JPWO2003031455A1 - Optically active dioxycyclohexane compound and method for producing optically active hydroxyethylenedioxycyclohexane compound - Google Patents
Optically active dioxycyclohexane compound and method for producing optically active hydroxyethylenedioxycyclohexane compound Download PDFInfo
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- JPWO2003031455A1 JPWO2003031455A1 JP2003534437A JP2003534437A JPWO2003031455A1 JP WO2003031455 A1 JPWO2003031455 A1 JP WO2003031455A1 JP 2003534437 A JP2003534437 A JP 2003534437A JP 2003534437 A JP2003534437 A JP 2003534437A JP WO2003031455 A1 JPWO2003031455 A1 JP WO2003031455A1
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 42
- -1 hydroxyethylenedioxycyclohexane compound Chemical class 0.000 title claims description 98
- 238000004519 manufacturing process Methods 0.000 title claims description 15
- 125000005843 halogen group Chemical group 0.000 claims abstract description 26
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 22
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims abstract description 19
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims abstract description 13
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical group [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims abstract description 12
- 125000006239 protecting group Chemical group 0.000 claims abstract description 12
- 239000007790 solid phase Substances 0.000 claims abstract description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 10
- 125000000547 substituted alkyl group Chemical group 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 9
- 238000007031 hydroxymethylation reaction Methods 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 description 63
- 239000002904 solvent Substances 0.000 description 57
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 43
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 43
- 239000000243 solution Substances 0.000 description 32
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 25
- 239000003795 chemical substances by application Substances 0.000 description 24
- 239000012043 crude product Substances 0.000 description 24
- 229920005989 resin Polymers 0.000 description 21
- 239000011347 resin Substances 0.000 description 21
- 238000010898 silica gel chromatography Methods 0.000 description 21
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000000706 filtrate Substances 0.000 description 15
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 15
- 239000000758 substrate Substances 0.000 description 15
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 13
- 238000009835 boiling Methods 0.000 description 13
- 239000007810 chemical reaction solvent Substances 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- 230000035484 reaction time Effects 0.000 description 13
- 238000005481 NMR spectroscopy Methods 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 11
- 238000007796 conventional method Methods 0.000 description 11
- 150000002576 ketones Chemical class 0.000 description 11
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 8
- 150000002118 epoxides Chemical class 0.000 description 7
- 239000002243 precursor Substances 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- 0 *[C@@](C[C@](*)C1)CC1=CBr Chemical compound *[C@@](C[C@](*)C1)CC1=CBr 0.000 description 5
- QKOHEJBTNOEACF-UHFFFAOYSA-N 7-oxabicyclo[4.1.0]heptan-5-one Chemical compound O=C1CCCC2OC12 QKOHEJBTNOEACF-UHFFFAOYSA-N 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- MFDVEPYIKFGBHC-UHFFFAOYSA-N C1C(CC(=CBr)CC1O[SiH3])O[SiH3] Chemical compound C1C(CC(=CBr)CC1O[SiH3])O[SiH3] MFDVEPYIKFGBHC-UHFFFAOYSA-N 0.000 description 5
- 150000001298 alcohols Chemical class 0.000 description 5
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000006138 lithiation reaction Methods 0.000 description 5
- 239000007800 oxidant agent Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 150000003710 vitamin D derivatives Chemical class 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- NDQDADDAKCOIHD-UHFFFAOYSA-N C1C(CC(=CBr)CC1O[SiH3])O Chemical compound C1C(CC(=CBr)CC1O[SiH3])O NDQDADDAKCOIHD-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 4
- YFTMLUSIDVFTKU-UHFFFAOYSA-M bromomethyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CBr)C1=CC=CC=C1 YFTMLUSIDVFTKU-UHFFFAOYSA-M 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 4
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 4
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- BSKFLZFJIHNDCZ-UHFFFAOYSA-N 2-(dibromomethylidene)-7-oxabicyclo[4.1.0]heptane Chemical compound C1CC2C(O2)C(=C(Br)Br)C1 BSKFLZFJIHNDCZ-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- QMJVMVSWVQBICA-UHFFFAOYSA-N C1C(CC(=O)C2C1O2)O[SiH3] Chemical compound C1C(CC(=O)C2C1O2)O[SiH3] QMJVMVSWVQBICA-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000007239 Wittig reaction Methods 0.000 description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 3
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 3
- 125000004665 trialkylsilyl group Chemical group 0.000 description 3
- DHKHKXVYLBGOIT-UHFFFAOYSA-N 1,1-Diethoxyethane Chemical compound CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 2
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- ZYKATZBRIDMIBH-UHFFFAOYSA-N C1C(CC(=C(Br)Br)C2C1O2)O[SiH3] Chemical compound C1C(CC(=C(Br)Br)C2C1O2)O[SiH3] ZYKATZBRIDMIBH-UHFFFAOYSA-N 0.000 description 2
- OESLYBDUHOWWLU-UHFFFAOYSA-N C1C(CC(=C(Br)Br)CC1O[SiH3])O Chemical compound C1C(CC(=C(Br)Br)CC1O[SiH3])O OESLYBDUHOWWLU-UHFFFAOYSA-N 0.000 description 2
- SMYBWWKDFZEMQF-UHFFFAOYSA-N C1C(CC(=CBr)C2C1O2)O[SiH3] Chemical compound C1C(CC(=CBr)C2C1O2)O[SiH3] SMYBWWKDFZEMQF-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
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- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
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- 125000002252 acyl group Chemical group 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000001639 boron compounds Chemical class 0.000 description 2
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 2
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- 238000006735 epoxidation reaction Methods 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
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- 238000000605 extraction Methods 0.000 description 2
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- 230000001590 oxidative effect Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
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- 239000003223 protective agent Substances 0.000 description 2
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- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 2
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- 239000011647 vitamin D3 Substances 0.000 description 2
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- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
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- 150000003839 salts Chemical class 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical class [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
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- 239000000725 suspension Substances 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000005607 tigloyl group Chemical group 0.000 description 1
- JSQJUDVTRRCSRU-UHFFFAOYSA-N tributyl(chloro)silane Chemical compound CCCC[Si](Cl)(CCCC)CCCC JSQJUDVTRRCSRU-UHFFFAOYSA-N 0.000 description 1
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- AJSTXXYNEIHPMD-UHFFFAOYSA-N triethyl borate Chemical compound CCOB(OCC)OCC AJSTXXYNEIHPMD-UHFFFAOYSA-N 0.000 description 1
- CPRPKIMXLHBUGA-UHFFFAOYSA-N triethyltin Chemical compound CC[Sn](CC)CC CPRPKIMXLHBUGA-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
- LYRCQNDYYRPFMF-UHFFFAOYSA-N trimethyltin Chemical compound C[Sn](C)C LYRCQNDYYRPFMF-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- NSPWVJAKNXJHEP-UHFFFAOYSA-N tripropyltin Chemical compound CCC[Sn](CCC)CCC NSPWVJAKNXJHEP-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 125000002348 vinylic group Chemical group 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/22—Tin compounds
