JP4330898B2 - Process for producing optically active 2-phenyl-2,3-dihydroxypropylazole derivative - Google Patents
Process for producing optically active 2-phenyl-2,3-dihydroxypropylazole derivative Download PDFInfo
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- JP4330898B2 JP4330898B2 JP2003035961A JP2003035961A JP4330898B2 JP 4330898 B2 JP4330898 B2 JP 4330898B2 JP 2003035961 A JP2003035961 A JP 2003035961A JP 2003035961 A JP2003035961 A JP 2003035961A JP 4330898 B2 JP4330898 B2 JP 4330898B2
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- methyl
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- 238000000034 method Methods 0.000 title claims description 25
- KUJKYSUCGVKANE-UHFFFAOYSA-N 2-phenyl-3-(1h-pyrrol-2-yl)propane-1,2-diol Chemical class C=1C=CC=CC=1C(O)(CO)CC1=CC=CN1 KUJKYSUCGVKANE-UHFFFAOYSA-N 0.000 title claims description 13
- -1 p-methoxybenzyl group Chemical group 0.000 claims description 136
- 238000006243 chemical reaction Methods 0.000 claims description 59
- 125000005843 halogen group Chemical group 0.000 claims description 48
- 238000004519 manufacturing process Methods 0.000 claims description 47
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 41
- 229910052799 carbon Inorganic materials 0.000 claims description 33
- 125000000623 heterocyclic group Chemical group 0.000 claims description 31
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 28
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 27
- 125000003277 amino group Chemical group 0.000 claims description 26
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 25
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 22
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 125000003368 amide group Chemical group 0.000 claims description 21
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 21
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 20
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 18
- 150000001721 carbon Chemical group 0.000 claims description 17
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 16
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 16
- 229910052751 metal Inorganic materials 0.000 claims description 15
- 239000002184 metal Substances 0.000 claims description 15
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 15
- 239000003153 chemical reaction reagent Substances 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 13
- 150000003852 triazoles Chemical class 0.000 claims description 13
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 11
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 11
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 11
- 125000003107 substituted aryl group Chemical group 0.000 claims description 11
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 11
