JPH04243870A - Oxaazabicyclo(3.3.0)octane derivative - Google Patents
Oxaazabicyclo(3.3.0)octane derivativeInfo
- Publication number
- JPH04243870A JPH04243870A JP816691A JP816691A JPH04243870A JP H04243870 A JPH04243870 A JP H04243870A JP 816691 A JP816691 A JP 816691A JP 816691 A JP816691 A JP 816691A JP H04243870 A JPH04243870 A JP H04243870A
- Authority
- JP
- Japan
- Prior art keywords
- mmol
- compound
- added
- solvent
- chcl3
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- JCPMZCGVPUGJJJ-UHFFFAOYSA-N 2,3,3a,4,5,6-hexahydropyrrolo[1,2-b][1,2]oxazole Chemical class C1CON2CCCC21 JCPMZCGVPUGJJJ-UHFFFAOYSA-N 0.000 title 1
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 125000001424 substituent group Chemical group 0.000 claims abstract description 7
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 abstract description 49
- 239000002904 solvent Substances 0.000 abstract description 21
- JWYOAMOZLZXDER-UHNVWZDZSA-N (1r,2s)-2-azaniumylcyclopentane-1-carboxylate Chemical compound N[C@H]1CCC[C@H]1C(O)=O JWYOAMOZLZXDER-UHNVWZDZSA-N 0.000 abstract description 5
- 230000001032 anti-candidal effect Effects 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- 238000010438 heat treatment Methods 0.000 abstract description 3
- LVCDXCQFSONNDO-UHFFFAOYSA-N n-benzylhydroxylamine Chemical class ONCC1=CC=CC=C1 LVCDXCQFSONNDO-UHFFFAOYSA-N 0.000 abstract description 3
- 230000001747 exhibiting effect Effects 0.000 abstract 1
- -1 methoxy, methyl Chemical group 0.000 description 63
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 54
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 28
- 239000000203 mixture Substances 0.000 description 24
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 20
- 239000000243 solution Substances 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 17
- 238000002329 infrared spectrum Methods 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000000126 substance Substances 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- 238000004440 column chromatography Methods 0.000 description 14
- 238000001816 cooling Methods 0.000 description 14
- 239000000741 silica gel Substances 0.000 description 14
- 229910002027 silica gel Inorganic materials 0.000 description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 230000003287 optical effect Effects 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 150000001299 aldehydes Chemical class 0.000 description 8
- 150000002576 ketones Chemical class 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 239000012267 brine Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 6
- RTEXIPZMMDUXMR-UHFFFAOYSA-N benzene;ethyl acetate Chemical compound CCOC(C)=O.C1=CC=CC=C1 RTEXIPZMMDUXMR-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- JWYOAMOZLZXDER-CRCLSJGQSA-N (1s,2r)-2-aminocyclopentane-1-carboxylic acid Chemical compound N[C@@H]1CCC[C@@H]1C(O)=O JWYOAMOZLZXDER-CRCLSJGQSA-N 0.000 description 5
- 239000004367 Lipase Substances 0.000 description 5
- 102000004882 Lipase Human genes 0.000 description 5
- 108090001060 Lipase Proteins 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 235000019421 lipase Nutrition 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 4
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000007800 oxidant agent Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 239000003810 Jones reagent Substances 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- RCTYPNKXASFOBE-UHFFFAOYSA-M chloromercury Chemical compound [Hg]Cl RCTYPNKXASFOBE-UHFFFAOYSA-M 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- ZJLMKPKYJBQJNH-UHFFFAOYSA-N propane-1,3-dithiol Chemical compound SCCCS ZJLMKPKYJBQJNH-UHFFFAOYSA-N 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Substances [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- BUEPEVBYNBQNED-SFYZADRCSA-N (1r,2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]cyclopentane-1-carboxylic acid Chemical compound CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1C(O)=O BUEPEVBYNBQNED-SFYZADRCSA-N 0.000 description 2
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 2
- WEQNVTGMDKWPRP-UHFFFAOYSA-N 4-(1,3-dithian-2-yl)butan-1-ol Chemical compound OCCCCC1SCCCS1 WEQNVTGMDKWPRP-UHFFFAOYSA-N 0.000 description 2
- USLRUYZDOLMIRJ-UHFFFAOYSA-N 5-Hexenal Chemical compound C=CCCCC=O USLRUYZDOLMIRJ-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- HETCEOQFVDFGSY-UHFFFAOYSA-N Isopropenyl acetate Chemical compound CC(=C)OC(C)=O HETCEOQFVDFGSY-UHFFFAOYSA-N 0.000 description 2
- 239000007836 KH2PO4 Substances 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- RZKYEQDPDZUERB-UHFFFAOYSA-N Pindone Chemical group C1=CC=C2C(=O)C(C(=O)C(C)(C)C)C(=O)C2=C1 RZKYEQDPDZUERB-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 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
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- SKCNIGRBPJIUBQ-UHFFFAOYSA-N chloroform;ethyl acetate Chemical compound ClC(Cl)Cl.CCOC(C)=O SKCNIGRBPJIUBQ-UHFFFAOYSA-N 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 125000001033 ether group Chemical group 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 2
- UIZVMOZAXAMASY-UHFFFAOYSA-N hex-5-en-1-ol Chemical compound OCCCCC=C UIZVMOZAXAMASY-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 2
- 239000012286 potassium permanganate Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- PYBFOHHUUMLRKD-UHFFFAOYSA-M sodium ethyl acetate chloride hydrate Chemical compound [OH-].[Na+].Cl.C(C)(=O)OCC PYBFOHHUUMLRKD-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 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 2
- JHCUAQXGKDRBOU-IUCAKERBSA-N tert-butyl n-[(1s,2r)-2-(hydroxymethyl)cyclopentyl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1CO JHCUAQXGKDRBOU-IUCAKERBSA-N 0.000 description 2
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- MBDOYVRWFFCFHM-SNAWJCMRSA-N (2E)-hexenal Chemical compound CCC\C=C\C=O MBDOYVRWFFCFHM-SNAWJCMRSA-N 0.000 description 1
- CIMHGQPZESAIPX-GQCTYLIASA-N (E)-7-hydroxyoct-5-enal Chemical compound OC(/C=C/CCCC=O)C CIMHGQPZESAIPX-GQCTYLIASA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- KAANTNXREIRLCT-UHFFFAOYSA-N 1-(triphenyl-$l^{5}-phosphanylidene)propan-2-one Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC(=O)C)C1=CC=CC=C1 KAANTNXREIRLCT-UHFFFAOYSA-N 0.000 description 1
- NILQLFBWTXNUOE-UHFFFAOYSA-N 1-aminocyclopentanecarboxylic acid Chemical compound OC(=O)C1(N)CCCC1 NILQLFBWTXNUOE-UHFFFAOYSA-N 0.000 description 1
- MVXFJLUGMFMJRQ-UHFFFAOYSA-N 3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c][1,2]oxazole Chemical compound C1ONC2CCCC21 MVXFJLUGMFMJRQ-UHFFFAOYSA-N 0.000 description 1
- RJAVRIXARDYGGB-UHFFFAOYSA-N 3-methoxy-2-phenylpropanoyl chloride Chemical compound COCC(C(Cl)=O)C1=CC=CC=C1 RJAVRIXARDYGGB-UHFFFAOYSA-N 0.000 description 1
- YBYUKBSXQLUQBR-UHFFFAOYSA-N 4-(1,3-dithian-2-yl)butanal Chemical compound O=CCCCC1SCCCS1 YBYUKBSXQLUQBR-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N Butyraldehyde Chemical compound CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 1
- 101100283604 Caenorhabditis elegans pigk-1 gene Proteins 0.000 description 1
- 229910004664 Cerium(III) chloride Inorganic materials 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 101000841267 Homo sapiens Long chain 3-hydroxyacyl-CoA dehydrogenase Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- 102100029107 Long chain 3-hydroxyacyl-CoA dehydrogenase Human genes 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- VPQDJSGQSNLEJE-UHFFFAOYSA-L [Cl-].[Cl-].[Ce+2] Chemical compound [Cl-].[Cl-].[Ce+2] VPQDJSGQSNLEJE-UHFFFAOYSA-L 0.000 description 1
- SZCZSVSCDYFBLS-UHFFFAOYSA-N [Na+].[Mn](=O)(=O)([O-])[O-].[K+] Chemical compound [Na+].[Mn](=O)(=O)([O-])[O-].[K+] SZCZSVSCDYFBLS-UHFFFAOYSA-N 0.000 description 1
- 230000000397 acetylating effect Effects 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 229940085868 calcium carbonate 250 mg Drugs 0.000 description 1
- VYLVYHXQOHJDJL-UHFFFAOYSA-K cerium(III) chloride Substances Cl[Ce](Cl)Cl VYLVYHXQOHJDJL-UHFFFAOYSA-K 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- VTHIKKVKIVQWHV-UHFFFAOYSA-N chromium(6+) oxygen(2-) pyridine Chemical compound [O-2].[O-2].[O-2].[Cr+6].C1=CC=NC=C1 VTHIKKVKIVQWHV-UHFFFAOYSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000006264 debenzylation 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
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 150000004688 heptahydrates Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 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
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 125000003965 isoxazolidinyl group Chemical group 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229960002523 mercuric chloride Drugs 0.000 description 1
- 229940100892 mercury compound Drugs 0.000 description 1
- 150000002731 mercury compounds Chemical class 0.000 description 1
- LWJROJCJINYWOX-UHFFFAOYSA-L mercury dichloride Chemical compound Cl[Hg]Cl LWJROJCJINYWOX-UHFFFAOYSA-L 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- MVVYGFJDUBYNTQ-UHFFFAOYSA-N n,n-diethylethanamine;methylsulfinylmethane;oxalyl dichloride Chemical compound CS(C)=O.ClC(=O)C(Cl)=O.CCN(CC)CC MVVYGFJDUBYNTQ-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
Description
【０００１】0001
【産業上の利用分野】光学活性なシス−２−アミノシク
ロペンタン−１−カルボン酸が微生物代謝産物として単
離され、ＦＲ−１０９６１５［Ｊ．Ａｎｔｉｂｉｏｔｉ
ｃｓ， ４３ ， １（１９９０） ］ またはシスペ
ンタシン［Ｊ．Ａｎｔｉｂｉｏｔｉｃｓ， ４２ ，
１７４９ ， １７５６（１９８９） ］ と命名され
てその高い抗カンジダ活性が報告されている。[Industrial Application Field] Optically active cis-2-aminocyclopentane-1-carboxylic acid was isolated as a microbial metabolite, and FR-109615 [J. Antibioti
cs, 43, 1 (1990)] or cispentacin [J. Antibiotics, 42,
1749, 1756 (1989)] and its high anti-Candida activity has been reported.
【０００２】0002
【従来技術】シス−２−アミノシクロペンタン−１−カ
ルボン酸の合成法は既に知られている（例えばＣｈｅｍ
．Ｂｅｒ．， ９２， １５９４（１９５９）， Ｊ．
Ａｎｔｉｂｉｏｔｉｃｓ， ４２， １７４９（１９８
９）等）。この方法によって得られる最終生成物のｄｌ
体は光学分割することにより、抗カンジダ活性を示す光
学活性な（１Ｒ，２Ｓ）−シス−２−アミノシクロペン
タン−１−カルボン酸に導かれている。[Prior Art] Methods for synthesizing cis-2-aminocyclopentane-1-carboxylic acid are already known (for example, in Chem.
．． Ber. , 92, 1594 (1959), J.
Antibiotics, 42, 1749 (198
9) etc.). dl of the final product obtained by this method
The compound was optically resolved to yield optically active (1R,2S)-cis-2-aminocyclopentane-1-carboxylic acid, which exhibits anti-Candida activity.
【０００３】0003
【発明が解決しようとする課題】発明者等は、化合物（
１）を中間体とすることにより、光学活性なシス−２−
アミノシクロペンタン−１−カルボン酸を得ることもで
きる合成法を見い出し本発明を完成した。[Problem to be solved by the invention] The inventors have developed a compound (
By using 1) as an intermediate, optically active cis-2-
The present invention was completed by discovering a synthetic method that can also produce aminocyclopentane-1-carboxylic acid.
【０００４】0004
【課題を解決するための手段】本発明は、式[Means for Solving the Problems] The present invention provides the formula
【０００５
】0005
]
【化２】[Case 2]
【０００６】を有するオキサアザビシクロ［３．３．０
］オクタン誘導体およびその塩。Oxazabicyclo [3.3.0
] Octane derivatives and their salts.
【０００７】式中、Ａｒは置換基を有してもよいフェニ
ル基を示し、Ｒは水素原子、α位に水酸基もしくは保護
された水酸基を有する炭素数１〜５個のアルキル基また
はα位に水酸基もしくは保護された水酸基を有する炭素
数７〜９個のアラルキル基を示す。In the formula, Ar represents a phenyl group which may have a substituent, and R represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms having a hydroxyl group or a protected hydroxyl group at the α position, or an alkyl group having 1 to 5 carbon atoms at the α position. An aralkyl group having 7 to 9 carbon atoms and having a hydroxyl group or a protected hydroxyl group.