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
下記一般式(1)および一般式(2)で表される光学活性ジオキシシクロヘキサン化合物またはその鏡像体。〔式中、Rはハロゲン原子、置換シリル基、置換ホウ素基または置換スズ基を表す。R′およびR″は互いに独立して置換アルキル基、ハロゲン原子、置換シリル基、置換ホウ素基または置換スズ基を表す。XおよびYは水素原子、水酸基の保護基または該保護基を末端に有する固相を表す。〕An optically active dioxycyclohexane compound represented by the following general formula (1) and general formula (2) or an enantiomer thereof. [Wherein, R represents a halogen atom, a substituted silyl group, a substituted boron group or a substituted tin group. R ′ and R ″ each independently represents a substituted alkyl group, a halogen atom, a substituted silyl group, a substituted boron group or a substituted tin group. X and Y each have a hydrogen atom, a hydroxyl protecting group or the protecting group at the end. Represents solid phase.]
Description
技術分野
本発明は、光学活性ジオキシシクロヘキサン化合物、および該化合物を用いた19−ノル−活性型ビタミンD誘導体合成の重要中間体である光学活性ヒドロキシエチレンジオキシシクロヘキサン化合物の製造方法に関する。
背景技術
従来から、活性型ビタミンD3(1,25−ジヒドロキシコレカルシフェロール)は、小腸におけるカルシウム輸送能、骨塩動員能などの生理活性が強く、そのため人の生理機能に重要な役割を果たすことが知られている。
また、その19−ノル−体には、血中のカルシウムイオン濃度を増加させることなく、腫瘍細胞の増殖抑制を行うという選択的な生理活性作用が報告されており、腎不全による続発生副甲状腺機能亢進症に対する臨床開発がなされている(Tetrahedron Letters,31,1823(1990)、Tetrahedron Letters,32,7663(1991),Tetrahedron Letters,33,2937(1992)等)。
一般式(3)で示される光学活性ヒドロキシエチレンジオキシシクロヘキサン化合物、例えば、下記化合物1(X=Y=t−ブチルジメチルシリル基)は、19−ノル−活性型ビタミンD誘導体を製造する際の最も重要な中間体の1つであるA環部分前駆体としてよく知られている。
(式中、TBSはt−ブチルジメチルシリル基を表す。)
このA環部分前駆体の製造方法としては、現在までのところ、例えば、スキーム1に示すように、▲1▼プロピオール酸のアルキルエステルとホモアリリックなエーテルとから11工程で製造する方法(Tetrahedron Letters,39,3359(1998),Tetrahedron Letters,39,3363(1998))、▲2▼ジエポキシペンタンとプロパルギルエーテルとから5工程で製造する方法(Tetrahedron Letters,37,7637(1996))等が知られている。
スキーム1
(式中、Bnはベンジル基、TBSはt−ブチルジメチルシリル基、MPMはp−メトキシフェニルメチル基、TBDPSはt−ブチルジフェニルシリル基を表す。)
しかしながら、上記スキーム1に記載されている製造方法は、いずれも出発物質からの工程数が長く、しかも、全工程のトータル収率が低い等の課題を抱えており、より実用的な製造方法の開発が望まれている。
そして、現在もA環部分前駆体の効率的製造方法の確立を目指して研究が盛んに行われているのが現状である。
発明の開示
本発明は、上記事情に鑑みなされたものであり、19−ノル−活性型ビタミンD誘導体を製造する際の重要中間体であるA環部分前駆体に効率的に変換可能な鍵中間体となる光学活性ジオキシシクロヘキサン化合物、および該化合物を用いたA環部分前駆体である光学活性ヒドロキシエチレンジオキシシクロヘキサン化合物の効率的な製造方法を提供することを目的とする。
本発明者らは、上記目的を達成するため、鋭意検討を重ねた結果、一般式(1)および一般式(2)で示される光学活性ジオキシシクロヘキサン化合物が、19−ノル−活性型ビタミンD誘導体製造におけるA環部分前駆体の重要な鍵中間体となり得ることを見いだすとともに、該化合物をヒドロキシメチル化することでA環部分前駆体である光学活性ヒドロキシエチレンジオキシシクロヘキサン化合物を効率的に製造できることを見いだし、本発明を完成するに至った。
すなわち、本発明は、
[1]下記一般式(1)
(式中、Rはハロゲン原子、置換シリル基、置換ホウ素基または置換スズ基を表す。XおよびYは水素原子、水酸基の保護基または該保護基を末端に有する固相を表す。)
で表されることを特徴とする光学活性ジオキシシクロヘキサン化合物またはその鏡像体、
[2]前記Rがハロゲン原子であることを特徴とする[1]の光学活性ジオキシシクロヘキサン化合物またはその鏡像体、
[3]下記一般式(2)
(式中、R′およびR″は互いに独立して置換アルキル基、ハロゲン原子、置換シリル基、置換ホウ素基または置換スズ基を表す。XおよびYは水素原子、水酸基の保護基または該保護基を末端に有する固相を表す。)
で表されることを特徴とする光学活性ジオキシシクロヘキサン化合物またはその鏡像体、
[4]前記R′およびR″がハロゲン原子であることを特徴とする[3]の光学活性ジオキシシクロヘキサン化合物またはその鏡像体、
[5]下記一般式(1)
(式中、Rはハロゲン原子、置換シリル基、置換ホウ素基または置換スズ基を表す。XおよびYは水素原子、水酸基の保護基または該保護基を末端に有する固相を表す。)
で表される光学活性ジオキシシクロヘキサン化合物に、ヒドロキシメチル化反応を行い、下記一般式(3)
(式中、XおよびYは水素原子、水酸基の保護基または該保護基を末端に有する固相を表す。)
で表される化合物を得ることを特徴とする光学活性ヒドロキシエチレンジオキシシクロヘキサン化合物の製造方法、
[6]前記Rがハロゲン原子であることを特徴とする[5]の光学活性ヒドロキシエチレンジオキシシクロヘキサン化合物の製造方法
を提供する。
発明を実施するための最良の形態
以下、本発明についてさらに詳しく説明する。
なお、本明細書中において、「n」はノルマルを、「i」はイソを、「s」はセカンダリーを、「t」はターシャリーを、「c」はシクロを、「o」はオルトを、「m」はメタを、「p」はパラを意味する。
上記一般式(1)において、置換基Rはハロゲン原子、置換シリル基、置換ホウ素基または置換スズ基を表す。
ここで、ハロゲン原子としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子が挙げられる。
置換シリル基としては、例えば、アルキル基、およびフェニル基(該フェニル基は、アルコキシ基で置換されていてもよい)から選ばれる3個の基によって置換された三置換シリル基が挙げられ、具体的には、トリメチルシリル、トリエチルシリル、トリイソプロピルシリル、ジエチルイソプロピルシリル、ジメチルイソプロピルシリル、t−ブチルジメチルシリル、テキシルジメチルシリル、ジフェニルメチルシリル、t−ブチルジフェニルシリル、t−ブチルジメトキシフェニルシリル、トリフェニルシリル等を例示できる。
置換ホウ素基としては、ジアルキルホウ素基(例えば、ジメチルホウ素、ジエチルホウ素、ジ−n−ブチルホウ素等が挙げられる)、ジアリールホウ素基(例えば、ジフェニルホウ素等が挙げられる)、ジアルコキシホウ素基(例えば、ジイソプロポキシホウ素、エチレンジオキシホウ素、テトラメチルエチレンジオキシホウ素等が挙げられる)等が挙げられる。
置換スズ基としては、トリアルキルスズ基(例えば、トリメチルスズ、トリエチルスズ、トリ−n−プロピルスズ、トリ−n−ブチルスズ、トリ−c−ヘキシルスズ等が挙げられる)、トリアリールスズ基(例えば、トリフェニルスズ等が挙げられる)等が挙げられる。
これらの中でも、置換基Rとして、ハロゲン原子、トリメチルシリル、テトラメチルエチレンジオキシホウ素、トリ−n−ブチルスズを用いることが好ましく、より好ましくはハロゲン原子、特に臭素原子が好適である。
上記一般式(2)における置換基R′およびR″は、互いに独立して置換アルキル基、ハロゲン原子、置換シリル基、置換ホウ素基、または置換スズ基を表す。
ここで、ハロゲン原子、置換シリル基、置換ホウ素基、および置換スズ基については、上記と同様のものを用いることができる。
置換アルキル基としては、直鎖、分岐または環状のC1〜6のアルキル基(該アルキル基は、ハロゲン原子で任意に置換されていてもよい)が挙げられ、例えば、メチル、エチル、n−プロピル、i−プロピル、c−プロピル、n−ブチル、i−ブチル、s−ブチル、t−ブチル、c−ブチル、1−メチル−c−プロピル、2−メチル−c−プロピル、n−ペンチル、1−メチル−n−ブチル、2−メチル−n−ブチル、3−メチル−n−ブチル、1,1−ジメチル−n−プロピル、1,2−ジメチル−n−プロピル、2,2−ジメチル−n−プロピル、1−エチル−n−プロピル、c−ペンチル、1−メチル−c−ブチル、2−メチル−c−ブチル、3−メチル−c−ブチル、1,2−ジメチル−c−プロピル、2,3−ジメチル−c−プロピル、1−エチル−c−プロピル、2−エチル−c−プロピル、n−ヘキシル、1−メチル−n−ペンチル、2−メチル−n−ペンチル、3−メチル−n−ペンチル、4−メチル−n−ペンチル、1,1−ジメチル−n−ブチル、1,2−ジメチル−n−ブチル、1,3−ジメチル−n−ブチル、2,2−ジメチル−n−ブチル、2,3−ジメチル−n−ブチル、3,3−ジメチル−n−ブチル、1−エチル−n−ブチル、2−エチル−n−ブチル、1,1,2−トリメチル−n−プロピル、1,2,2−トリメチル−n−プロピル、1−エチル−1−メチル−n−プロピル、1−エチル−2−メチル−n−プロピル、c−ヘキシル、1−メチル−c−ペンチル、2−メチル−c−ペンチル、3−メチル−c−ペンチル、1−エチル−c−ブチル、2−エチル−c−ブチル、3−エチル−c−ブチル、1,2−ジメチル−c−ブチル、1,3−ジメチル−c−ブチル、2,2−ジメチル−c−ブチル、2,3−ジメチル−c−ブチル、2,4−ジメチル−c−ブチル、3,3−ジメチル−c−ブチル、1−n−プロピル−c−プロピル、2−n−プロピル−c−プロピル、1−i−プロピル−c−プロピル、2−i−プロピル−c−プロピル、1,2,2−トリメチル−c−プロピル、1,2,3−トリメチル−c−プロピル、2,2,3−トリメチル−c−プロピル、1−エチル−2−メチル−c−プロピル、2−エチル−1−メチル−c−プロピル、2−エチル−2−メチル−c−プロピル、2−エチル−3−メチル−c−プロピル等が挙げられる。
置換基R′およびR″として、両方ともハロゲン原子、一方がメチルで他方がハロゲン原子、一方がエチルで他方がハロゲン原子、一方がn−ブチルで他方がハロゲン原子のものを用いることが好ましく、より好ましくは両方ともハロゲン原子のもの、特に、両方とも臭素原子のものが好適である。
上記一般式(1)および一般式(2)において、置換基XおよびYは水素原子、水酸基の保護基または該保護基を末端に有する固相を表す。
水酸基の保護基としては、例えば、C1〜7アシル基(例えば、ホルミル、アセチル、フルオロアセチル、ジフルオロアセチル、トリフルオロアセチル、クロロアセチル、ジクロロアセチル、トリクロロアセチル、プロピオニル、ピバロイル、チグロイル等が挙げられる)、アリールカルボニル基(例えば、ベンゾイル、ベンゾイルホルミル、ベンゾイルプロピオニル、フェニルプロピオニル等が挙げられる)、C1〜4アルコキシカルボニル基(例えば、メトキシカルボニル、エトキシカルボニル、n−プロポキシカルボニル、i−プロポキシカルボニル、n−ブトキシカルボニル、i−ブトキシカルボニル、t−ブトキシカルボニル、t−アミルオキシカルボニル、ビニルオキシカルボニル、アリルオキシカルボニル、2−(トリメチルシリル)エトキシカルボニル、2,2,2−トリクロロエトキシカルボニル等が挙げられる)、アリールオキシカルボニル基(例えば、ベンジルオキシカルボニル、p−ニトロベンジルオキシカルボニル、p−メトキシベンジルオキシカルボニル等が挙げられる)、C1〜4アルキルアミノカルボニル基(例えば、メチルカルバモイル、エチルカルバモイル、n−プロピルカルバモイル等が挙げられる)、アリールアミノカルボニル基(例えば、フェニルカルバモイル等が挙げられる)、トリアルキルシリル基(例えば、トリメチルシリル、トリエチルシリル、トリイソプロピルシリル、ジエチルイソプロピルシリル、ジメチルイソプロピルシリル、ジ−t−ブチルメチルシリル、イソプロピルジメチルシリル、t−ブチルジメチルシリル、テキシルジメチルシリル等が挙げられる)、トリアルキルアリールシリル基(例えば、ジフェニルメチルシリル、t−ブチルジフェニルシリル、t−ブチルジメトキシフェニルシリル、トリフェニルシリル等が挙げられる)等が挙げられる。
水酸基の保護基を末端に有する固相としては、例えば、カルボニル基樹脂末端、カルボニルオキシ基樹脂末端、カルボニルアミノ基樹脂末端、シリル基樹脂末端等が挙げられる。
用いられる樹脂としては、ポリスチレン樹脂、PEG−ポリスチレン樹脂、PGA樹脂等が挙げられる。
これらの中でも、置換基XおよびYとして、C1〜7アシル基、C1〜4アルコキシカルボニル基、トリアルキルシリル基、トリアルキルアリールシリル基、シリル基樹脂末端等を用いることが好ましく、特に好ましくは、トリアルキルシリル基、トリアルキルアリールシリル基、シリル基樹脂末端等である。
なお、置換基XおよびYは、互いに同一でもよく異なっていてもよい。
次に、上記一般式(1)で示される光学活性ジオキシシクロヘキサン化合物の製造方法について説明する。
この化合物は従来知られていない新規な化合物であり、例えば、化合物5(R=臭素原子、X=Y=t−ブチルジメチルシリル基)は下記スキーム2に示す方法により製造することができる。
スキーム2
(式中、TBSはt−ブチルジメチルシリル基を表す。)
すなわち、出発原料である光学活性シクロヘキセノン化合物2をエポキシ化し、シクロヘキセノンオキシド体3とした後、ケトンにブロムメチレン化導入反応をしてブロムメチレンシクロヘキセンオキシド体4とし、最後にエポキシドを還元し、生じた水酸基をシリル化することにより製造することができる。
最初のエポキシ化反応の酸化剤としては、特に限定されるものではなく、例えば、過酢酸、過安息香酸、m−クロロ過安息香酸等の過酸類、過酸化水素、酸素等が挙げられ、好ましくは、過酸化水素である。
酸化剤の使用量は、通常、基質に対して0.8〜50モル倍の範囲であり、特に、1.0〜20モル倍の範囲が好ましい。
反応溶媒としては、当該反応条件下において安定であり、かつ、不活性で反応を妨げないものであれば特に制限はなく、例えば、以下に示す溶媒を用いることができる。
具体的には、水、アルコール類(例えば、メタノール、エタノール、プロパノール、ブタノール、オクタノール等)、セロソルブ類(例えば、メトキシエタノール、エトキシエタノール等)、非プロトン性極性有機溶媒類(例えば、ジメチルホルムアミド、ジメチルスルホキシド、ジメチルアセトアミド、テトラメチルウレア、スルホラン、N−メチルピロリドン、N,N−ジメチルイミダゾリジノン等)、エーテル類(例えば、ジエチルエーテル、ジイソプロピルエーテル、t−ブチルメチルエーテル、テトラヒドロフラン、ジオキサン等)、脂肪族炭化水素類(例えば、ペンタン、ヘキサン、c−ヘキサン、オクタン、デカン、デカリン、石油エーテル等)、芳香族炭化水素類(ベンゼン、クロロベンゼン、o−ジクロロベンゼン、ニトロベンゼン、トルエン、キシレン、メシチレン、テトラリン等)、ハロゲン化炭化水素類(例えば、クロロホルム、ジクロロメタン、ジクロロエタン、四塩化炭素等)、ケトン類(アセトン、メチルエチルケトン、メチルブチルケトン、メチルイソブチルケトン等)、低級脂肪族酸エステル(例えば、酢酸メチル、酢酸エチル、酢酸ブチル、プロピオン酸メチル等)、アルコキシアルカン類(例えば、ジメトキシエタン、ジエトキシエタン等)、ニトリル類(例えば、アセトニトリル、プロピオニトリル、ブチロニトリル等)等の溶媒が挙げられる。これらの溶媒は反応の起こり易さに従って適宜選択され、1種単独でまたは2種以上混合して用いることができる。なお、必要に応じて適当な脱水剤や乾燥剤をにより水分を除去し、非水溶媒として用いてもよい。
反応温度は、通常、−100℃から使用する溶媒の沸点まで可能であるが、好ましくは−50〜50℃の範囲で行うのがよい。
反応時間は、通常、0.1〜1000時間である。
反応終了後は、適当な溶媒により目的物を抽出し、溶媒を減圧濃縮して粗物を得ることができる。さらに、シリカゲルカラムクロマトグラフィー等の常法による精製を行うことで、純粋なシクロヘキセノンオキシド体3を単離することができる。
次に、ケトンへのブロムメチレン化導入反応としては、例えば、ブロムメチルトリフェニルホスホニウムブロマイドを用いたウィティッヒ反応、または、例えばジイソプロピルブロムメチルホスホネートを用いたホーナー・エモンズ反応等が挙げられ、好ましくは、ブロムメチルトリフェニルホスホニウムブロマイドを用いたウィティッヒ反応である。
この場合、ブロムメチルトリフェニルホスホニウムブロマイドの使用量は、通常、基質に対して0.8〜20モル倍の範囲であり、特に、1.0〜5.0モル倍の範囲が好ましい。
反応溶媒としては、反応に関与しないものであれば特に制限はなく、上記した溶媒のうち、ケトン類溶媒以外の溶媒を用いることができる。