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 10
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 10
- 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 claims description 10
- 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 claims description 10
- 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 claims description 10
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 9
- 230000003287 optical effect Effects 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- 125000002252 acyl group Chemical group 0.000 claims description 7
- 150000001298 alcohols Chemical class 0.000 claims description 7
- 125000005587 carbonate group Chemical group 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 claims 9
- 125000004187 tetrahydropyran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 9
- 150000002118 epoxides Chemical class 0.000 claims 4
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 37
- 239000000243 solution Substances 0.000 description 35
- 150000001875 compounds Chemical class 0.000 description 29
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 26
- 239000000203 mixture Substances 0.000 description 26
- 239000002904 solvent Substances 0.000 description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- 125000006239 protecting group Chemical group 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 13
- 125000003545 alkoxy group Chemical group 0.000 description 13
- 239000002585 base Substances 0.000 description 13
- 229910052801 chlorine Inorganic materials 0.000 description 13
- 229910052740 iodine Inorganic materials 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 125000001309 chloro group Chemical group Cl* 0.000 description 12
- 125000001424 substituent group Chemical group 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 11
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 11
- 229910052731 fluorine Inorganic materials 0.000 description 11
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 11
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 11
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 10
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 10
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 10
- 125000000753 cycloalkyl group Chemical group 0.000 description 10
- 125000001153 fluoro group Chemical group F* 0.000 description 10
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
- 239000000543 intermediate Substances 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000012299 nitrogen atmosphere Substances 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- 150000002924 oxiranes Chemical class 0.000 description 7
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 239000003429 antifungal agent Substances 0.000 description 6
