JP2009517413A - エポキシブタノール中間体の製造方法 - Google Patents
エポキシブタノール中間体の製造方法 Download PDFInfo
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- JP2009517413A JP2009517413A JP2008542575A JP2008542575A JP2009517413A JP 2009517413 A JP2009517413 A JP 2009517413A JP 2008542575 A JP2008542575 A JP 2008542575A JP 2008542575 A JP2008542575 A JP 2008542575A JP 2009517413 A JP2009517413 A JP 2009517413A
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- compound
- hal
- same meaning
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 71
- -1 aryl sulfonic acid ester Chemical class 0.000 claims abstract description 38
- 239000002904 solvent Substances 0.000 claims abstract description 34
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 16
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 11
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 10
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 7
- 150000002148 esters Chemical class 0.000 claims abstract description 6
- 230000000269 nucleophilic effect Effects 0.000 claims abstract description 6
- 125000003709 fluoroalkyl group Chemical group 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 43
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 34
- 239000000203 mixture Substances 0.000 claims description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- 239000002585 base Substances 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- AZFNGPAYDKGCRB-XCPIVNJJSA-M [(1s,2s)-2-amino-1,2-diphenylethyl]-(4-methylphenyl)sulfonylazanide;chlororuthenium(1+);1-methyl-4-propan-2-ylbenzene Chemical compound [Ru+]Cl.CC(C)C1=CC=C(C)C=C1.C1=CC(C)=CC=C1S(=O)(=O)[N-][C@@H](C=1C=CC=CC=1)[C@@H](N)C1=CC=CC=C1 AZFNGPAYDKGCRB-XCPIVNJJSA-M 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 235000010289 potassium nitrite Nutrition 0.000 claims description 7
- 239000004304 potassium nitrite Substances 0.000 claims description 7
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 6
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 claims description 6
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical group [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- QUGUFLJIAFISSW-UHFFFAOYSA-N 1,4-difluorobenzene Chemical compound FC1=CC=C(F)C=C1 QUGUFLJIAFISSW-UHFFFAOYSA-N 0.000 claims description 4
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims description 3
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 235000010288 sodium nitrite Nutrition 0.000 claims description 3