【０００８】Ａｒの置換基を有してもよいフェニル基の
置換基は、たとえばメトキシ、メチル、エチル、ニトロ
、シアノ、メトキシカルボニル、弗素、塩素または臭素
原子等があげられ、これらの同一または異なる置換基を
１〜２個有してもよい。[0008] Examples of the substituent of the phenyl group which may have a substituent for Ar include methoxy, methyl, ethyl, nitro, cyano, methoxycarbonyl, fluorine, chlorine or bromine atom, and these may be the same or different. It may have 1 to 2 substituents.
【０００９】Ｒのα位に水酸基を有するアルキル基は、
たとえばヒドロキシメチル、１−ヒドロキシエチル、１
−ヒドロキシプロピル、１−ヒドロキシブチル、１−ヒ
ドロキシ−２−メチルプロピル、１−ヒドロキシ−２，
２−ジメチルプロピルがあげられる。[0009] The alkyl group having a hydroxyl group at the α-position of R is
For example, hydroxymethyl, 1-hydroxyethyl, 1
-Hydroxypropyl, 1-hydroxybutyl, 1-hydroxy-2-methylpropyl, 1-hydroxy-2,
2-dimethylpropyl is mentioned.
【００１０】Ｒのα位に水酸基を有するアラルキル基は
、たとえば１−ヒドロキシ−１−フェニルメチル、１−
ヒドロキシ−２−フェニルエチル、１−ヒドロキシ−２
−フェニルプロピルがあげられる。[0010] The aralkyl group having a hydroxyl group at the α-position of R is, for example, 1-hydroxy-1-phenylmethyl, 1-
Hydroxy-2-phenylethyl, 1-hydroxy-2
-Phenylpropyl.
【００１１】Ｒのα位に保護された水酸基を有するアル
キル基およびアラルキル基における水酸基の保護基は、
特に限定はなく一般的なアルコール性水酸基保護基であ
る。好ましくはトリメチルシリル、ｔｅｒｔ−ブチルジ
メチルシリル、トリフェニルシリルなどのシリル基、ベ
ンジル、ｐ−メトキシベンジルなどのアラルキル基、ホ
ルミル、アセチル、プロピオニル、ピバリル、ベンゾイ
ルなどのアシル基、アリルオキシカルボニル、ベンジル
オキシカルボニル、トリクロロエトキシカルボニルなど
の置換アルコキシカルボニル基、テトラヒドロピラニル
、メトキシメチル、１−エトキシエチルなどのエーテル
基があげられる。The protecting group for the hydroxyl group in the alkyl group and aralkyl group having a hydroxyl group protected at the α-position of R is:
There is no particular limitation, and it is a general alcoholic hydroxyl protecting group. Preferred are silyl groups such as trimethylsilyl, tert-butyldimethylsilyl, and triphenylsilyl, aralkyl groups such as benzyl and p-methoxybenzyl, acyl groups such as formyl, acetyl, propionyl, pivalyl, and benzoyl, allyloxycarbonyl, and benzyloxycarbonyl. , substituted alkoxycarbonyl groups such as trichloroethoxycarbonyl, and ether groups such as tetrahydropyranyl, methoxymethyl, and 1-ethoxyethyl.
【００１２】好適な化合物（１）として、Ａｒがフェニ
ル、ｐ−トリル、ｐ−メトキシフェニル、ｐ−ニトロフ
ェニルまたはｐ−シアノフェニルであり、Ｒが水素原子
、１−ヒドロキシエチル、１−ヒドロキシプロピル、ヒ
ドロキシフェニルメチル、１−ヒドロキシ−２−フェニ
ルエチル、１−アセトキシエチルまたは１−ｔｅｒｔ−
ブチルジメチルシリルオキシエチルである化合物（１）
があげられる。[0012] As a preferred compound (1), Ar is phenyl, p-tolyl, p-methoxyphenyl, p-nitrophenyl or p-cyanophenyl, and R is a hydrogen atom, 1-hydroxyethyl, 1-hydroxypropyl. , hydroxyphenylmethyl, 1-hydroxy-2-phenylethyl, 1-acetoxyethyl or 1-tert-
Compound (1) which is butyldimethylsilyloxyethyl
can be given.
【００１３】本発明に用いた出発物質である一般式（２
）を有する化合物は、次のようにして得ることが出来る
。The starting material used in the present invention, the general formula (2
) can be obtained as follows.
【００１４】すなわち、Ｒが水素原子である化合物（２
）はアルコール（３）を酸化することによって得られる
。That is, the compound (2) in which R is a hydrogen atom
) can be obtained by oxidizing alcohol (3).
【００１５】[0015]
【化３】[Chemical formula 3]
【００１６】Ｒがα位に水酸基もしくは保護された水酸
基を有するアルキル基あるいはアラルキル基である化合
物（２）は以下に示すルートによって作ることが出来る
。Compound (2) in which R is an alkyl group or an aralkyl group having a hydroxyl group or a protected hydroxyl group at the α-position can be produced by the route shown below.
【００１７】[0017]
【化４】[C4]
【００１８】式中Ｒ′は、Ｒからヒドロキシメチル基な
ど（ −ＣＨ（ＯＨ）− ， −ＣＨ（ＯＲ″）−）を
除いた基を示す。Ｒ″は水酸基の保護基を示す。In the formula, R' represents a group obtained by removing a hydroxymethyl group or the like (-CH(OH)-, -CH(OR'')-). R'' represents a hydroxyl-protecting group.
【００１９】ジヒドロピラン（４）と１，３−プロパン
ジチオールを酸触媒の存在下に反応させてアルコール（
５）を得る。反応に用いられる溶媒はエーテル、テトラ
ヒドロフラン、ベンゼン、塩化メチレンなどの非プロト
ン性溶媒が好ましく、酸触媒としては、三弗化ホウ素エ
ーテル錯体、ｐ−トルエンスルホン酸、塩化スズなどを
用いる。反応温度は−２０℃ないし室温であり、反応時
間は５分間〜１時間である。Dihydropyran (4) and 1,3-propanedithiol are reacted in the presence of an acid catalyst to form alcohol (
5) is obtained. The solvent used in the reaction is preferably an aprotic solvent such as ether, tetrahydrofuran, benzene, or methylene chloride, and the acid catalyst used is boron trifluoride ether complex, p-toluenesulfonic acid, tin chloride, or the like. The reaction temperature is -20°C to room temperature, and the reaction time is 5 minutes to 1 hour.
【００２０】アルコール（５）からアルデヒド（６）を
得る反応は酸化剤を用いて行うことが出来る。酸化剤と
しては、酸化クロム（ＶＩ）−ピリジン錯体や塩化オキ
サリル−ジメチルスルホキシド−トリエチルアミンの組
み合わせなどが用いられ反応溶媒は塩化メチレンが好適
である。反応温度は−７８℃ないし室温であり反応時間
は５分間〜２時間である。The reaction for obtaining aldehyde (6) from alcohol (5) can be carried out using an oxidizing agent. As the oxidizing agent, a chromium (VI) oxide-pyridine complex or a combination of oxalyl chloride-dimethylsulfoxide-triethylamine is used, and methylene chloride is preferred as the reaction solvent. The reaction temperature is -78°C to room temperature, and the reaction time is 5 minutes to 2 hours.
【００２１】アルデヒド（６）からα，β−不飽和ケト
ン（８）を製造する工程はウィッティヒ反応を用いて行
われる。アルデヒド（６）に対して一般式（７）を有す
るウィッティヒ試薬を加熱下反応させることによってケ
トン（８）を得ることができる。反応に用いられる溶媒
はベンゼン、トルエン、キシレンなどの芳香族炭化水素
が好ましく、反応温度は５０℃ないし溶媒の沸点であり
、反応時間は１〜５時間である。The process of producing α,β-unsaturated ketone (8) from aldehyde (6) is carried out using Wittig reaction. Ketone (8) can be obtained by reacting aldehyde (6) with a Wittig reagent having general formula (7) under heating. The solvent used in the reaction is preferably an aromatic hydrocarbon such as benzene, toluene, or xylene, the reaction temperature is 50°C to the boiling point of the solvent, and the reaction time is 1 to 5 hours.
【００２２】不飽和ケトン（８）から一般式（９）を有
するアルコール化合物を得る反応は、水素化リチウムア
ルミニウム、水素化ホウ素リチウム、水素化ホウ素ナト
リウム−塩化セリウム（ＩＩＩ） 等の還元剤を用いて
行うことが出来る。また不飽和ケトン（８）を不斉還元
試薬を用いて還元を行えば、光学活性なアルコール（９
ａ）またはその対掌体（９ｂ）を得ることが出来る。さ
らにラセミ体のアルコール（９）は、次式に示すように
酵素反応を利用して光学活性な両対掌体に分割すること
が出来る。すなわち、ラセミ体アルコール（９）をジイ
ソプロピルエーテルのような非プロトン性溶媒中で過剰
の酢酸イソプロペニルの存在下リパーゼと室温付近で攪
拌すれば光学活性なアルコール（９ａ）とその対掌体に
相当するアセチル体 （１０ａ）を得ることが出来、両
者はカラムクロマトグラフィー等で、容易に分離できる
。アセチル誘導体（１０ａ） は酸あるいはアルカリを
用いて加水分解すれば（９ａ）の対掌体である光学活性
なアルコール（９ｂ）に誘導できる。また、ラセミ体ア
ルコール（９）を通常の化学反応によりアセチル化して
得られるラセミ体アセテート（１０ ′） （Ｒ″がア
セチル基である化合物（１０））を同じリパーゼを用い
る加水分解反応に付すと、光学活性なアルコール（９ｂ
）とその対掌体に相当するアセテート（１０ｂ） を得
ることが出来る。アセチル誘導体（１０ｂ） は酸ある
いはアルカリを用いて加水分解すれば先に述べた光学活
性なアルコール（９ａ）に誘導できる。The reaction to obtain the alcohol compound having the general formula (9) from the unsaturated ketone (8) is carried out using a reducing agent such as lithium aluminum hydride, lithium borohydride, sodium borohydride-cerium (III) chloride, etc. It can be done by Furthermore, if the unsaturated ketone (8) is reduced using an asymmetric reducing reagent, the optically active alcohol (9) can be reduced.
a) or its enantiomer (9b) can be obtained. Furthermore, racemic alcohol (9) can be split into optically active enantiomers using an enzymatic reaction as shown in the following formula. That is, if racemic alcohol (9) is stirred with lipase in an aprotic solvent such as diisopropyl ether in the presence of excess isopropenyl acetate at around room temperature, it will produce optically active alcohol (9a) and its enantiomer. The acetyl form (10a) can be obtained, and both can be easily separated by column chromatography or the like. Acetyl derivative (10a) can be induced to optically active alcohol (9b), which is the enantiomer of (9a), by hydrolysis using acid or alkali. Furthermore, when racemic acetate (10') (compound (10) in which R'' is an acetyl group) obtained by acetylating racemic alcohol (9) by a normal chemical reaction is subjected to a hydrolysis reaction using the same lipase. , optically active alcohol (9b
) and its enantiomer, acetate (10b), can be obtained. The acetyl derivative (10b) can be derived into the optically active alcohol (9a) mentioned above by hydrolysis using an acid or an alkali.
【００２３】[0023]
【化５】[C5]
【００２４】[0024]
【化６】[C6]
【００２５】上述した方法によって得られるラセミ体ア
ルコール（９）あるいは光学活性なアルコール（９ａ）
および（９ｂ）の水酸基は一般的なアルコール性水酸基
の保護基で修飾することにより（１０）に導くことが出
来る。例えば、トリメチルシリル、ｔｅｒｔ−ブチルジ
メチルシリル、トリフェニルシリル等のシリル基を保護
基とする（１０）を製造する場合は、相当するシリル化
剤をトリエチルアミンのような三級アミンの存在下に反
応させることによって得られる。ベンジルあるいはｐ−
メトキシベンジルなどのアラルキル基を保護基とする化
合物（１０）も通常のエーテル化の方法を用いて得るこ
とができる。水酸基の保護基がホルミル、アセチル、プ
ロピオニル、ピバリル、ベンゾイルなどのアシル基、ア
リルオキシカルボニル、ベンジルオキシカルボニル、ト
リクロロエトキシカルボニルなどの置換アルコキシカル
ボニル基、テトラヒドロピラニル、メトキシメチル、１
−エトキシエチルなどのエーテル基である化合物（１０
）も通常の方法によって得ることができる。Racemic alcohol (9) or optically active alcohol (9a) obtained by the above method
The hydroxyl group of (9b) can be modified with a general alcoholic hydroxyl protecting group to lead to (10). For example, when producing (10) in which a silyl group such as trimethylsilyl, tert-butyldimethylsilyl, or triphenylsilyl is used as a protecting group, a corresponding silylating agent is reacted in the presence of a tertiary amine such as triethylamine. obtained by benzyl or p-
Compound (10) having an aralkyl group such as methoxybenzyl as a protecting group can also be obtained using a conventional etherification method. Protecting groups for hydroxyl groups include acyl groups such as formyl, acetyl, propionyl, pivalyl, benzoyl, substituted alkoxycarbonyl groups such as allyloxycarbonyl, benzyloxycarbonyl, trichloroethoxycarbonyl, tetrahydropyranyl, methoxymethyl, etc.