反応温度は、通常、−100℃から使用する溶媒の沸点まで可能であるが、好ましくは−50〜50℃の範囲で行うのがよい。
反応時間は、通常、0.1〜1000時間である。
反応終了後は、適当な溶媒により目的物を抽出し、溶媒を減圧濃縮して粗物を得ることができる。さらに、シリカゲルカラムクロマトグラフィー等の常法による精製を行うことで、純粋なブロムメチレンシクロヘキセンオキシド体4を単離することができる。
最後に、得られたブロムメチレンシクロヘキセンオキシド体4のエポキシドを還元、水酸基をシリル化することにより化合物5が得られる。
エポキシドの還元剤としては、特に限定されるものではなく、例えば、水素化ジイソブチルアルミニウム、水素化ホウ素ナトリウム、水素化アルミニウムリチウム、水素化ビスメトキシエトキシアルミニウムナトリウム等が挙げられ、好ましくは、水素化ジイソブチルアルミニウムである。
還元剤の使用量は、通常、基質に対して0.5〜20モル倍の範囲であり、特に、1.0〜10モル倍の範囲が好ましい。
反応溶媒としては、反応に関与しないものであれば特に制限はなく、上記した溶媒のうち、水、ケトン類、エステル類溶媒以外の溶媒を用いることができる。
反応温度は、通常、−100℃から使用する溶媒の沸点まで可能であるが、好ましくは−80〜50℃の範囲で行うのがよい。
反応時間は、通常、0.1〜1000時間である。
反応終了後は、適当な溶媒により目的物を抽出し、溶媒を減圧濃縮して粗物を得ることができる。さらに、シリカゲルカラムクロマトグラフィー等の常法による精製を行うことで、純粋なヒドロキシル体を単離することができる。
上記のようにして得られたヒドロキシル体の水酸基を保護する保護試剤としては、特に限定されるものではなく、例えば、アシル化剤、オキシカルボニル化剤、アミノカルボニル化剤、シリル化剤等が挙げられ、好ましくはシリル化剤である。
このようなシリル化剤としても、特に限定はなく、例えば、トリメチルシリルクロライド、t−ブチルジメチルシリルクロライド、ジフェニル−t−ブチルシリルクロライド等が挙げられる。
シリル化剤の使用量は、通常、基質に対して0.5〜20モル倍の範囲であり、特に、1.0〜10モル倍の範囲が好ましい。
この場合、反応を促進させるために、反応系に塩基を共存させることもでき、このような塩基としては、ジエチルアミン、トリエチルアミン、トリ−n−プロピルアミン、トリ−n−ブチルアミン、DBU、N−メチルモルホリン、N,N−ジメチルアニリン等のアミン類、ピリジン、メチルエチルピリジン、ルチジン、4−N,N−ジメチルアミノピリジン等のピリジン類、イミダゾール、ピラゾールが挙げられ、好ましくは、イミダゾールである。
塩基の使用量は、通常、基質に対して0.5〜20モル倍の範囲であり、特に、1.0〜10モル倍の範囲が好ましい。
反応溶媒としては、反応に関与しないものであれば特に制限はなく、上記した溶媒のうち、水、アルコール類以外の溶媒を用いることができる。
反応温度は、通常、−100℃から使用する溶媒の沸点まで可能であるが、好ましくは−50〜50℃の範囲で行うのがよい。
反応時間は、通常、0.1〜1000時間である。
反応終了後は、適当な溶媒により目的物を抽出し、溶媒を減圧濃縮して粗物を得ることができる。さらに、シリカゲルカラムクロマトグラフィー等の常法による精製を行うことで、純粋な化合物5を単離することができる。
上記スキーム2において、ブロムメチレンシクロヘキセンオキシド体4のエポキシドを還元した後、生じた水酸基を、反応性シリル基を末端に持つ樹脂と反応させることにより、シリル基樹脂末端を持つ化合物6(R=臭素原子、XまたはYのどちらか一方=t−ブチルジメチルシリル基、他方=シリル基樹脂末端)を製造することができる。
このような化合物6は、固相担持されているため、反応系から容易に分離でき、コンビナトリアルケミストリーや自動合成装置による高速合成に適している。
また、上記一般式(1)で示される化合物として、例えば、化合物7(R=テトラメチルエチレンジオキシホウ素、X=Y=t−ブチルジメチルシリル基)は下記スキーム3に示す方法により製造することができる。
スキーム3
(式中、TBSはt−ブチルジメチルシリル基を表す。)
すなわち、上記で得られた化合物5を原料として、該化合物をリチオ化した後、ホウ素化剤で処理することにより製造することができる。
リチオ化剤としては、例えば、n−ブチルリチウム、s−ブチルリチウム、t−ブチルリチウム等を挙げることができる。
リチオ化剤の使用量は、通常、基質に対して0.5〜20モル倍の範囲であり、特に、1.0〜10モル倍の範囲が好ましい。
反応溶媒としては、反応に関与しないものであれば特に制限はなく、上記した溶媒のうち、水、アルコール類、ケトン類、エステル類以外の溶媒を用いることができる。
反応温度は、通常、−100℃から使用する溶媒の沸点まで可能であるが、好ましくは−80〜0℃の範囲で行うのがよい。
反応時間は、通常、0.1〜1000時間である。
リチオ化した化合物は単離せずに、反応系にそのままホウ素化剤を加えてホウ素化合物とする。さらに、得られたホウ素化合物をピナコールで処理することにより、化合物7を合成することができる。
ここでホウ素化剤としては、特に限定されるものではなく、例えば、トリメトキシボラン、トリエトキシボラン、トリイソプロポキシボラン等が挙げられる。
ホウ素化剤の使用量は、通常、基質に対して0.5〜20モル倍の範囲であり、特に、1.0〜10モル倍の範囲が好ましい。
反応溶媒としては、反応に関与しないものであれば特に制限はなく、リチオ化に使用した溶媒をそのまま用いることができる。
反応温度は、通常、−100℃から使用する溶媒の沸点まで可能であるが、好ましくは−80〜50℃の範囲で行うのがよい。
反応時間は、通常、0.1〜1000時間である。
反応終了後は、適当な溶媒により目的物を抽出し、溶媒を減圧濃縮して粗物を得ることができる。
さらに、シリカゲルカラムクロマトグラフィー等の常法による精製を行うことで、純粋な化合物7を単離することができる。
また、一般式(1)で示される化合物として、例えば、化合物8(R=トリメチルシリル、X=Y=t−ブチルジメチルシリル基)は下記スキーム4に示す方法により製造することができる。
スキーム4
(式中、TBSはt−ブチルジメチルシリル基、Meはメチル基を表す。)
すなわち、上記で得られた化合物5を原料として、リチオ化した後、シリル化剤で処理することにより製造することができる。
リチオ化剤としては、上記と同様の試剤を挙げることができる。
リチオ化剤の使用量は、通常、基質に対して0.5〜20モル倍の範囲であり、特に、1.0〜10モル倍の範囲が好ましい。
反応溶媒としては、反応に関与しないものであれば特に制限はなく、上記した溶媒のうち、水、アルコール類、ケトン類、エステル類以外の溶媒を用いることができる。
反応温度は、通常、−100℃から使用する溶媒の沸点まで可能であるが、好ましくは−80〜0℃の範囲で行うのがよい。
反応時間は、通常、0.1〜1000時間である。
リチオ化した化合物は単離せずに、反応系にそのままシリル化剤を加えてシリル化する。
シリル化剤としては、特に限定されるものではなく、例えば、クロルトリメチルシラン、ブロムトリメチルシラン、クロルトリエチルシラン、ブロムトリエチルシラン、クロルトリ−n−ブチルシラン、ブロムトリ−n−ブチルシラン、クロルトリ−n−オクチルシラン、ブロムトリ−n−オクチルシラン、クロルトリフェニルシラン、ブロムトリフェニルシラン等が挙げられる。
シリル化剤の使用量は、通常、基質に対して0.5〜20モル倍の範囲であり、特に、1.0〜10モル倍の範囲が好ましい。
反応溶媒としては、反応に関与しないものであれば特に制限はなく、リチオ化に使用した溶媒をそのまま用いることができる。
反応温度は、通常、−100℃から使用する溶媒の沸点まで可能であるが、好ましくは−80〜50℃の範囲で行うのがよい。
反応時間は、通常、0.1〜1000時間である。
反応終了後は、適当な溶媒により目的物を抽出し、溶媒を減圧濃縮して粗物を得ることができる。
さらに、シリカゲルカラムクロマトグラフィー等の常法による精製を行うことで、純粋な化合物8を単離することができる。
なお、一般式(1)で示される光学活性ジオキシシクロヘキサン化合物を製造する際の出発原料となる光学活性シクロヘキセノン化合物2は、スキーム5に示されようにTetrahedron Letters,38,8299(1997)、J.Am.Chem.Soc.,121,3640(1999)に記載の方法にしたがって製造することができる。
スキーム5
(式中、TBSはt−ブチルジメチルシリル基を表す。)
すなわち、光学活性クロルヒドリンエステル9をヨウ素化して、ヨードヒドリン体10とし、次いで水酸基をシリル化して、シロキシ体11とし、さらにビニルグリニャール試剤を反応させてホモアリルエーテル体12とし、最後にTiで環化することにより製造することができる。
次に、一般式(2)で示される光学活性ジオキシシクロヘキサン化合物の製造方法について説明する。
この化合物も従来知られていない新規な化合物であり、例えば、化合物14(R′=R″=臭素原子、X=Y=t−ブチルジメチルシリル基)は、下記スキーム6に示す方法により製造することができる。
スキーム6
(式中、TBSはt−ブチルジメチルシリル基を表す。)
すなわち、出発原料である光学活性シクロヘキセノン化合物2をエポキシ化し、シクロヘキセノンオキシド体3とした後、ケトンにジブロムメチレン化導入反応をしてジブロムメチレンシクロヘキセンオキシド体13とし、最後にエポキシドを還元、水酸基をシリル化することにより製造することができる。
最初のエポキシ化反応の酸化剤としては、一般式(1)で示される化合物で示したものと同様のものを用いることができる。
酸化剤の使用量は、通常、基質に対して0.8〜50モル倍の範囲であり、特に、1.0〜20モル倍の範囲が好ましい。
反応溶媒としては、反応に関与しないものであれば特に制限はなく、上記した溶媒を用いることができる。
反応温度は、通常、−100℃から使用する溶媒の沸点まで可能であるが、好ましくは−50〜50℃の範囲で行うのがよい。
反応時間は、通常、0.1〜1000時間である。
反応終了後は、適当な溶媒により目的物を抽出し、溶媒を減圧濃縮して粗物を得ることができる。
さらに、シリカゲルカラムクロマトグラフィー等の常法による精製を行うことで、純粋なシクロヘキセノンオキシド体3を単離することができる。
次に、ケトンへのジブロムメチレン化導入反応としては、特に限定されるものではなく、例えば、四塩化炭素およびトリフェニルホスフィンを用いたウィティッヒ反応が挙げられる。
四塩化炭素の使用量は、通常、基質に対して0.8〜20モル倍の範囲であり、特に、1.0〜5.0モル倍の範囲が好ましい。
トリフェニルホスフィンの使用量は、通常、基質に対して0.8〜20モル倍の範囲であり、特に、1.0〜5.0モル倍の範囲が好ましい。
反応溶媒としては、反応に関与しないものであれば特に制限はなく、上記した溶媒のうち、ケトン類以外の溶媒を用いることができる。
反応温度は、通常、−100℃から使用する溶媒の沸点まで可能であるが、好ましくは−50〜50℃の範囲で行うのがよい。
反応時間は、通常、0.1〜1000時間である。
反応終了後は、適当な溶媒により目的物を抽出し、溶媒を減圧濃縮して粗物を得ることができる。
さらに、シリカゲルカラムクロマトグラフィー等の常法による精製を行うことで、純粋なジブロムメチレンシクロヘキセンオキシド体13を単離することができる。
最後に、得られたジブロムメチレンシクロヘキセンオキシド体13のエポキシドを還元、水酸基をシリル化することにより化合物14が得られる。
ここで、エポキシドの還元剤としては、前述と同様のものが挙げられるが、特に、水素化ジイソブチルアルミニウムを用いることが好ましい。
還元剤の使用量は、通常、基質に対して0.5〜20モル倍の範囲であり、特に、1.0〜10モル倍の範囲が好ましい。
反応溶媒としては、反応に関与しないものであれば特に制限はなく、上記した溶媒のうち、水、ケトン類、エステル類以外の溶媒を用いることができる。
反応温度は、通常、−100℃から使用する溶媒の沸点まで可能であるが、好ましくは−80〜50℃の範囲で行うのがよい。
反応時間は、通常、0.1〜1000時間である。
反応終了後は、適当な溶媒により目的物を抽出し、溶媒を減圧濃縮して粗物を得ることができる。
さらに、シリカゲルカラムクロマトグラフィー等の常法による精製を行うことで、純粋なヒドロキシル体を単離することができる。
水酸基を保護する保護試剤としては、上記と同様のものが挙げられるが、シリル化剤を用いることが好ましい。
ここで、シリル化剤の種類およびその使用量、反応促進剤としての塩基の種類およびその使用量、ならび反応条件についても、上記と同様である。
シリル化反応終了後は、適当な溶媒により目的物を抽出し、溶媒を減圧濃縮して粗物を得ることができる。
さらに、シリカゲルカラムクロマトグラフィー等の常法による精製を行うことで、純粋な化合物14を単離することができる。
次に、一般式(3)で示される光学活性ヒドロキシエチレンジオキシシクロヘキサン化合物の製造方法について説明する。
当該化合物は、上記で得られた、一般式(1)で示される光学活性ジオキシシクロヘキサン化合物に、ヒドロキシメチル化反応を行うことにより製造することができる。
例えば、化合物1(X=Y=t−ブチルジメチルシリル基)は、上記化合物5をリチオ化後、ホルムアルデヒドと反応させることにより製造することができる。
リチオ化剤としては、例えば、n−ブチルリチウム、s−ブチルリチウム、t−ブチルリチウム等が挙げられる。
リチオ化剤の使用量は、通常、基質に対して0.5〜20モル倍の範囲であり、特に、1.0〜10モル倍の範囲が好ましい。
反応溶媒としては、反応に関与しないものであれば特に制限はなく、上記した溶媒のうち、水、アルコール類、ケトン類、エステル類以外の溶媒を用いることができる。
反応温度は、通常、−100℃から使用する溶媒の沸点まで可能であるが、好ましくは−80〜0℃の範囲で行うのがよい。
反応時間は、通常、0.1〜1000時間である。
リチオ化した化合物は単離せず、反応系にそのままホルムアルデヒドを加え、ヒドロキシメチル化を行う。
ホルムアルデヒドの使用量は、通常、基質に対して0.5〜20モル倍の範囲であり、特に、1.0〜10モル倍の範囲が好ましい。
反応溶媒としては、反応に関与しないものであれば特に制限はなく、リチオ化に使用した溶媒をそのまま用いることができる。
反応温度は、通常、−100℃から使用する溶媒の沸点まで可能であるが、好ましくは−80〜50℃の範囲で行うのがよい。
反応時間は、通常、0.1〜1000時間である。
反応終了後は、適当な溶媒により目的物を抽出し、溶媒を減圧濃縮して粗物を得ることができる。
さらに、シリカゲルカラムクロマトグラフィー等の常法による精製を行うことで、純粋な光学活性ヒドロキシエチレンジオキシシクロヘキサン化合物1を単離することができる。
以下、実施例を挙げて本発明をより具体的に説明するが、本発明は以下の実施例に限定されるものではない。
[実施例1] シクロヘキセノンオキシド体3の合成
(式中、TBSはt−ブチルジメチルシリル基を表す。)
氷冷した光学活性5−シロキシ−2−シクロヘキセノン2(226mg,1.0mmol)と35%過酸化水素水(0.8mL,10mmol)との混合液に、メタノール(38mL)および3モル/L水酸化ナトリウム水溶液(33mL,0.1mmol)を加えた。混合溶液を氷冷下で6時間攪拌した後、飽和塩化アンモニウム水溶液(3mL)を加えた。
その後、エーテル(5mL)で3回抽出し、有機層を無水硫酸マグネシウムで乾燥した。
ろ過後、ろ液を減圧下濃縮して得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製し、光学活性5−シロキシ−2,3−エポキシシクロヘキサノン3を収率83%(204mg)で得た。
1H NMRおよびGC分析から立体異性体比は>95:<5であった。
1H NMR(300MHz,CDCl3)δ4.22−4.33(m,1H,CHOSi),3.54−3.59(m,1H,CH2CHO),3.26(d,J=3.9Hz,1H,C(=O)CHO),2.77(dd,J=3.0,15.3Hz,1H,one of CH2C(=O)),2.39(dd,J=4.2,15.3Hz,1H,one of CH2),2.19(dd,J=4.2,15.3Hz,1H,one of CH2C(=O)),2.00(dt,J=15.3,3.3Hz,1H,one of CH2),0.85(s,9H,t−Bu),0.04 and 0.03(2s,6H,2SiCH3).
13C NMR(75MHz,CDCl3)δ204.8,67.3,55.4,54.7,44.9,32.9,25.5,17.8,−5.0,−5.1.
IR(neat)2929,2888,2857,1726,1472,1406,1361,1331,1255,1075,1031,985,935,871,837,778,715cm−1.
[実施例2] ブロムメチレンシクロヘキセンオキシド体4の合成
(式中、TBSはt−ブチルジメチルシリル基を表す。)
ブロムメチルトリフェニルホスホニウムブロマイド(567mg,1.3mmol)のトルエン(2mL)縣濁液に、室温下でカリウムビストリメチルシリルアミド(0.5M/トルエン液,2.6mL,1.3mmol)を加え、そのまま室温下で30分撹拌した。
この混合溶液を0℃に冷却した後、5−シロキシ−2,3−エポキシシクロヘキサノン3(242mg,1.0mmol)のトルエン溶液を加え、その反応液を30分かけて室温まで昇温した。
反応液を減圧下濃縮し、得られた残渣にジエチルエーテル(2mL)とヘキサン(40mL)とを加え、析出した結晶をセライトでろ過した。
ろ液を減圧下濃縮して得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製し、1−ブロムメチレン−5−シロキシ−2,3−エポキシシクロヘキサン4を収率82%(262mg)で得た。
1H NMR(300MHz,CDCl3)δ0.06(s,6H),0.86(s,9H),1.81(ddd,J=2.4,6.9,15.0Hz,1H),2.16(ddd,J=2.1,8.4,15.9Hz,1H),2.27(dd,J=3.9,15.0Hz,1H),2.42(br d,J=15.9Hz,1H),3.38−3.45(m,1H),3.49(d,4.2Hz,1H),3.87−4.02(m,1H),6.48(br s,1H).