- 239000012453 solvate Substances 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 125000002346 iodo group Chemical group I* 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 125000006661 (C4-C6) heterocyclic group Chemical group 0.000 claims 3
- NLPHXWGWBKZSJC-UHFFFAOYSA-N 4-acetylbenzonitrile Chemical compound CC(=O)C1=CC=C(C#N)C=C1 NLPHXWGWBKZSJC-UHFFFAOYSA-N 0.000 claims 1
- 238000006202 Sharpless epoxidation reaction Methods 0.000 claims 1
- ZGSDJMADBJCNPN-UHFFFAOYSA-N [S-][NH3+] Chemical compound [S-][NH3+] ZGSDJMADBJCNPN-UHFFFAOYSA-N 0.000 claims 1
- NAGJZTKCGNOGPW-UHFFFAOYSA-N dithiophosphoric acid Chemical compound OP(O)(S)=S NAGJZTKCGNOGPW-UHFFFAOYSA-N 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 239000011541 reaction mixture Substances 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 18
- 239000012074 organic phase Substances 0.000 description 17
- 239000000243 solution Substances 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000007787 solid Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 238000001914 filtration Methods 0.000 description 9
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 9
- 235000019341 magnesium sulphate Nutrition 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 0 CC([C@]1(c2cc(*)c(*)cc2N*)OC1)O Chemical compound CC([C@]1(c2cc(*)c(*)cc2N*)OC1)O 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 5
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 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 4
- JMTUKLDCKFYSIK-WKEGUHRASA-N (1s)-1-[(2s)-2-(2,5-difluorophenyl)oxiran-2-yl]ethanol Chemical compound C=1C(F)=CC=C(F)C=1[C@@]1([C@@H](O)C)CO1 JMTUKLDCKFYSIK-WKEGUHRASA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 238000006751 Mitsunobu reaction Methods 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000000843 anti-fungal effect Effects 0.000 description 3
- 229940121375 antifungal agent Drugs 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 150000003983 crown ethers Chemical class 0.000 description 3
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 3
- IRDLUHRVLVEUHA-UHFFFAOYSA-N diethyl dithiophosphate Chemical compound CCOP(S)(=S)OCC IRDLUHRVLVEUHA-UHFFFAOYSA-N 0.000 description 3
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 3
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 3
- HUEOYXUALXBOSZ-LHLIQPBNSA-N (1r)-1-[(2r)-2-(2,4-difluorophenyl)oxiran-2-yl]ethanol Chemical compound C=1C=C(F)C=C(F)C=1[C@]1([C@H](O)C)CO1 HUEOYXUALXBOSZ-LHLIQPBNSA-N 0.000 description 2
- JMTUKLDCKFYSIK-LHLIQPBNSA-N (1r)-1-[(2r)-2-(2,5-difluorophenyl)oxiran-2-yl]ethanol Chemical compound C=1C(F)=CC=C(F)C=1[C@]1([C@H](O)C)CO1 JMTUKLDCKFYSIK-LHLIQPBNSA-N 0.000 description 2