- Compounds that are ether groups such as ethoxyethyl (10
) can also be obtained by conventional methods.
【００２６】上述のアルコール化合物（９）あるいはそ
の水酸基が保護された化合物（１０）は、２価の水銀化
合物例えば塩化第二水銀を作用させて加水分解を行うこ
とにより、本発明の出発物質として用いられるアルデヒ
ド誘導体（２）に導くことが出来る。The above-mentioned alcohol compound (9) or the compound (10) with its hydroxyl group protected can be hydrolyzed by the action of a divalent mercury compound, such as mercuric chloride, to prepare it as a starting material for the present invention. This can lead to the aldehyde derivative (2) used.
【００２７】一般式（２）を有する化合物とＮ−ベンジ
ルヒドロキシルアミン誘導体（ＡｒＣＨ２ＮＯＨ） を
１当量ずつ、ベンゼン、トルエン、クロロホルム、塩化
メチレン、エーテル、テトラヒドロフラン、ジオキサン
などの溶媒中で混合し、０℃ないし室温で５分間〜２時
間静置することにより容易に一般式（１１）を有する化
合物が得られる。化合物（１１）を含む反応液から溶媒
を留去して得られる粗製の化合物（１１）をあらためて
ベンゼン、トルエン、キシレンなどに溶かし、５０℃な
いし溶媒の沸点で２時間ないし１０時間加熱することに
より一般式（１）を有する化合物を得ることが出来る。One equivalent of the compound having the general formula (2) and the N-benzylhydroxylamine derivative (ArCH2NOH) are mixed in a solvent such as benzene, toluene, chloroform, methylene chloride, ether, tetrahydrofuran, dioxane, etc., and the mixture is heated at 0°C. A compound having the general formula (11) can be easily obtained by allowing the mixture to stand for 5 minutes to 2 hours at room temperature. By dissolving the crude compound (11) obtained by distilling off the solvent from the reaction solution containing compound (11) in benzene, toluene, xylene, etc., and heating it at 50 ° C. or the boiling point of the solvent for 2 to 10 hours. A compound having general formula (1) can be obtained.
【００２８】ここに得られる化合物（１）は以下に示す
ルートによりシス−２−アミノシクロペンタン−１−カ
ルボン酸（ＦＲ − １０９６１５ ＝シスペンタシン
）に導くことが出来る。すなわち、化合物（１）をパラ
ジウム−炭素を触媒として用いる水素化分解によって、
脱ベンジル化およびイソキサゾリジン環の開環を行うと
、アミノアルコール誘導体（１２）が得られる。化合物
（１２）のアミノ基をｔ−ブトキシカルボニル基で保護
して化合物（１３）としたのち（置換基Ｒ中のα位水酸
基が保護されている場合は脱保護したのち）、ジョーン
ズ試薬あるいは過マンガン酸カリ−メタ過ヨウ素酸ソー
ダなどを用いて酸化するとカルボン酸（１４）が得られ
る。化合物（１４）のアミノ保護基を除去すればシス−
２−アミノシクロペンタン−１−カルボン酸（１５）を
得ることが出来る。Compound (1) obtained here can be led to cis-2-aminocyclopentane-1-carboxylic acid (FR-109615 = cispentacine) by the route shown below. That is, by hydrogenolysis of compound (1) using palladium-carbon as a catalyst,
Debenzylation and opening of the isoxazolidine ring provides the amino alcohol derivative (12). After protecting the amino group of compound (12) with a t-butoxycarbonyl group to obtain compound (13) (after deprotecting the α-hydroxyl group in substituent R if it is protected), Jones reagent or Carboxylic acid (14) is obtained by oxidation using potassium manganate-sodium metaperiodate or the like. If the amino protecting group of compound (14) is removed, cis-
2-Aminocyclopentane-1-carboxylic acid (15) can be obtained.
【００２９】[0029]
【化７】[C7]
【００３０】以下に化合物（２） および（１） の製
造法を参考例および実施例によって示す。The method for producing compounds (2) and (1) will be shown below using Reference Examples and Examples.
【００３１】実施例１ （±）−シス−２−ベンジル
−３−オキサ−２−アザビシクロ［３．３．０］オクタ
ンExample 1 (±)-cis-2-benzyl-3-oxa-2-azabicyclo[3.3.0]octane
【００３２】[0032]
【化８】[Chemical formula 8]
【００３３】ピリジン１９ｇ（０．２４ｍｏｌ ）のジ
クロロメタン溶液（３００ｍｌ）に、攪拌しながら１２
ｇ（０．１２ｍｏｌ ）の酸化クロム（ＶＩ）を１５分
かけて少しずつ加えた。さらに室温にて３０分攪拌の後
、氷冷下５−ヘキセン−１−オール２．０ｇ（０．０２
ｍｏｌ ）のジクロロメタン溶液（８ｍｌ）を滴下し、
氷冷下５０分間攪拌した。その後硫酸水素カリウムの粉
を加えて酸化剤を沈殿させ、上澄みをフロリジルのカラ
ムに通じた。沈殿はエーテルで数回洗い、その洗液もカ
ラムに通じた。流出液（計 １．２ ｌ ）には５−
ヘキセナールが含まれていたが、揮発性のため精製せず
、溶液のまま次の反応に付した。精製した５−ヘキセナ
ールのＮＭＲ スペクトル（ＣＤＣｌ３）δｐｐｍ ：
０．７−２．５（６Ｈ，ｍ），４．８−４．９（１Ｈ，
ｍ），５．０−５．２（１Ｈ，ｍ），５．４−６．２（
１Ｈ，ｍ），９．８２（１Ｈ，ｔ，Ｊ＝２Ｈｚ）。To a dichloromethane solution (300 ml) of 19 g (0.24 mol) of pyridine was added 12 mol of pyridine with stirring.
g (0.12 mol) of chromium (VI) oxide was added portionwise over 15 minutes. After further stirring at room temperature for 30 minutes, 2.0 g (0.02 g of 5-hexen-1-ol) was added under ice cooling.
mol) dichloromethane solution (8 ml) was added dropwise,
The mixture was stirred for 50 minutes under ice cooling. Thereafter, potassium hydrogen sulfate powder was added to precipitate the oxidizing agent, and the supernatant was passed through a Florisil column. The precipitate was washed several times with ether, and the washings were also passed through the column. The effluent (total 1.2 l) contains 5-
Although hexenal was contained, it was not purified due to its volatility and was subjected to the next reaction as a solution. NMR spectrum of purified 5-hexenal (CDCl3) δppm:
0.7-2.5 (6H, m), 4.8-4.9 (1H,
m), 5.0-5.2 (1H, m), 5.4-6.2 (
1H, m), 9.82 (1H, t, J=2Hz).
【００３４】上で得た５−ヘキセナールの溶液にＮ−ベ
ンジルヒドロキシルアミン２．２ｇ（１８ｍｍｏｌ）を
加え、室温で２時間放置した。減圧で溶媒を留去して得
られた固形物をベンゼン１００ｍｌに溶かし、７０℃で
２．５時間攪拌した。減圧で溶媒を留去し、残留物をシ
リカゲル７０ｇを用いるカラムクロマトグラフィーに付
し、酢酸エチル−ヘキサン（０：２０〜３：１７）で溶
出し、３．２８ｇ（８１％収率）の目的化合物を油状物
として得た。ＩＲスペクトル（ＣＨＣｌ３）νｍａｘ
ｃｍ−１ ：２９７０，２８９０，１６０５，１５０
０，１４５５，１０３０，１０１５，７００。ＮＭＲ
スペクトル（ＣＤＣｌ３）δｐｐｍ ：１．４−１．８
（６Ｈ，ｍ），３．０２（１Ｈ，ｍ），３．３６５（１
Ｈ，ｍ），３．４２６（１Ｈ，ｄｄ，Ｊ＝９，６Ｈｚ）
，３．８７７と３．９６１（各１Ｈ，ＡＢｑ ，Ｊ＝１
３．２Ｈｚ），４．１３９（１Ｈ，ｔ，Ｊ＝９Ｈｚ），
７．３０−７．４５（５Ｈ，ｍ）。2.2 g (18 mmol) of N-benzylhydroxylamine was added to the 5-hexenal solution obtained above, and the mixture was allowed to stand at room temperature for 2 hours. The solid substance obtained by distilling off the solvent under reduced pressure was dissolved in 100 ml of benzene and stirred at 70°C for 2.5 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography using 70 g of silica gel and eluted with ethyl acetate-hexane (0:20 to 3:17) to obtain 3.28 g (81% yield) of the desired product. The compound was obtained as an oil. IR spectrum (CHCl3) νmax
cm-1: 2970, 2890, 1605, 150
0,1455,1030,1015,700. NMR
Spectrum (CDCl3) δppm: 1.4-1.8
(6H, m), 3.02 (1H, m), 3.365 (1
H, m), 3.426 (1H, dd, J=9,6Hz)
, 3.877 and 3.961 (each 1H, ABq , J=1
3.2Hz), 4.139 (1H, t, J=9Hz),
7.30-7.45 (5H, m).
【００３５】参考例１（ａ） （±）−シス−２−（
ｔｅｒｔ−ブチルオキシカルボニルアミノ）シクロペン
タン−１−メタノールReference Example 1(a) (±)-cis-2-(
tert-butyloxycarbonylamino)cyclopentane-1-methanol
【００３６】[0036]
【化９】[Chemical formula 9]
【００３７】（±）−シス−２−ベンジル−３−オキサ
−２−アザビシクロ［３．３．０］オクタン３．３９ｇ
（１６．７ｍｍｏｌ）の酢酸溶液（１１０ｍｌ）に、１
０％パラジウム炭素触媒１．７０ｇを加え、水素１気圧
下室温にて１８時間攪拌した。触媒を濾去し、減圧で溶
媒を留去した。残留物をテトラヒドロフラン５０ｍｌに
溶かし、氷冷下トリエチルアミン６．０ｇ（５９ｍｍｏ
ｌ）、ジ炭酸ジｔｅｒｔ−ブチル４．５ｇ（２１ｍｍｏ
ｌ）を加え、室温にて３０分攪拌した。さらにトリエチ
ルアミン３．０ｇ（３０ｍｍｏｌ）、ジ炭酸ジｔｅｒｔ
−ブチル３．０ｇ（１４ｍｍｏｌ）を追加し、室温にて
３０分攪拌した。反応液を酢酸エチルでうすめ、食塩水
で洗い、減圧で溶媒を留去し、ヘキサンより再結晶して
、融点１１１−１１２℃を有する針状晶として２．７ｇ
の標記化合物を得た。母液はシリカゲルカラムクロマト
グラフィーに付し、更に０．３４ｇの標記化合物（合計
８５％収率）を得た。ＩＲスペクトル（ＣＨＣｌ３）ν
ｍａｘ ｃｍ−１：３４６０，２９６０，１６８５，１
５０２，１３６８，１１６０。ＮＭＲ スペクトル（Ｃ
ＤＣｌ３）δｐｐｍ ：１．１３（１Ｈ，ｍ），１．４
５７（９Ｈ，ｓ），１．４０−１．７５（４Ｈ，ｍ），
１． ９９２（１Ｈ，ｍ），２．１３３（１Ｈ，ｍ），
３．３８３（１Ｈ，ｔ，Ｊ＝１２Ｈｚ），３．５７６（
１Ｈ，ｄｄ，Ｊ＝１２，４Ｈｚ），４．１０（１Ｈ，ｑ
−ｌｉｋｅ，Ｊ＝６Ｈｚ），４． ５（１Ｈ，ｂｒ）。(±)-cis-2-benzyl-3-oxa-2-azabicyclo[3.3.0]octane 3.39 g
(16.7 mmol) in acetic acid solution (110 ml), 1
1.70 g of 0% palladium on carbon catalyst was added, and the mixture was stirred at room temperature under 1 atm of hydrogen for 18 hours. The catalyst was filtered off and the solvent was distilled off under reduced pressure. The residue was dissolved in 50 ml of tetrahydrofuran, and 6.0 g (59 mmol) of triethylamine was added under ice cooling.
l), di-tert-butyl dicarbonate 4.5 g (21 mmo
1) was added, and the mixture was stirred at room temperature for 30 minutes. Additionally, 3.0 g (30 mmol) of triethylamine, ditert dicarbonate,
3.0 g (14 mmol) of -butyl was added and stirred at room temperature for 30 minutes. The reaction solution was diluted with ethyl acetate, washed with brine, the solvent was distilled off under reduced pressure, and recrystallized from hexane to give 2.7 g of needle crystals with a melting point of 111-112°C.
The title compound was obtained. The mother liquor was subjected to silica gel column chromatography to further obtain 0.34 g of the title compound (85% yield in total). IR spectrum (CHCl3) ν
max cm-1: 3460, 2960, 1685, 1
502, 1368, 1160. NMR spectrum (C
DCl3) δppm: 1.13 (1H, m), 1.4
57 (9H, s), 1.40-1.75 (4H, m),
1. 992 (1H, m), 2.133 (1H, m),
3.383 (1H, t, J = 12Hz), 3.576 (
1H, dd, J=12,4Hz), 4.10(1H, q
-like, J=6Hz), 4. 5 (1H, br).