13C NMR(75MHz,CDCl3)δ−4.7,−4.6,18.1,25.8,33.9,35.4,54.1,54,7,64.3,109.2,137.5.
IR(neat)2928,2856,1621,1471,1360,1254,1092,876,836,777cm−1
[実施例3] 光学活性ジオキシシクロヘキサン化合物5の合成
(式中、TBSはt−ブチルジメチルシリル基を表す。)
氷冷下、1−ブロムメチレン−5−シロキシ−2,3−エポキシシクロヘキサン4(100mg,0.313mmol)のTHF(3mL)溶液に、水素化ジイソブチルアルミニウム(1.0M/ヘキサン液,0.94mL,0.94mmol)を加え、そのまま0℃で15時間攪拌した。
反応液に、水(0.18mL)、フッ化ナトリウム(1g)、セライト(1g)を加えて、その混合液をセライトでろ過した。
ろ液を減圧下濃縮して得られた1−ブロムメチレン−3−ヒドロキシ−5−シロキシシクロヘキサンの粗生成物は、そのまま次の反応に用いた。
1H NMR(300MHz,CDCl3)δ0.07 and 0.09(2s,6H),0.88(s,9H),1.42(d,J=5.1Hz,1H,OH),1.74(ddd,J=3.6,7.2,13.2Hz,1H),1.83(ddd,J=3.9,6.9,13.2Hz,1H),2.15(dd,J=7.5,13.5Hz,1H),2.43−2.54(m,2H),4.04−4.16(m,2H),6.02(brs).
13C NMR(75MHz,CDCl3)δ−4.9,−4.7,18.1,25.8,39.2,42.5,43.1,66.9(two carbons),101.9,138.8.
上記で得られた1−ブロムメチレン−3−ヒドロキシ−5−シロキシシクロヘキサンの粗生成物とイミダゾール(43mg,0.63mmol)とのジメチルホルムアミド(1mL)溶液に、0℃でt−ブチルジメチルシリルクロライド(71mg,0.47mmol)を加え、室温で12時間攪拌した。
飽和重曹水(3mL)を加えた後、ヘキサン(4mL)で3回抽出した。有機層を乾燥(無水硫酸マグネシウム)し、ろ過後、ろ液を減圧下濃縮して得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製し、1−ブロムメチレン−3,5−ジシロキシシクロヘキサン5を収率68%(93mg)で得た。
1H NMR(300MHz,CDCl3)δ0.04(s,6H),0.06 and 0.09(2s,each 3H),0.87 and 0.89(2s,each 9H),1.62−1.84(m,2H),2.09(ddd,J=0.9,7.5,13.5Hz,1H),2.30−2.48(m,3H),4.02−4.15(m,2H),5.94(br s,1H).
13C NMR(75MHz,CDCl3)δ−4.86,−4.74,−4.67,−4.64,18.16,18.20,25.87,25.90,39.2,43.2,43.6,67.1,67.4,101.2,139.3.
IR(neat)2953,2857,1637,1471,1361,1255,1099,1025,914,836,775cm−1.
[実施例4] 光学活性ジオキシシクロヘキサン化合物7の合成
(式中、TBSはt−ブチルジメチルシリル基を表す。)
1−ブロムメチレン−3,5−ジシロキシシクロヘキサン5(348mg,0.80mmol)のジエチルエーテル(3mL)溶液に、t−ブチルリチウム(1.35M/ペンタン液,1.30mL,1.76mmol)を−78℃で加え、そのまま−78℃で1時間撹拌した。
トリイソプロポキシボラン(2.0M/ジエチルエーテル液,0.6mL,1.2mmol)を、−78℃で加え、反応液を4時間かけて室温に昇温した後、飽和塩化アンモニウム水溶液(8mL)と酢酸エチル(8mL)とを加えた。
続いて、酢酸エチル(6mL)で2回抽出し、有機層を減圧下濃縮した。
残渣に酢酸エチル(3mL)を加えて溶解し、これに、ピナコール(113mg,0.96mmol)と硫酸マグネシウム(1.0g)とを加えて、室温下12時間撹拌した。
ろ過後、ろ液を減圧下濃縮して得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製し、化合物7を収率93%(415mg)で得た。
1H NMR(300MHz,CDCl3)δ5.12(s,1H),4.03−4.11(m,2H),2.67(dd,J=3.6,13.2Hz,1H),2.54(dd,J=6.9,13.2,Hz,1H),2.36(dd,J=3.6,12.9Hz,1H),2.13(dd,J=7.5,12.9Hz,1H),1.62−1.76(m,2H),1.22(s,6H),1.21(s,6H),0.86(s,9H),0.84(s,9H),0.043,0.036,0.008 and 0.004(4s,each 3H).
13C NMR(75MHz,CDCl3)δ160.1,115.6(br s),82.5,68.3,67.9,48.0,43.1,40.8,25.8,25.7,24.9,24.6,18.1,17.9,−4.9,−5.0,−5.1,−5.2.
IR(neat)2954,2856,1645,1471,1386,1256,1096,1028,837,775cm−1.
[実施例5] 光学活性ジオキシシクロヘキサン化合物8の合成
(式中、TBSはt−ブチルジメチルシリル基、Meはメチル基を表す。)
1−ブロムメチレン−3,5−ジシロキシシクロヘキサン5(174mg,0.40mmol)のジエチルエーテル(2mL)溶液に、t−ブチルリチウム(1.35M/ペンタン液,0.65mL,0.88mmol)を−78℃で加え、そのまま−78℃で1時間撹拌した。
次に、クロルトリメチルシラン(76μL,0.6mmol)を、−78℃で加え、反応液を3時間かけて室温に昇温した後、飽和塩化アンモニウム水溶液(4mL)を加えた。
続いて、ジエチルエーテル(3mL)で2回抽出し、有機層を乾燥(硫酸マグネシウム)した。
ろ過後、ろ液を減圧下濃縮して得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製し、化合物8を収率89%(153mg)で得た。
1H NMR(300MHz,CDCl3)δ5.22(s,1H),4.01−4.13(m,2H),2.49(dd,J=3.6,12.9Hz,1H),2.32(dd,J=3.0,13.2Hz,1H),2.08−2.17(m,2H),1.73−1.83(m,1H),1.56−1.67(m,1H),0.89 and 0.86(2s,each 9H),0.097(s,9H),0.06 and 0.03(2s,each 6H).
13C NMR(75MHz,CDCl3)δ152.3,126.0,68.1,67.6,47.9,43.1,42.8,26.0,25.8,18.3,0.5,−4.5,−4.59,−4.62,−4.7.
IR(neat)2952,2857,1624,1472,1362,1250,1098,1028,836,774,691cm−1.
[実施例6] ジブロムメチレンシクロヘキセンオキシド体13の合成
(式中、TBSはt−ブチルジメチルシリル基を表す。)
四臭化炭素(830mg,2.5mmol)のジクロルメタン(3mL)溶液に、0℃でトリフェニルホスフィン(1.31g,5.0mmol)を加え、そのまま0℃で5分撹拌した。
2−メチル−2−ブテン(1.4mL,12.5mmol)を加え5分撹拌した後、5−シロキシ−2,3−エポキシシクロヘキサノン3(242mg,1.0mmol)のジクロルメタン(3mL)溶液を0℃で加え、その反応液を30分撹拌した。
その後、反応液をヘキサン(30mL)で希釈し、セライトでろ過した。
ろ液を減圧下濃縮して得られた1−ジブロムメチレン−5−シロキシ−2,3−エポキシシクロヘキサンの粗生成物は、そのまま次の反応に用いた。
1H NMR(300MHz,CDCl3)δ3.85−3.95(m,2H),3.40−3.44(m,1H),2.52(dd,J=3.6,15.3Hz,1H),2.28(dd,J=4.5,15.0Hz,1H),2.11(dd,J=6.0,15.3Hz,1H),1.75(ddd,J=2.7,7.8,15.0Hz,1H),0.87(s,9H),0.061(s,3H),0.05(s,3H).
13C NMR(75MHz,CDCl3)δ137.0,93.6,64.3,54.6,53.8,39.2,33.5,25.8,18.1,−4.66,−4.74.
[実施例7] 光学活性ジオキシシクロヘキサン化合物14の合成
(式中、TBSはt−ブチルジメチルシリル基を表す。)
氷冷下、実施例6で得られた1−ジブロムメチレン−5−シロキシ−2,3−エポキシシクロヘキサン粗生成物のヘキサン(5mL)溶液に、水素化ジイソブチルアルミニウム(0.96M/ヘキサン液,2.08mL,2.0mmol)を加え、そのまま0℃で1時間攪拌した。
反応液に、水(0.36mL)を0℃で注意深く加えた後30分撹拌し、フッ化ナトリウム(1g)とセライト(1g)とを加えて、その混合液をセライトでろ過した。
ろ液を減圧下濃縮して得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製し、1−ジブロムメチレン−3−ヒドロキシ−5−シロキシシクロヘキサンを収率74%(287mg)で得た。
[α]24 D=+10.68(c1.47 CHCl3).
1H NMR(300MHz,CDCl3)δ4.80−4.20(m,2H),2.73(dd,J=3.9,13.5Hz,1H),2.42−2.56(m,2H),2.38(dd,J=7.5,13.5Hz,1H),1.68−1.86(m,2H),1.58(s,1H),0.88(s,9H),0.081(s,3H),0.064(s,3H).
13C NMR(75MHz,CDCl3)δ139.3,85.8,66.8,66.6,42.4,42.2,41.9,25.7,17.9,−5.07,−5.14.
IR(neat)3350,2928,2856,1470,1254,1103,908,837,776cm−1.
Anal.Calc.for C13H24Br2O2Si:C,39.01;H,6.04.Found:C,38.91;H,5.94.
上記で得られた1−ジブロムメチレン−3−ヒドロキシ−5−シロキシシクロヘキサン(272mg,0.7mmol)とイミダゾール(95mg,1.4mmol)とのジメチルホルムアミド(2mL)溶液に、0℃でt−ブチルジメチルシリルクロライド(136mg,0.9mmol)を加え、室温で12時間攪拌した。
水(2mL)を加えた後、ジエチルエーテル(6mL)で3回抽出した。有機層を乾燥(無水硫酸マグネシウム)し、ろ過後、ろ液を減圧下濃縮して得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製し、1−ジブロムメチレン−3,5−ジシロキシシクロヘキサン14を収率96%(348mg)で得た。
[α]30 D=+2.27(c1.21 CHCl3).
1H NMR(300MHz,CDCl3)δ4.06−4.14(m,2H),2.56(dd,J=3.3,13.5Hz,2H),2.37(dd,J=7.2,13.8Hz,2H),1.69(t,J=5.4Hz,2H),0.892(s,9H),0.889(s,9H),0.079(s,3H),0.062(s,3H).
13C NMR(75MHz,CDCl3)δ139.9,85.1,67.0,42.8,42.5,18.0,−5.08,−5.14.
IR(neat)2928,2856,1471,1362,1256,1092,1027,958,838,695cm−1.
Anal.Calc.for C19H38Br2O2Si2:C,44.36;H,7.44.Found:C,44.40;H,7.45.
[実施例8] 光学活性ヒドロキシエチレンジオキシシクロヘキサン化合物1の合成
(式中、TBSはt−ブチルジメチルシリル基を表す。)
1−ブロムメチレン−3,5−ジシロキシシクロヘキサン5(40.3mg,0.1mmol)のジエチルエーテル(1mL)溶液に、−78℃でt−ブチルリチウム(1.7M/ペンタン液,0.14mL,0.24mmol)を加え、1時間かけて−20℃まで昇温した。
これに、過剰量のホルムアルデヒド(ジエチルエーテル溶液)を加えた後、室温に昇温した。
飽和塩化アンモニウム水溶液を加えた後、ジエチルエーテルで抽出し、有機層を乾燥(無水硫酸マグネシウム)した。
ろ過後、ろ液を減圧下濃縮して得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製し、1−(2−ヒドロキシエチリデン)−3,5−ジシロキシシクロヘキサン1を収率52%(17.7mg)で得た。
1H NMR(300MHz,CDCl3)δ5.60(t,J=7.2Hz,vinylic),3.95−4.20(m,4H,CHO and CH2O),2.25−2.40(m,2H),2.18(dd,J=3.3,13.2Hz,1H,allylic),2.05(dd,J=8.1,13.2Hz,1H,allylic),1.75−1.86(m,1H),1.69(br s,1H,OH),1.63(dd,J=3.0,9.0Hz,1H,CH2),0.87(s,18H,t−Bu),0.06(s,6H,SiCH3),0.05 and 0.04(2s,each 3H,SiCH3).
13C NMR(75MHz,CDCl3)d 138.2,125.2,68.1,67.9,58.4,45.6,43.4,36.6,25.9,18.2,−4.57,−4.66,−4.70,−4.74.
IR(neat)3367,2928,2856,1654,1472,1361,1253,1109,1084,1082,835,774cm−1.
[実施例9] 光学活性ジオキシシクロヘキサン化合物15の合成
(式中、TBSはt−ブチルジメチルシリル基を表す。Buは、n−ブチル基を表す。)
1−ブロムメチレン−3,5−ジシロキシシクロヘキサン5(348mg,0.80mmol)のジエチルエーテル(3mL)溶液に、t−ブチルリチウム(1.35M/ペンタン液,1.30mL,1.76mmol)を−78℃で加え、そのまま−78℃で1時間撹拌した。
続いて、クロルトリ−n−ブチルスズ(0.434mL,1.2mmol)を、−78℃で加え、反応液を3時間かけて室温に昇温した。
飽和重曹水(10mL)を加えた後、反応液をヘキサン(10mL)で2回抽出し、有機層を乾燥(硫酸マグネシウム)した。
硫酸マグネシウムをろ過後、ろ液を減圧下濃縮して得られた粗生成物を、シリカゲルカラムクロマトグラフィーで精製して、化合物15を収率93%(481mg)で得た。
1H NMR(CDCl3)δ5.47(s,1H),3.99−4.13(m,2H),2.33−2.40(m,2H),2.22(dd,J=3.9,13.5Hz,1H),2.11(dd,J=9.6,12.9Hz,1H),1.82−1.90(m,1H),1.43−1.61(m,7H),1.24−1.38(m,6H),0.78−1.06(m,6H),0.89(t,J=8.1Hz,9H),0.90(s,18H),0.067 and 0.062(2s,each 3H),0.030(s,6H);
13C NMR(CDCl3)δ152.1,124.1,68.3,67.7,47.1,46.5,43.1,29.3,27.4,26.0,25.8,18.2,18.1,13.8,10.3,−4.5,−4.6,−4.8;
IR(neat)2926,2862,1613,1463,1376,1361,1255,1099,836,775,691;
[α]25 D−14.3(c7.90,CHCl3);.