- ANFZGSBFEPFDNR-VUWPPUDQSA-N (2s)-1-morpholin-4-yl-2-(oxan-2-yloxy)propan-1-one Chemical compound O([C@@H](C)C(=O)N1CCOCC1)C1CCCCO1 ANFZGSBFEPFDNR-VUWPPUDQSA-N 0.000 description 2
- GYINCLTUOQLIMI-ZETCQYMHSA-N (2s)-3-(2,5-difluorophenyl)but-3-en-2-ol Chemical compound C[C@H](O)C(=C)C1=CC(F)=CC=C1F GYINCLTUOQLIMI-ZETCQYMHSA-N 0.000 description 2
- UEMGWPRHOOEKTA-UHFFFAOYSA-N 1,3-difluorobenzene Chemical compound FC1=CC=CC(F)=C1 UEMGWPRHOOEKTA-UHFFFAOYSA-N 0.000 description 2
- VFTFKUDGYRBSAL-UHFFFAOYSA-N 15-crown-5 Chemical compound C1COCCOCCOCCOCCO1 VFTFKUDGYRBSAL-UHFFFAOYSA-N 0.000 description 2
- LJANCPRIUMHGJE-UHFFFAOYSA-N 4-(2-bromoacetyl)benzonitrile Chemical compound BrCC(=O)C1=CC=C(C#N)C=C1 LJANCPRIUMHGJE-UHFFFAOYSA-N 0.000 description 2
- OTLNPYWUJOZPPA-UHFFFAOYSA-N 4-nitrobenzoic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UWTATZPHSA-N D-lactic acid Chemical compound C[C@@H](O)C(O)=O JVTAAEKCZFNVCJ-UWTATZPHSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 239000004593 Epoxy Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical group CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- NECOGGLJUBBIKF-DAIXLEOSSA-N N1N=CN=C1.FC1=C(C=C(C=C1)F)[C@@](CN1N=CN=C1)([C@@H](C)O)O Chemical compound N1N=CN=C1.FC1=C(C=C(C=C1)F)[C@@](CN1N=CN=C1)([C@@H](C)O)O NECOGGLJUBBIKF-DAIXLEOSSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- QQIRAVWVGBTHMJ-UHFFFAOYSA-N [dimethyl-(trimethylsilylamino)silyl]methane;lithium Chemical compound [Li].C[Si](C)(C)N[Si](C)(C)C QQIRAVWVGBTHMJ-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 150000001983 dialkylethers Chemical class 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- OPAHEYNNJWPQPX-RCDICMHDSA-N ravuconazole Chemical compound C=1SC([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=1C1=CC=C(C#N)C=C1 OPAHEYNNJWPQPX-RCDICMHDSA-N 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
- 239000007858 starting material Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- JMTUKLDCKFYSIK-LDWIPMOCSA-N (1r)-1-[(2s)-2-(2,5-difluorophenyl)oxiran-2-yl]ethanol Chemical compound C=1C(F)=CC=C(F)C=1[C@@]1([C@H](O)C)CO1 JMTUKLDCKFYSIK-LDWIPMOCSA-N 0.000 description 1
- REHMWFXPLWURSF-RXMQYKEDSA-N (2r)-1-(2,4-difluorophenyl)-2-hydroxypropan-1-one Chemical compound C[C@@H](O)C(=O)C1=CC=C(F)C=C1F REHMWFXPLWURSF-RXMQYKEDSA-N 0.000 description 1
- WYBYSZZTJKCLBE-PRHODGIISA-N (2r,3r)-2-(2,5-difluorophenyl)-1-(1,2,4-triazol-1-yl)butane-2,3-diol Chemical compound C([C@@](O)([C@H](O)C)C=1C(=CC=C(F)C=1)F)N1C=NC=N1 WYBYSZZTJKCLBE-PRHODGIISA-N 0.000 description 1
