JP2709807B2 - Process for producing 3-chloro-4-silyloxy-2-cyclopenten-1-ones - Google Patents
Process for producing 3-chloro-4-silyloxy-2-cyclopenten-1-onesInfo
- Publication number
- JP2709807B2 JP2709807B2 JP8327444A JP32744496A JP2709807B2 JP 2709807 B2 JP2709807 B2 JP 2709807B2 JP 8327444 A JP8327444 A JP 8327444A JP 32744496 A JP32744496 A JP 32744496A JP 2709807 B2 JP2709807 B2 JP 2709807B2
- Authority
- JP
- Japan
- Prior art keywords
- chloro
- cyclopenten
- silyloxy
- formula
- cis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- NVTFHZSUAGTHCY-UHFFFAOYSA-N 3-chloro-4-silyloxycyclopent-2-en-1-one Chemical class ClC1=CC(CC1O[SiH3])=O NVTFHZSUAGTHCY-UHFFFAOYSA-N 0.000 title claims description 8
- 238000000034 method Methods 0.000 title description 9
- 239000000203 mixture Substances 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000006239 protecting group Chemical group 0.000 claims description 5
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 10
- -1 triethylsilyl Chemical group 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- 108090000371 Esterases Proteins 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 229940088598 enzyme Drugs 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 description 6
- WHGMARMOSLBUAP-UHFFFAOYSA-N CC(=O)OC1CC(C(=C1)Cl)O[SiH3] Chemical compound CC(=O)OC1CC(C(=C1)Cl)O[SiH3] WHGMARMOSLBUAP-UHFFFAOYSA-N 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 150000003208 punaglandins Chemical class 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 108090000604 Hydrolases Proteins 0.000 description 4
- 102000004157 Hydrolases Human genes 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 241000228212 Aspergillus Species 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- JJYKJUXBWFATTE-UHFFFAOYSA-N mosher's acid Chemical compound COC(C(O)=O)(C(F)(F)F)C1=CC=CC=C1 JJYKJUXBWFATTE-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- MXXLYYREABZMBI-UHFFFAOYSA-N (3-chloro-4-hydroxycyclopent-2-en-1-yl) acetate Chemical compound CC(=O)OC1CC(O)C(Cl)=C1 MXXLYYREABZMBI-UHFFFAOYSA-N 0.000 description 2
- HSQFVBWFPBKHEB-UHFFFAOYSA-N 2,3,4-trichlorophenol Chemical compound OC1=CC=C(Cl)C(Cl)=C1Cl HSQFVBWFPBKHEB-UHFFFAOYSA-N 0.000 description 2
- NZCDMVXFZYESRK-UHFFFAOYSA-N 2-silyloxycyclopent-2-en-1-one Chemical class [SiH3]OC1=CCCC1=O NZCDMVXFZYESRK-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- NVTFHZSUAGTHCY-RXMQYKEDSA-N C1[C@H](C(=CC1=O)Cl)O[SiH3] Chemical class C1[C@H](C(=CC1=O)Cl)O[SiH3] NVTFHZSUAGTHCY-RXMQYKEDSA-N 0.000 description 2
- 229910004664 Cerium(III) chloride Inorganic materials 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000235648 Pichia Species 0.000 description 2
- 101001134452 Sus scrofa Pancreatic triacylglycerol lipase Proteins 0.000 description 2
- 241001395202 Telesto Species 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- RRKTZKIUPZVBMF-IBTVXLQLSA-N brucine Chemical compound O([C@@H]1[C@H]([C@H]2C3)[C@@H]4N(C(C1)=O)C=1C=C(C(=CC=11)OC)OC)CC=C2CN2[C@@H]3[C@]41CC2 RRKTZKIUPZVBMF-IBTVXLQLSA-N 0.000 description 2
- RRKTZKIUPZVBMF-UHFFFAOYSA-N brucine Natural products C1=2C=C(OC)C(OC)=CC=2N(C(C2)=O)C3C(C4C5)C2OCC=C4CN2C5C31CC2 RRKTZKIUPZVBMF-UHFFFAOYSA-N 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- VYLVYHXQOHJDJL-UHFFFAOYSA-K cerium trichloride Chemical compound Cl[Ce](Cl)Cl VYLVYHXQOHJDJL-UHFFFAOYSA-K 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000010575 fractional recrystallization Methods 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- FNNGVFSPTDIHJP-UHFFFAOYSA-N (3-chloro-4-oxocyclopent-2-en-1-yl) acetate Chemical compound CC(=O)OC1CC(=O)C(Cl)=C1 FNNGVFSPTDIHJP-UHFFFAOYSA-N 0.000 description 1