Anal.Calcd.for C31H66O2Si2Sn:C,57.66;H,10.30.Found:C,57.28;H,10.32.
[実施例10] 光学活性ジオキシシクロヘキサン化合物6の合成
50mLシュレーカー反応チューブ(アルドリッチ社製)に、PS−DESレジン(アルゴノート製,0.6〜1.0mmol/g,1.00g)を仕込み、減圧下30分乾燥した後、アルゴンでパージした。
これに、1,3−ジクロロ−5,5−ジメチルヒダントイン(443mg,2.25mmol)の塩化メチレン(11mL)溶液を加え、室温下2時間ゆっくり撹拌した。
アルゴン下で反応液をろ過し、得られた樹脂を塩化メチレン(20mL)で3回、さらにTHF(20mL)で3回洗浄した後、減圧下乾燥した。
続いて、樹脂を入れた反応チューブに、実施例3で得られた1−ブロムメチレン−3−ヒドロキシ−5−シロキシシクロヘキサン(723mg,2.25mmol)とイミダゾール(180mg,2.63mmol)の塩化メチレン(25mL)溶液を加え、室温下4時間ゆっくりと撹拌した。
反応液をろ過し、得られた樹脂をエーテル(18mL)で2回洗浄した。
ろ液を水(20mL)で2回洗浄した後、有機層を乾燥(硫酸マグネシウム)し、硫酸マグネシウムをろ過後、ろ液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィーで処理して原料の1−ブロムメチレン−3−ヒドロキシ−5−シロキシシクロヘキサン(382mg,1.19mmol)を回収した。
樹脂は、THF−水(3/1(v/v),12mL)で3回、エタノール(12mL)で2回、さらにエーテル(18mL)で2回洗浄した後、減圧下終夜で乾燥し、シリル基樹脂末端を持つ固相担持光学活性ビニリデンシクロヘキサン化合物5を回収原料からの基準による収率90%(1.31g)で得た。
得られた樹脂のローディングは、樹脂をフッ化水素酸−ピリジンで分解した後、生成したアルコール体を1HNMRで分析することにより、0.738mmol/gと決定した。
すなわち、シリンジ型のPP反応器(EYELA RT5−S100,武田理化製)に樹脂(144mg)とTHF(3mL)を仕込み、これにフッ化水素酸−ピリジン(0.1mL)を加え、室温下6時間撹拌した。
反応液に、内部標準物質として1,4−ジブロモベンゼン(25.6mg)を加えた後、THF(3mL)でろ過した。
ろ液に酢酸エチル(4mL)を加え、飽和重曹水(3mL)で洗浄し、さらに水層より酢酸エチル(3mL)で2回抽出した。
合わせた有機層を乾燥(硫酸マグネシウム)し、硫酸マグネシウムをろ過後、ろ液を減圧下濃縮して得られた残渣を1HNMRで分析した。
その結果、ブロモメチレンシクロヘキサンジオールは0.1063mmolであり、樹脂のローディングは0.738mmol/gと計算された。
本発明によれば、19−ノル−活性型ビタミンD誘導体および活性型ビタミンD3誘導体を製造する際の重要中間体である光学活性ヒドロキシエチレンジオキシシクロヘキサン化合物を、光学活性ジオキシシクロヘキサン化合物を用いることで、比較的簡便に、かつ、効率的に製造することができる。Technical field
The present invention relates to an optically active dioxycyclohexane compound and a method for producing an optically active hydroxyethylenedioxycyclohexane compound which is an important intermediate for the synthesis of a 19-nor-active vitamin D derivative using the compound.
Background art
Conventionally, active vitamin D3(1,25-dihydroxycholecalciferol) is known to have a strong physiological activity such as calcium transport ability and bone salt mobilization ability in the small intestine, and therefore plays an important role in human physiological functions.
In addition, the 19-nor body has been reported to have a selective physiologically active effect of suppressing the growth of tumor cells without increasing the calcium ion concentration in the blood. Clinical development for hyperfunction has been made (Tetrahedron Letters, 31, 1823 (1990), Tetrahedron Letters, 32, 7663 (1991), Tetrahedron Letters, 33, 2937 (1992), etc.).
Optically active hydroxyethylenedioxycyclohexane compound represented by the general formula (3), for example, the following compound1(X = Y = t-butyldimethylsilyl group) is well known as an A-ring partial precursor, which is one of the most important intermediates in the production of 19-nor-active vitamin D derivatives.
(In the formula, TBS represents a t-butyldimethylsilyl group.)
As a method for producing this A-ring partial precursor, for example, as shown in Scheme 1, (1) a method of producing an alkyl ester of propiolic acid and homoallylic ether in 11 steps (Tetrahedron Letters, 39, 3359 (1998), Tetrahedron Letters, 39, 3363 (1998)), and (2) a method of producing in 5 steps from diepoxypentane and propargyl ether (Tetrahedron Letters, 37, 7637 (1996)). ing.
Scheme 1
(In the formula, Bn represents a benzyl group, TBS represents a t-butyldimethylsilyl group, MPM represents a p-methoxyphenylmethyl group, and TBDPS represents a t-butyldiphenylsilyl group.)
However, each of the production methods described in the above scheme 1 has problems such as a long number of steps from the starting material and a low total yield of all steps, and a more practical production method. Development is desired.
At present, research is actively conducted with the aim of establishing an efficient method for producing the A-ring partial precursor.
Disclosure of the invention
The present invention has been made in view of the above circumstances, and becomes a key intermediate that can be efficiently converted into an A-ring partial precursor, which is an important intermediate in the production of a 19-nor-active vitamin D derivative. It is an object of the present invention to provide an optically active dioxycyclohexane compound and an efficient method for producing an optically active hydroxyethylenedioxycyclohexane compound that is an A-ring partial precursor using the compound.
As a result of intensive studies to achieve the above object, the present inventors have found that the optically active dioxycyclohexane compound represented by the general formula (1) and the general formula (2) is a 19-nor-active vitamin D. It is found that it can be an important key intermediate of the A-ring partial precursor in the production of derivatives, and the compound is hydroxymethylated to efficiently produce an optically active hydroxyethylenedioxycyclohexane compound that is the A-ring partial precursor The inventors have found what can be done and have completed the present invention.
That is, the present invention
[1] The following general formula (1)
(In the formula, R represents a halogen atom, a substituted silyl group, a substituted boron group or a substituted tin group. X and Y represent a hydrogen atom, a hydroxyl protecting group or a solid phase having the protecting group at the end.)
An optically active dioxycyclohexane compound represented by the formula:
[2] The optically active dioxycyclohexane compound or an enantiomer thereof according to [1], wherein R is a halogen atom,
[3] The following general formula (2)
(In the formula, R ′ and R ″ each independently represents a substituted alkyl group, a halogen atom, a substituted silyl group, a substituted boron group or a substituted tin group. X and Y are a hydrogen atom, a hydroxyl protecting group or the protecting group. Represents a solid phase having a terminal.)
An optically active dioxycyclohexane compound represented by the formula:
[4] The optically active dioxycyclohexane compound or an enantiomer thereof according to [3], wherein R ′ and R ″ are halogen atoms.
[5] The following general formula (1)
(In the formula, R represents a halogen atom, a substituted silyl group, a substituted boron group or a substituted tin group. X and Y represent a hydrogen atom, a hydroxyl protecting group or a solid phase having the protecting group at the end.)
A hydroxymethylation reaction is performed on the optically active dioxycyclohexane compound represented by the following general formula (3):
(Wherein X and Y represent a hydrogen atom, a protecting group for a hydroxyl group, or a solid phase having the protecting group at the end)
A process for producing an optically active hydroxyethylenedioxycyclohexane compound, characterized by:
[6] The process for producing an optically active hydroxyethylenedioxycyclohexane compound according to [5], wherein R is a halogen atom
I will provide a.
BEST MODE FOR CARRYING OUT THE INVENTION
Hereinafter, the present invention will be described in more detail.
In the present specification, “n” is normal, “i” is iso, “s” is secondary, “t” is tertiary, “c” is cyclo, and “o” is ortho. , “M” means meta, and “p” means para.
In the general formula (1), the substituent R represents a halogen atom, a substituted silyl group, a substituted boron group or a substituted tin group.
Here, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
Examples of the substituted silyl group include a trisubstituted silyl group substituted with three groups selected from an alkyl group and a phenyl group (the phenyl group may be substituted with an alkoxy group). Specifically, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, dimethylisopropylsilyl, t-butyldimethylsilyl, texyldimethylsilyl, diphenylmethylsilyl, t-butyldiphenylsilyl, t-butyldimethoxyphenylsilyl, tri Examples thereof include phenylsilyl.
Examples of the substituted boron group include dialkyl boron groups (for example, dimethylboron, diethylboron, di-n-butylboron and the like), diarylboron groups (for example, diphenylboron and the like), dialkoxyboron groups (for example, , Diisopropoxyboron, ethylenedioxyboron, tetramethylethylenedioxyboron and the like).
Examples of substituted tin groups include trialkyltin groups (for example, trimethyltin, triethyltin, tri-n-propyltin, tri-n-butyltin, tri-c-hexyltin, etc.), triaryltin groups (for example, triaryltin groups). And phenyl tin).
Among these, as the substituent R, it is preferable to use a halogen atom, trimethylsilyl, tetramethylethylenedioxyboron, or tri-n-butyltin, more preferably a halogen atom, particularly a bromine atom.
In the general formula (2), the substituents R ′ and R ″ each independently represent a substituted alkyl group, a halogen atom, a substituted silyl group, a substituted boron group, or a substituted tin group.
Here, the same thing as the above can be used about a halogen atom, a substituted silyl group, a substituted boron group, and a substituted tin group.
Examples of the substituted alkyl group include linear, branched, or cyclic C1-6 alkyl groups (the alkyl group may be optionally substituted with a halogen atom). Examples thereof include methyl, ethyl, and n-propyl. I-propyl, c-propyl, n-butyl, i-butyl, s-butyl, t-butyl, c-butyl, 1-methyl-c-propyl, 2-methyl-c-propyl, n-pentyl, 1 -Methyl-n-butyl, 2-methyl-n-butyl, 3-methyl-n-butyl, 1,1-dimethyl-n-propyl, 1,2-dimethyl-n-propyl, 2,2-dimethyl-n -Propyl, 1-ethyl-n-propyl, c-pentyl, 1-methyl-c-butyl, 2-methyl-c-butyl, 3-methyl-c-butyl, 1,2-dimethyl-c-propyl, 2 , 3-Dimethyl-c-propyl Pill, 1-ethyl-c-propyl, 2-ethyl-c-propyl, n-hexyl, 1-methyl-n-pentyl, 2-methyl-n-pentyl, 3-methyl-n-pentyl, 4-methyl- n-pentyl, 1,1-dimethyl-n-butyl, 1,2-dimethyl-n-butyl, 1,3-dimethyl-n-butyl, 2,2-dimethyl-n-butyl, 2,3-dimethyl- n-butyl, 3,3-dimethyl-n-butyl, 1-ethyl-n-butyl, 2-ethyl-n-butyl, 1,1,2-trimethyl-n-propyl, 1,2,2-trimethyl- n-propyl, 1-ethyl-1-methyl-n-propyl, 1-ethyl-2-methyl-n-propyl, c-hexyl, 1-methyl-c-pentyl, 2-methyl-c-pentyl, 3- Methyl-c-pentyl, 1-ethyl-c- Til, 2-ethyl-c-butyl, 3-ethyl-c-butyl, 1,2-dimethyl-c-butyl, 1,3-dimethyl-c-butyl, 2,2-dimethyl-c-butyl, 2, 3-dimethyl-c-butyl, 2,4-dimethyl-c-butyl, 3,3-dimethyl-c-butyl, 1-n-propyl-c-propyl, 2-n-propyl-c-propyl, 1- i-propyl-c-propyl, 2-i-propyl-c-propyl, 1,2,2-trimethyl-c-propyl, 1,2,3-trimethyl-c-propyl, 2,2,3-trimethyl- c-propyl, 1-ethyl-2-methyl-c-propyl, 2-ethyl-1-methyl-c-propyl, 2-ethyl-2-methyl-c-propyl, 2-ethyl-3-methyl-c- And propyl.
As substituents R ′ and R ″, it is preferable to use both halogen atoms, one of which is methyl and the other is a halogen atom, one is ethyl and the other is a halogen atom, one is n-butyl and the other is a halogen atom, More preferably, both are halogen atoms, and particularly preferably both are bromine atoms.
In the above general formulas (1) and (2), the substituents X and Y represent a hydrogen atom, a hydroxyl protecting group, or a solid phase having the protecting group at the end.
Examples of the hydroxyl-protecting group include C1-7 acyl groups (for example, formyl, acetyl, fluoroacetyl, difluoroacetyl, trifluoroacetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, propionyl, pivaloyl, tigloyl and the like). , Arylcarbonyl groups (for example, benzoyl, benzoylformyl, benzoylpropionyl, phenylpropionyl, etc.), C1-4 alkoxycarbonyl groups (for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n- Butoxycarbonyl, i-butoxycarbonyl, t-butoxycarbonyl, t-amyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 2- (trimethyl) Yl) ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, etc.), aryloxycarbonyl groups (for example, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, etc.), C1-4 alkylaminocarbonyl group (for example, methylcarbamoyl, ethylcarbamoyl, n-propylcarbamoyl etc.), arylaminocarbonyl group (for example, phenylcarbamoyl etc.), trialkylsilyl group (for example, trimethylsilyl, Triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, dimethylisopropylsilyl, di-t-butylmethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, Hexyl dimethyl silyl, and the like), trialkyl aryl silyl group (e.g., diphenylmethyl silyl, t- butyl diphenyl silyl, t- butyl dimethoxyphenylsilyl, triphenylsilyl and the like) and the like.
Examples of the solid phase having a hydroxyl protecting group at the end include a carbonyl group resin end, a carbonyloxy group resin end, a carbonylamino group resin end, and a silyl group resin end.