- 229940121375 antifungal agent Drugs 0.000 description 6
- 238000009835 boiling Methods 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 6
- 239000006188 syrup Substances 0.000 description 6
- 235000020357 syrup Nutrition 0.000 description 6
- KXONLHJJNRJCDT-YVEFUNNKSA-N ClC[C@]([C@H](C)OCC1=CC=CC=C1)(O)C1=C(C=C(C=C1)F)F Chemical compound ClC[C@]([C@H](C)OCC1=CC=CC=C1)(O)C1=C(C=C(C=C1)F)F KXONLHJJNRJCDT-YVEFUNNKSA-N 0.000 description 5
- 239000007818 Grignard reagent Substances 0.000 description 5
- 239000003905 agrochemical Substances 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- 150000004795 grignard reagents Chemical class 0.000 description 5
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L magnesium chloride Substances [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 5
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 4
- 239000004215 Carbon black (E152) Substances 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000005456 alcohol based solvent Substances 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 244000309464 bull Species 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 239000003759 ester based solvent Substances 0.000 description 4
- 239000004210 ether based solvent Substances 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 4
- 150000002430 hydrocarbons Chemical class 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 229910052749 magnesium Inorganic materials 0.000 description 4
- 239000011777 magnesium Substances 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- 239000008096 xylene Substances 0.000 description 4
- LSCNANBNVFQJDJ-PRHODGIISA-N (2r,3r)-2-(2,4-difluorophenyl)-1-(1,2,4-triazol-1-yl)butane-2,3-diol Chemical compound C([C@@](O)([C@H](O)C)C=1C(=CC(F)=CC=1)F)N1C=NC=N1 LSCNANBNVFQJDJ-PRHODGIISA-N 0.000 description 3
- RHUBGEQUCZBUQT-VIFPVBQESA-N (3S)-1-chloro-3-phenylmethoxybutan-2-one Chemical compound ClCC(=O)[C@H](C)OCC1=CC=CC=C1 RHUBGEQUCZBUQT-VIFPVBQESA-N 0.000 description 3
- MGHBDQZXPCTTIH-UHFFFAOYSA-N 1-bromo-2,4-difluorobenzene Chemical compound FC1=CC=C(Br)C(F)=C1 MGHBDQZXPCTTIH-UHFFFAOYSA-N 0.000 description 3
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- RKOTXQYWCBGZLP-UHFFFAOYSA-N N-[(2,4-difluorophenyl)methyl]-2-ethyl-9-hydroxy-3-methoxy-1,8-dioxospiro[3H-pyrido[1,2-a]pyrazine-4,3'-oxolane]-7-carboxamide Chemical compound CCN1C(OC)C2(CCOC2)N2C=C(C(=O)NCC3=C(F)C=C(F)C=C3)C(=O)C(O)=C2C1=O RKOTXQYWCBGZLP-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 3
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 3
- 238000010306 acid treatment Methods 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 description 3
- 125000002524 organometallic group Chemical group 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 2