- YNCKAQVPQJWLJW-UHFFFAOYSA-N (4-oxocyclopent-2-en-1-yl) acetate Chemical compound CC(=O)OC1CC(=O)C=C1 YNCKAQVPQJWLJW-UHFFFAOYSA-N 0.000 description 1
- DARXTDHGVADBRO-SNVBAGLBSA-N (4r)-4-[tert-butyl(dimethyl)silyl]oxy-3-chlorocyclopent-2-en-1-one Chemical compound CC(C)(C)[Si](C)(C)O[C@@H]1CC(=O)C=C1Cl DARXTDHGVADBRO-SNVBAGLBSA-N 0.000 description 1
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 1
- RJQBGNKWXCSKTG-UHFFFAOYSA-N 4-[tert-butyl(dimethyl)silyl]oxy-2-chlorocyclopent-2-en-1-one Chemical compound CC(C)(C)[Si](C)(C)OC1CC(=O)C(Cl)=C1 RJQBGNKWXCSKTG-UHFFFAOYSA-N 0.000 description 1
- DARXTDHGVADBRO-UHFFFAOYSA-N 4-[tert-butyl(dimethyl)silyl]oxy-3-chlorocyclopent-2-en-1-one Chemical compound CC(C)(C)[Si](C)(C)OC1CC(=O)C=C1Cl DARXTDHGVADBRO-UHFFFAOYSA-N 0.000 description 1
- HSYSCPBUWMIKMI-UHFFFAOYSA-N 4-silyloxycyclopent-2-en-1-one Chemical compound [SiH3]OC1CC(=O)C=C1 HSYSCPBUWMIKMI-UHFFFAOYSA-N 0.000 description 1
- 241000235389 Absidia Species 0.000 description 1
- 108010022752 Acetylcholinesterase Proteins 0.000 description 1
- 102000012440 Acetylcholinesterase Human genes 0.000 description 1
- 241000590020 Achromobacter Species 0.000 description 1
- 241000908198 Actinomucor Species 0.000 description 1
- 241000223651 Aureobasidium Species 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000186146 Brevibacterium Species 0.000 description 1
- HWXKQIPKEXKNJK-UHFFFAOYSA-N C1CC(C(=C1)Cl)O[SiH3] Chemical class C1CC(C(=C1)Cl)O[SiH3] HWXKQIPKEXKNJK-UHFFFAOYSA-N 0.000 description 1
- NVTFHZSUAGTHCY-YFKPBYRVSA-N C1[C@@H](C(=CC1=O)Cl)O[SiH3] Chemical class C1[C@@H](C(=CC1=O)Cl)O[SiH3] NVTFHZSUAGTHCY-YFKPBYRVSA-N 0.000 description 1
- WHGMARMOSLBUAP-VDTYLAMSSA-N CC(=O)O[C@H]1C[C@@H](C(=C1)Cl)O[SiH3] Chemical compound CC(=O)O[C@H]1C[C@@H](C(=C1)Cl)O[SiH3] WHGMARMOSLBUAP-VDTYLAMSSA-N 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 241000588881 Chromobacterium Species 0.000 description 1
- 241001337994 Cryptococcus <scale insect> Species 0.000 description 1
- 241000195493 Cryptophyta Species 0.000 description 1
- 241000371644 Curvularia ravenelii Species 0.000 description 1
- BZKFMUIJRXWWQK-UHFFFAOYSA-N Cyclopentenone Chemical class O=C1CCC=C1 BZKFMUIJRXWWQK-UHFFFAOYSA-N 0.000 description 1
- 241000178951 Endomyces Species 0.000 description 1
- 241000588722 Escherichia Species 0.000 description 1
- 241000589565 Flavobacterium Species 0.000 description 1
- 241000159512 Geotrichum Species 0.000 description 1
- 108010093096 Immobilized Enzymes Proteins 0.000 description 1
- 241000186660 Lactobacillus Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- 241000235395 Mucor Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- PCVZYBAHORNORZ-WUJLRWPWSA-N O[C@@H](C[C@@H]1O[SiH3])C=C1Cl Chemical class O[C@@H](C[C@@H]1O[SiH3])C=C1Cl PCVZYBAHORNORZ-WUJLRWPWSA-N 0.000 description 1
- 241000192001 Pediococcus Species 0.000 description 1
- 241000228143 Penicillium Species 0.000 description 1
- 241000223252 Rhodotorula Species 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 241000223259 Trichoderma Species 0.000 description 1