- ZEISVRBYWRSORY-DAIXLEOSSA-N (2r,3r)-2-(2,5-difluorophenyl)-1-(1,2,4-triazol-1-yl)butane-2,3-diol;oxalic acid Chemical compound OC(=O)C(O)=O.C([C@@](O)([C@H](O)C)C=1C(=CC=C(F)C=1)F)N1C=NC=N1 ZEISVRBYWRSORY-DAIXLEOSSA-N 0.000 description 1
- PKRHUCFPMFLUSS-LLTODGECSA-N (2s)-1-(2,5-difluorophenyl)-2-(oxan-2-yloxy)propan-1-one Chemical compound O([C@@H](C)C(=O)C=1C(=CC=C(F)C=1)F)C1CCCCO1 PKRHUCFPMFLUSS-LLTODGECSA-N 0.000 description 1
- LEJLUUHSOFWJSW-UHFFFAOYSA-N 1-(oxiran-2-yl)ethanol Chemical class CC(O)C1CO1 LEJLUUHSOFWJSW-UHFFFAOYSA-N 0.000 description 1
- XQQZRZQVBFHBHL-UHFFFAOYSA-N 12-crown-4 Chemical compound C1COCCOCCOCCO1 XQQZRZQVBFHBHL-UHFFFAOYSA-N 0.000 description 1
- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-UHFFFAOYSA-N 0.000 description 1
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 1
- ZRPAUEVGEGEPFQ-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]pyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2 ZRPAUEVGEGEPFQ-UHFFFAOYSA-N 0.000 description 1
- OTLNPYWUJOZPPA-UHFFFAOYSA-M 4-nitrobenzoate Chemical compound [O-]C(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-M 0.000 description 1
- CONKBQPVFMXDOV-QHCPKHFHSA-N 6-[(5S)-5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-2-oxo-1,3-oxazolidin-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C[C@H]1CN(C(O1)=O)C1=CC2=C(NC(O2)=O)C=C1 CONKBQPVFMXDOV-QHCPKHFHSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- YSAVZVORKRDODB-UHFFFAOYSA-N Diethyl tartrate Chemical compound CCOC(=O)C(O)C(O)C(=O)OCC YSAVZVORKRDODB-UHFFFAOYSA-N 0.000 description 1
- UDPADZGIWCBYQB-LEMICQRHSA-N FC1=CC=C(C=C1)F.FC1=C(C=C(C=C1)F)C([C@H](C)OC1OCCCC1)=O Chemical compound FC1=CC=C(C=C1)F.FC1=C(C=C(C=C1)F)C([C@H](C)OC1OCCCC1)=O UDPADZGIWCBYQB-LEMICQRHSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- FYJKEHKQUPSJDH-UHFFFAOYSA-N [dimethyl-(trimethylsilylamino)silyl]methane;potassium Chemical compound [K].C[Si](C)(C)N[Si](C)(C)C FYJKEHKQUPSJDH-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- UYJXRRSPUVSSMN-UHFFFAOYSA-P ammonium sulfide Chemical compound [NH4+].[NH4+].[S-2] UYJXRRSPUVSSMN-UHFFFAOYSA-P 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- DIOQZVSQGTUSAI-NJFSPNSNSA-N decane Chemical compound CCCCCCCCC[14CH3] DIOQZVSQGTUSAI-NJFSPNSNSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 229910000358 iron sulfate Inorganic materials 0.000 description 1
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- LPEKGGXMPWTOCB-GSVOUGTGSA-N methyl (R)-lactate Chemical compound COC(=O)[C@@H](C)O LPEKGGXMPWTOCB-GSVOUGTGSA-N 0.000 description 1