- LSCNANBNVFQJDJ-PELKAZGASA-N (2s,3r)-2-(2,4-difluorophenyl)-1-(1,2,4-triazol-1-yl)butane-2,3-diol Chemical compound C([C@](O)([C@H](O)C)C=1C(=CC(F)=CC=1)F)N1C=NC=N1 LSCNANBNVFQJDJ-PELKAZGASA-N 0.000 description 2
- GLXBESPTJANBLW-YOXFSPIKSA-N (3r)-1-chloro-3-(oxan-2-yloxy)butan-2-one Chemical compound ClCC(=O)[C@@H](C)OC1CCCCO1 GLXBESPTJANBLW-YOXFSPIKSA-N 0.000 description 2
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 2
- ASNHGEVAWNWCRQ-UHFFFAOYSA-N 4-(hydroxymethyl)oxolane-2,3,4-triol Chemical compound OCC1(O)COC(O)C1O ASNHGEVAWNWCRQ-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical class CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 206010017533 Fungal infection Diseases 0.000 description 2
- 206010061598 Immunodeficiency Diseases 0.000 description 2
- 208000031888 Mycoses Diseases 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- VNDYJBBGRKZCSX-UHFFFAOYSA-L Zinc bromide Inorganic materials Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 2
- UFIOMDAOMMSINM-MRXNPFEDSA-N [Si](C1=CC=CC=C1)(C1=CC=CC=C1)(C(C)(C)C)O[C@@H](C(CCl)=O)C Chemical compound [Si](C1=CC=CC=C1)(C1=CC=CC=C1)(C(C)(C)C)O[C@@H](C(CCl)=O)C UFIOMDAOMMSINM-MRXNPFEDSA-N 0.000 description 2
- 150000001241 acetals Chemical group 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 150000007980 azole derivatives Chemical class 0.000 description 2
- 229910052788 barium Inorganic materials 0.000 description 2
- 229910052790 beryllium Inorganic materials 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- VYLVYHXQOHJDJL-UHFFFAOYSA-K cerium trichloride Chemical compound Cl[Ce](Cl)Cl VYLVYHXQOHJDJL-UHFFFAOYSA-K 0.000 description 2
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 229940043279 diisopropylamine Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 230000010354 integration Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 229910000103 lithium hydride Inorganic materials 0.000 description 2
- CQRPUKWAZPZXTO-UHFFFAOYSA-M magnesium;2-methylpropane;chloride Chemical compound [Mg+2].[Cl-].C[C-](C)C CQRPUKWAZPZXTO-UHFFFAOYSA-M 0.000 description 2
- QUXHCILOWRXCEO-UHFFFAOYSA-M magnesium;butane;chloride Chemical compound [Mg+2].[Cl-].CCC[CH2-] QUXHCILOWRXCEO-UHFFFAOYSA-M 0.000 description 2
- RMHOGFJEHWOPLT-UHFFFAOYSA-M magnesium;di(propan-2-yl)azanide;chloride Chemical compound Cl[Mg+].CC(C)[N-]C(C)C RMHOGFJEHWOPLT-UHFFFAOYSA-M 0.000 description 2
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 2
- 229910052987 metal hydride Inorganic materials 0.000 description 2
- 150000004681 metal hydrides Chemical class 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 230000006340 racemization Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- FDRCDNZGSXJAFP-UHFFFAOYSA-M sodium chloroacetate Chemical compound [Na+].[O-]C(=O)CCl FDRCDNZGSXJAFP-UHFFFAOYSA-M 0.000 description 2