- NQFXCLQVFRWOLD-UHFFFAOYSA-N [4-[tert-butyl(dimethyl)silyl]oxy-3-chlorocyclopent-2-en-1-yl] acetate Chemical compound CC(=O)OC1CC(O[Si](C)(C)C(C)(C)C)C(Cl)=C1 NQFXCLQVFRWOLD-UHFFFAOYSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 229940022698 acetylcholinesterase Drugs 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- XTKDAFGWCDAMPY-UHFFFAOYSA-N azaperone Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCN(C=2N=CC=CC=2)CC1 XTKDAFGWCDAMPY-UHFFFAOYSA-N 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- NWZXFAYYQNFDCA-UHFFFAOYSA-N cyclopenten-1-ol Chemical class OC1=CCCC1 NWZXFAYYQNFDCA-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 150000002617 leukotrienes Chemical class 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 125000001244 punaglandin group Chemical group 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 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
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 239000003021 water soluble solvent Substances 0.000 description 1
Description
【発明の詳細な説明】
【0001】
【発明の属する技術分野】本発明は、3−クロロ−4−
シリルオキシ−2−シクロペンテン−1−オン類の新規
な製造方法に関する。さらに詳しくは、優れた制癌作
用、抗ウイルス作用を有するプナグランジン類を製造す
るにあたり、有用な化合物となり得る3−クロロ−4−
シリルオキシ−2−シクロペンテン−1−オン類の製造
方法に関する。
【0002】
【従来の技術】近年、オアフ島で採集された舟底に着生
するテレスト・リイーセイ(Telesto riis
ei)からプロスタグランジン類縁物質であるプナグラ
ンジンが単離された〔月刊薬事、24巻、41頁(19
86);ショイヤーら、J.Am.Chem.So
c.,107,2976(1985)〕。その立体構造
は、最近下記式で表わされることが判明した。
【0003】
【化3】
【0004】〔野依ら、J.Am.Chem.So
c.,108,5021(1986);山田ら、J.A
m.Chem.Soc.,108,5019(198
6)〕。プナグランジン類は生理作用として制癌作用を
有することが知られている〔福島ら、第43回日本癌学
会要旨集、905頁(1984);アドバンスズ イン
プロスタグランジン トロンボキサン アンド ロイコ
トリエン リサーチ、15巻、415頁(1985)、
レーバン プレス(ニューヨーク)発行〕。プナグラン
ジン類の合成に関しては、代表的なものとして<スキー
ム1>に示すルートが知られている〔野依ら、J.A
m.Chem.Soc.,108,5021(198
6)〕。それによれば、プナグランジン(5)は光学活
性な(4R)−3−クロロ−4−tert−ブチルジメ
チルシリルオキシ−2−シクロペンテン−1−オン
(1)に、ω側鎖、α側鎖を順次結合することにより得
られている。また、プナグランジン(5)の12位の不
斉は化合物(1)の4位の不斉より誘導されている。故
にプナグランジン(5)の合成において光学活性な3−
クロロ−4−tert−ブチルジメチルシリルオキシ−
2−シクロペンテン−1−オンは、プナグランジン類の
極めて重要な合成中間体と言える。
【0005】
【化4】
【0006】本発明者らはかかる点に着目し、光学活性
な3−クロロ−4−シリルオキシ−2−シクロペンテン
−1−オン類や、4−シリルオキシ−2−シクロペンテ
ン−1−オンの合成に関し鋭意研究を重ねた結果、本発
明に到達したものである。
【0007】従来、光学活性な3−クロロ−4−シリル
オキシ−2−シクロペンテン−1−オンの合成法として
は、テトラヘドロン レタース、17巻、1539〜1
542頁(1979)に記載の方法が知られている。<
スキーム2>
【0008】
【化5】
【0009】すなわち、トリクロロフェノール(6)よ
り得られる3,5,5−トリクロロ−1,4−ジヒドロ
キシシクロペント−1−カルボン酸(7)を(−)−ブ
ルシンとの塩とし、この塩の分別再結晶によって(1
S,4S)−トリクロロ−1,4−ジヒドロキシシクロ
ペント−1−カルボン酸を得る。これより3工程にて
(4R)−3−クロロ−4−シリルオキシ−2−シクロ
ペンテン−1−オン類としている。しかしながら、この
方法は化合物(6)から化合物(7)への収率が低く、
ブルシンという高価な試薬を使っての分別再結晶という
繁雑な操作を必要とする。又、化合物(10)及び(1
1)は極めて不安定である。以上のことより、プナグラ
ンジン類の重要合成中間体である光学活性な3−クロロ
−4−シリルオキシ−2−シクロペンテン−1−オンを
大量に得ることは従来非常に困難であった。
【0010】
【発明が解決しようとする課題】本発明者らは、プナグ
ランジン類の有用な合成中間体である光学活性な3−ク
ロロ−4−シリルオキシ−2−シクロペンテン−1−オ
ンを安価に工業的に製造し得る方法について鋭意検討を
重ねた結果、本発明に到達した。
【0011】
【課題を解決するための手段】本発明においては、式
[I]で表わされるシス−3−クロロ−4−シリルオキ
シ−2−シクロペンテン−1−オール類
【0012】
【化6】
【0013】(式中、R1は水酸基の保護基であるシリ
ル基を表わし、*は不斉中心を表わし、これに由来する
立体異性体が存在するが、本発明においては(1S,4
R)であるか、(1R,4S)、または両者の任意の割
合の混合物である。)を酸化することにより、式[II
I]、
【0014】
【化7】
【0015】(式中、R1は水酸基の保護基であるシリ
ル基を表わし、*は不斉中心を表わし、これに由来する
立体異性体が存在するが、本発明においては4Rである
か、4S、または両者の任意の割合の混合物である。)
で表わされる3−クロロ−4−シリルオキシ−2−シク
ロペンテン−1−オン類を効率よく製造することができ
る。化合物[I]及び[III]において、R1は水酸
基の保護基であるシリル基を表わすが、その具体例とし
ては、トリメチルシリル、トリエチルシリル、イソプロ
ピルジメチルシリル、tert−ブチルジメチルシリ
ル、(フェニルジメチルメチル)ジメチルシリル、(ト
リフェニルメチル)ジメチルシリル、tert−ブチル
ジフェニルシリル、メチルジイソプロピルシリル、メチ
ルジtert−ブチルシリル、トリベンジルシリル、ト
リ−p−キシリルシリル、トリイソプロピルシリル、ト
リフェニルシリル等がある。これらのうち、tert−
ブチルジメチルシリルが特に好ましい。
【0016】化合物[I]より[III]への酸化反応
は、ピリジニウムクロロクロメート(PCC)、あるい
はピリジニウムジクロメート(PDC)を用いて、塩化
メチレンあるいは、ジメチルホルムアミド中、必要なら
ばモレキュラーシーブスを加えて行うことができる。P
CCあるいはPDCの使用量は、式[I]で表わされる
シス−3−クロロ−4−シリルオキシ−2−シクロペン
テン−1−オール類に対して等モル〜7倍モル、好まし
くは2〜4倍モルである。PCCを用いるか、PDCを
用いるかは、シリル保護基の安定性により、適宜、選択