- DDCYYCUMAFYDDU-UHFFFAOYSA-N methyl thiohypochlorite Chemical compound CSCl DDCYYCUMAFYDDU-UHFFFAOYSA-N 0.000 description 1
- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 description 1
- JNMIXMFEVJHFNY-UHFFFAOYSA-M methyl(triphenyl)phosphanium;iodide Chemical compound [I-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 JNMIXMFEVJHFNY-UHFFFAOYSA-M 0.000 description 1
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 1
- DIOQZVSQGTUSAI-UHFFFAOYSA-N n-butylhexane Natural products CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- RAFRTSDUWORDLA-UHFFFAOYSA-N phenyl 3-chloropropanoate Chemical compound ClCCC(=O)OC1=CC=CC=C1 RAFRTSDUWORDLA-UHFFFAOYSA-N 0.000 description 1
- ZAEQTGTVGUJEFV-UHFFFAOYSA-N phenylmethanesulfonate;pyridin-1-ium Chemical compound C1=CC=[NH+]C=C1.[O-]S(=O)(=O)CC1=CC=CC=C1 ZAEQTGTVGUJEFV-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 125000004187 tetrahydropyran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical class OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- KEPJZBFFLDRKSF-UHFFFAOYSA-M trimethylsulfoxonium bromide Chemical compound [Br-].C[S+](C)(C)=O KEPJZBFFLDRKSF-UHFFFAOYSA-M 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/08—Compounds containing oxirane rings with hydrocarbon radicals, substituted by halogen atoms, nitro radicals or nitroso radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
- C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
-
- 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)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Epoxy Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pyrane Compounds (AREA)
Abstract
Description
Halは、フルオロ又はクロロを表し、
R1及びR2は、互いに独立して、水素又はHalの意味の一つを表す)で表される化合物の製造方法であって;
この方法において、式(II):
この方法において、1,4−ジフルオロベンゼンを、塩基存在下、式(III−a):
PrGは、式(IV−a)中と同じ意味を有し、
R3は、メチル又はエチルを表し、且つ
R4は、メチル、エチル若しくはメトキシを表すか、又は、
R3及びR4は、それらと結合する窒素原子と一緒になって、窒素又は酸素から選択される0個又は1個又は2個のいずれかのさらなるヘテロ原子を有する4員〜6員の複素環基を表す)で表される化合物と反応させる、上記方法にも関する。
(2S)−1−(2,5−ジフルオロ−フェニル)−2−(テトラヒドロ−ピラン−2−イルオキシ)−プロパン−1−オン
1,4−ジフルオロベンゼン(1.8g、15.8mmol)及び(2S)−1−モルホリン−4−イル−2−(テトラヒドロ−ピラン−2−イルオキシ)−プロパン−1−オン(3g、10.5mmol)を、乾燥THF(15ml)中に溶解した。混合物を0℃に冷却し、次いでリチウムジイソプロピルアミン(2M THF/ヘプタン溶液、7.9ml、15.8mmol)を20分間かけて滴下した。混合物をさらに2時間、0℃にて攪拌した。次いで、飽和塩化アンモニウム溶液を用いて、反応を停止した。反応混合物を酢酸エチルで抽出した。有機相を水及び塩水で洗浄し、次いで硫酸マグネシウムで乾燥した。固体を濾過して、溶媒を減圧下で除去した。粗生成物をシリカゲルクロマトグラフィーにかけた(溶離液:石油エーテル/酢酸エチル 50:1〜30:1)。HPLC純度96.2%の、1.31gの黄色結晶物質(収率44.8%)を得た。
1(S)−[2−(2,5−ジフルオロ−フェニル)−1−メチル−アリルオキシ]−テトラヒドロ−ピラン