【００３８】（ｂ） （±）−シス−２−（ｔｅｒｔ
−ブチルオキシカルボニルアミノ）シクロペンタン−１
−カルボン酸(b) (±)-cis-2-(tert
-butyloxycarbonylamino)cyclopentane-1
-carboxylic acid
【００３９】[0039]
【化１０】[Chemical formula 10]
【００４０】（±）−シス−２−（ｔｅｒｔ−ブチルオ
キシカルボニルアミノ）シクロペンタン−１−メタノー
ル３３９ｍｇ（１．５８ｍｍｏｌ）のアセトン３４ｍｌ
溶液に、酸化クロム（ＶＩ） ６３４ｍｇ（６．３ｍｍ
ｏｌ）、水２．４ｍｌ、濃硫酸０．５５ｍｌより調製し
たジョーンズ試薬を、氷冷下少しずつ滴下した。氷冷に
て５０分攪拌後、２−プロパノールを少量加えて過剰の
酸化剤を分解し、酢酸エチル−食塩水で抽出した。有機
層を食塩水で洗い、減圧で溶媒を留去した。残留物をシ
リカゲル５ｇを用いるカラムクロマトグラフィーに付し
、酢酸エチル−ベンゼン（０：１〜１：１）で溶出し、
３０５ｍｇの標記化合物（８４％収率）を油状物として
得た。ＩＲスペクトル （ＣＨＣｌ３）νｍａｘ ｃｍ
−１：３４５０，３３２０，２９８０，１７０５，１５
００，１４０８，１３７０，１１６５。ＮＭＲ スペク
トル（ＣＤＣｌ３ ＋ Ｄ２Ｏ）δｐｐｍ ：１．４５
０（９Ｈ，ｓ），１．４０−１．７５（２Ｈ，ｍ），１
．７５−２．２０（４Ｈ，ｍ），３．０−３．２（１Ｈ
，ｂｒ），４．０−４．３（１Ｈ，ｂｒ）。(±)-cis-2-(tert-butyloxycarbonylamino)cyclopentane-1-methanol 339 mg (1.58 mmol) in acetone 34 ml
Add 634 mg (6.3 mm) of chromium (VI) oxide to the solution.
Jones reagent prepared from 2.4 ml of water and 0.55 ml of concentrated sulfuric acid was added dropwise little by little under ice-cooling. After stirring for 50 minutes under ice cooling, a small amount of 2-propanol was added to decompose the excess oxidizing agent, and the mixture was extracted with ethyl acetate-brine. The organic layer was washed with brine, and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography using 5 g of silica gel and eluted with ethyl acetate-benzene (0:1 to 1:1).
305 mg of the title compound (84% yield) was obtained as an oil. IR spectrum (CHCl3) νmax cm
-1:3450,3320,2980,1705,15
00,1408,1370,1165. NMR spectrum (CDCl3 + D2O) δppm: 1.45
0 (9H, s), 1.40-1.75 (2H, m), 1
．． 75-2.20 (4H, m), 3.0-3.2 (1H
, br), 4.0-4.3 (1H, br).
【００４１】（ｃ） （±）−シス−２−アミノシク
ロペンタン−１−カルボン酸(c) (±)-cis-2-aminocyclopentane-1-carboxylic acid
【００４２】[0042]
【化１１】[Chemical formula 11]
【００４３】（±）−シス−２−（ｔｅｒｔ−ブチルオ
キシカルボニルアミノ）シクロペンタン−１−カルボン
酸１５０ｍｇに、４Ｎ塩化水素ジオキサン溶液を加え、
室温にて２０分攪拌した。減圧にて溶媒と塩化水素を蒸
発させ、残分を水に溶かしＩＲ−１２０Ｂ（Ｈ＋）型の
イオン交換カラムに定着させ水で洗った。次に０．５Ｍ
アンモニア水を流して溶出し、減圧にて濃縮して得られ
た固体を水−アセトンから再結晶して、１７０℃で分解
する結晶として標記化合物４０ｍｇ（４７％収率）を得
た。ＩＲスペクトル（ＫＢｒ）νｍａｘ ｃｍ−１：２
９７５，２８７２，１６２９，１５２１，１４６３，１
４５２，１２４４。ＮＭＲ スペクトル（Ｄ２Ｏ ，
外部標準テトラメチルシラン使用）δｐｐｍ ：１．４
５−１．７０（４Ｈ，ｍ），１．８０−１．９５（２Ｈ
，ｍ），２．５６９（１Ｈ，ｔｄ ，Ｊ＝８，６Ｈｚ）
，３．５１５（１Ｈ，ｔｄ ，Ｊ＝６，４Ｈｚ）。A 4N hydrogen chloride dioxane solution was added to 150 mg of (±)-cis-2-(tert-butyloxycarbonylamino)cyclopentane-1-carboxylic acid,
The mixture was stirred at room temperature for 20 minutes. The solvent and hydrogen chloride were evaporated under reduced pressure, and the residue was dissolved in water, fixed on an IR-120B (H+) type ion exchange column, and washed with water. Next 0.5M
The solid was eluted with aqueous ammonia and concentrated under reduced pressure, and the resulting solid was recrystallized from water-acetone to obtain 40 mg (47% yield) of the title compound as crystals that decomposed at 170°C. IR spectrum (KBr) νmax cm-1:2
975, 2872, 1629, 1521, 1463, 1
452,1244. NMR spectrum (D2O,
(using external standard tetramethylsilane) δppm: 1.4
5-1.70 (4H, m), 1.80-1.95 (2H
, m), 2.569 (1H, td, J=8,6Hz)
, 3.515 (1H, td, J=6,4Hz).
【００４４】実施例２ （１Ｒ，４Ｓ，５Ｓ）−２−
ベンジル−４−［（Ｓ）−１−ヒドロキシエチル］−３
−オキサ−２−アザビシクロ［３．３．０］オクタンExample 2 (1R, 4S, 5S)-2-
Benzyl-4-[(S)-1-hydroxyethyl]-3
-oxa-2-azabicyclo[3.3.0]octane
【
００４５】[
0045
【化１２】[Chemical formula 12]
【００４６】参考例２（ｆ） で得られる（Ｓ） −
（Ｅ） −７−ヒドロキシ−５−オクテナール４１ｍｇ
（０．２９ｍｍｏｌ）をクロロホルム３ｍｌに溶かした
中へＮ−ベンジルヒドロキシルアミン３７ｍｇ（０．３
０ｍｍｏｌ）を加え、減圧にて溶媒を留去した。さらに
ベンゼンで３回共沸後、ベンゼン４ｍｌに溶かし油浴上
で６時間加熱還流した。反応液を濃縮後、シリカゲル１
ｇを用いるカラムクロマトグラフィーに付し、酢酸エチ
ル−ベンゼン（０：４〜１：３）で溶出して６８ｍｇ（
９５％収率）の目的化合物を油状物として得た。この製
品は約６％のジアステレオマーを含んでいた。比旋光度
［α］Ｄ２５ −５０．５°（ｃ＝２．２９，ＣＨＣｌ
３ ）。ＩＲスペクトル（ＣＨＣｌ３）νｍａｘ ｃｍ
−１：３４５０，２９５０，２８８０，１６００，１５
００，１４５５，１０３０。ＮＭＲ スペクトル（ＣＤ
Ｃｌ３）δｐｐｍ ：１．１７３（３Ｈ，ｄ，Ｊ＝６．
５Ｈｚ），１．３０−１．７０（５Ｈ，ｍ），１．７０
−１．９０（１Ｈ，ｍ），２．６０−２．７０（１Ｈ，
ｍ），３．２５−３．４０（１Ｈ，ｂｒ），３．４２７
（１Ｈ，ｔ，Ｊ＝６．５Ｈｚ），３．７５０（１Ｈ，ｑ
ｕｉｎｔｅｔ ，Ｊ＝６．５Ｈｚ），３．９３２と４．
００２（各１Ｈ，ＡＢｑ ，Ｊ＝１３Ｈｚ），７．２−
７．４（５Ｈ，ｍ）。(S) − obtained in Reference Example 2(f)
(E) -7-hydroxy-5-octenal 41 mg
(0.29 mmol) was dissolved in 3 ml of chloroform, and 37 mg (0.3
0 mmol) was added thereto, and the solvent was distilled off under reduced pressure. After azeotropic distillation with benzene three times, the mixture was dissolved in 4 ml of benzene and heated under reflux on an oil bath for 6 hours. After concentrating the reaction solution, silica gel 1
68 mg (
The desired compound (95% yield) was obtained as an oil. This product contained approximately 6% diastereomers. Specific optical rotation [α] D25 -50.5° (c = 2.29, CHCl
3). IR spectrum (CHCl3) νmax cm
-1:3450,2950,2880,1600,15
00,1455,1030. NMR spectrum (CD
Cl3) δppm: 1.173 (3H, d, J=6.
5Hz), 1.30-1.70 (5H, m), 1.70
-1.90 (1H, m), 2.60-2.70 (1H,
m), 3.25-3.40 (1H, br), 3.427
(1H, t, J=6.5Hz), 3.750 (1H, q
uintet, J=6.5Hz), 3.932 and 4.
002 (each 1H, ABq, J=13Hz), 7.2-
7.4 (5H, m).
【００４７】参考例２（ａ） ４−（１，３−ジチア
ン−２−イル）ブタノールReference Example 2 (a) 4-(1,3-dithian-2-yl)butanol
【００４８】[0048]
【化１３】[Chemical formula 13]
【００４９】１，３−プロパンジチオール８．６ｇ（８
０ｍｍｏｌ）、２，３−ジヒドロ（１Ｈ）ピラン１０．
０ｇ（１２０ｍｍｏｌ）を乾燥ジクロロメタン５０ｍｌ
に溶かした。氷冷下この中に三フッ化ホウ素エチルエー
テル錯体０．５ｍｌを加え、室温にて５０分攪拌した。
再び氷冷し、ジヒドロピラン４．０ｇ（４８ｍｍｏｌ）
を追加し、室温にて４０分攪拌した。次にメタノール３
０ｍｌを加え、室温にて４時間攪拌した。反応液に重曹
水を加え、ジクロロメタンで抽出した。濃縮後残留物を
減圧蒸留し、５Ｔｏｒｒ，１７３−１８３℃の沸点を有
する標記化合物１０．３ｇ（１，３−プロパンジチオー
ルよりの収率６７％）を得た。ＩＲスペクトル（ｌｉｑ
）νｍａｘ ｃｍ−１：３４００，２９３４，２９０２
，２８６０，１４２２。ＮＭＲ スペクトル（ＣＤＣｌ
３）δｐｐｍ ：１．２−２．２（８Ｈ，ｍ），２．５
−３．１（４Ｈ，ｍ），３．４−３．９（２Ｈ ，ｍ）
，４．０５（１Ｈ ，ｔ，Ｊ＝７Ｈｚ）。8.6 g of 1,3-propanedithiol (8
0 mmol), 2,3-dihydro(1H)pyran 10.
0g (120mmol) in 50ml of dry dichloromethane
It was dissolved in 0.5 ml of boron trifluoride ethyl ether complex was added to this under ice cooling, and the mixture was stirred at room temperature for 50 minutes. Cool on ice again and add 4.0 g (48 mmol) of dihydropyran.
was added and stirred at room temperature for 40 minutes. Next, methanol 3
0 ml was added and stirred at room temperature for 4 hours. Aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted with dichloromethane. After concentration, the residue was distilled under reduced pressure to obtain 10.3 g (67% yield from 1,3-propanedithiol) of the title compound having a boiling point of 5 Torr and 173-183°C. IR spectrum (liq
) νmax cm-1: 3400, 2934, 2902
, 2860, 1422. NMR spectrum (CDCl
3) δppm: 1.2-2.2 (8H, m), 2.5
-3.1 (4H, m), 3.4-3.9 (2H, m)
, 4.05 (1H, t, J=7Hz).
【００５０】（ｂ） ４−（１，３−ジチアン−２−
イル）ブタナール(b) 4-(1,3-dithiane-2-
il) butanal
【００５１】[0051]
【化１４】[Chemical formula 14]
【００５２】塩化オキザリル９．９３ｇ（７８ｍｍｏｌ
） を乾燥ジクロロメタン１５０ｍｌに溶かし−７０℃
に冷却した中へ、ジメチルスルホキシド６．５ｇ（８３
ｍｍｏｌ）を滴下し、１５分攪拌した。その中へ４−（
１，３−ジチアン−２−イル）ブタノール７．５２ｇ（
３９ｍｍｏｌ ，ジクロロメタン３０ｍｌに溶かしたも
の）を滴下し、−７０℃にて４０分攪拌した。さらにト
リエチルアミン１７ｇ（１６８ｍｍｏｌ）を加えた後、
−５℃まで２時間かけて昇温した。反応液を食塩水−ジ
クロロメタンで抽出し、有機層より減圧にて溶媒を蒸発
させた。残留物をシリカゲル１００ｇを用いるカラムク
ロマトグラフィーに付し、ベンゼンで溶出して６．１５
ｇ（８３％収率）の標記化合物を油状物として得た。Ｉ
Ｒスペクトル（ＣＨＣｌ３）νｍａｘ ｃｍ−１：１７
３０。ＮＭＲ スペクトル（ＣＤＣｌ３）δｐｐｍ ：
１．４−２．２（６Ｈ，ｍ），２．２−２．７（２Ｈ，
ｍ），２．７−３．０（４Ｈ，ｍ），４．０４（ｔ−ｌ
ｉｋｅ，Ｊ＝７Ｈｚ），９．８２（１Ｈ，ｔ，Ｊ＝２Ｈ
ｚ）。[0052] Oxalyl chloride 9.93g (78mmol
) in 150 ml of dry dichloromethane at -70°C.