する。溶媒の使用量は、DMFを用いる場合には、PD
Cの3〜10倍容が好ましい。塩化メチレンを用いる場
合には、PCCの10〜15倍容が好ましい。また、溶
媒として、塩化メチレンを用いる場合には、モレキュラ
ーシーブス4Aを加えるのが好ましく、その使用量はP
CCの等量〜2倍量が好ましい。反応温度は、PCCを
用いる場合も、PDCを用いる場合も、0〜10℃が好
ましい。反応時間は、上記式[I]のシリルエーテルで
の種類によって異なるが、通常1〜20時間の範囲で行
われ、好ましくは、1〜5時間である。
【0017】反応終了後、抽出用有機溶媒、たとえば、
ジエチルエーテルで反応液を希釈し、水洗、乾燥、濃縮
乾固する。乾固して得られたものは、カラムクロマトグ
ラフイ等で精製、分離される。かくして、上記式[II
I]で表わされるプナグランジン類の合成において有用
な化合物となる3−クロロ−4−シリルオキシ−2−シ
クロペンテン−1−オン類が効率よく得られる。本発明
において、光学活性な(1S,4R)−シス−3−クロ
ロ−4−シリルオキシ−2−シクロペンテン−1−オー
ルからは、光学活性な(4R)−3−クロロ−4−シリ
ルオキシ−2−シクロペンテン−1−オン類が得られ
る。又、(1R,4S)−シス−3−クロロ−4−シリ
ルオキシ−2−シクロペンテン−1−オールからは、光
学活性な(4S)−3−クロロ−4−シリルオキシ−2
−シクロペンテン−1−オン類が得られる。天然型プナ
グランジン類は(4R)−3−クロロ−4−シリルオキ
シ−2−シクロペンテン−1−オン類から<スキーム1
>に示した方法により合成できるが、類縁体合成上、
(4S)−3−クロロ−4−シリルオキシ−2−シクロ
ペンテン−1−オン類も重要な化合物である。
【0018】なお、本発明において、式[I]の化合物
は、式[II]で表わされる3−アセトキシ−5−シリ
ルオキシ−1−クロロシクロペンテン類
【0019】
【化8】
【0020】(式中、R1は前記の定義の通りである)
を、加水分解酵素を用いて不斉加水分解し得ることがで
きる。すなわち、シス体のどちらか一方の光学活性体と
して、あるいは、シス体の両者の任意の割合の混合物と
して、シス−3−クロロ−4−シリルオキシ−2−シク
ロペンテン−1−オール類を得ることができる。トラン
ス−3−アセトキシ−5−シリルオキシ−1−クロロー
シクロペンテン類は加水分解されずに残る。加水分解酵
素としては、例えば、肝臓エステラーゼ、すい臓エステ
ラーゼ、アセチルコリンエステラーゼ等の動物エステラ
ーゼ、あるいは植物エステラーゼ、が挙げられ、さらに
は以下に示す各属に属する微生物や地衣類、藻類などの
微生物より得られる加水分解酵素が挙げられる。
【0021】Rhodotorula、Trichod
erma、Candida、Hansenula、Ps
eudomonas、Bacillus、Nocard
ia、Achromobacter、Chromoba
cterium、Flavobacterium、Rh
izopus、Mucor、Aspergillus、
Alkaligenes、Torulopsis、Co
rynebacterium、Endomyces、S
accharomyces、Arthrobacte
r、Helminthosporium、Brevib
acterium、Escherichia、Citr
obacter、Absidia、Micrococc
us、Pediococcus、Klebsiell
a、Geotrichum、Lactobacillu
s、Cryptococcus、Pichia、Aur
eobasidium、Actinomucor、En
terobacter、Microbacteriu
m、Penicillium、Schizophyll
um。
【0022】用いられる加水分解酵素の使用形態として
は、精製酵素、粗酵素、酵素含有物、微生物培養液、培
養物、菌体、培養ロ液、またはそれらを処理した物など
で、必要に応じ種々の形態で用いることができる。ま
た、樹脂に固定化して、固定化酵素として用いることが
できる。不斉加水分解反応は、式[II]で表わされる
3−アセトキシ−5−シリルオキシ−1−クロロ−シク
ロペンテン類と、上記の加水分解酵素、好ましくは豚肝
臓エステラーゼ、豚すい臓リパーゼ、Pseudomo
nas由来の精製又は粗酵素、Aspergillus
由来の精製又は粗酵素を、通常緩衝液中、又は有機溶媒
と緩衝液の混合液中、必要ならば界面活性剤を加えて激
しく攪拌することにより行うことができる。
【0023】また、光学活性な(1S,4R)−シス−
3−クロロ−4−シリルオキシ−2−シクロペンテン−
1−オール類を得る場合は、豚すい臓エステラーゼを用
いるのが特に好ましく、(1R,4S)−シス−3−ク
ロロ−4−シリルオキシ−2−シクロペンテン−1−オ
ール類を得る場合は、豚肝臓エステラーゼを用いるのが
特に好ましい。
【0024】有機溶媒と緩衝液の混合液を用いる場合に
使用される有機溶媒は、通常水溶性の溶媒、例えばメタ
ノール、エタノール等のアルコール類、アセトン、メチ
ルエチルケトン等のケトン類、アセトニトリル、プロピ
オニトリル等のニトリル類などが使用できる。緩衝液は
リン酸ナトリウム、リン酸カリウム、クエン酸ナトリウ
ム等の通常用いられる緩衝液が使用できる。反応温度は
−10℃〜+30℃、反応時間は2〜50時間が好まし
いが、これに限定されるものではない。
【0025】反応終了後、加水分解反応液を必要に応じ
てろ過し、メチルイソブチルケトン、酢酸エチル、ジエ
チルエーテル、ジクロロメタン等の有機溶媒により抽出
し、有機層を濃縮カラムクロマト精製を行うことによ
り、目的とするシス−3−クロロ−4−シリルオキシ−
2−シクロペンテン−1−オール類を得ることができ
る。なお、シス−3−クロロ−4−シリルオキシ−2−
シクロペンテン−1−オール類の光学純度は、対応する
α−メトキシ−α−トリフルオロメチルフェニル酢酸
(MTPA)エステルの、400MHzNMRスペクト
ルから決定した。また、トランス−3−クロロ−4−シ
リルオキシ−2−シクロペンテン−1−オール類が不斉
加水分解物中に混入していないことは、やはりMTPA
エステルとして、高速液体クロマトグラフィーにより確
認した。
【0026】なお、式[II]で表わされる3−アセト
キシ−5−シリルオキシ−1−クロロシクロペンテン類
は、<スキーム3>で表わされる方法で合成できる。す
なわち、既知の方法(特開昭57−62236号公報)
により得られる4−ヒドロキシ−2−シクロペンテン−
1−オン(12)を、アセチル化後、塩素の付加とHC
lの脱離を行い、4−アセトキシ−2−クロロ−2−シ
クロペンテン−1−オン(14)とする。次いで、3塩
化セリウム存在下、メタノール中水素化ホウ素ナトリウ
ムで還元し、2−クロロ−4−アセトキシ−2−シクロ
ペンテン−1−オールを得る。このものを適当な塩基の
存在下、トリアルキルクロロシランによってアルコール
部分をシリルエーテルにすることにより得ることができ
る。化合物(13)、(14)、(15)および式[I
I]で表わされる3−アセトキシ−5−シリルオキシ−
1−クロロシクロペンテン類はいずれも安定な化合物で
あり、収率よく得ることができるものである。
【0027】
【化9】
【0028】式[II]で表わされる3−アセトキシ−
5−シリルオキシ−1−クロロシクロペンテン類にはそ
の3位と5位に2つの不斉炭素が存在し、(3S,5
R)と(3R,5S)のシス体、および(3S,5S)
と(3R,5R)のトランス体がある。<スキーム3>
の方法によって得られる式[II]で表わされる3−ア
セトキシ−5−シリルオキシ−1−クロロシクロペンテ
ン類は、それら4つの立体異性体の混合物である。
【0029】
【発明の実施の形態】以下、実施例により本発明を詳細
に説明する。
参考例1
4−アセトキシ−2−クロロ−2−シクロペンテン−1
−オン
4−ヒドロキシ−2−シクロペンテン−1−オン30.