メチルトリフェニルホスホニウムヨージド(11.1g、27.7mmol)を、乾燥THF(100ml)中に懸濁した。反応混合物を氷浴中で冷却した。ナトリウムビス(トリメチルシリル)アミド溶液(1M THF溶液、30ml)を、20℃以下の温度を維持するような速度で添加した。反応混合物を15℃で3時間攪拌し、次いで、−78℃で冷却した。次いで、(2S)−1−(2,5−ジフルオロ−フェニル)−2−(テトラヒドロ−ピラン−2−イルオキシ)−プロパン−1−オン(5.0g、15.7mmol、THF(20ml)溶液中)を、−70℃以下の温度を維持するような速度で、先の混合物に添加した。混合物をこの温度において5分間攪拌し、次いで10℃にて17時間攪拌した。
2(S)−3−(2,5−ジフルオロ−フェニル)−ブト−3−エン−2−オール
1(S)−[2−(2,5−ジフルオロ−フェニル)−1−メチル−アリルオキシ]−テトラヒドロ−ピラン(5.79g、20.4mmol))をメタノール(40ml)中に溶解した。ピリジニウムトルエンスルフォナート(2.61g、10.4mmol)を添加し、混合物を35℃にて12時間攪拌した。溶媒を減圧下で除去した。残留物を酢酸エチル(40ml)中に溶かし固体を濾過により除去した。粗生成物をシリカゲルクロマトグラフィーにかけた(溶離液:石油エーテル/酢酸エチル 200:1〜50:1)。HPLC純度96.2%、eeが99.2%の、3.45gの黄色の油(収率81.4%)を得た。
1(R)−[2(S)−(2,5−ジフルオロ−フェニル)−オキシラニル]−エタノール
L−(+)−酒石酸ジエチル(7.9g、38.2mmol)を、−30℃にて乾燥塩化メチレン(250ml)中に溶解し、モレキュラーシーブ4Aを添加した(8g)。チタンテトライソプロポキシド(TIPO)(10.8g、36.5mmol)を混合物へ加えた。混合物を30℃にて1時間攪拌した。次いで、乾燥塩化メチレン(50ml)中に溶解した2(S)−3−(2,5−ジフルオロ−フェニル)−ブト−3−エン−2−オール(7g、33.2mmol)をゆっくりと添加した。混合物を30℃にて1時間攪拌した。次いで、Tert−ブチルヒドロペルオキシド(TBHP)(デカン中の5.5M溶液、13.2ml、73.1mmol)を−25℃にて滴下した。混合物を−25℃にて12時間攪拌した。反応混合物を10℃に加温し、硫酸鉄(18g)及び酒石酸(18g)の水(300ml)溶液を添加した。混合物を10℃にて30分間攪拌した。相を分離し、水相を、塩化メチレン(3×250ml)を用いて3回抽出した。あわせた有機相に対し、1M 水酸化ナトリウム水溶液(100ml)を添加し、混合物を1時間攪拌した。相を分離し、水相を、塩化メチレン(2×250ml)を用いて2回抽出した。有機相を硫酸マグネシウムで乾燥した。固体を濾過して、溶媒を減圧下で除去した。粗生成物をシリカゲルクロマトグラフィーにかけた(溶離液:石油エーテル/酢酸エチル 20:1)。HPLC純度82%の、6.55gの黄色の油(収率82%)を得た。
1(S)−[2(S)−(2,5−ジフルオロ−フェニル)−オキシラニル]−エタノール
1(R)−[2(S)−(2,5−ジフルオロ−フェニル)−オキシラニル]−エタノール(500mg、2.34mmol;HPLC純度93%)を、乾燥塩化メチレン(25ml)中に溶解した。乾燥ピリジン(0.38ml;4.67mmol)を添加し、反応混合物を0℃に冷却した。次いで、トリフルオロメタンスルホン酸無水物(0.88ml、5.14mmol)を滴下した。反応混合物を0℃にて15分間攪拌した。次いで、5滴の5%硫酸水溶液(5ml)を添加し、相を分離した。水相を酢酸エチルにて3回抽出した(3×20ml)。合わせた有機相をまず2M塩酸水溶液(20ml)、飽和重炭酸塩(20ml)、及び最後に塩水(20ml)で洗浄した。有機相を硫酸マグネシウムで乾燥した。固体を濾過して除き、溶媒を減圧下で除去した。得られた粗油(0.766g)を続く変換のために使用した。
(2R,3R)−2−(2,5−ジフルオロ−フェニル)−1−[1,2,4]−トリアゾール−1−イル−ブタン−2,3−ジオール
1,2,4−トリアゾール(274mg、3.89mmol)をDMSO(3ml)中に溶解する。水素化ナトリウム(124mg、パラフィン中の60%懸濁液、3.24mmol)を添加し、反応混合物を70℃にて1時間加熱した。反応混合物を室温に冷却し、DMSO(2ml)中に溶解した1(S)−[2(S)−(2,5−ジフルオロ−フェニル)−オキシラニル]−エタノール(275mg、1.3mmol)を10分間にわたりゆっくりと添加した。次いで反応混合物を70℃に3時間加熱した。溶媒を蒸発した。残留物を酢酸エチル(10ml)及び水(5ml)中に溶かした。相を分離した。水相を酢酸エチルにて3回抽出した(3×5ml)。合わせた有機相を水で2回洗浄した(2×5ml)。有機相を硫酸マグネシウムで乾燥した。固体を濾過して除き、溶媒を減圧下で除去した。粗生成物を酢酸エチル(16ml)中に溶解した。シュウ酸(164mg、1.3mmol)を添加し、溶液を30分間攪拌した。混合物を0℃にて一晩保存した。結晶性の(2R,3R)−2−(2,5−ジフルオロ−フェニル)−1−[1,2,4]トリアゾール−1−イル−ブタン−2,3−ジオールオキサラートを濾過した。結晶をヘキサンで洗浄し、真空下で乾燥した。所望の化合物を、白色粉末(337mg)として得た;収率66.7%、95%を上回る光学純度(NMRにおいてその他の異性体は見られない)。
(2(R),3(S))−1−[2−(2,5−ジフルオロ−フェニル)−3−メチル−オキシラニルメチル]−1H−[1,2,4]トリアゾール
(2R,3R)−2−(2,5−ジフルオロ−フェニル)−1−[1,2,4]−トリアゾール−1−イル−ブタン−2,3−ジオール(324mg、1.20mmol)を塩化メチレン(13ml)中に溶解した。トリエチルアミン(0.59ml、4.2mmol)を反応混合物に添加した。反応混合物を0℃に冷却し、塩化メチレン(4ml)中に溶解したメタンスルフォニルクロリド(0.21ml、2.72mmol)を添加した。反応混合物を0℃にて4時間攪拌した。次いで、6M水酸化ナトリウム溶液(0.98ml)を添加した。反応混合物を室温にて一晩攪拌した。溶媒を蒸発した。残留物を酢酸エチル(15ml)及び水(8ml)中に溶かした。相を分離した。水相を酢酸エチルにて3回抽出した(3×10ml)。合わせた有機相を水で2回洗浄した(2×5ml)。有機相を硫酸マグネシウムで乾燥した。固体を濾過して除き、溶媒を減圧下で除去した。粗化合物をクロマトグラフィーにかけ(溶離液:酢酸エチル/石油エーテル:1:2)、所望の化合物を白色結晶(116mg)として得た;収率38.5%。HPLC純度:99.5%、ee:99.99%。