Examples of the resin used include polystyrene resin, PEG-polystyrene resin, and PGA resin.
Among these, as the substituents X and Y, it is preferable to use a C1-7 acyl group, a C1-4 alkoxycarbonyl group, a trialkylsilyl group, a trialkylarylsilyl group, a silyl group resin terminal, and the like, particularly preferably A trialkylsilyl group, a trialkylarylsilyl group, a silyl group resin terminal, and the like.
The substituents X and Y may be the same or different from each other.
Next, a method for producing the optically active dioxycyclohexane compound represented by the general formula (1) will be described.
This compound is a novel compound not conventionally known, for example, a compound5(R = bromine atom, X = Y = t-butyldimethylsilyl group) can be produced by the method shown in the following scheme 2.
Scheme 2
(In the formula, TBS represents a t-butyldimethylsilyl group.)
That is, the optically active cyclohexenone compound that is the starting material2Is epoxidized to form cyclohexenone oxide3Then, bromethylene cyclohexene oxide is reacted by introducing bromomethylene into ketone.4Finally, the epoxide can be reduced and the resulting hydroxyl group can be silylated.
The oxidizing agent for the first epoxidation reaction is not particularly limited, and examples thereof include peracids such as peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, hydrogen peroxide, oxygen, and the like. Is hydrogen peroxide.
The amount of the oxidizing agent used is usually in the range of 0.8 to 50 mol times, particularly preferably in the range of 1.0 to 20 mol times with respect to the substrate.
The reaction solvent is not particularly limited as long as it is stable under the reaction conditions and is inert and does not interfere with the reaction. For example, the following solvents can be used.
Specifically, water, alcohols (eg, methanol, ethanol, propanol, butanol, octanol, etc.), cellosolves (eg, methoxyethanol, ethoxyethanol, etc.), aprotic polar organic solvents (eg, dimethylformamide, Dimethyl sulfoxide, dimethylacetamide, tetramethylurea, sulfolane, N-methylpyrrolidone, N, N-dimethylimidazolidinone, etc.), ethers (eg, diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, etc.) Aliphatic hydrocarbons (eg, pentane, hexane, c-hexane, octane, decane, decalin, petroleum ether), aromatic hydrocarbons (benzene, chlorobenzene, o-dichlorobenzene, nitro) Benzene, toluene, xylene, mesitylene, tetralin, etc.), halogenated hydrocarbons (eg, chloroform, dichloromethane, dichloroethane, carbon tetrachloride, etc.), ketones (acetone, methyl ethyl ketone, methyl butyl ketone, methyl isobutyl ketone, etc.), lower Aliphatic acid esters (eg, methyl acetate, ethyl acetate, butyl acetate, methyl propionate, etc.), alkoxyalkanes (eg, dimethoxyethane, diethoxyethane, etc.), nitriles (eg, acetonitrile, propionitrile, butyronitrile, etc.) ) And the like. These solvents are appropriately selected according to the ease of reaction, and can be used alone or in combination of two or more. If necessary, the water may be removed with a suitable dehydrating agent or desiccant and used as a non-aqueous solvent.
The reaction temperature is usually from −100 ° C. to the boiling point of the solvent used, but it is preferably carried out in the range of −50 to 50 ° C.
The reaction time is usually 0.1 to 1000 hours.
After completion of the reaction, the target product can be extracted with an appropriate solvent, and the solvent can be concentrated under reduced pressure to obtain a crude product. Furthermore, by performing purification by conventional methods such as silica gel column chromatography, pure cyclohexenone oxide form3Can be isolated.
Next, examples of the reaction for introducing bromomethylene into a ketone include a Wittig reaction using bromomethyltriphenylphosphonium bromide, or a Horner-Emmons reaction using diisopropylbrommethylphosphonate, for example. Wittig reaction using bromomethyltriphenylphosphonium bromide.
In this case, the amount of bromomethyltriphenylphosphonium bromide used is usually in the range of 0.8 to 20 mol times, particularly preferably in the range of 1.0 to 5.0 mol times relative to the substrate.
The reaction solvent is not particularly limited as long as it does not participate in the reaction, and among the above-mentioned solvents, solvents other than ketone solvents can be used.
The reaction temperature is usually from −100 ° C. to the boiling point of the solvent used, but it is preferably carried out in the range of −50 to 50 ° C.
The reaction time is usually 0.1 to 1000 hours.
After completion of the reaction, the target product can be extracted with an appropriate solvent, and the solvent can be concentrated under reduced pressure to obtain a crude product. Furthermore, pure bromethylenecyclohexene oxide is obtained by purifying by a conventional method such as silica gel column chromatography.4Can be isolated.
Finally, the bromethylenecyclohexene oxide obtained4Compounds by reducing epoxides and silylating hydroxyl groups5Is obtained.
The reducing agent of the epoxide is not particularly limited, and examples thereof include diisobutylaluminum hydride, sodium borohydride, lithium aluminum hydride, sodium bismethoxyethoxyaluminum hydride, and preferably diisobutyl hydride. Aluminum.
The amount of the reducing agent used is usually in the range of 0.5 to 20 mol times relative to the substrate, particularly preferably in the range of 1.0 to 10 mol times.
The reaction solvent is not particularly limited as long as it does not participate in the reaction, and among the above solvents, solvents other than water, ketones and ester solvents can be used.
The reaction temperature is usually from −100 ° C. to the boiling point of the solvent used, but it is preferably carried out in the range of −80 to 50 ° C.
The reaction time is usually 0.1 to 1000 hours.
After completion of the reaction, the target product can be extracted with an appropriate solvent, and the solvent can be concentrated under reduced pressure to obtain a crude product. Furthermore, a pure hydroxyl body can be isolated by performing purification by a conventional method such as silica gel column chromatography.
The protective agent for protecting the hydroxyl group of the hydroxyl product obtained as described above is not particularly limited, and examples thereof include acylating agents, oxycarbonylating agents, aminocarbonylating agents, silylating agents and the like. Preferably, it is a silylating agent.
Such a silylating agent is not particularly limited, and examples thereof include trimethylsilyl chloride, t-butyldimethylsilyl chloride, diphenyl-t-butylsilyl chloride and the like.
The amount of the silylating agent used is usually in the range of 0.5 to 20 mol times, particularly preferably in the range of 1.0 to 10 mol times relative to the substrate.
In this case, in order to accelerate the reaction, a base may be present in the reaction system, and examples of such base include diethylamine, triethylamine, tri-n-propylamine, tri-n-butylamine, DBU, N-methyl. Examples thereof include amines such as morpholine and N, N-dimethylaniline, pyridines such as pyridine, methylethylpyridine, lutidine and 4-N, N-dimethylaminopyridine, imidazole and pyrazole, and preferably imidazole.
The amount of the base used is usually in the range of 0.5 to 20 mol times, particularly preferably in the range of 1.0 to 10 mol times relative to the substrate.
The reaction solvent is not particularly limited as long as it does not participate in the reaction, and among the above solvents, solvents other than water and alcohols can be used.
The reaction temperature is usually from −100 ° C. to the boiling point of the solvent used, but it is preferably carried out in the range of −50 to 50 ° C.
The reaction time is usually 0.1 to 1000 hours.
After completion of the reaction, the target product can be extracted with an appropriate solvent, and the solvent can be concentrated under reduced pressure to obtain a crude product. Furthermore, by purifying by a conventional method such as silica gel column chromatography, a pure compound5Can be isolated.
In Scheme 2 above, bromethylenecyclohexene oxide form4After reduction of the epoxide of the compound, the resulting hydroxyl group is reacted with a resin having a reactive silyl group at the end to produce a compound having a silyl group resin end6(R = bromine atom, either X or Y = t-butyldimethylsilyl group, the other = silyl group resin terminal) can be produced.
Such compounds6Since it is supported on a solid phase, it can be easily separated from the reaction system, and is suitable for high-speed synthesis by combinatorial chemistry or an automatic synthesizer.
Moreover, as a compound shown by the said General formula (1), for example, a compound7(R = tetramethylethylenedioxyboron, X = Y = t-butyldimethylsilyl group) can be produced by the method shown in the following scheme 3.
Scheme 3
(In the formula, TBS represents a t-butyldimethylsilyl group.)
That is, the compound obtained above5Can be produced by lithiation of the compound and treatment with a boronating agent.
Examples of the lithiating agent include n-butyllithium, s-butyllithium, t-butyllithium and the like.
The amount of the lithiating agent used is usually in the range of 0.5 to 20 mol times relative to the substrate, and particularly preferably in the range of 1.0 to 10 mol times.
The reaction solvent is not particularly limited as long as it does not participate in the reaction, and among the above solvents, solvents other than water, alcohols, ketones, and esters can be used.
The reaction temperature is usually from −100 ° C. to the boiling point of the solvent used, but it is preferably carried out in the range of −80 to 0 ° C.
The reaction time is usually 0.1 to 1000 hours.
Without isolating the lithiated compound, a boronating agent is added to the reaction system as it is to obtain a boron compound. Further, by treating the obtained boron compound with pinacol, the compound7Can be synthesized.
Here, the boronating agent is not particularly limited, and examples thereof include trimethoxyborane, triethoxyborane, triisopropoxyborane and the like.
The amount of the boronating agent used is usually in the range of 0.5 to 20 mol times relative to the substrate, and particularly preferably in the range of 1.0 to 10 mol times.
The reaction solvent is not particularly limited as long as it does not participate in the reaction, and the solvent used for lithiation can be used as it is.
The reaction temperature is usually from −100 ° C. to the boiling point of the solvent used, but it is preferably carried out in the range of −80 to 50 ° C.
The reaction time is usually 0.1 to 1000 hours.
After completion of the reaction, the target product can be extracted with an appropriate solvent, and the solvent can be concentrated under reduced pressure to obtain a crude product.
Furthermore, by purifying by a conventional method such as silica gel column chromatography, a pure compound7Can be isolated.
Moreover, as a compound shown by General formula (1), for example, a compound8(R = trimethylsilyl, X = Y = t-butyldimethylsilyl group) can be produced by the method shown in Scheme 4 below.
Scheme 4
(In the formula, TBS represents a t-butyldimethylsilyl group, and Me represents a methyl group.)
That is, the compound obtained above5Can be produced by treating with silylating agent and then treating with silylating agent.
Examples of the lithiating agent include the same reagents as described above.
The amount of the lithiating agent used is usually in the range of 0.5 to 20 mol times relative to the substrate, and particularly preferably in the range of 1.0 to 10 mol times.
The reaction solvent is not particularly limited as long as it does not participate in the reaction, and among the above solvents, solvents other than water, alcohols, ketones, and esters can be used.
The reaction temperature is usually from −100 ° C. to the boiling point of the solvent used, but it is preferably carried out in the range of −80 to 0 ° C.
The reaction time is usually 0.1 to 1000 hours.
The lithiated compound is not isolated but is silylated by adding a silylating agent to the reaction system as it is.
The silylating agent is not particularly limited. For example, chlorotrimethylsilane, bromotrimethylsilane, chlorotriethylsilane, bromotriethylsilane, chlorotri-n-butylsilane, bromotri-n-butylsilane, chlorotri-n-octylsilane , Bromotri-n-octylsilane, chlorotriphenylsilane, bromotriphenylsilane, and the like.
The amount of the silylating agent used is usually in the range of 0.5 to 20 mol times, particularly preferably in the range of 1.0 to 10 mol times relative to the substrate.
The reaction solvent is not particularly limited as long as it does not participate in the reaction, and the solvent used for lithiation can be used as it is.
The reaction temperature is usually from −100 ° C. to the boiling point of the solvent used, but it is preferably carried out in the range of −80 to 50 ° C.
The reaction time is usually 0.1 to 1000 hours.
After completion of the reaction, the target product can be extracted with an appropriate solvent, and the solvent can be concentrated under reduced pressure to obtain a crude product.
Furthermore, by purifying by a conventional method such as silica gel column chromatography, a pure compound8Can be isolated.
In addition, the optically active cyclohexenone compound used as a starting material when manufacturing the optically active dioxycyclohexane compound represented by the general formula (1)2Tetrahedron Letters, 38, 8299 (1997), J. et al. Am. Chem. Soc. 121, 3640 (1999).
Scheme 5
(In the formula, TBS represents a t-butyldimethylsilyl group.)
That is, optically active chlorohydrin ester9Iodized, iodohydrin body10And then silylated the hydroxyl group to produce a siloxy compound11And then react with a vinyl Grignard reagent to form a homoallyl ether.12And finally cyclized with Ti.
Next, the manufacturing method of the optically active dioxycyclohexane compound shown by General formula (2) is demonstrated.
This compound is also a novel compound that has not been known so far, for example, a compound14(R ′ = R ″ = bromine atom, X = Y = t-butyldimethylsilyl group) can be produced by the method shown in Scheme 6 below.
Scheme 6
(In the formula, TBS represents a t-butyldimethylsilyl group.)
That is, the optically active cyclohexenone compound that is the starting material2Is epoxidized to form cyclohexenone oxide3Then, dibromethylene cyclohexene oxide is obtained by introducing dibromomethylene into the ketone.13Finally, the epoxide is reduced and the hydroxyl group is silylated.
As the oxidant for the first epoxidation reaction, the same oxidant as that represented by the compound represented by the general formula (1) can be used.
The amount of the oxidizing agent used is usually in the range of 0.8 to 50 mol times, particularly preferably in the range of 1.0 to 20 mol times with respect to the substrate.
The reaction solvent is not particularly limited as long as it does not participate in the reaction, and the above-mentioned solvents can be used.
The reaction temperature is usually from −100 ° C. to the boiling point of the solvent used, but it is preferably carried out in the range of −50 to 50 ° C.
The reaction time is usually 0.1 to 1000 hours.
After completion of the reaction, the target product can be extracted with an appropriate solvent, and the solvent can be concentrated under reduced pressure to obtain a crude product.
Furthermore, by performing purification by conventional methods such as silica gel column chromatography, pure cyclohexenone oxide form3Can be isolated.
Next, the dibromomethylene introduction reaction to the ketone is not particularly limited, and examples thereof include a Wittig reaction using carbon tetrachloride and triphenylphosphine.
The amount of carbon tetrachloride used is usually in the range of 0.8 to 20 mole times relative to the substrate, and particularly preferably in the range of 1.0 to 5.0 mole times.
The amount of triphenylphosphine used is usually in the range of 0.8 to 20 mol times relative to the substrate, and particularly preferably in the range of 1.0 to 5.0 mol times.
The reaction solvent is not particularly limited as long as it does not participate in the reaction, and solvents other than ketones can be used among the solvents described above.