- 238000000527 sonication Methods 0.000 description 2
- 229910052712 strontium Inorganic materials 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- LSCNANBNVFQJDJ-QPUJVOFHSA-N (2r,3s)-2-(2,4-difluorophenyl)-1-(1,2,4-triazol-1-yl)butane-2,3-diol Chemical compound C([C@@](O)([C@@H](O)C)C=1C(=CC(F)=CC=1)F)N1C=NC=N1 LSCNANBNVFQJDJ-QPUJVOFHSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 201000002909 Aspergillosis Diseases 0.000 description 1
- 208000036641 Aspergillus infections Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- OLIBVNMJDNNSKI-UHFFFAOYSA-N CC(C)(C)[Mg] Chemical compound CC(C)(C)[Mg] OLIBVNMJDNNSKI-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000222122 Candida albicans Species 0.000 description 1
- 206010007134 Candida infections Diseases 0.000 description 1
- 229910004664 Cerium(III) chloride Inorganic materials 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 229910021592 Copper(II) chloride Inorganic materials 0.000 description 1
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- QNAYBMKLOCPYGJ-UWTATZPHSA-N L-Alanine Natural products C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 208000001388 Opportunistic Infections Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- QAKBALAAEHZEKL-UHFFFAOYSA-N [Cu].[Li]c1ccccc1 Chemical class [Cu].[Li]c1ccccc1 QAKBALAAEHZEKL-UHFFFAOYSA-N 0.000 description 1
- RIUFSTRETWGIIW-UHFFFAOYSA-N [Cu]C1=CC=CC=C1 Chemical class [Cu]C1=CC=CC=C1 RIUFSTRETWGIIW-UHFFFAOYSA-N 0.000 description 1
- ADSXDBCZNVXTRD-UHFFFAOYSA-N [Mg]C1=CC=CC=C1 Chemical class [Mg]C1=CC=CC=C1 ADSXDBCZNVXTRD-UHFFFAOYSA-N 0.000 description 1
- VVFMKHRTYGDEPI-UHFFFAOYSA-N [Ti]C1=CC=CC=C1 Chemical class [Ti]C1=CC=CC=C1 VVFMKHRTYGDEPI-UHFFFAOYSA-N 0.000 description 1
- GQDCUDAXOMFYFV-UHFFFAOYSA-N [Zn]C1=CC=CC=C1 Chemical class [Zn]C1=CC=CC=C1 GQDCUDAXOMFYFV-UHFFFAOYSA-N 0.000 description 1
- YVDWMBAZNAOWHG-UHFFFAOYSA-N acetic acid;1h-pyrrole Chemical class CC(O)=O.C=1C=CNC=1 YVDWMBAZNAOWHG-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 125000005336 allyloxy group Chemical group 0.000 description 1
- 150000003978 alpha-halocarboxylic acids Chemical class 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 159000000009 barium salts Chemical class 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- NJAPCAIWQRPQPY-UHFFFAOYSA-N benzyl hydrogen carbonate Chemical group OC(=O)OCC1=CC=CC=C1 NJAPCAIWQRPQPY-UHFFFAOYSA-N 0.000 description 1