2g(0.308モル)をTHF1500mlに溶解
し、無水酢酸47.2g(0.462モル)と、酢酸ソ
ーダ50.5g(0.616モル)を加え、35℃で1
5時間攪拌した。反応液に冷水300mlを加え、酢酸
エチル200mlで3回抽出した。抽出液を10%−食
塩水100mlで洗浄後、無水硫酸マグネシウムで乾燥
した。ろ過後、減圧濃縮して4−アセトキシ−2−シク
ロペンテン−1−オンを37.9g得た。これをエーテ
ル540mlに溶解し、室温で塩素を吹き込んだ。反応
が完結するまで90分間を要した。チッ素を吹き込ん
で、過剰の塩素を除いた後、トリエチルアミン100m
lを5〜15℃でゆっくりと滴下した。反応液に10%
−塩化アンモニウム水溶液500mlを加え、分液し
た。水層はエーテル300mlで2回抽出した。抽出液
を10%−食塩水300ml、2N−塩酸500ml、
10%−食塩水300mlで洗浄し、無水硫酸マグネシ
ウムで乾燥した。ろ過後、減圧濃縮して目的物の粗結晶
47.0gを得た。エーテル−ヘキサンより再結晶して
27.0gの無色の結晶を得た。
【0030】収率 50%、融点 55℃。
NMR(CDCl3)δH=(60MHz):2.08
(3H,s),2.36(1H,dd,J=2.0 a
nd 18.0Hz),2.93(1H,dd,J=
6.4 and 18.0Hz),5.75(1H,
m),7.50(1H,d,J=3.0Hz)。
IR(film)ν(neat):1740(s)、1
610(m)、1400(m)、1378(m)、13
46(m)、1290(m)、1240(s)、117
0(m)、1036(m)、976(m)、957
(m)cm−1。
【0031】参考例2
3−アセトキシ−5−tert−ブチルジメチルシリル
オキシ−1−クロロシクロペンテン
4−アセトキシ−2−クロロ−2−シクロペンテン−1
−オン27.0g(0.155モル)を、メタノール7
50mlに溶解した。塩化第一セリウム63.7g
(0.171モル)を加え、水素化ホウ素ナトリウム
6.4g(0.169モル)を数回に分けて、22〜2
5℃で加えた。20〜23℃で20分間攪拌した後、飽
和塩化アンモニウム水溶液150mlを加え、減圧濃縮
した。濃縮残分に0.5N−塩酸400mlを加え、エ
ーテル300mlで3回抽出した。抽出液を飽和食塩水
で洗浄後、硫酸マグネシウムで乾燥した。ろ過後、減圧
濃縮して、4−アセトキシ−2−クロロ−2−シクロペ
ンテン−1−オールを22.4g得た。これをDMF2
20mlに溶解し、tert−ブチルジメチルクロロシ
ラン24.0g(0.159モル)、イミダゾール1
3.0g(0.191モル)を加え、室温で5時間攪拌
した。水1100mlを加え、エーテル200mlで4
回抽出した。抽出液を飽和食塩水で洗浄後、硫酸マグネ
シウムで乾燥した。ろ過後、減圧濃縮して、淡黄色オイ
ルを47g得た。シリカゲルカラムクロマトで精製して
目的とする化合物32.3gを無色のオイルで得た。
(収率71%)
【0032】n24 D=1.4604。NMR(CDC
l3)δH=(60MHz):0.11(6H,s),
0.91(9H,s),2.01 and 2.03
(3H,s),4.50 and 4.82(1H,
m),5.17〜5.77(1H,m),5.87(1
H,m)。
IR(film)ν(neat):1750(s)、1
634(m)、1480(m)、1470(m)、14
50(m)、1370(m)、1242(s)、113
5(m)、1082(m)、1030(m)、950
(m)、861(m)、839(m)、779(m)c
m−1。
【0033】参考例3
4−tert−ブチルジメチルシリルオキシ−3−クロ
ロ−2−シクロペンテン−1−オール
3−アセトキシ−5−tert−ブチルジメチルシリル
オキシ−1−クロロシクロペンテン30.0g(0.1
03モル)を、メタノール600mlに溶解した。pH
=7のリン酸緩衝液1800ml、豚すい臓リパーゼ1
5.0gを加え、15℃で12時間攪拌した。加水分解
液をエーテル1000mlで3回抽出し、硫酸マグネシ
ウムで乾燥した。ろ過した後、減圧濃縮して、無色のオ
イル29.0gを得た。シリカゲルカラムクロマトで精
製分離し、トランスの原料アセテートとシス(1R,4
S)の原料アセテートとの混合物21.2g回収した。
目的とするシス(1S,4R)の化合物を、無色のオイ
ルで6.4g得た。
【0034】収率25.0%。
[α]25 D=−31.7゜(C=0.75,MeO
H)
光学純度=95%ee以上。n25 D=1.4711。
NMR(CDCl3)δH=(100MHz):0.1
3(3H,s),0.15(3H,s),0.93(9
H,s),1.61(1H,t,J=4.3Hz),
1.74(1H,t,J=4.3Hz),2.80(1
H,dt,J=7.0 and 14.2Hz),4.
48(1H,dd,J=4.3 and7.0Hz),
5.94(1H,d,J=2.6Hz)。
IR(film)ν(neat):3370(s)、1
630(m)、1478(m)、1467(m)、13
65(m)、1259(s)、1172(m)、113
2(s)、1086(s)、1030(s)、1004
(m)、941(m)、861(s)、840(s)、
800(m)、780(m)cm−1。
【0035】実施例1
4−tert−ブチルジメチルシリルオキシ−3−クロ
ロ−2−シクロペンテン−1−オン
参考例3で得た(1S,4R)−シス−3−クロロ−4
−tert−ブチルジメチルシリルオキシ−2−シクロ
ペンテン−1−オール5.10g(20.5ミリモル)
をDMF100mlに溶解した。5℃に冷却し、ピリジ
ニウムジクロメート27.0g(71.8ミリモル)を
加えた。5℃で3時間攪拌した。反応液に水600ml
を加え、ヘキサン100mlで3回抽出した。抽出液を
10%食塩水で洗浄し、硫酸マグネシウムで乾燥した。
ろ過した後、減圧濃縮して、淡黄色オイルを得た。シリ
カゲルカラムクロマトで精製分離して目的とする化合物
を、無色オイルで4.61g得た(収率91%)。
【0036】[α]25 D=+16.2゜(C=1.
1,n−ヘキサン)
n24 D=1.4734。[θ]24 333=−694
0。
NMR(CDCl3)δH=(60MHz):0.16
(3H,s),0.18(3H,s),0.93(9
H,s),2.37(1H,dd,J=2.2and
17.6Hz),2.83(1H,dd,J=5.8
and 17.6Hz),4.78(1H,defor
med,dd,J=2.2 and 5.8Hz),
6.19(1H,d,J=1.4Hz)。
IR(film)ν(neat):1730(s)、1
597(m)、1474(ω)、1360(ω)、12
60(s)、1230(ω)、1180(ω)、116
0(ω)、1110(s)、1060(ω)、993
(ω)、940(m)、868(m)、839(s)、
780(m)cm−1。Description: BACKGROUND OF THE INVENTION 1. Field of the Invention
The present invention relates to a novel method for producing silyloxy-2-cyclopenten-1-ones. More specifically, 3-chloro-4- compound which can be a useful compound in producing pnaglandins having an excellent anticancer action and antiviral action.