1(S)−[2(S)−(2,5−ジフルオロ−フェニル)−オキシラニル]−エタノール
DEAD(870mg、2mmol)及びp−ニトロ安息香酸(337mg、2mmol)を乾燥THF(3ml)中に溶解し、この溶液を0℃に冷却した。次いで、1(R)−[2(S)−(2,5−ジフルオロ−フェニル)−オキシラニル]−エタノール(100mg;0.5mmol)及びトリフェニルホスフィン(524mg、2mmol)を乾燥THF(10ml)中に溶解したものを、10℃以下の温度を維持するような速度で、滴下した。次いで混合物を、20℃にて20時間反応させ、反応終了した。溶媒の半分を減圧下で除去した。反応混合物を、ジエチルエーテル(80ml)を用いて希釈し、飽和塩化アンモニウム溶液を用いて洗浄した。有機相を硫酸マグネシウムで乾燥した。固体を濾過して除き、溶媒を減圧下で除去した。残留物をメタノール(25ml)中に溶解し、炭酸カリウム(450mg)を用いて処理した。反応混合物を飽和塩化アンモニウム溶液(30ml)にて希釈した。反応混合物を酢酸エチル(2×20ml)で抽出した。あわせた有機相を水(2×30ml)及び塩水(2×30ml)を用いて洗浄した。有機相を硫酸マグネシウムで乾燥した。固体を濾過して除き、溶媒を減圧下で除去した。粗残留物をクロマトグラフィーにより精製した(石油エーテル/酢酸エチル 20:1)。53mg(収率:53%)の所望の1(S)−[2(S)−(2,5−ジフルオロ−フェニル)−オキシラニル]−エタノールを、無色油状物質として得た。HPLC純度は76%であった。
(2R,3R)−2−(2,5−ジフルオロ−フェニル)−1−[1,2,4]−トリアゾール−1−イル−ブタン−2,3−ジオール
1,2,4−トリアゾール(7mg、0.1mmol)をDMF(0.5ml)中に溶解した。水素化ナトリウム(4.4mg、60%飽和パラフィン懸濁液、0.1mmol)を添加し、反応混合物を70℃へと1時間加熱した。反応混合物を室温へと冷却し、1(S)−[2(S)−(2,5−ジフルオロ−フェニル)−オキシラニル]−エタノール(5mg、0.025mmol、実施例8より)DMF(0.5ml)溶液をゆっくりと添加した。反応混合物を次いで70℃へと3時間加熱した。溶媒を蒸発した。残留物を、酢酸エチル(5ml)及び水(3ml)に溶かした。相を分離した。水相を、酢酸エチル(3×5ml)を用いて3回抽出した。合わせた有機相を水で2回洗浄した(2×5ml)。有機相を硫酸ナトリウムで乾燥した。固体を濾過して除き、溶媒を減圧下で除去した。5mgの(2R,3R)−2−(2,5−ジフルオロ−フェニル)−1−[1,2,4]−トリアゾール−1−イル−ブタン−2,3−ジオールを、淡黄色の油として得た。この化合物をキラルHPLCにより分析した。ジアステレオマーの過剰量は、94%であることがわかった。
Claims (20)
- 前記アルキル又はアリールスルホン酸エステルが、トリフルオロメチルスルホン酸エステルである、請求項1記載の方法。
- アルカリ金属亜硝酸塩が、亜硝酸ナトリウム又は亜硝酸カリウムである、請求項1又は2記載の方法。
- クラウンエステルが、亜硝酸カリウムを使用する場合には、18−クラウン−6エステルであり、亜硝酸ナトリウムを使用する場合には、15−クラウン−3−エーテルである、請求項1〜3のいずれか1項記載の方法。
- アルカリ金属亜硝酸塩が亜硝酸カリウムである、請求項3又は4記載の方法。
- ジメチルスルホキシド(DMSO)、N,N−ジメチルホルムアミド(DMF)、1,3−ジメチル−3,4,5,6−テトラヒドロ−2(1H)−ピリミジノン(DMPU)、テトラヒドロフラン(THF)、ジオキサン、ホルムアミド及びそれらの混合物から選択される溶媒が、極性非求核性溶媒として使用される、請求項1〜5のいずれか1項記載の方法。
- 式(I)において、Halがフルオロを表し、R1及びR2の一方が水素を表し、もう一方がフルオロを表す、請求項1〜6のいずれか1項記載の方法。
- R1がフルオロを表し、R2が水素を表す、請求項7記載の方法。
- 式(V):
(式中、
Halは、フルオロ又はクロロを表し、
Xは、ヨード又はブロモを表し、
R1及びR2は、互いに独立して、水素、フルオロ又はクロロを表す)で表される化合物を、まず初めに、マグネシウムと反応させ、次いで、得られた生成物を、式(III):
(式中、
PrGは、ヒドロキシル保護基を表し、
R3は、メチル又はエチルを表し、且つ
R4は、メチル、エチル若しくはメトキシを表すか、又は、R3及びR4は、それらと結合する窒素原子と一緒になって、窒素又は酸素から選択される0個又は1個又は2個のいずれかのさらなるヘテロ原子を有する4員〜6員の複素環基を表す)で表される化合物と反応させて、式(VI):
(式中、
PrGは、式(III)中と同じ意味を有し、且つ
R1及びR2は、式(V)中と同じ意味を有する)で表される化合物を得る、請求項1〜8のいずれか1項記載の方法。 - R3及びR4が、それらと結合する窒素原子と一緒になって、モルホリン−4−イル残基を表す、請求項9又は10記載の方法。
- R3及びR4が、それらと結合する窒素原子と一緒になって、モルホリン−4−イル残基を表す、請求項18記載の方法。
- PrGが2−テトラヒドロピラニル残基を表す、請求項18又は19記載の方法。
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