- ATBAMAFKBVZNFJ-UHFFFAOYSA-N beryllium atom Chemical compound [Be] ATBAMAFKBVZNFJ-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 201000003984 candidiasis Diseases 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000009920 chelation Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- OPHUWKNKFYBPDR-UHFFFAOYSA-N copper lithium Chemical compound [Li].[Cu] OPHUWKNKFYBPDR-UHFFFAOYSA-N 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000006612 decyloxy group Chemical group 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000011982 enantioselective catalyst Substances 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000005912 ethyl carbonate group Chemical group 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
- 229960004884 fluconazole Drugs 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 125000004970 halomethyl group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- UKJFVOWPUXSBOM-UHFFFAOYSA-N hexane;oxolane Chemical compound C1CCOC1.CCCCCC UKJFVOWPUXSBOM-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 125000006301 indolyl methyl group Chemical group 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- 150000002680 magnesium Chemical class 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- PKMBLJNMKINMSK-UHFFFAOYSA-N magnesium;azanide Chemical compound [NH2-].[NH2-].[Mg+2] PKMBLJNMKINMSK-UHFFFAOYSA-N 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- VYUWVGDHZQNXOP-VIFPVBQESA-N methyl (2s)-2-phenylmethoxypropanoate Chemical compound COC(=O)[C@H](C)OCC1=CC=CC=C1 VYUWVGDHZQNXOP-VIFPVBQESA-N 0.000 description 1
- 125000005911 methyl carbonate group Chemical group 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- AFFLGGQVNFXPEV-UHFFFAOYSA-N n-decene Natural products CCCCCCCCC=C AFFLGGQVNFXPEV-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 125000005447 octyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 125000000109 phenylethoxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical class [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- AHIHJODVQGBOND-UHFFFAOYSA-N propan-2-yl hydrogen carbonate Chemical group CC(C)OC(O)=O AHIHJODVQGBOND-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005412 pyrazyl group Chemical group 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 125000005554 pyridyloxy group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 229910052701 rubidium Inorganic materials 0.000 description 1
- IGLNJRXAVVLDKE-UHFFFAOYSA-N rubidium atom Chemical compound [Rb] IGLNJRXAVVLDKE-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005297 thienyloxy group Chemical group S1C(=CC=C1)O* 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
Landscapes
- Pyrane Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
【０００１】
【発明の属する技術分野】
本発明は、医農薬分野をはじめ多方面において製造上の重要な化合物である光学活性２−フェニル−２，３−ジヒドロキシプロピルアゾール誘導体の短工程な新規製造法に関するものである。
【０００２】
【従来の技術】
近年、ＡＩＤＳ等の感染による免疫不全患者の増加や高度医療の進展または高齢者の増加等による免疫力低下患者の増大によって、いわゆる日和見感染症に代表される真菌感染症が問題となっている。特に免疫低下者にとって、カンジタ症やアスペルギルス症等の深在性の真菌感染症は、生命にも拘わる重篤な場合も少なくなく、医療現場においては注意すべき感染症の一つである。 従来、これら感染症に対してはフルコナゾールに代表されるアゾール系の抗真菌剤が多用されてきたが、近年、耐性菌の出現や基本的な作用不足が指摘されるようになり、より広範囲な菌種に有効でより強力な治療薬の開発が望まれている（医薬ジャーナル, vol37(7), pp.115-119）。