The present invention relates to a method for producing silyloxy-2-cyclopenten-1-ones. [0002] In recent years, Telesto risi (Telesto risi), which has settled on the bottom of a boat collected on Oahu.
ei), a prostaglandin-related substance, pnaglandin, was isolated [Monthly Pharmaceutical Affairs, vol. 24, p. 41 (19)
86); Shoyer et al. Am. Chem. So
c. , 107, 2976 (1985)]. The three-dimensional structure has recently been found to be represented by the following formula. [0003] [Noyori et al. Am. Chem. So
c. , 108, 5021 (1986); Yamada et al. A
m. Chem. Soc. , 108, 5019 (198
6)]. It is known that punagrangins have an anticancer action as a physiological action [Fukushima et al., The 43rd Annual Meeting of the Cancer Society of Japan, p. 905 (1984); Advanced Improstaglandin Thromboxane and Leukotriene Research, Vol. 415, (1985),
Published by Reyban Press (New York)]. With regard to the synthesis of pulaglandins, the route shown in <Scheme 1> is known as a typical example [Noyori et al., J. Am. A
m. Chem. Soc. , 108, 5021 (198
6)]. According to the report, punaglandin (5) is obtained by sequentially adding an ω side chain and an α side chain to (4R) -3-chloro-4-tert-butyldimethylsilyloxy-2-cyclopenten-1-one (1). It is obtained by bonding. Further, the chirality at the 12-position of punaglandin (5) is derived from the chirality at the 4-position of compound (1). Therefore, the optically active 3- in the synthesis of punaglandin (5)
Chloro-4-tert-butyldimethylsilyloxy-
2-Cyclopenten-1-one can be said to be a very important synthetic intermediate of pulagrangins. [0005] The present inventors have paid attention to this point, and are keen on the synthesis of optically active 3-chloro-4-silyloxy-2-cyclopenten-1-ones and 4-silyloxy-2-cyclopenten-1-one. As a result of repeated studies, the present invention has been achieved. Heretofore, as a method for synthesizing optically active 3-chloro-4-silyloxy-2-cyclopenten-1-one, tetrahedron letters, Vol. 17, pp. 1539-1
The method described on page 542 (1979) is known. <
Scheme 2> That is, 3,5,5-trichloro-1,4-dihydroxycyclopent-1-carboxylic acid (7) obtained from trichlorophenol (6) is converted into a salt with (−)-brucine, and By fractional recrystallization (1
(S, 4S) -Trichloro-1,4-dihydroxycyclopent-1-carboxylic acid is obtained. Thus, (4R) -3-chloro-4-silyloxy-2-cyclopenten-1-ones were obtained in three steps. However, this method has a low yield from compound (6) to compound (7),
A complicated operation of fractional recrystallization using an expensive reagent called brucine is required. Compounds (10) and (1)
1) is extremely unstable. From the above, it has been very difficult to obtain a large amount of optically active 3-chloro-4-silyloxy-2-cyclopenten-1-one, which is an important synthetic intermediate for pulagrangins. DISCLOSURE OF THE INVENTION The present inventors have produced an optically active 3-chloro-4-silyloxy-2-cyclopenten-1-one which is a useful synthetic intermediate for pulagrangins at low cost. As a result of intensive studies on a method that can be manufactured in a specific manner, the present invention has been achieved. In the present invention, cis-3-chloro-4-silyloxy-2-cyclopenten-1-ol represented by the formula [I] is represented by the following formula: (In the formula, R 1 represents a silyl group which is a protecting group for a hydroxyl group, * represents an asymmetric center, and stereoisomers derived therefrom exist. In the present invention, (1S, 4)
R), (1R, 4S), or a mixture of both in any proportion. ) By oxidation of the formula [II
I], embedded image (Wherein, R 1 represents a silyl group which is a protecting group for a hydroxyl group, * represents an asymmetric center, and a stereoisomer derived therefrom exists. 4S, or a mixture of both in any proportion.)
The 3-chloro-4-silyloxy-2-cyclopenten-1-one represented by the formula can be efficiently produced. In the compounds [I] and [III], R 1 represents a silyl group which is a protecting group for a hydroxyl group, and specific examples thereof include trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl and (phenyldimethylmethyl). ) Dimethylsilyl, (triphenylmethyl) dimethylsilyl, tert-butyldiphenylsilyl, methyldiisopropylsilyl, methylditert-butylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triisopropylsilyl, triphenylsilyl and the like. Of these, tert-
Butyldimethylsilyl is particularly preferred. The oxidation reaction from compound [I] to [III] is carried out by using pyridinium chlorochromate (PCC) or pyridinium dichromate (PDC) and adding molecular sieves in methylene chloride or dimethylformamide if necessary. Can be done. P
CC or PDC is used in an amount of 1 to 7 moles, preferably 2 to 4 moles, per mole of the cis-3-chloro-4-silyloxy-2-cyclopenten-1-ol represented by the formula [I]. It is. Whether to use PCC or PDC is appropriately selected depending on the stability of the silyl protecting group. When DMF is used, the amount of solvent used is PD
It is preferably 3 to 10 times the volume of C. When methylene chloride is used, the volume is preferably 10 to 15 times the volume of PCC. When methylene chloride is used as the solvent, it is preferable to add molecular sieves 4A.
An equivalent to twice the amount of CC is preferred. The reaction temperature is preferably from 0 to 10 ° C. both when using PCC and when using PDC. The reaction time varies depending on the type of the silyl ether of the formula [I], but is usually in the range of 1 to 20 hours, preferably 1 to 5 hours. After completion of the reaction, an organic solvent for extraction, for example,
The reaction solution is diluted with diethyl ether, washed with water, dried and concentrated to dryness. The product obtained by drying is purified and separated by column chromatography or the like. Thus, the above formula [II
3-Chloro-4-silyloxy-2-cyclopenten-1-one, which is a useful compound in the synthesis of pulagrangins represented by I], can be obtained efficiently. In the present invention, from optically active (1S, 4R) -cis-3-chloro-4-silyloxy-2-cyclopenten-1-ol, optically active (4R) -3-chloro-4-silyloxy-2-ol is obtained. Cyclopenten-1-ones are obtained. From (1R, 4S) -cis-3-chloro-4-silyloxy-2-cyclopenten-1-ol, optically active (4S) -3-chloro-4-silyloxy-2 is obtained.
-Cyclopenten-1-ones are obtained. Natural pulagrangins are derived from (4R) -3-chloro-4-silyloxy-2-cyclopenten-1-one <Scheme 1
> Can be synthesized by the method described in
(4S) -3-Chloro-4-silyloxy-2-cyclopenten-1-ones are also important compounds. In the present invention, the compound of the formula [I] is a 3-acetoxy-5-silyloxy-1-chlorocyclopentene represented by the formula [II]: Wherein R 1 is as defined above.