6.5 g of dimethyl sulfoxide (83 g
mmol) was added dropwise and stirred for 15 minutes. Into it 4-(
1,3-dithian-2-yl)butanol 7.52g (
39 mmol dissolved in 30 ml of dichloromethane) was added dropwise and stirred at -70°C for 40 minutes. After further adding 17 g (168 mmol) of triethylamine,
The temperature was raised to -5°C over 2 hours. The reaction solution was extracted with brine-dichloromethane, and the solvent was evaporated from the organic layer under reduced pressure. The residue was subjected to column chromatography using 100 g of silica gel and eluted with benzene to give a concentration of 6.15
g (83% yield) of the title compound as an oil. I
R spectrum (CHCl3) νmax cm-1:17
30. NMR spectrum (CDCl3) δppm:
1.4-2.2 (6H, m), 2.2-2.7 (2H,
m), 2.7-3.0 (4H, m), 4.04 (t-l
ike, J=7Hz), 9.82(1H,t,J=2H
z).
【００５３】（ｃ） （Ｅ）−７−（１，３−ジチア
ン−２−イル）−３−ヘプテン−２−オン(c) (E)-7-(1,3-dithian-2-yl)-3-hepten-2-one
【００５４】[0054]
【化１５】[Chemical formula 15]
【００５５】４−（１，３−ジチアン−２−イル）ブタ
ナール６．１５ｇ（３２ｍｍｏｌ）、トリフェニルホス
ホラニリデン−２−プロパノン１３．０ｇ（４１ｍｍｏ
ｌ）、トルエン７０ｍｌの混合物を油浴上９０℃に加熱
して３時間攪拌した。溶媒を減圧にて留去し、残留物を
熱ベンゼン少量に溶かし、ヘキサンを加えて冷却し、析
出した不溶物を濾去した。濾液を濃縮し、シリカゲル２
００ｇを用いるカラムクロマトグラフィーに付し、ベン
ゼンで溶出して、４．６ｇ（６２％収率）の標記化合物
を油状物として得た。ＩＲスペクトル（ＣＨＣｌ３）ν
ｍａｘ ｃｍ−１ ：２９６０，１６８０，１６３０
，１４３０，１３６５，１２６０，９８０。ＮＭＲ ス
ペクトル（ＣＤＣｌ３）δｐｐｍ ：１．２−２．３（
８Ｈ，ｍ），２．２４（３Ｈ，ｓ），２．５−３．０（
４Ｈ，ｍ），４．０２（１Ｈ，ｔ−ｌｉｋｅ，Ｊ＝７Ｈ
ｚ），６．０５（１Ｈ，ｄ−ｌｉｋｅ，Ｊ＝１６Ｈｚ）
，６．７８（１Ｈ，ｄｔ，Ｊ＝１６，６Ｈｚ）。4-(1,3-dithian-2-yl)butanal 6.15 g (32 mmol), triphenylphosphoranylidene-2-propanone 13.0 g (41 mmol)
A mixture of 1) and 70 ml of toluene was heated to 90°C on an oil bath and stirred for 3 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in a small amount of hot benzene, hexane was added and the mixture was cooled, and the precipitated insoluble matter was filtered off. Concentrate the filtrate and apply silica gel 2
Column chromatography using 00g and eluting with benzene gave 4.6g (62% yield) of the title compound as an oil. IR spectrum (CHCl3) ν
max cm-1: 2960, 1680, 1630
, 1430, 1365, 1260, 980. NMR spectrum (CDCl3) δppm: 1.2-2.3(
8H, m), 2.24 (3H, s), 2.5-3.0 (
4H, m), 4.02 (1H, t-like, J=7H
z), 6.05 (1H, d-like, J=16Hz)
, 6.78 (1H, dt, J=16,6Hz).
【００５６】（ｄ） （±）−（Ｅ）−７−（１，３
−ジチアン−２−イル）−３−ヘプテン−２−オール(d) (±)-(E)-7-(1,3
-dithian-2-yl)-3-hepten-2-ol
【
００５７】[
0057
【化１６】[Chemical formula 16]
【００５８】（Ｅ）−７−（１，３−ジチアン−２−イ
ル）−３−ヘプテン−２−オン４．５ｇ（２０ｍｍｏｌ
）をエタノール７０ｍｌに溶かし、塩化セリウム（ＩＩ
Ｉ）７水和物７．６５ｇ（２１ｍｍｏｌ）を加えた。氷
冷下水素化ホウ素ナトリウム０．９５ｇ（２８ｍｍｏｌ
）を加え、室温にて０．７時間攪拌した。氷冷下塩化ア
ンモニウム水溶液を加えた後、酢酸エチルで抽出、食塩
水で洗浄した。減圧で濃縮して得られた残留物をシリカ
ゲル６０ｇを用いるカラムクロマトグラフィーに付し、
酢酸エチル−ベンゼン（０：１００〜７：９３）で溶出
し、４．４ｇ（９７％収率）の標記化合物を油状物とし
て得た。ＩＲスペクトル（ＣＨＣｌ３）νｍａｘ ｃｍ
−１：３４５０，３０００，２９５０，１４２５，１２
８０，９７０。ＮＭＲ スペクトル（ＣＤＣｌ３）δｐ
ｐｍ ：１．２４（３Ｈ， ｄ， Ｊ＝６Ｈｚ），１．
３−２．３（９Ｈ，ｍ），２．７−３．０（４Ｈ，ｍ）
，４．０５（１Ｈ，ｔ，Ｊ＝７Ｈｚ），３．９−４．５
（１Ｈ，ｍ），５．５−５．７（２Ｈ，ｍ）。(E)-7-(1,3-dithian-2-yl)-3-hepten-2-one 4.5 g (20 mmol
) in 70 ml of ethanol, and dissolve cerium (II) chloride in 70 ml of ethanol.
I) 7.65 g (21 mmol) of heptahydrate was added. Sodium borohydride 0.95g (28mmol) under ice cooling
) and stirred at room temperature for 0.7 hour. After adding an aqueous ammonium chloride solution under ice-cooling, the mixture was extracted with ethyl acetate and washed with brine. The residue obtained by concentrating under reduced pressure was subjected to column chromatography using 60 g of silica gel,
Elution with ethyl acetate-benzene (0:100 to 7:93) gave 4.4 g (97% yield) of the title compound as an oil. IR spectrum (CHCl3) νmax cm
-1:3450,3000,2950,1425,12
80,970. NMR spectrum (CDCl3) δp
pm: 1.24 (3H, d, J=6Hz), 1.
3-2.3 (9H, m), 2.7-3.0 (4H, m)
, 4.05 (1H, t, J=7Hz), 3.9-4.5
(1H, m), 5.5-5.7 (2H, m).
【００５９】（ｅ） （Ｒ）−（Ｅ）−７−（１，３
−ジチアン−２−イル）−３−ヘプテン−２−イル
アセタート および（Ｓ）−（Ｅ）−７−（１，３−
ジチアン−２−イル）−３−ヘプテン−２−オール(e) (R)-(E)-7-(1,3
-dithian-2-yl)-3-hepten-2-yl
acetate and (S)-(E)-7-(1,3-
dithian-2-yl)-3-hepten-2-ol
【０
０６０】0
060]
【化１７】[Chemical formula 17]
【００６１】（±）−（Ｅ）−７−（１，３−ジチアン
−２−イル）−３−ヘプテン−２−オール８１５ｍｇ（
３．５ｍｍｏｌ）、酢酸イソプロペニル１．２ｍｌ（１
１ｍｍｏｌ）、リパーゼＰＳアマノ８００ｍｇ、イソプ
ロピルエーテル８ｍｌの混合物を室温で３．５時間攪拌
した。反応液を濾過し、沈殿をアセトンで洗った。濾液
と洗液をあわせて濃縮し、シリカゲル１５ｇを用いるカ
ラムクロマトグラフィーに付した。ベンゼン溶出分画よ
り４０５ｍｇの（Ｒ）−（Ｅ）−７−（１，３−ジチア
ン−２−イル）−３−ヘプテン−２−イル アセター
ト（４２％収率，７９％ｅｅ）が油状物として得られた
。非旋光度［α］Ｄ２５ ＋３５．２°（ｃ＝１．６８
，ＣＨＣｌ３ ）。ＩＲスペクトル（ＣＨＣｌ３）νｍ
ａｘｃｍ−１：２９５０，１７２０，１３７２，１２５
０，１０４０。ＮＭＲ スペクトル（ＣＤＣｌ３）δｐ
ｐｍ ：１．２７（３Ｈ，ｄ，Ｊ＝６Ｈｚ），１．４−
２．４（８Ｈ，ｍ），２．０１（３Ｈ，ｓ），２．６−
３．０（４Ｈ，ｍ），４．０５（１Ｈ，ｔ−ｌｉｋｅ，
Ｊ＝７Ｈｚ），５．１−５．８（３Ｈ，ｍ）。さらに酢
酸エチル−ベンゼン（７：９３）分画より３５８ｍｇの
（Ｓ）−（Ｅ）−７−（１，３−ジチアン−２−イル）
−３−ヘプテン−２−オール（４４％回収率，８４％ｅ
ｅ）が油状物として回収された。比旋光度［α］Ｄ２５
−５．２°（ｃ＝１．６３，ＣＨＣｌ３ ）。上述お
よび後述の光学活性な（Ｅ）−７−（１，３−ジチアン
−２−イル）−３−ヘプテン−２−オールは常法により
ピリジン中 （Ｒ）−３，３，３−トリフルオロ−２−
メトキシ−２−フェニルプロピオニル＝クロリドを室温
で作用させる事によりＭＴＰＡエステルとし、液体クロ
マトグラフィー（島津Ｓｈｉｍ−ｐａｃｋ ＣＬＣ−Ｓ
ＩＬ（Ｍ） 、ヘキサン−酢酸エチル（９７：３）、１
ｍｌ／分、２５４ｎｍ）によりジアステレオマー比を求
め、ｅｅ値を決定した。また、上述および後述の光学活
性な（Ｅ）−７−（１，３−ジチアン−２−イル）−３
−ヘプテン−２−イル アセタートは常法によりメタ
ノール−水混合溶媒中室温で炭酸カリウムを作用させる
事により光学活性な（Ｅ）−７−（１，３−ジチアン−
２−イル）−３−ヘプテン−２−オールとし、その比旋
光度よりｅｅ値を上記および後記のように決定した。(±)-(E)-7-(1,3-dithian-2-yl)-3-hepten-2-ol 815 mg (
3.5 mmol), isopropenyl acetate 1.2 ml (1
A mixture of 1 mmol), 800 mg of lipase PS Amano, and 8 ml of isopropyl ether was stirred at room temperature for 3.5 hours. The reaction solution was filtered, and the precipitate was washed with acetone. The filtrate and washing solution were combined and concentrated, and subjected to column chromatography using 15 g of silica gel. From the benzene elution fraction, 405 mg of (R)-(E)-7-(1,3-dithian-2-yl)-3-hepten-2-yl acetate (42% yield, 79% ee) was obtained as an oil. obtained as. Non-optical rotation [α] D25 +35.2° (c=1.68
, CHCl3). IR spectrum (CHCl3) νm
axcm-1:2950,1720,1372,125
0,1040. NMR spectrum (CDCl3) δp
pm: 1.27 (3H, d, J=6Hz), 1.4-
2.4 (8H, m), 2.01 (3H, s), 2.6-
3.0 (4H, m), 4.05 (1H, t-like,
J=7Hz), 5.1-5.8 (3H, m). Furthermore, 358 mg of (S)-(E)-7-(1,3-dithian-2-yl) was extracted from the ethyl acetate-benzene (7:93) fraction.
-3-hepten-2-ol (44% recovery, 84%e
e) was recovered as an oil. Specific optical rotation [α] D25
-5.2° (c=1.63, CHCl3). The optically active (E)-7-(1,3-dithian-2-yl)-3-hepten-2-ol described above and below is prepared by preparing (R)-3,3,3-trifluoro in pyridine by a conventional method. -2-
MTPA ester was obtained by reacting methoxy-2-phenylpropionyl chloride at room temperature, and liquid chromatography (Shimadzu Shim-pack CLC-S
IL(M), hexane-ethyl acetate (97:3), 1
ml/min, 254 nm) to determine the diastereomer ratio and determine the ee value. In addition, the optically active (E)-7-(1,3-dithian-2-yl)-3 described above and below
-Hepten-2-yl acetate can be converted into optically active (E)-7-(1,3-dithiane-
2-yl)-3-hepten-2-ol, and the ee value was determined from its specific rotation as described above and below.