The reaction temperature is usually from −100 ° C. to the boiling point of the solvent used, but it is preferably carried out in the range of −50 to 50 ° C.
The reaction time is usually 0.1 to 1000 hours.
After completion of the reaction, the target product can be extracted with an appropriate solvent, and the solvent can be concentrated under reduced pressure to obtain a crude product.
Furthermore, pure dibromomethylenecyclohexene oxide is obtained by purifying by conventional methods such as silica gel column chromatography.13Can be isolated.
Finally, the obtained dibromomethylenecyclohexene oxide form13Compounds by reducing epoxides and silylating hydroxyl groups14Is obtained.
Here, examples of the epoxide reducing agent include the same as those described above, but it is particularly preferable to use diisobutylaluminum hydride.
The amount of the reducing agent used is usually in the range of 0.5 to 20 mol times relative to the substrate, particularly preferably in the range of 1.0 to 10 mol times.
The reaction solvent is not particularly limited as long as it does not participate in the reaction, and among the above solvents, solvents other than water, ketones, and esters can be used.
The reaction temperature is usually from −100 ° C. to the boiling point of the solvent used, but it is preferably carried out in the range of −80 to 50 ° C.
The reaction time is usually 0.1 to 1000 hours.
After completion of the reaction, the target product can be extracted with an appropriate solvent, and the solvent can be concentrated under reduced pressure to obtain a crude product.
Furthermore, a pure hydroxyl body can be isolated by performing purification by a conventional method such as silica gel column chromatography.
Examples of the protective agent for protecting the hydroxyl group include those described above, but it is preferable to use a silylating agent.
Here, the kind of silylating agent and its use amount, the kind of base as a reaction accelerator and its use amount, and the reaction conditions are the same as described above.
After completion of the silylation reaction, the target product can be extracted with an appropriate solvent, and the solvent can be concentrated under reduced pressure to obtain a crude product.
Furthermore, by purifying by a conventional method such as silica gel column chromatography, a pure compound14Can be isolated.
Next, a method for producing the optically active hydroxyethylenedioxycyclohexane compound represented by the general formula (3) will be described.
The compound can be produced by subjecting the optically active dioxycyclohexane compound represented by the general formula (1) obtained above to a hydroxymethylation reaction.
For example, the compound1(X = Y = t-butyldimethylsilyl group) is the above compound5Can be produced by reacting with formaldehyde after lithiation.
Examples of the lithiating agent include n-butyllithium, s-butyllithium, t-butyllithium and the like.
The amount of the lithiating agent used is usually in the range of 0.5 to 20 mol times relative to the substrate, and particularly preferably in the range of 1.0 to 10 mol times.
The reaction solvent is not particularly limited as long as it does not participate in the reaction, and among the above solvents, solvents other than water, alcohols, ketones, and esters can be used.
The reaction temperature is usually from −100 ° C. to the boiling point of the solvent used, but it is preferably carried out in the range of −80 to 0 ° C.
The reaction time is usually 0.1 to 1000 hours.
The lithiated compound is not isolated, but formaldehyde is added to the reaction system as it is to perform hydroxymethylation.
The amount of formaldehyde used is usually in the range of 0.5 to 20 mol times relative to the substrate, and particularly preferably in the range of 1.0 to 10 mol times.
The reaction solvent is not particularly limited as long as it does not participate in the reaction, and the solvent used for lithiation can be used as it is.
The reaction temperature is usually from −100 ° C. to the boiling point of the solvent used, but it is preferably carried out in the range of −80 to 50 ° C.
The reaction time is usually 0.1 to 1000 hours.
After completion of the reaction, the target product can be extracted with an appropriate solvent, and the solvent can be concentrated under reduced pressure to obtain a crude product.
Furthermore, pure optically active hydroxyethylenedioxycyclohexane compound is obtained by performing purification by conventional methods such as silica gel column chromatography.1Can be isolated.
EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated more concretely, this invention is not limited to a following example.
Example 1 Cyclohexenone oxide3Synthesis of
(In the formula, TBS represents a t-butyldimethylsilyl group.)
Ice-cooled optically active 5-siloxy-2-cyclohexenone2To a mixture of (226 mg, 1.0 mmol) and 35% aqueous hydrogen peroxide (0.8 mL, 10 mmol), methanol (38 mL) and a 3 mol / L aqueous sodium hydroxide solution (33 mL, 0.1 mmol) were added. . After the mixed solution was stirred for 6 hours under ice cooling, a saturated aqueous ammonium chloride solution (3 mL) was added.
Then, it extracted 3 times with ether (5 mL), and the organic layer was dried with anhydrous magnesium sulfate.
After filtration, the crude product obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography, and optically active 5-siloxy-2,3-epoxycyclohexanone.3Was obtained in a yield of 83% (204 mg).
1The stereoisomer ratio was> 95: <5 from 1 H NMR and GC analysis.
11 H NMR (300 MHz, CDCl3) 4.22-4.33 (m, 1H, CHOSi), 3.54-3.59 (m, 1H, CH2CHO), 3.26 (d, J = 3.9 Hz, 1H, C (= O) CHO), 2.77 (dd, J = 3.0, 15.3 Hz, 1H, one of CH2C (= O)), 2.39 (dd, J = 4.2, 15.3 Hz, 1H, one of CH2), 2.19 (dd, J = 4.2, 15.3 Hz, 1H, one of CH2C (= O)), 2.00 (dt, J = 15.3, 3.3 Hz, 1H, one of CH2), 0.85 (s, 9H, t-Bu), 0.04 and 0.03 (2s, 6H, 2SiCH)3).
13C NMR (75 MHz, CDCl3) 204.8, 67.3, 55.4, 54.7, 44.9, 32.9, 25.5, 17.8, -5.0, -5.1.
IR (neat) 2929, 2888, 2857, 1726, 1472, 1406, 1361, 1331, 1255, 1075, 1031, 985, 935, 871, 837, 778, 715 cm-1.
[Example 2] Bromethylenecyclohexene oxide4Synthesis of
(In the formula, TBS represents a t-butyldimethylsilyl group.)
To a toluene (2 mL) suspension of bromomethyltriphenylphosphonium bromide (567 mg, 1.3 mmol) was added potassium bistrimethylsilylamide (0.5 M / toluene solution, 2.6 mL, 1.3 mmol) at room temperature. Stir at room temperature for 30 minutes.
After cooling this mixed solution to 0 ° C., 5-siloxy-2,3-epoxycyclohexanone3(242 mg, 1.0 mmol) in toluene was added and the reaction was warmed to room temperature over 30 minutes.
The reaction mixture was concentrated under reduced pressure, diethyl ether (2 mL) and hexane (40 mL) were added to the resulting residue, and the precipitated crystals were filtered through celite.
The crude product obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography to obtain 1-bromomethylene-5-siloxy-2,3-epoxycyclohexane.4Was obtained in a yield of 82% (262 mg).
11 H NMR (300 MHz, CDCl3) 0.06 (s, 6H), 0.86 (s, 9H), 1.81 (ddd, J = 2.4, 6.9, 15.0 Hz, 1H), 2.16 (ddd, J = 2.1, 8.4, 15.9 Hz, 1H), 2.27 (dd, J = 3.9, 15.0 Hz, 1H), 2.42 (brd, J = 15.9 Hz, 1H), 3.38-3.45 (m, 1H), 3.49 (d, 4.2 Hz, 1H), 3.87-4.02 (m, 1H), 6.48 (brs, 1H).
13C NMR (75 MHz, CDCl3) Δ-4.7, -4.6, 18.1, 25.8, 33.9, 35.4, 54.1, 54, 7, 64.3, 109.2, 137.5.
IR (neat) 2928, 2856, 1621, 1471, 1360, 1254, 1092, 876, 836, 777 cm-1
[Example 3] Optically active dioxycyclohexane compound5Synthesis of
(In the formula, TBS represents a t-butyldimethylsilyl group.)
1-bromomethylene-5-siloxy-2,3-epoxycyclohexane under ice cooling4To a solution of (100 mg, 0.313 mmol) in THF (3 mL) was added diisobutylaluminum hydride (1.0 M / hexane solution, 0.94 mL, 0.94 mmol), and the mixture was stirred at 0 ° C. for 15 hours.
Water (0.18 mL), sodium fluoride (1 g), and celite (1 g) were added to the reaction solution, and the mixture was filtered through celite.
The crude product of 1-bromomethylene-3-hydroxy-5-siloxycyclohexane obtained by concentrating the filtrate under reduced pressure was directly used in the next reaction.
11 H NMR (300 MHz, CDCl3) Δ 0.07 and 0.09 (2s, 6H), 0.88 (s, 9H), 1.42 (d, J = 5.1 Hz, 1H, OH), 1.74 (ddd, J = 3. 6, 7.2, 13.2 Hz, 1H), 1.83 (ddd, J = 3.9, 6.9, 13.2 Hz, 1H), 2.15 (dd, J = 7.5, 13. 5Hz, 1H), 2.43-2.54 (m, 2H), 4.04-4.16 (m, 2H), 6.02 (brs).
13C NMR (75 MHz, CDCl3) Δ-4.9, -4.7, 18.1, 25.8, 39.2, 42.5, 43.1, 66.9 (two carbons), 101.9, 138.8.
To a dimethylformamide (1 mL) solution of the crude product of 1-bromomethylene-3-hydroxy-5-siloxycyclohexane obtained above and imidazole (43 mg, 0.63 mmol) at 0 ° C., t-butyldimethylsilyl chloride. (71 mg, 0.47 mmol) was added, and the mixture was stirred at room temperature for 12 hours.
Saturated aqueous sodium hydrogen carbonate (3 mL) was added, and the mixture was extracted 3 times with hexane (4 mL). The organic layer was dried (anhydrous magnesium sulfate) and filtered, and then the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to obtain 1-bromomethylene-3,5-disiloxycyclohexane.5Was obtained in a yield of 68% (93 mg).
11 H NMR (300 MHz, CDCl3) Δ 0.04 (s, 6H), 0.06 and 0.09 (2s, each 3H), 0.87 and 0.89 (2s, each 9H), 1.62-1.84 (m, 2H) , 2.09 (ddd, J = 0.9, 7.5, 13.5 Hz, 1H), 2.30-2.48 (m, 3H), 4.02-4.15 (m, 2H), 5.94 (br s, 1H).
13C NMR (75 MHz, CDCl3)-4.86, -4.74, -4.67, -4.64, 18.16, 18.20, 25.87, 25.90, 39.2, 43.2, 43.6, 67.1, 67.4, 101.2, 139.3.
IR (neat) 2953, 2857, 1637, 1471, 1361, 1255, 1099, 1025, 914, 836, 775 cm-1.
[Example 4] Optically active dioxycyclohexane compound7Synthesis of
(In the formula, TBS represents a t-butyldimethylsilyl group.)
1-bromomethylene-3,5-disiloxycyclohexane5(348 mg, 0.80 mmol) in diethyl ether (3 mL) was added t-butyllithium (1.35 M / pentane solution, 1.30 mL, 1.76 mmol) at −78 ° C., and left at −78 ° C. for 1 hour. Stir.
Triisopropoxyborane (2.0 M / diethyl ether solution, 0.6 mL, 1.2 mmol) was added at −78 ° C., and the reaction solution was warmed to room temperature over 4 hours, and then saturated aqueous ammonium chloride solution (8 mL). And ethyl acetate (8 mL) were added.
Subsequently, the mixture was extracted twice with ethyl acetate (6 mL), and the organic layer was concentrated under reduced pressure.
Ethyl acetate (3 mL) was added to the residue for dissolution, and pinacol (113 mg, 0.96 mmol) and magnesium sulfate (1.0 g) were added thereto and stirred at room temperature for 12 hours.
After filtration, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to obtain a compound.7Was obtained in 93% yield (415 mg).
11 H NMR (300 MHz, CDCl3) Δ 5.12 (s, 1H), 4.03-4.11 (m, 2H), 2.67 (dd, J = 3.6, 13.2 Hz, 1H), 2.54 (dd, J = 6.9, 13.2, Hz, 1H), 2.36 (dd, J = 3.6, 12.9 Hz, 1H), 2.13 (dd, J = 7.5, 12.9 Hz, 1H) 1.62-1.76 (m, 2H), 1.22 (s, 6H), 1.21 (s, 6H), 0.86 (s, 9H), 0.84 (s, 9H), 0.043, 0.036, 0.008 and 0.004 (4s, each 3H).
13C NMR (75 MHz, CDCl3) 160.1, 115.6 (br s), 82.5, 68.3, 67.9, 48.0, 43.1, 40.8, 25.8, 25.7, 24.9, 24 6, 18.1, 17.9, -4.9, -5.0, -5.1, -5.2.
IR (neat) 2954, 2856, 1645, 1471, 1386, 1256, 1056, 1028, 837, 775 cm-1.
Example 5 Optically Active Dioxycyclohexane Compound8Synthesis of
(In the formula, TBS represents a t-butyldimethylsilyl group, and Me represents a methyl group.)
1-bromomethylene-3,5-disiloxycyclohexane5(174 mg, 0.40 mmol) in diethyl ether (2 mL) was added t-butyllithium (1.35 M / pentane solution, 0.65 mL, 0.88 mmol) at −78 ° C., and left at −78 ° C. for 1 hour. Stir.
Next, chlorotrimethylsilane (76 μL, 0.6 mmol) was added at −78 ° C., and the reaction solution was warmed to room temperature over 3 hours, followed by addition of a saturated aqueous ammonium chloride solution (4 mL).
Subsequently, extraction was performed twice with diethyl ether (3 mL), and the organic layer was dried (magnesium sulfate).
After filtration, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to obtain a compound.8Was obtained in 89% yield (153 mg).
11 H NMR (300 MHz, CDCl3) Δ 5.22 (s, 1H), 4.01-4.13 (m, 2H), 2.49 (dd, J = 3.6, 12.9 Hz, 1H), 2.32 (dd, J = 3.0, 13.2 Hz, 1H), 2.08-2.17 (m, 2H), 1.73-1.83 (m, 1H), 1.56-1.67 (m, 1H), 0.89 and 0.86 (2s, each 9H), 0.097 (s, 9H), 0.06 and 0.03 (2s, each 6H).
13C NMR (75 MHz, CDCl3) 152.3, 126.0, 68.1, 67.6, 47.9, 43.1, 42.8, 26.0, 25.8, 18.3, 0.5, -4.5, -4.59, -4.62, -4.7.
IR (neat) 2952, 2857, 1624, 1472, 1362, 1250, 1098, 1028, 836, 774, 691 cm-1.