Can be asymmetrically hydrolyzed using a hydrolase. That is, cis-3-chloro-4-silyloxy-2-cyclopenten-1-ols can be obtained as either one of the cis isomers or as a mixture of both cis isomers in any ratio. it can. The trans-3-acetoxy-5-silyloxy-1-chloro-cyclopentene remains without hydrolysis. Examples of the hydrolase include animal esterases such as liver esterase, pancreatic esterase, and acetylcholinesterase, and plant esterases.Furthermore, microorganisms belonging to the following genera, lichens, and microorganisms such as algae can be obtained. Hydrolytic enzymes. Rhodotorula, Trichod
erma, Candida, Hansenula, Ps
Eudomonas, Bacillus, Nocard
ia, Achromobacter, Chromoba
cterium, Flavobacterium, Rh
izopus, Mucor, Aspergillus,
Alkaligenes, Toulopsis, Co
rynebacterium, Endomyces, S
accaromyces, Arthrobacterte
r, Helminthosporium, Brevib
acterium, Escherichia, Citr
obactor, Absidia, Micrococc
us, Pediococcus, Klebsiell
a, Geotrichum, Lactobacillu
s, Cryptococcus, Pichia, Aur
eobasidium, Actinomucor, En
terobacter, Microbacteriu
m, Penicillium, Schizophyll
um. The form of use of the hydrolase used may be a purified enzyme, a crude enzyme, an enzyme-containing substance, a culture solution of a microorganism, a culture, a cell, a culture broth, or a product obtained by treating them, if necessary. It can be used in various forms. Further, it can be immobilized on a resin and used as an immobilized enzyme. The asymmetric hydrolysis reaction is carried out by reacting 3-acetoxy-5-silyloxy-1-chloro-cyclopentene represented by the formula [II] with the above-mentioned hydrolase, preferably pig liver esterase, pig pancreatic lipase, Pseudomo.
Purified or Crude Enzyme from Aspergillus, Aspergillus
Purification or crude enzyme of the origin can be carried out usually in a buffer solution or a mixture of an organic solvent and a buffer solution, if necessary, by adding a surfactant and stirring vigorously. Further, optically active (1S, 4R) -cis-
3-chloro-4-silyloxy-2-cyclopentene-
When 1-ols are obtained, it is particularly preferable to use pig pancreatic esterase. When (1R, 4S) -cis-3-chloro-4-silyloxy-2-cyclopenten-1-ol is obtained, pig liver is used. It is particularly preferred to use esterases. When a mixture of an organic solvent and a buffer is used, the organic solvent used is usually a water-soluble solvent, for example, alcohols such as methanol and ethanol, ketones such as acetone and methyl ethyl ketone, acetonitrile and propionitrile. And the like can be used. As the buffer, a commonly used buffer such as sodium phosphate, potassium phosphate, and sodium citrate can be used. The reaction temperature is preferably −10 ° C. to + 30 ° C., and the reaction time is preferably 2 to 50 hours, but is not limited thereto. After completion of the reaction, the hydrolysis reaction solution is filtered, if necessary, extracted with an organic solvent such as methyl isobutyl ketone, ethyl acetate, diethyl ether, dichloromethane, and the like, and the organic layer is purified by concentrated column chromatography. Desired cis-3-chloro-4-silyloxy-
2-cyclopenten-1-ols can be obtained. In addition, cis-3-chloro-4-silyloxy-2-
The optical purity of the cyclopenten-1-ols was determined from the 400 MHz NMR spectrum of the corresponding α-methoxy-α-trifluoromethylphenylacetic acid (MTPA) ester. Furthermore, the fact that trans-3-chloro-4-silyloxy-2-cyclopenten-1-ols were not mixed in the asymmetric hydrolyzate was also confirmed by MTPA.
The ester was confirmed by high performance liquid chromatography. The 3-acetoxy-5-silyloxy-1-chlorocyclopentene represented by the formula [II] can be synthesized by the method represented by <Scheme 3>. That is, a known method (JP-A-57-62236)
4-hydroxy-2-cyclopentene-
After acetylation of 1-one (12), addition of chlorine and HC
1 is eliminated to give 4-acetoxy-2-chloro-2-cyclopenten-1-one (14). Subsequently, reduction is performed with sodium borohydride in methanol in the presence of cerium trichloride to obtain 2-chloro-4-acetoxy-2-cyclopenten-1-ol. It can be obtained by converting the alcohol moiety to a silyl ether with a trialkylchlorosilane in the presence of a suitable base. Compounds (13), (14), (15) and Formula [I
I] 3-acetoxy-5-silyloxy-
1-chlorocyclopentenes are all stable compounds and can be obtained in good yield. Embedded image 3-acetoxy- represented by the formula [II]
5-silyloxy-1-chlorocyclopentenes have two asymmetric carbons at the 3- and 5-positions, and (3S, 5
R) and the cis form of (3R, 5S), and (3S, 5S)
And (3R, 5R) trans forms. <Scheme 3>
The 3-acetoxy-5-silyloxy-1-chlorocyclopentenes represented by the formula [II] obtained by the method described above are mixtures of these four stereoisomers. Hereinafter, the present invention will be described in detail with reference to examples. Reference Example 1 4-acetoxy-2-chloro-2-cyclopentene-1
-One 4-hydroxy-2-cyclopenten-1-one 30.
2 g (0.308 mol) was dissolved in 1500 ml of THF, and 47.2 g (0.462 mol) of acetic anhydride and 50.5 g (0.616 mol) of sodium acetate were added.
Stir for 5 hours. 300 ml of cold water was added to the reaction solution, and extracted three times with 200 ml of ethyl acetate. The extract was washed with 100% 10% saline solution and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 37.9 g of 4-acetoxy-2-cyclopenten-1-one. This was dissolved in 540 ml of ether, and chlorine was blown in at room temperature. It took 90 minutes to complete the reaction. After blowing excess nitrogen to remove excess chlorine, triethylamine 100m
1 was slowly added dropwise at 5 to 15 ° C. 10% in the reaction solution
-500 ml of an aqueous ammonium chloride solution was added, and the mixture was separated. The aqueous layer was extracted twice with 300 ml of ether. The extract was combined with 10% -salt 300 ml, 2N-hydrochloric acid 500 ml,
It was washed with 300 ml of 10% saline solution and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 47.0 g of crude crystals of the desired product. Recrystallization from ether-hexane gave 27.0 g of colorless crystals. Yield 50%, melting point 55 ° C. NMR (CDCl 3 ) δH = (60 MHz): 2.08
(3H, s), 2.36 (1H, dd, J = 2.0 a
nd 18.0 Hz), 2.93 (1H, dd, J =
6.4 and 18.0 Hz), 5.75 (1H,
m), 7.50 (1H, d, J = 3.0 Hz). IR (film) v (neat): 1740 (s), 1
610 (m), 1400 (m), 1378 (m), 13
46 (m), 1290 (m), 1240 (s), 117
0 (m), 1036 (m), 976 (m), 957
(M) cm- 1 . Reference Example 2 3-acetoxy-5-tert-butyldimethylsilyloxy-1-chlorocyclopentene 4-acetoxy-2-chloro-2-cyclopentene-1
27.0 g (0.155 mol) of methanol
Dissolved in 50 ml. 63.7 g of cerous chloride
(0.171 mol), and 6.4 g (0.169 mol) of sodium borohydride was divided into several portions to give 22 to 2
Added at 5 ° C. After stirring at 20 to 23 ° C for 20 minutes, 150 ml of a saturated aqueous ammonium chloride solution was added, and the mixture was concentrated under reduced pressure. 400 ml of 0.5 N hydrochloric acid was added to the concentrated residue, and the mixture was extracted three times with 300 ml of ether. The extract was washed with brine and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 22.4 g of 4-acetoxy-2-chloro-2-cyclopenten-1-ol. This is DMF2
Dissolved in 20 ml, tert-butyldimethylchlorosilane 24.0 g (0.159 mol), imidazole 1
3.0 g (0.191 mol) was added, and the mixture was stirred at room temperature for 5 hours. Add 1100 ml of water, and add 4
Extracted times. The extract was washed with brine and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 47 g of a pale yellow oil. Purification by silica gel column chromatography gave 32.3 g of the desired compound as a colorless oil.