【００６２】（ｆ） （Ｓ）−（Ｅ）−７−ヒドロシ
キ−５−オクテナール(f) (S)-(E)-7-hydroxy-5-octenal
【００６３】[0063]
【化１８】[Chemical formula 18]
【００６４】参考例２（ｅ）で得た（Ｓ）−（Ｅ）−７
−（１，３−ジチアン−２−イル）−３−ヘプテン−２
−オール１３３ｍｇ（０．５７ｍｍｏｌ）、塩化水銀（
ＩＩ） ３４０ｍｇ（１．３ｍｍｏｌ）、炭酸カルシウ
ム２５０ｍｇ（２．５ｍｍｏｌ）、アセトニトリル４ｍ
ｌ、水１ｍｌの混合物を油浴上５時間加熱還流した。冷
後酢酸エチルを加え濾過した。濾液を飽和食塩水で洗い
、減圧にて溶媒を蒸発させて得られた残留物を、シリカ
ゲル２ｇを用いるカラムクロマトグラフィーに付し、酢
酸エチル−ベンゼン（０：５〜１：４）で溶出し、４１
ｍｇ（５０％収率）の標記化合物と４０ｍｇの原料（３
０％回収率）を得た。比旋光度［α］Ｄ２５ −１２．
９°（ｃ＝１．６５，ＣＨＣｌ３）。ＩＲスペクトル（
ＣＨＣｌ３）νｍａｘ ｃｍ−１： ３４３０ ，
２９２０ ， １７２０ ， ９６８。ＮＭＲ スペク
トル（ＣＤＣｌ３）δｐｐｍ ：１．２５９（３Ｈ，ｄ
，Ｊ＝６Ｈｚ），１．７３３（２Ｈ ，ｑｕｉｎｔｅｔ
，Ｊ＝７Ｈｚ），２．０８（２Ｈ， ｍ），２．４５（
２Ｈ， ｔｄ，Ｊ＝７，２Ｈｚ），４．２６７（１Ｈ，
ｑｕｉｎｔｅｔ，Ｊ＝６Ｈｚ），５．５４６（１Ｈ，ｄ
ｄ，Ｊ＝１５，５Ｈｚ），５．６１３（１Ｈ，ｄｄ ，
Ｊ＝１５，６Ｈｚ），９．７７１（１Ｈ，ｔ，Ｊ＝２Ｈ
ｚ）。(S)-(E)-7 obtained in Reference Example 2(e)
-(1,3-dithian-2-yl)-3-heptene-2
-ol 133 mg (0.57 mmol), mercury chloride (
II) 340 mg (1.3 mmol), calcium carbonate 250 mg (2.5 mmol), acetonitrile 4 m
1 ml of water was heated under reflux on an oil bath for 5 hours. After cooling, ethyl acetate was added and filtered. The filtrate was washed with saturated brine and the solvent was evaporated under reduced pressure. The resulting residue was subjected to column chromatography using 2 g of silica gel and eluted with ethyl acetate-benzene (0:5 to 1:4). , 41
mg (50% yield) of the title compound and 40 mg of raw material (3
0% recovery rate) was obtained. Specific optical rotation [α] D25 -12.
9° (c=1.65, CHCl3). IR spectrum (
CHCl3) νmax cm-1: 3430,
2920, 1720, 968. NMR spectrum (CDCl3) δppm: 1.259 (3H, d
, J=6Hz), 1.733(2H, quintet
, J=7Hz), 2.08 (2H, m), 2.45 (
2H, td, J = 7, 2Hz), 4.267 (1H,
quintet, J=6Hz), 5.546(1H, d
d, J=15,5Hz), 5.613(1H, dd,
J=15,6Hz), 9.771(1H,t, J=2H
z).
【００６５】（ｇ） （１Ｒ，２Ｓ）−１−（ｔｅｒ
ｔ−ブチルオキシカルボニルアミノ）−２−［（１Ｓ，
２Ｓ）−１，２−ジヒドロキシプロピル］シクロペンタ
ン(g) (1R,2S)-1-(ter
t-butyloxycarbonylamino)-2-[(1S,
2S)-1,2-dihydroxypropyl]cyclopentane
【００６６】[0066]
【化１９】[Chemical formula 19]
【００６７】実施例２で得た（１Ｒ，４Ｓ，５Ｓ）−２
−ベンジル−４−［（Ｓ） −１−ヒドロキシエチル］
−３−オキサ−２−アザビシクロ［３．３．０］オクタ
ン６８ｍｇ（０．２３ｍｍｏｌ）を実施例１（ｂ） と
同様に処理し、シリカゲル２ｇを用いるカラムクロマト
グラフィーに付し酢酸エチル−ベンゼン（０：１〜１：
１）で溶出し５８ｍｇ（９８％収率）の標記化合物を油
状物として得た。比旋光度［α］Ｄ２５ ＋２３．８°
（ｃ＝１．８６，ＣＨＣｌ３ ）。ＩＲスペクトル（Ｃ
ＨＣｌ３）νｍａｘ ｃｍ−１：３４５０，２９７０，
１６８０，１５００，１３３０，１１６０，９９０。Ｎ
ＭＲ スペクトル（ＣＤＣｌ３）δｐｐｍ ：１．２５
（１Ｈ，ｍ），１．２６６（３Ｈ，ｄ，Ｊ＝６ｈｚ），
１．４５５（９Ｈ，ｓ），１．５３−１．６５（２Ｈ，
ｍ），１．６５−１．８５（２Ｈ，ｍ），１．８５−２
．０３（１Ｈ，ｍ），２．０３−２．２０（１Ｈ，ｍ）
，３．１５１（１Ｈ，ｄｄ，Ｊ＝１０，２Ｈｚ），３．
６７３（１Ｈ，ｑｄ，Ｊ＝６，２Ｈｚ），４．１２２（
１Ｈ，ｑ−ｌｉｋｅ，Ｊ＝６Ｈｚ），４．５１（１Ｈ，
ｂｒ ｄ，Ｊ＝７Ｈｚ）。(1R,4S,5S)-2 obtained in Example 2
-benzyl-4-[(S)-1-hydroxyethyl]
68 mg (0.23 mmol) of -3-oxa-2-azabicyclo[3.3.0]octane was treated in the same manner as in Example 1(b), subjected to column chromatography using 2 g of silica gel, and ethyl acetate-benzene ( 0:1~1:
1) to obtain 58 mg (98% yield) of the title compound as an oil. Specific optical rotation [α] D25 +23.8°
(c=1.86, CHCl3). IR spectrum (C
HCl3) νmax cm-1: 3450, 2970,
1680, 1500, 1330, 1160, 990. N
MR spectrum (CDCl3) δppm: 1.25
(1H, m), 1.266 (3H, d, J=6hz),
1.455 (9H, s), 1.53-1.65 (2H,
m), 1.65-1.85 (2H, m), 1.85-2
．． 03 (1H, m), 2.03-2.20 (1H, m)
, 3.151 (1H, dd, J=10,2Hz), 3.
673 (1H, qd, J=6,2Hz), 4.122 (
1H, q-like, J=6Hz), 4.51 (1H,
br d, J=7Hz).
【００６８】（ｈ） （１Ｓ，２Ｒ）−２−（ｔｅｒ
ｔ−ブチルオキシカルボニルアミノ）シクロペンタン−
１−カルボン酸(h) (1S,2R)-2-(ter
t-Butyloxycarbonylamino)cyclopentane-
1-carboxylic acid
【００６９】[0069]
【化２０】[C20]
【００７０】参考例２（ｇ） で得た（１Ｒ，２Ｓ）−
１−（ｔｅｒｔ−ブチルオキシカルボニルアミノ）−２
−［（１Ｓ，２Ｓ）−１，２−ジヒドロキシプロピル］
シクロペンタン３１ｍｇ（０．１２ｍｍｏｌ）をアセト
ン４ｍｌに溶かした中へ参考例１（ｂ） と同様に調製
したジョーンズ試薬を氷冷下２時間かけて適量滴下した
。参考例１（ｂ） と同様に処理精製し１４．３ｍｇ（
５２％収率）の標記化合物を油状物として得た。比旋光
度［α］Ｄ ＋１５．７°（ｃ＝１．１２，ＣＨＣｌ３
）。（ｉ） （１Ｓ，２Ｒ）−（＋）−シス−２−
アミノシクロペンタン−１−カルボン酸(1R,2S)- obtained in Reference Example 2(g)
1-(tert-butyloxycarbonylamino)-2
-[(1S,2S)-1,2-dihydroxypropyl]
An appropriate amount of Jones reagent prepared in the same manner as in Reference Example 1(b) was added dropwise to a solution of 31 mg (0.12 mmol) of cyclopentane in 4 ml of acetone over 2 hours under ice cooling. Processed and purified in the same manner as in Reference Example 1(b), 14.3 mg (
The title compound was obtained as an oil (52% yield). Specific optical rotation [α]D +15.7° (c=1.12, CHCl3
). (i) (1S,2R)-(+)-cis-2-
Aminocyclopentane-1-carboxylic acid
【００７１】[0071]
【化２１】[C21]
【００７２】参考例２（ｈ）で得た（１Ｓ，２Ｒ）−２
−（ｔｅｒｔ−ブチルオキシカルボニルアミノ）シクロ
ペンタン−１−カルボン酸１４．３ｍｇ（０．０６２ｍ
ｍｏｌ）を参考例１（ｃ）と同様に処理し３．８ｍｇ（
４７％収率）の標記化合物を固形物として得た。比旋光
度［α］Ｄ２５ ＋６．１（ｃ＝０．３８，ＣＨＣｌ３
）。ＮＭＲ スペクトルは参考例１（ｃ） で述べた
化合物のそれと一致した。(1S,2R)-2 obtained in Reference Example 2(h)
-(tert-butyloxycarbonylamino)cyclopentane-1-carboxylic acid 14.3 mg (0.062 m
mol) was treated in the same manner as in Reference Example 1(c) to obtain 3.8 mg (
47% yield) of the title compound was obtained as a solid. Specific optical rotation [α] D25 +6.1 (c=0.38, CHCl3
). The NMR spectrum was consistent with that of the compound described in Reference Example 1(c).
【００７３】実施例３ （１Ｓ，４Ｒ，５Ｒ）−２−
ベンジル−４−［（Ｒ）−１−ヒドロキシエチル］−３
−オキサ−２−アザビシクロ［３．３．０］ オクタン
Example 3 (1S,4R,5R)-2-
Benzyl-4-[(R)-1-hydroxyethyl]-3
-oxa-2-azabicyclo[3.3.0] octane
【００７４】[0074]
【化２２】[C22]
【００７５】参考例３（ｃ） で得られる（Ｒ） −（
Ｅ） −７−ヒドロキシ−５−オクテナール１．１３ｇ
（８．０ｍｍｏｌ）をベンゼン２０ｍｌに溶かした中へ
、Ｎ−ベンジルヒドロキシルアミン９７０ｍｇ（７．９
ｍｍｏｌ）を加え、ロータリーエバポレータを用いて３
回ベンゼンにて共沸した。残留物をベンゼン１００ｍｌ
に溶かし、３時間加熱還流した。減圧で溶媒を留去し、
シリカゲル３０ｇを用いるカラムクロマトグラフィー付
し、酢酸エチル−クロロホルム（０：１００〜６：９４
）で溶出して１．６７ｇ（８５％収率）のジアステレオ
マー混合物（１５：１）を得た。さらにこの混合物を酢
酸エチル−クロロホルム（１：１０）を用いるローバー
カラムに付してジアステレオマーを分離し、各々油状物
として単離した。主ジアステレオマー（１Ｓ，４Ｒ，５
Ｒ）−２−ベンジル−４−［（Ｒ）−１−ヒドロキシエ
チル］−３−オキサ−２−アザビシクロ［３．３．０］
オクタン：比旋光度［α］Ｄ２５ ＋６０．４°（ｃ
＝２．２６，ＣＨＣｌ３ ）。ＮＭＲ スペクトルは実
施例２で述べた化合物のそれと一致した。副生ジアステ
レオマー（１Ｒ，４Ｓ，５Ｓ）−２−ベンジル−４−［
（Ｒ）−１−ヒドロキシエチル］−３−オキサ−２−ア
ザビシクロ［３．３．０］ オクタン：比旋光度［α］
Ｄ２５ −７１．６°（ｃ＝２．２６，ＣＨＣｌ３ ）
。ＩＲスペクトル（ＣＨＣｌ３） νｍａｘ ｃｍ−１
：３４５０，２９５０，２８７０，１６００，１５９０
，１４４８，１３６０，１０３０。ＮＭＲ スペクトル
（ＣＤＣｌ３）δｐｐｍ ：１．１４３（３Ｈ，ｄ，Ｊ
＝７Ｈｚ），１．３−１．７（５Ｈ，ｍ），１．８１８
（１Ｈ，ｍ），２．９４３（１Ｈ，ｂｒ ｑ，Ｊ＝７Ｈ
ｚ），３．１−３．３（１Ｈ，ｂｒ ），３．４９８（
１Ｈ，ｄｄ，Ｊ＝７，３Ｈｚ），３．９５７（２Ｈ，ｓ
），４．０３１（１Ｈ，ｑｄ，Ｊ＝７，３Ｈｚ）。(R) −( obtained in Reference Example 3(c))
E) -7-hydroxy-5-octenal 1.13g
(8.0 mmol) was dissolved in 20 ml of benzene, and 970 mg (7.9
mmol) and evaporated using a rotary evaporator.