[Example 6] Dibromomethylenecyclohexene oxide13Synthesis of
(In the formula, TBS represents a t-butyldimethylsilyl group.)
To a solution of carbon tetrabromide (830 mg, 2.5 mmol) in dichloromethane (3 mL) was added triphenylphosphine (1.31 g, 5.0 mmol) at 0 ° C., and the mixture was stirred at 0 ° C. for 5 min.
After adding 2-methyl-2-butene (1.4 mL, 12.5 mmol) and stirring for 5 minutes, 5-siloxy-2,3-epoxycyclohexanone3A solution of (242 mg, 1.0 mmol) in dichloromethane (3 mL) was added at 0 ° C., and the reaction was stirred for 30 minutes.
Thereafter, the reaction solution was diluted with hexane (30 mL) and filtered through celite.
The crude product of 1-dibromomethylene-5-siloxy-2,3-epoxycyclohexane obtained by concentrating the filtrate under reduced pressure was directly used in the next reaction.
11 H NMR (300 MHz, CDCl3) Δ 3.85-3.95 (m, 2H), 3.40-3.44 (m, 1H), 2.52 (dd, J = 3.6, 15.3 Hz, 1H), 2.28 ( dd, J = 4.5, 15.0 Hz, 1H), 2.11 (dd, J = 6.0, 15.3 Hz, 1H), 1.75 (ddd, J = 2.7, 7.8, 15.0 Hz, 1H), 0.87 (s, 9H), 0.061 (s, 3H), 0.05 (s, 3H).
13C NMR (75 MHz, CDCl3) 137.0, 93.6, 64.3, 54.6, 53.8, 39.2, 33.5, 25.8, 18.1, -4.66, -4.74.
Example 7 Optically Active Dioxycyclohexane Compound14Synthesis of
(In the formula, TBS represents a t-butyldimethylsilyl group.)
Under ice cooling, diisobutylaluminum hydride (0.96 M / hexane solution, hexane (5 mL) solution of 1-dibromomethylene-5-siloxy-2,3-epoxycyclohexane crude product obtained in Example 6 was added. 2.08 mL, 2.0 mmol) was added, and the mixture was stirred at 0 ° C. for 1 hour.
Water (0.36 mL) was carefully added to the reaction mixture at 0 ° C., and the mixture was stirred for 30 min. Sodium fluoride (1 g) and celite (1 g) were added, and the mixture was filtered through celite.
The crude product obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography to obtain 1-dibromomethylene-3-hydroxy-5-siloxycyclohexane in a yield of 74% (287 mg).
[Α]24 D= 10.68 (c1.47 CHCl3).
11 H NMR (300 MHz, CDCl3) Δ 4.80-4.20 (m, 2H), 2.73 (dd, J = 3.9, 13.5 Hz, 1H), 2.42-2.56 (m, 2H), 2.38 ( dd, J = 7.5, 13.5 Hz, 1H), 1.68-1.86 (m, 2H), 1.58 (s, 1H), 0.88 (s, 9H), 0.081 ( s, 3H), 0.064 (s, 3H).
13C NMR (75 MHz, CDCl3) 139.3, 85.8, 66.8, 66.6, 42.4, 42.2, 41.9, 25.7, 17.9, -5.07, -5.14.
IR (neat) 3350, 2928, 2856, 1470, 1254, 1103, 908, 837, 776 cm-1.
Anal. Calc. for C13H24Br2O2Si: C, 39.01; H, 6.04. Found: C, 38.91; H, 5.94.
To a solution of 1-dibromomethylene-3-hydroxy-5-siloxycyclohexane (272 mg, 0.7 mmol) obtained above and imidazole (95 mg, 1.4 mmol) in dimethylformamide (2 mL) at 0 ° C., t- Butyldimethylsilyl chloride (136 mg, 0.9 mmol) was added, and the mixture was stirred at room temperature for 12 hours.
Water (2 mL) was added, and the mixture was extracted 3 times with diethyl ether (6 mL). The organic layer is dried (anhydrous magnesium sulfate), filtered, and the filtrate is concentrated under reduced pressure. The resulting crude product is purified by silica gel column chromatography, and 1-dibromomethylene-3,5-disiloxycyclohexane is purified.14Was obtained in a yield of 96% (348 mg).
[Α]30 D= +2.27 (c1.21 CHCl3).
11 H NMR (300 MHz, CDCl3) Δ 4.06-4.14 (m, 2H), 2.56 (dd, J = 3.3, 13.5 Hz, 2H), 2.37 (dd, J = 7.2, 13.8 Hz, 2H) ), 1.69 (t, J = 5.4 Hz, 2H), 0.892 (s, 9H), 0.889 (s, 9H), 0.079 (s, 3H), 0.062 (s, 3H).
13C NMR (75 MHz, CDCl3) 139.9, 85.1, 67.0, 42.8, 42.5, 18.0, -5.08, -5.14.
IR (neat) 2928, 2856, 1471, 1362, 1256, 1092, 1027, 958, 838, 695 cm-1.
Anal. Calc. for C19H38Br2O2Si2: C, 44.36; H, 7.44. Found: C, 44.40; H, 7.45.
[Example 8] Optically active hydroxyethylenedioxycyclohexane compound1Synthesis of
(In the formula, TBS represents a t-butyldimethylsilyl group.)
1-bromomethylene-3,5-disiloxycyclohexane5To a solution of (40.3 mg, 0.1 mmol) in diethyl ether (1 mL) was added t-butyllithium (1.7 M / pentane solution, 0.14 mL, 0.24 mmol) at −78 ° C. over 1 hour— The temperature was raised to 20 ° C.
An excess amount of formaldehyde (diethyl ether solution) was added thereto, and then the temperature was raised to room temperature.
A saturated aqueous ammonium chloride solution was added, followed by extraction with diethyl ether, and the organic layer was dried (anhydrous magnesium sulfate).
After filtration, the crude product obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography to give 1- (2-hydroxyethylidene) -3,5-disiloxycyclohexane.1Was obtained in a yield of 52% (17.7 mg).
11 H NMR (300 MHz, CDCl3) Δ 5.60 (t, J = 7.2 Hz, vinylic), 3.95-4.20 (m, 4H, CHO and CH2O), 2.25-2.40 (m, 2H), 2.18 (dd, J = 3.3, 13.2 Hz, 1H, allic), 2.05 (dd, J = 8.1, 13 .2 Hz, 1 H, allic), 1.75-1.86 (m, 1 H), 1.69 (br s, 1 H, OH), 1.63 (dd, J = 3.0, 9.0 Hz, 1 H , CH2), 0.87 (s, 18H, t-Bu), 0.06 (s, 6H, SiCH)3), 0.05 and 0.04 (2s, each 3H, SiCH3).
13C NMR (75 MHz, CDCl3) D 138.2, 125.2, 68.1, 67.9, 58.4, 45.6, 43.4, 36.6, 25.9, 18.2, -4.57, -4. 66, -4.70, -4.74.
IR (neat) 3367, 2928, 2856, 1654, 1472, 1361, 1253, 1109, 1084, 1082, 835, 774 cm-1.
[Example 9] Optically active dioxycyclohexane compound15Synthesis of
(In the formula, TBS represents a t-butyldimethylsilyl group. Bu represents an n-butyl group.)
1-bromomethylene-3,5-disiloxycyclohexane5(348 mg, 0.80 mmol) in diethyl ether (3 mL) was added t-butyllithium (1.35 M / pentane solution, 1.30 mL, 1.76 mmol) at −78 ° C., and left at −78 ° C. for 1 hour. Stir.
Subsequently, chlorotri-n-butyltin (0.434 mL, 1.2 mmol) was added at −78 ° C., and the reaction solution was warmed to room temperature over 3 hours.
After adding saturated sodium bicarbonate water (10 mL), the reaction solution was extracted twice with hexane (10 mL), and the organic layer was dried (magnesium sulfate).
After filtering the magnesium sulfate, the crude product obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography to give a compound.15Was obtained in a yield of 93% (481 mg).
11 H NMR (CDCl3) Δ 5.47 (s, 1H), 3.99-4.13 (m, 2H), 2.33-2.40 (m, 2H), 2.22 (dd, J = 3.9, 13. 5Hz, 1H), 2.11 (dd, J = 9.6, 12.9Hz, 1H), 1.82-1.90 (m, 1H), 1.43-1.61 (m, 7H), 1.24-1.38 (m, 6H), 0.78-1.06 (m, 6H), 0.89 (t, J = 8.1 Hz, 9H), 0.90 (s, 18H), 0.067 and 0.062 (2s, each 3H), 0.030 (s, 6H);
13C NMR (CDCl3) 152.1, 124.1, 68.3, 67.7, 47.1, 46.5, 43.1, 29.3, 27.4, 26.0, 25.8, 18.2, 18 1, 13.8, 10.3, -4.5, -4.6, -4.8;
IR (neat) 2926, 2862, 1613, 1463, 1376, 1361, 1255, 1099, 836, 775, 691;
[Α]25 D-14.3 (c7.90, CHCl3) ;.
Anal. Calcd. for C31H66O2Si2Sn: C, 57.66; H, 10.30. Found: C, 57.28; H, 10.32.
Example 10 Optically Active Dioxycyclohexane Compound6Synthesis of
A 50 mL Schreaker reaction tube (manufactured by Aldrich) was charged with PS-DES resin (manufactured by Argonaut, 0.6 to 1.0 mmol / g, 1.00 g), dried under reduced pressure for 30 minutes, and then purged with argon.
To this was added a solution of 1,3-dichloro-5,5-dimethylhydantoin (443 mg, 2.25 mmol) in methylene chloride (11 mL), and the mixture was slowly stirred at room temperature for 2 hours.
The reaction solution was filtered under argon, and the resulting resin was washed 3 times with methylene chloride (20 mL) and 3 times with THF (20 mL), and then dried under reduced pressure.
Subsequently, in a reaction tube containing the resin, methylene chloride of 1-bromomethylene-3-hydroxy-5-siloxycyclohexane (723 mg, 2.25 mmol) and imidazole (180 mg, 2.63 mmol) obtained in Example 3 was used. (25 mL) solution was added and stirred slowly at room temperature for 4 hours.
The reaction solution was filtered, and the resulting resin was washed twice with ether (18 mL).
The filtrate was washed twice with water (20 mL), the organic layer was dried (magnesium sulfate), the magnesium sulfate was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was treated with silica gel column chromatography. The starting material 1-bromomethylene-3-hydroxy-5-siloxycyclohexane (382 mg, 1.19 mmol) was recovered.
The resin was washed three times with THF-water (3/1 (v / v), 12 mL), twice with ethanol (12 mL), and further twice with ether (18 mL), and then dried overnight under reduced pressure. A solid-supported optically active vinylidenecyclohexane compound 5 having a base resin terminal was obtained in a yield of 90% (1.31 g) based on the recovered material.
The obtained resin was loaded by decomposing the resin with hydrofluoric acid-pyridine,1It was determined to be 0.738 mmol / g by analysis by HNMR.
That is, a syringe type PP reactor (EYELA RT5-S100, manufactured by Rika Takeda) was charged with resin (144 mg) and THF (3 mL), and hydrofluoric acid-pyridine (0.1 mL) was added thereto, and this was performed at room temperature. Stir for hours.
1,4-Dibromobenzene (25.6 mg) was added to the reaction solution as an internal standard substance, and then filtered with THF (3 mL).
Ethyl acetate (4 mL) was added to the filtrate, washed with saturated aqueous sodium hydrogen carbonate (3 mL), and further extracted twice with ethyl acetate (3 mL) from the aqueous layer.
The combined organic layers were dried (magnesium sulfate), filtered through magnesium sulfate, and the filtrate was concentrated under reduced pressure to give a residue.1Analyzed by HNMR.
As a result, bromomethylenecyclohexanediol was 0.1063 mmol, and the resin loading was calculated to be 0.738 mmol / g.
According to the present invention, 19-nor-active vitamin D derivatives and active vitamin D3By using an optically active dioxycyclohexane compound, an optically active hydroxyethylenedioxycyclohexane compound, which is an important intermediate when producing a derivative, can be produced relatively easily and efficiently.
Claims (6)
(式中、Rはハロゲン原子、置換シリル基、置換ホウ素基または置換スズ基を表す。XおよびYは水素原子、水酸基の保護基または該保護基を末端に有する固相を表す。)
で表されることを特徴とする光学活性ジオキシシクロヘキサン化合物またはその鏡像体。The following general formula (1)
(In the formula, R represents a halogen atom, a substituted silyl group, a substituted boron group or a substituted tin group. X and Y represent a hydrogen atom, a hydroxyl protecting group or a solid phase having the protecting group at the end.)
An optically active dioxycyclohexane compound or an enantiomer thereof, characterized by:
(式中、R′およびR″は互いに独立して置換アルキル基、ハロゲン原子、置換シリル基、置換ホウ素基または置換スズ基を表す。XおよびYは水素原子、水酸基の保護基または該保護基を末端に有する固相を表す。)
で表されることを特徴とする光学活性ジオキシシクロヘキサン化合物またはその鏡像体。The following general formula (2)
(In the formula, R ′ and R ″ each independently represents a substituted alkyl group, a halogen atom, a substituted silyl group, a substituted boron group or a substituted tin group. X and Y are a hydrogen atom, a hydroxyl protecting group or the protecting group. Represents a solid phase having a terminal.)
An optically active dioxycyclohexane compound or an enantiomer thereof, characterized by:
(式中、Rはハロゲン原子、置換シリル基、置換ホウ素基または置換スズ基を表す。XおよびYは水素原子、水酸基の保護基または該保護基を末端に有する固相を表す。)
で表される光学活性ジオキシシクロヘキサン化合物に、ヒドロキシメチル化反応を行い、下記一般式(3)
(式中、XおよびYは水素原子、水酸基の保護基または該保護基を末端に有する固相を表す。)
で表される化合物を得ることを特徴とする光学活性ヒドロキシエチレンジオキシシクロヘキサン化合物の製造方法。The following general formula (1)
(In the formula, R represents a halogen atom, a substituted silyl group, a substituted boron group or a substituted tin group. X and Y represent a hydrogen atom, a hydroxyl protecting group or a solid phase having the protecting group at the end.)
A hydroxymethylation reaction is performed on the optically active dioxycyclohexane compound represented by the following general formula (3):
(Wherein X and Y represent a hydrogen atom, a protecting group for a hydroxyl group, or a solid phase having the protecting group at the end)
A process for producing an optically active hydroxyethylenedioxycyclohexane compound, characterized in that:
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