【０００３】
一方、近年開発中のアゾール系の抗真菌剤は、構造がより複雑化する傾向にあり、特にアゾールメチル基が結合する不斉炭素およびそれに連続して存在する不斉炭素部位をいかに効率よく構築するかが大きな技術上の問題点となっている（J.Med.Chem., Vol.41, pp.1869-1882, 1998）。しかし現在に至るまで、工業的な観点から、安価でかつ安定的な製造方法は確立されていない。
【０００４】
以下に従来の製造技術に関して述べる。
連続する不斉部位の構築方法として、いずれの場合もα−ヒドロキシフェニルケトン誘導体を経由して、ケトン基に対するジアステレオ選択的な増炭エポキシ化を行なうことで構築している（Chem.Pharm.Bull., Vol.41(6), pp.1035-1042, 1993）。しかし従来の製造法は、（１）ジアステレオ選択性が約４：１と悪く、（２）目的とする異性体のみ単離しようとすると低収率であり、（３）工程数が長く、単離、精製工程が極めて煩雑であり、（４）反応条件によってはラセミ化する等、工業的に見て極めて問題のある製造方法であった。加えて、α−ヒドロキシフェニルケトン誘導体自体の製造方法も多工程（Bioorg.Med.Chem.Lett., vol1(7), pp.349-352, 1991）、または不斉触媒等の高価な反応試薬（Tetrahedron Letters, vol37(36), pp.6531-6534, 1996）を必要とし、工業的な製造方法としては十分満足するものではなかった。近年、これらの既存法を改良したL-アラニンを出発原料とする新規な製造法も報告されているが（US6300522）、α−ヒドロキシフェニルケトン誘導体を経由する点において根本的な問題を解決には至っておらず、必ずしも工業的に満足する製造方法ではなかった。
【０００５】
このように、より有用な新規アゾール系の抗真菌剤の開発が望まれているにも拘わらず、２つの不斉炭素を有する光学活性な化合物であるため、従来の製造技術では、工業的な観点から安価でかつ安定的な製造方法は確立されておらず、これら中間体化合物に関して、より効率的な新規製造法の早急な開発が望まれている。
【０００６】
【特許文献１】
米国特許第6300522号公報
【０００７】
【非特許文献１】
医薬ジャーナル, vol.37(7), pp.115-119
【０００８】
【非特許文献２】
J.Med.Chem., Vol.41, pp.1869-1882, 1998
【０００９】
【非特許文献３】
Chem.Pharm.Bull., Vol.41(6), pp.1035-1042, 1993
【００１０】
【非特許文献４】
Tetrahedron Letters, vol.37(36), pp.6531-6534, 1996
【００１１】
【発明が解決しようとする課題】
本発明の課題は、医・農薬分野における有用な化合物であり、特に光学活性なアゾール系抗真菌剤の製造過程において極めて重要な中間体となる、光学活性２−フェニル−２，３−ジヒドロキシプロピルアゾール誘導体の製造に関して、工業的な観点から、短い工程で安価にかつ安定的に製造する方法と新規な中間体を提供することである。
【００１２】
【課題を解決するための手段】
本発明者らは、上記課題を解決する為に鋭意検討を重ねた結果、光学活性なα−ヒドロキシカルボン酸誘導体を出発原料とし、ハロ酢酸誘導体と反応させ、医農薬の非常に重要な中間体である光学活性なハロメチルケトン誘導体を製造し、さらに、アルキル化反応を、保護基の選択と反応条件によって、自由にアンチあるいはシン配置にできる、高ジアステレオ選択的反応を見出し、医農薬の非常に重要な中間体である光学活性ハロメチルアルコール誘導体を製造し、さらにトリアゾールまたはイミダゾールと反応させ、光学活性アゾールメチルアルコール誘導体を製造し、さらに、選択的に脱保護を行うことで、医農薬の非常に重要な中間体である光学活性２−フェニル−２，３−ジヒドロキシプロピルアゾール誘導体を得るまったく新しい製造ルートを見出した。
【００１３】
上記反応ルートにおいては、反応に伴なうラセミ化がほとんど無く、高い光学純度で望む立体配置を有する化合物を選択的に製造できることを見出した。特に、光学活性なα−ヒドロキシカルボン酸誘導体として安価な乳酸誘導体を利用し、保護基としてシリル系の保護基を用い、光学活性な新規シリルオキシ−ハロアルキルケトン誘導体を経由し、非常に高いシン選択性でアルキル化が行えることを見出し、光学活性なアゾール系抗真菌剤の製造のために極めて重要な中間体である新規光学活性シリルオキシ−ハロメチルアルコール誘導体および光学活性シリルオキシ−エポキシド誘導体を得られることを見出した。これらにより、光学活性なアゾール系抗真菌剤の製造のために極めて重要な中間体であり、高い光学純度で望む立体配置を有する２−フェニル−２，３−ジヒドロキシプロピルアゾール誘導体の製造が、工業的な観点から短い工程で安価にかつ安定的に行い得ることが可能となり、本発明を完成するに至った。
【００１４】
すなわち、本発明は以下の[１]〜[９]に記載のとおりである。
[１] 一般式（１）[化９]
【００１５】
【化９】
（式中Ｒ１は置換されてもよいアルキル基、置換されてもよいアラルキル基、置換されてもよいアリール基または置換されてもよいヘテロ環を示し、Ｒ２は水酸基の保護基としてのエーテル系の保護基、アセタール系の保護基またはシリル系の保護基を示し、Ｒ３は水酸基、ハロゲン原子、置換されていてもよいアシル基、置換されてもよいカーボネート基、置換されてもよいアルキルオキシ基、置換されてもよいアラルキルオキシ基、置換されてもよいフェノキシ基または置換されてもよいアミノ基を示し、炭素原子上の＊は不斉炭素を意味し、Ｒ配置あるいはＳ配置を取ることができる。）で表されるα−ヒドロキシカルボン酸誘導体と、一般式（２）[化１０]
【００１７】
【化１０】
（式中、Ｒ４は水素原子、置換されてもよいアルキル基、置換されてもよいアラルキル基、置換されてもよいアリール基、アルカリ金属またはアルカリ土類金属を示し、Ｘはハロゲン原子を示す。）で表されるハロ酢酸誘導体を塩基性条件下反応させ、一般式（３）[化１１]
【００１９】
