H、ｓ）、2.8〜3.4
（2H、complex）、3.64、3.68（計3H、各
ｓ）、3.76（3H、ｓ）、4.5〜５（1H、
complex）、5.04、5.1（計2H、各bs）、5.86
（1H、ｓ）、6.5〜7.0（7H、complex）、7.0
〜7.5（5H、bs） IRν KBr nax cm -1 : 1700, 1740 NMR (CDCl 3 ) δ: 2.78 (3H, s), 2.8-3.4
(2H, complex), 3.64, 3.68 (total 3H, each s), 3.76 (3H, s), 4.5~5 (1H,
complex), 5.04, 5.1 (total 2H, each bs), 5.86
(1H, s), 6.5-7.0 (7H, complex), 7.0
~7.5 (5H, bs)
Claims (1)
ホルミル基、メチル基、メトキシ基、メトキシカ
ルボニルエチル基又は２−（Ｎ−メチル−Ｎ−ｔ
−ブトキシカルボニルアミノ）−２−ベンジルオ
キシカルボニル−エチル基で置換されたフエニル
基であり、R″はＨまたはＮ−メチル−Ｎ−ベン
ジルオキシカルボニルアミノ基であり、ＲはＨ
又はメチル基であり、ＲはＨまたはアセチル基を
示す、 で表わされるビフエニルエーテル化合物。 ２ 一般式【式】又は 【式】 ただし、R′は少くとも１つのハロゲン原子、
ホルミル基、メチル基、メトキシ基、メトキシカ
ルボニルエチル基又は２−（Ｎ−メチル−Ｎ−ｔ
−ブトキシカルボニルアミノ）−２−ベンジルオ
キシカルボニル−エチル基で置換されたフエニル
基であり、R″はＨまたはＮ−メチル−Ｎ−ベン
ジルオキシカルボニルアミノ基であり、ＲはＨ
またはメチル基であり、Ｒ′′′′はＨまたはアシル
基を示す、 で表わされるエーテル化合物を還元し、所望によ
りアセチル化することを特徴とする、 一般式 ただし、R′は少くとも１つのハロゲン原子、
ホルミル基、メチル基、メトキシ基、メトキシカ
ルボニルエチル基又は２−（Ｎ−メチル−Ｎ−ｔ
−ブトキシカルボニルアミノ）−２−ベンジルオ
キシカルボニル−エチル基で置換されたフエニル
基であり、R″はＨまたはＮ−メチル−Ｎ−ベン
ジルオキシカルボニルアミノ基であり、ＲはＨ
又はメチル基であり、ＲはＨまたはアセチル基を
示す、 で表わされるビフエニルエーテル化合物の製造方
法。[Claims] 1. General formula: However, R' is at least one halogen atom,
formyl group, methyl group, methoxy group, methoxycarbonylethyl group or 2-(N-methyl-N-t
-butoxycarbonylamino)-2-benzyloxycarbonyl-ethyl group, R″ is H or N-methyl-N-benzyloxycarbonylamino group, R is H
or a methyl group, and R represents H or an acetyl group. 2 General formula [Formula] or [Formula] However, R' is at least one halogen atom,
formyl group, methyl group, methoxy group, methoxycarbonylethyl group or 2-(N-methyl-N-t
-butoxycarbonylamino)-2-benzyloxycarbonyl-ethyl group, R″ is H or N-methyl-N-benzyloxycarbonylamino group, R is H
or a methyl group, and R''''' represents H or an acyl group, characterized in that the ether compound represented by the following is reduced and optionally acetylated: However, R' is at least one halogen atom,
formyl group, methyl group, methoxy group, methoxycarbonylethyl group or 2-(N-methyl-N-t
-butoxycarbonylamino)-2-benzyloxycarbonyl-ethyl group, R″ is H or N-methyl-N-benzyloxycarbonylamino group, R is H
or a methyl group, and R represents H or an acetyl group.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57158422A JPS5948442A (en) | 1982-09-11 | 1982-09-11 | Novel biphenyl ether and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57158422A JPS5948442A (en) | 1982-09-11 | 1982-09-11 | Novel biphenyl ether and its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5948442A JPS5948442A (en) | 1984-03-19 |
| JPH0254331B2 true JPH0254331B2 (en) | 1990-11-21 |
Family
ID=15671406
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP57158422A Granted JPS5948442A (en) | 1982-09-11 | 1982-09-11 | Novel biphenyl ether and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5948442A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS58192853A (en) * | 1982-05-06 | 1983-11-10 | Toubishi Yakuhin Kogyo Kk | Novel biphenyl ether and preparation thereof |
-
1982
- 1982-09-11 JP JP57158422A patent/JPS5948442A/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS58192853A (en) * | 1982-05-06 | 1983-11-10 | Toubishi Yakuhin Kogyo Kk | Novel biphenyl ether and preparation thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5948442A (en) | 1984-03-19 |
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