The mixture was azeotroped with benzene. Pour the residue into 100ml of benzene.
and heated under reflux for 3 hours. Remove the solvent under reduced pressure,
Column chromatography using 30 g of silica gel and ethyl acetate-chloroform (0:100-6:94)
) to give 1.67 g (85% yield) of a diastereomeric mixture (15:1). Further, this mixture was subjected to a Lorber column using ethyl acetate-chloroform (1:10) to separate diastereomers, each of which was isolated as an oil. Main diastereomer (1S,4R,5
R)-2-benzyl-4-[(R)-1-hydroxyethyl]-3-oxa-2-azabicyclo[3.3.0]
Octane: Specific rotation [α] D25 +60.4° (c
=2.26, CHCl3). The NMR spectrum was consistent with that of the compound described in Example 2. By-product diastereomer (1R,4S,5S)-2-benzyl-4-[
(R)-1-hydroxyethyl]-3-oxa-2-azabicyclo[3.3.0] Octane: Specific optical rotation [α]
D25 -71.6° (c=2.26, CHCl3)
. IR spectrum (CHCl3) νmax cm-1
:3450,2950,2870,1600,1590
, 1448, 1360, 1030. NMR spectrum (CDCl3) δppm: 1.143 (3H, d, J
=7Hz), 1.3-1.7 (5H, m), 1.818
(1H, m), 2.943 (1H, br q, J=7H
z), 3.1-3.3 (1H, br), 3.498 (
1H, dd, J=7,3Hz), 3.957(2H,s
), 4.031 (1H, qd, J=7,3Hz).
【００７６】参考例３（ａ） （±）−（Ｅ）−７−
（１，３−ジチアン−２−イル）−３−ヘプテン−２−
イル アセタートReference Example 3(a) (±)-(E)-7-
(1,3-dithian-2-yl)-3-heptene-2-
il acetate
【００７７】[0077]
【化２３】[C23]
【００７８】（±） −７−（１，３ −ジチアン−２
−イル）−３−ヘプテン−２−オール５．８ｇ（２５ｍ
ｍｏｌ）をピリジン５０ｍｌに溶かし、氷冷下１２ｍｌ
（０．１６ｍｏｌ）の無水酢酸を加え、終夜放置した。
氷冷下メタノール２０ｍｌを加え、１５分攪拌した。反
応液を減圧下濃縮した後、酢酸エチル−食塩水で抽出し
た。有機層を食塩水で洗った後減圧で溶媒を留去し、そ
の残留物をシリカゲル８０ｇを用いるカラムクロマトグ
ラフィーに付しベンゼンで溶出して目的化合物６．５ｇ
（９５％収率）を油状物として得た。(±) -7-(1,3-dithiane-2
-yl)-3-hepten-2-ol 5.8 g (25 m
Dissolve mol) in 50 ml of pyridine and add 12 ml under ice-cooling.
(0.16 mol) of acetic anhydride was added and left overnight. 20 ml of methanol was added under ice-cooling, and the mixture was stirred for 15 minutes. The reaction solution was concentrated under reduced pressure, and then extracted with ethyl acetate-brine. After washing the organic layer with brine, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography using 80 g of silica gel and eluted with benzene to obtain 6.5 g of the target compound.
(95% yield) was obtained as an oil.
【００７９】（ｂ） （Ｒ）−（Ｅ）−７−（１，３
−ジチアン−２−イル）−３−ヘプテン−２−オール(b) (R)-(E)-7-(1,3
-dithian-2-yl)-3-hepten-2-ol
【
００８０】[
0080
【化２４】[C24]
【００８１】（±）−７−（１，３−ジチアン−２−イ
ル）−３−ヘプテン−２−イル アセタート６．６ｇ
（２４ｍｍｏｌ）、１Ｍ ＫＨ２ＰＯ４ −１Ｍ Ｋ２
ＨＰＯ４ 緩衝液５０ｍｌ（各５０ｍｍｏｌ）、アセト
ン４００ｍｌ、リパーゼＰＳアマノ６．６ｇの混合物を
室温で１２時間攪拌した。さらにリパーゼを６ｇ追加し
、３５−４０℃で１８時間攪拌した。反応混合物を濾過
し、濾液を酢酸エチル−食塩水に分配した。有機層を減
圧で濃縮して得た残留物を参考例２（ｅ）と同様にして
精製し、（Ｓ）−（Ｅ）−７−（１，３−ジチアン−２
−イル）−３−ヘプテン−２−イル アセタート（［
α］Ｄ −２２．９°（ｃ＝１．７６，ＣＨＣｌ３ ）
，５１％ｅｅ）３．９ｇ（５９％回収率）および（Ｒ）
−（Ｅ）−７−（１，３−ジチアン−２−イル）−３−
ヘプテン−２−オール（［α］Ｄ ＋６．３°（ｃ＝１
．０６，ＣＨＣｌ３ ），９７％ｅｅ）２．０ｇ（３６
％収率）を各々油状物として得た。(±)-7-(1,3-dithian-2-yl)-3-hepten-2-yl acetate 6.6 g
(24 mmol), 1M KH2PO4 -1M K2
A mixture of 50 ml of HPO4 buffer (50 mmol each), 400 ml of acetone, and 6.6 g of lipase PS Amano was stirred at room temperature for 12 hours. Further, 6 g of lipase was added and stirred at 35-40°C for 18 hours. The reaction mixture was filtered and the filtrate was partitioned between ethyl acetate and brine. The residue obtained by concentrating the organic layer under reduced pressure was purified in the same manner as in Reference Example 2(e) to obtain (S)-(E)-7-(1,3-dithiane-2
-yl)-3-hepten-2-yl acetate ([
α]D −22.9° (c=1.76, CHCl3)
, 51%ee) 3.9g (59% recovery) and (R)
-(E)-7-(1,3-dithian-2-yl)-3-
Hepten-2-ol ([α]D +6.3° (c=1
．． 06, CHCl3 ), 97%ee) 2.0 g (36
% yield) were obtained in each case as an oil.
【００８２】（ｃ） （Ｒ）−（Ｅ）−７−ヒドロキ
シ−５−オクテナール(c) (R)-(E)-7-hydroxy-5-octenal
【００８３】[0083]
【化２５】[C25]
【００８４】参考例３（ｂ）で得た（Ｒ）−（Ｅ）−７
−（１，３−ジチアン−２−イル）−３−ヘプテン−２
−オール１．９９ｇ（８．６ｍｍｏｌ，９７％ｅｅ）、
塩化水銀（ＩＩ）８．０ｇ（２９ｍｍｏｌ）、炭酸カル
シウム７．５ｇ（７５ｍｍｏｌ）、アセトニトリル８０
ｍｌ、水３２ｍｌの混合物を７時間加熱還流した。参考
例２（ｆ）と同様に精製し、１．１４ｇ（９３％収率）
の標記化合物を油状物として得た。比旋光度［α］Ｄ２
５ ＋２４．４°（ｃ＝１．２６，ＣＨＣｌ３ ）。（
ｄ） （１Ｓ，２Ｒ）−１−（ｔｅｒｔ−ブチルオキ
シカルボニルアミノ）−２−［（１Ｒ，２Ｒ）−１，２
−ジヒドロキシプロピル］シクロペンタン(R)-(E)-7 obtained in Reference Example 3(b)
-(1,3-dithian-2-yl)-3-heptene-2
-All 1.99g (8.6mmol, 97%ee),
Mercury chloride (II) 8.0 g (29 mmol), calcium carbonate 7.5 g (75 mmol), acetonitrile 80
ml and 32 ml of water was heated under reflux for 7 hours. Purified in the same manner as Reference Example 2(f), 1.14 g (93% yield)
The title compound was obtained as an oil. Specific optical rotation [α]D2
5 +24.4° (c=1.26, CHCl3). (
d) (1S,2R)-1-(tert-butyloxycarbonylamino)-2-[(1R,2R)-1,2
-dihydroxypropyl]cyclopentane
【００８５】[0085]
【化２６】[C26]
【００８６】実施例３で得た（１Ｓ，４Ｒ，５Ｒ）−２
−ベンジル−４−［（Ｒ）−１−ヒドロキシエチル］−
３−オキサ−２−アザビシクロ［３．３．０］オクタン
１．１７ｇ（３．９ｍｍｏｌ） を参考例１（ａ） と
同様に処理し、シリカゲル４０ｇを用いるカラムクロマ
トグラフィーで精製し、０．９５ｇ（９３％収率）の標
記化合物を油状物として得た。比旋光度［α］Ｄ２５
−３４．１°（ｃ＝１．０７，ＣＨＣｌ３ ）。ＩＲお
よびＮＭＲ スペクトルは参考例２（ｇ） で述べた化
合物のものと一致した。(1S,4R,5R)-2 obtained in Example 3
-Benzyl-4-[(R)-1-hydroxyethyl]-
1.17 g (3.9 mmol) of 3-oxa-2-azabicyclo[3.3.0]octane was treated in the same manner as in Reference Example 1(a) and purified by column chromatography using 40 g of silica gel to give 0.95 g. (93% yield) of the title compound was obtained as an oil. Specific optical rotation [α] D25
-34.1° (c=1.07, CHCl3). The IR and NMR spectra were consistent with those of the compound described in Reference Example 2(g).
【００８７】（ｅ） （１Ｒ，２Ｓ）−２−（ｔｅｒ
ｔ−ブチルオキシカルボニルアミノ）シクロペンタン−
１−カルボン酸(e) (1R,2S)-2-(ter
t-Butyloxycarbonylamino)cyclopentane-
1-carboxylic acid
【００８８】[0088]
【化２７】[C27]
【００８９】参考例３（ｄ）で得た（１Ｓ，２Ｒ）−１
−（ｔｅｒｔ−ブチルオキシカルボニルアミノ）−２−
［（１Ｒ，２Ｒ）−１，２−ジヒドロキシプロピル］シ
クロペンタン０．９２ｇ（３．６ｍｍｏｌ）をアセトン
６０ｍｌに溶かした中へ、１Ｍ Ｋ２ＨＰＯ４ −１Ｍ
ＫＨ２ＰＯ４ 緩衝液１２ｍｌ（各１２ｍｍｏｌ）を
加えた。この中にメタ過ヨウ素酸ナトリウム２．７ｇ（
１３ｍｍｏｌ）、過マンガン酸カリウム７０ｍｇ（０．
４４ｍｍｏｌ） を溶かした水溶液（３０ｍｌ）を氷
冷下加え、３時間攪拌しながら室温まで昇温した。過マ
ンガン酸カリウム７０ｍｇ（０．４４ｍｍｏｌ）を追加
し、さらに室温にて１．５時間攪拌した。反応液に酢酸
エチルと食塩水を加え、塩酸を加えて酸性とした。油層
を分取し食塩水で洗浄し、溶媒を減圧で留去した。残留
物をシリカゲル２０ｇを用いるカラムクロマトグラフィ
ーに付し、酢酸エチル−ベンゼン（０：５−２：３）で
溶出し７４０ｍｇ（６１％収率）の標記化合物を固体と
して得た。比旋光度［α］Ｄ２５ ＝−２９．６°（ｃ
＝１．５６，ＣＨＣｌ３ ）。（ｆ） （１Ｒ，２Ｓ
）−（−） −シス−２−アミノシクロペンタン−１−
カルボン酸(1S,2R)-1 obtained in Reference Example 3(d)
-(tert-butyloxycarbonylamino)-2-
[(1R,2R)-1,2-dihydroxypropyl]cyclopentane (0.92 g (3.6 mmol)) dissolved in 60 ml of acetone, 1M K2HPO4 -1M
12 ml of KH2PO4 buffer (12 mmol each) was added. In this, 2.7 g of sodium metaperiodate (
13 mmol), potassium permanganate 70 mg (0.