(Yield: 71%) n 24 D = 1.4604. NMR (CDC
l 3 ) δH = (60 MHz): 0.11 (6H, s),
0.91 (9H, s), 2.01 and 2.03
(3H, s), 4.50 and 4.82 (1H,
m), 5.17 to 5.77 (1H, m), 5.87 (1
H, m). IR (film) ν (neat): 1750 (s), 1
634 (m), 1480 (m), 1470 (m), 14
50 (m), 1370 (m), 1242 (s), 113
5 (m), 1082 (m), 1030 (m), 950
(M), 861 (m), 839 (m), 779 (m) c
m- 1 . Reference Example 3 4-tert-butyldimethylsilyloxy-3-chloro-2-cyclopenten-1-ol 3-acetoxy-5-tert-butyldimethylsilyloxy-1-chlorocyclopentene 30.0 g (0.1
03 mol) was dissolved in 600 ml of methanol. pH
= 7, 1800 ml of phosphate buffer, pig pancreatic lipase 1
5.0 g was added, and the mixture was stirred at 15 ° C. for 12 hours. The hydrolyzate was extracted three times with 1000 ml of ether and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 29.0 g of a colorless oil. Purified and separated by silica gel column chromatography, the raw material acetate and cis (1R, 4
21.2 g of a mixture with the raw material acetate of S) was recovered.
6.4 g of the desired cis (1S, 4R) compound was obtained as a colorless oil. [0034] Yield 25.0%. [Α] 25 D = −31.7 ° (C = 0.75, MeO
H) Optical purity = 95% ee or more. n 25 D = 1.4711. NMR (CDCl 3 ) δH = (100 MHz): 0.1
3 (3H, s), 0.15 (3H, s), 0.93 (9
H, s), 1.61 (1H, t, J = 4.3 Hz),
1.74 (1H, t, J = 4.3 Hz), 2.80 (1
H, dt, J = 7.0 and 14.2 Hz), 4.
48 (1H, dd, J = 4.3 and 7.0 Hz),
5.94 (1H, d, J = 2.6 Hz). IR (film) ν (neat): 3370 (s), 1
630 (m), 1478 (m), 1467 (m), 13
65 (m), 1259 (s), 1172 (m), 113
2 (s), 1086 (s), 1030 (s), 1004
(M), 941 (m), 861 (s), 840 (s),
800 (m), 780 (m) cm -1 . Example 1 4-tert-butyldimethylsilyloxy-3-chloro-2-cyclopenten-1-one (1S, 4R) -cis-3-chloro-4 obtained in Reference Example 3.
-Tert-butyldimethylsilyloxy-2-cyclopenten-1-ol 5.10 g (20.5 mmol)
Was dissolved in 100 ml of DMF. After cooling to 5 ° C., 27.0 g (71.8 mmol) of pyridinium dichromate were added. Stirred at 5 ° C for 3 hours. 600 ml of water in the reaction solution
And extracted three times with 100 ml of hexane. The extract was washed with 10% saline and dried over magnesium sulfate.
After filtration, the filtrate was concentrated under reduced pressure to obtain a pale yellow oil. Purification and separation by silica gel column chromatography gave 4.61 g of the desired compound as a colorless oil (yield 91%). [Α] 25 D = + 16.2 ゜ (C = 1.
1, n-hexane) n 24 D = 1.4734. [Θ] 24 333 = -694
0. NMR (CDCl 3 ) δH = (60 MHz): 0.16
(3H, s), 0.18 (3H, s), 0.93 (9
H, s), 2.37 (1H, dd, J = 2.2 and
17.6 Hz), 2.83 (1H, dd, J = 5.8)
and 17.6Hz), 4.78 (1H, default)
med, dd, J = 2.2 and 5.8 Hz),
6.19 (1H, d, J = 1.4 Hz). IR (film) v (neat): 1730 (s), 1
597 (m), 1474 (ω), 1360 (ω), 12
60 (s), 1230 (ω), 1180 (ω), 116
0 (ω), 1110 (s), 1060 (ω), 993
(Ω), 940 (m), 868 (m), 839 (s),
780 (m) cm -1 .
Claims (1)
し、*は不斉中心を表わし、これに由来する立体異性体
が存在するが、本発明においては(1S,4R)である
か、(1R,4S)、または両者の任意の割合の混合物
である。)で表わされるシス−3−クロロ−4−シリル
オキシ−2−シクロペンテン−1−オール類を酸化する
ことを特徴とする、式[III]、 【化2】 (式中、R1は水酸基の保護基であるシリル基を表わ
し、*は不斉中心を表わし、これに由来する立体異性体
が存在するが、本発明においては4Rであるか、4S、
または両者の任意の割合の混合物である。)で表わされ
る3−クロロ−4−シリルオキシ−2−シクロペンテン
−1−オン類の製造法。(57) [Claims] Formula [I], embedded image (In the formula, R 1 represents a silyl group which is a protecting group for a hydroxyl group, * represents an asymmetric center, and stereoisomers derived therefrom exist. In the present invention, it is (1S, 4R) , (1R, 4S), or a mixture of both in any proportions.) Wherein cis-3-chloro-4-silyloxy-2-cyclopenten-1-ol is oxidized. [III], embedded image (Wherein, R 1 represents a silyl group which is a protecting group for a hydroxyl group, * represents an asymmetric center, and a stereoisomer derived therefrom exists. In the present invention, 4R or 4S,
Or a mixture of both in an arbitrary ratio. A method for producing 3-chloro-4-silyloxy-2-cyclopenten-1-one represented by the formula:
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