An aqueous solution (30 ml) containing 44 mmol) was added under ice cooling, and the temperature was raised to room temperature while stirring for 3 hours. 70 mg (0.44 mmol) of potassium permanganate was added, and the mixture was further stirred at room temperature for 1.5 hours. Ethyl acetate and brine were added to the reaction solution, and hydrochloric acid was added to make it acidic. The oil layer was separated and washed with brine, and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography using 20 g of silica gel and eluted with ethyl acetate-benzene (0:5-2:3) to obtain 740 mg (61% yield) of the title compound as a solid. Specific optical rotation [α] D25 = -29.6° (c
= 1.56, CHCl3). (f) (1R,2S
)-(-)-cis-2-aminocyclopentane-1-
carboxylic acid
【００９０】[0090]
【化２８】[C28]
【００９１】参考例３（ｅ）で得た（１Ｒ，２Ｓ）−２
−（ｔｅｒｔ−ブチルオキシカルボニルアミノ）シクロ
ペンタン−１−カルボン酸４１９ｍｇ（１．８３ｍｍｏ
ｌ）を参考例１（ｃ）と同様に処理し水−アセトンより
再結晶して、２２７℃より分解する標記化合物の１次結
晶１３９ｍｇと、２２０℃より分解する２次結晶４９ｍ
ｇ（８０％合計収率）とを得た。１次結晶の比旋光度［
α］Ｄ２５ −９．１°（ｃ＝１．２３，Ｈ２Ｏ ）Ｉ
Ｒスペクトル（ＫＢｒ） νｍａｘ ｃｍ−１：２９６
０，２１９１，１６４８，１５４５，１４１２，１３３
６，１３０９，１１６７。ＮＭＲ スペクトルは参考例
１（ｃ） で述べた化合物のそれと一致した。(1R,2S)-2 obtained in Reference Example 3(e)
-(tert-butyloxycarbonylamino)cyclopentane-1-carboxylic acid 419 mg (1.83 mmo
l) was treated in the same manner as in Reference Example 1(c) and recrystallized from water-acetone to obtain 139 mg of primary crystals of the title compound that decomposes at 227°C and 49 m of secondary crystals that decompose at 220°C.
g (80% total yield). Specific rotation of primary crystal [
α]D25 -9.1° (c=1.23, H2O)I
R spectrum (KBr) νmax cm-1:296
0,2191,1648,1545,1412,133
6,1309,1167. The NMR spectrum was consistent with that of the compound described in Reference Example 1(c).
【００９２】実施例４ （１Ｒ，４Ｓ，５Ｓ）−２−
ベンジル−４−［（Ｒ）−１−アセトキシエチル］−３
−オキサ−２−アザビシクロ［３．３．０］オクタンお
よび（１Ｓ，４Ｒ，５Ｒ）−２−ベンジル−４−［（Ｒ
）−１−アセトキシエチル］−３−オキサ−２−アザビ
シクロ［３．３．０］オクタンExample 4 (1R, 4S, 5S)-2-
Benzyl-4-[(R)-1-acetoxyethyl]-3
-oxa-2-azabicyclo[3.3.0]octane and (1S,4R,5R)-2-benzyl-4-[(R
)-1-acetoxyethyl]-3-oxa-2-azabicyclo[3.3.0]octane
【００９３】[0093]
【化２９】[C29]
【００９４】（Ｒ）−（Ｅ）−７−（１，３−ジチアン
−２−イル）−３−ヘプテン−２−イル アセタート
３４ｍｇ（０．１２ｍｍｏｌ）を順に参考例２（ｆ）
および実施例２と同様にして反応させシリカゲルカラム
クロマトグラフィーにより精製して標記化合物２７ｍｇ
（収率８０％）を油状物として得た。これは（１Ｒ，４
Ｓ，５Ｒ）−体［Ａ］を主とする２：１のジアステレオ
マー混合物であった。ＩＲスペクトル（ＣＨＣｌ３）ν
ｍａｘ ｃｍ−１：１７２０。ＮＭＲ スペクトル（Ｃ
ＤＣｌ３）δｐｐｍ ：１．２４６（３Ｈ×２／３ ，
ｄ，Ｊ＝６Ｈｚ），１．２５７（３Ｈ×１／３ ，ｄ，
Ｊ＝６Ｈｚ），１．２−１．９（６Ｈ，ｍ），２．０４
０（３Ｈ，ｓ），２．６−２．８（１Ｈ，ｍ），３．２
−３．３（１Ｈ，ｍ），３．５−３．７（１Ｈ，ｍ），
３．８５２および４．０８２（各１Ｈ×１／３ ，ＡＢ
ｑ ，Ｊ＝１３Ｈｚ），３．８８３と４．０３６（各１
Ｈ×２／３ ，ＡＢｑ ，Ｊ＝１３Ｈｚ），５．０−５
．１（１Ｈ，ｍ），７．２−７．４（５Ｈ，ｍ）。34 mg (0.12 mmol) of (R)-(E)-7-(1,3-dithian-2-yl)-3-hepten-2-yl acetate was added in order to Reference Example 2(f).
and was reacted in the same manner as in Example 2 and purified by silica gel column chromatography to obtain 27 mg of the title compound.
(yield 80%) was obtained as an oil. This is (1R, 4
It was a 2:1 diastereomer mixture mainly consisting of the S,5R)-isomer [A]. IR spectrum (CHCl3) ν
max cm-1:1720. NMR spectrum (C
DCl3) δppm: 1.246 (3H×2/3,
d, J=6Hz), 1.257 (3H×1/3, d,
J=6Hz), 1.2-1.9 (6H, m), 2.04
0 (3H, s), 2.6-2.8 (1H, m), 3.2
-3.3 (1H, m), 3.5-3.7 (1H, m),
3.852 and 4.082 (1H x 1/3 each, AB
q, J=13Hz), 3.883 and 4.036 (1 each
H×2/3, ABq, J=13Hz), 5.0-5
．． 1 (1H, m), 7.2-7.4 (5H, m).
【００９５】実施例５ （１Ｓ，４Ｒ，５Ｒ）−２−
ベンジル−４−［（Ｓ）−１−（ｔｅｒｔ−ブチルジメ
チルシリルオキシ）エチル］−３−オキサ−２−アザビ
シクロ［３．３．０］オクタンおよび（１Ｒ，４Ｓ，５
Ｓ）−２−ベンジル−４−［（Ｓ）−１−（ｔｅｒｔ−
ブチルジメチルシリルオキシ）エチル］−３−オキサ−
２−アザビシクロ［３．３．０］ オクタンExample 5 (1S, 4R, 5R)-2-
Benzyl-4-[(S)-1-(tert-butyldimethylsilyloxy)ethyl]-3-oxa-2-azabicyclo[3.3.0]octane and (1R,4S,5
S)-2-benzyl-4-[(S)-1-(tert-
butyldimethylsilyloxy)ethyl]-3-oxa-
2-azabicyclo[3.3.0] octane
【００９６】[0096]
【化３０】[C30]
【００９７】２−［（Ｓ）−（Ｅ）−６−（ｔｅｒｔ−
ブチルジメチルシリルオキシ）−４−ヘプテニル］−１
，３−ジチアン７５ｍｇ（０．２２ｍｍｏｌ）を順に参
考例２（ｆ） および実施例２と同様にして反応させた
。反応混合物を濃縮後ローバーカラムに付し酢酸エチル
−ヘキサン（１９：１）で溶出して標記化合物４６ｍｇ
（収率５９％）を油状物として得た。これは１：１のジ
アステレオマー混合物であった。ＩＲスペクトル（ＣＨ
Ｃｌ３） νｍａｘ ｃｍ−１：２９６０，１２５５，
８３５。ＮＭＲ スペクトル（ＣＤＣｌ３）δｐｐｍ
：０．０２４，０．０３６．０．０６１，０．０８９（
各３Ｈ×１／２ ，ｓ），０．８４８と０．９０２（各
９Ｈ×１／２ ，ｓ），１．１２５と１．１３６（各３
Ｈ×１／２ ，ｄ，Ｊ＝６Ｈｚ），１．１−２．１（５
Ｈ，ｍ），２．５−２．７（１Ｈ，ｍ），２．８−３．
０（１Ｈ，ｍ），３．１−３．３（１Ｈ，ｍ），３．３
７３（１／２ Ｈ，ｄｄ，Ｊ＝７，５Ｈｚ），３．４８
６（１／２ Ｈ，ｄｄ，Ｊ＝７，６Ｈｚ），３．７−４
．１（３Ｈ，ｍ），７．２−７．４（５Ｈ，ｍ）
参考例４ ２−［（Ｓ）−（Ｅ）−６−（ｔｅｒｔ−
ブチルジメチルシリルオキシ）−４−ヘプテニル］−１
，３−ジチアン2-[(S)-(E)-6-(tert-
butyldimethylsilyloxy)-4-heptenyl]-1
, 3-dithiane (75 mg, 0.22 mmol) were reacted in the same manner as in Reference Example 2(f) and Example 2. After concentrating the reaction mixture, it was applied to a Lorber column and eluted with ethyl acetate-hexane (19:1) to obtain 46 mg of the title compound.
(yield 59%) was obtained as an oil. This was a 1:1 diastereomeric mixture. IR spectrum (CH
Cl3) νmax cm-1: 2960, 1255,
835. NMR spectrum (CDCl3) δppm
:0.024,0.036.0.061,0.089(
3H x 1/2, s each), 0.848 and 0.902 (9H x 1/2, s each), 1.125 and 1.136 (3H each
H×1/2, d, J=6Hz), 1.1-2.1(5
H, m), 2.5-2.7 (1H, m), 2.8-3.
0 (1H, m), 3.1-3.3 (1H, m), 3.3
73 (1/2 H, dd, J=7,5Hz), 3.48
6 (1/2 H, dd, J=7,6Hz), 3.7-4
．． 1 (3H, m), 7.2-7.4 (5H, m) Reference example 4 2-[(S)-(E)-6-(tert-
butyldimethylsilyloxy)-4-heptenyl]-1
,3-dithiane
【００９８】[0098]
【化３１】[Chemical formula 31]
【００９９】（Ｓ）−（Ｅ）−７−（１，３−ジチアン
−２−イル）−３−ヘプテン−２−オール６１．８ｍｇ
（０．２７ｍｍｏｌ）のジメチルホルムアミド（１．２
ｍｏｌ ）溶液に氷冷下ｔｅｒｔ−ブチルジメチルシリ
ルクロリド６０ｍｇ（０．４０ｍｍｏｌ）およびイミダ
ゾール４０ｍｇ（０．５９ｍｍｏｌ）を加え、１．２時
間かけて室温まで昇温させながら攪拌した。ベンゼン−
炭酸水素ナトリウム水溶液で抽出し、有機層を乾燥後シ
リカゲル２ｇを用いるカラムクロマトグラフィーに付し
、酢酸エチル−ヘキサン（０：１００−４：９６）で溶
出し７５ｍｇ（収率８１％）の標記化合物を油状物とし
て得た。ＩＲスペクトル（ＣＨＣｌ３）νｍａｘ ｃｍ
−１：２９４０，２８００，１７３０，１４６０，１２
５０，９７０，８３５。ＮＭＲ スペクトル （ＣＤＣ
ｌ３）δｐｐｍ ：０．０４（６Ｈ，ｓ），０．８８（
９Ｈ，ｓ），１．１６（３Ｈ，ｄ，Ｊ＝６Ｈｚ），１．
３−２．３（８Ｈ，ｍ），２．６−３．０（４Ｈ，ｍ）
，４．０３（１Ｈ，ｔ），３．９−４．５（１Ｈ，ｍ）
，５．４−５．６（２Ｈ，ｍ）。(S)-(E)-7-(1,3-dithian-2-yl)-3-hepten-2-ol 61.8 mg
(0.27 mmol) of dimethylformamide (1.2
60 mg (0.40 mmol) of tert-butyldimethylsilyl chloride and 40 mg (0.59 mmol) of imidazole were added to the solution under ice cooling, and the mixture was stirred while raising the temperature to room temperature over 1.2 hours. Benzene-
After extraction with an aqueous sodium hydrogen carbonate solution, the organic layer was dried and subjected to column chromatography using 2 g of silica gel, eluting with ethyl acetate-hexane (0:100-4:96) to obtain 75 mg (yield 81%) of the title compound. was obtained as an oil. IR spectrum (CHCl3) νmax cm
-1:2940,2800,1730,1460,12
50,970,835. NMR spectrum (CDC
l3) δppm: 0.04 (6H, s), 0.88 (
9H, s), 1.16 (3H, d, J=6Hz), 1.
3-2.3 (8H, m), 2.6-3.0 (4H, m)
, 4.03 (1H, t), 3.9-4.5 (1H, m)
, 5.4-5.6 (2H, m).
Claims (1)
導体およびその塩。式中、Ａｒは置換基を有してもよい
フェニル基を示し、Ｒは水素原子、α位に水酸基もしく
は保護された水酸基を有する炭素数１〜５個のアルキル
基またはα位に水酸基もしくは保護された水酸基を有す
る炭素数７〜９個のアラルキル基を示す。Claim 1: An oxazabicyclo[3.3.0]octane derivative having the formula: [Image Omitted] and a salt thereof. In the formula, Ar represents a phenyl group which may have a substituent, R is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms having a hydroxyl group or a protected hydroxyl group at the α-position, or a hydroxyl group or a protected hydroxyl group at the α-position. represents an aralkyl group having 7 to 9 carbon atoms and having a hydroxyl group.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP816691A JPH04243870A (en) | 1991-01-28 | 1991-01-28 | Oxaazabicyclo(3.3.0)octane derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP816691A JPH04243870A (en) | 1991-01-28 | 1991-01-28 | Oxaazabicyclo(3.3.0)octane derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH04243870A true JPH04243870A (en) | 1992-08-31 |
Family
ID=11685753
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP816691A Pending JPH04243870A (en) | 1991-01-28 | 1991-01-28 | Oxaazabicyclo(3.3.0)octane derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH04243870A (en) |
-
1991
- 1991-01-28 JP JP816691A patent/JPH04243870A/en active Pending
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