【化１１】
（式中Ｒ１、Ｒ２、Ｘおよび＊は前記と同義である。）で表されるハロメチルケトン誘導体を製造し、さらに該ハロメチルケトン誘導体を一般式（４）[化１２]
【００２１】
【化１２】
（式中Ｒ５およびＲ６は互いに独立してハロゲン原子、アルキルオキシカルボニル基、アリールオキシカルボニル基、置換されてもよいアミノ基、置換されてもよいアミド基、置換されてもよいアルキル基、置換されてもよいアルキルオキシ基、置換されてもよいアラルキル基、置換されてもよいアラルキルオキシ基、置換されてもよいフェニル基、置換されてもよいフェニルオキシ基、置換されてもよいヘテロ環または置換されてもよいヘテロ環オキシ基を示し、ＡはＬｉ、ＭｇＸ、ＺｎＸ、ＴｉＸ3、Ｔｉ（ＯＲ７）3、ＣｕＸまたはＣｕＬｉを示す。ただし、Ｘはハロゲン原子を示し、Ｒ７は低級アルキル基を示す。）で表されるフェニル金属試薬をジアステレオ選択的に反応させ、一般式（５）[化１３]
【００２３】
【化１３】
（式中Ｒ１、Ｒ２、Ｒ５、Ｒ６、Ｘおよび＊は前記と同義である。）で表される光学活性ハロメチルアルコール誘導体を製造し、さらに該光学活性ハロメチルアルコール誘導体をトリアゾールまたはイミダゾールと反応させ、一般式（６）[化１４]
【００２５】
【化１４】
（式中Ｒ１、Ｒ２、Ｒ５、Ｒ６および＊は前記と同義である。Ｙは炭素原子又は窒素原子を示す。）で表される光学活性アゾールメチルアルコール誘導体を製造し、さらに該光学活性アゾールメチルアルコール誘導体を選択的に脱保護することで一般式（７）[化１５]
【００２７】
【化１５】
（式中Ｒ１、Ｒ５、Ｒ６、Ｙおよび＊は前記と同義である。）で表される光学活性２−フェニル−２，３−ジヒドロキシプロピルアゾール誘導体を製造する方法であり、
[２] 一般式（１）（式中Ｒ１、Ｒ２、Ｒ３＊は前記と同義である。）で表されるα−ヒドロキシカルボン酸誘導体と、一般式（２）（式中、Ｒ４、Ｘは前記と同義である。）で表されるハロ酢酸誘導体を塩基性条件下反応させ、一般式（３）（式中Ｒ１、Ｒ２、Ｘおよび＊は前記と同義である。）で表されるハロメチルケトン誘導体を製造し、さらに該ハロメチルケトン誘導体に一般式（４）（式中Ｒ５、Ｒ６、Ａ、Ｘ、Ｒ７は前記と同義である。）で表されるフェニル金属試薬をジアステレオ選択的に反応させ、一般式（８）[化１６]
【００２９】
【化１６】
（式中Ｒ１、Ｒ２、Ｒ５、Ｒ６、および＊は前記と同義である。）で表される光学活性エポキシド誘導体を製造し、さらに該光学活性エポキシド誘導体をトリアゾールまたはイミダゾールと反応させ、一般式（６）（式中Ｒ１、Ｒ２、Ｒ５、Ｒ６、Ｙおよび＊は前記と同義である。）で表される光学活性アゾールメチルアルコール誘導体を製造し、さらに該光学活性アゾールメチルアルコール誘導体を選択的に脱保護することで一般式（７）（式中Ｒ１、Ｒ５、Ｒ６、Ｙおよび＊は前記と同義である。）で表される光学活性２−フェニル−２，３−ジヒドロキシプロピルアゾール誘導体を製造する方法であり、
[３] 一般式（３）（式中Ｒ１、Ｒ２、Ｘおよび＊は前記と同義である。）で表されるハロメチルケトン誘導体と、一般式（４）（式中Ｒ５、Ｒ６、Ａは前記と同義である。）で表されるフェニル金属試薬をジアステレオ選択的に反応させ、一般式（５）（式中Ｒ１、Ｒ２、Ｒ５、Ｒ６、Ｘおよび＊は前記と同義である。）で表される光学活性ハロメチルアルコール誘導体を製造する方法であり、
[４] 一般式（３）（式中Ｒ１、Ｒ２、Ｘおよび＊は前記と同義である。）で表されるハロメチルケトン誘導体と、一般式（４）（式中Ｒ５、Ｒ６、Ａは前記と同義である。）で表されるフェニル金属試薬をジアステレオ選択的に反応させ、一般式（８）（式中Ｒ１、Ｒ２、Ｒ５、Ｒ６、Ｘおよび＊は前記と同義である。）で表される光学活性エポキシド誘導体を製造する方法であり、
[５] 一般式（５）（式中Ｒ１、Ｒ２、Ｒ５、Ｒ６、Ｘおよび＊は前記と同義である。）で表される光学活性ハロメチルアルコール誘導体、あるいは一般式（８）（式中Ｒ１、Ｒ２、Ｒ５、Ｒ６、Ｘおよび＊は前記と同義である。）で表される光学活性エポキシド誘導体と、トリアゾールまたはイミダゾールと反応させ、一般式（６）（式中Ｒ１、Ｒ２、Ｒ５、Ｒ６、Ｙおよび＊は前記と同義である。）で表される光学活性アゾールメチルアルコール誘導体を製造する方法であり、
[６] 一般式（６）（式中Ｒ１、Ｒ２、Ｒ５、Ｒ６、Ｙおよび＊は前記と同義である。）で表される光学活性アゾールメチルアルコール誘導体を脱保護し、一般式（７）（式中Ｒ１、Ｒ５、Ｒ６、Ｙおよび＊は前記と同義である。）で表される光学活性２−フェニル−２，３−ジヒドロキシプロピルアゾール誘導体を製造する方法であり、
[７] Ｒ１がメチル基である［１］から［６］の何れか一項に記載の製造法であり、
[８] Ｒ１がメチル基、Ｒ５、Ｒ６がハロゲン原子である［１］から［６］の何れか一項に記載の製造法であり、
[９] 一般式（５）においてＲ１がメチル基、Ｒ５、Ｒ６がハロゲン原子である光学活性ハロメチルアルコール誘導体である。
【００３１】
【発明の実施の形態】
次に本発明の化合物についてさらに詳細に説明する。
本発明において「置換されてもよいアルキル基」とは、アルキル基の任意の位置が置換されてもよいアルキル基を意味する。アルキル基としては、メチル基、エチル基、イソプロピル基、tert-ブチル基、ペンチル基、ヘキシル基、オクチル基、デシル基またはアリル基等を挙げることができる。置換基としては、水酸基、メトキシ基、ベンジルオキシ基またはメトキシエトキシ基等のアルコキシ基、フェノキシ基、ニトロ基、アミノ基、アミド基、カルボキシル基、アルコキシカルボニル基、フェノキシカルボニル基あるいはフッ素原子、塩素原子、臭素原子またはヨウ素原子等のハロゲン原子等を挙げることができる。
【００３２】
本発明において「置換されてもよいアラルキル基」とは、アラルキル基の任意の位置が置換されてもよいアラルキル基を意味する。アラルキル基としては、ベンジル基、ナフチルメチル基、フェニルエチル基または９−フルオレニルメチル基等が挙げられる。置換基としては、メチル基、tert-ブチル基またはベンジル基等のアルキル基、シクロプロパン、シクロペンタンまたはシクロヘキサン等のシクロアルキル基、フェニル基、水酸基、メトキシ基、ベンジルオキシ基またはメトキシエトキシ基等のアルコキシ基、フェノキシ基、ニトロ基、アミノ基、アミド基、カルボキシル基、アルコキシカルボニル基、フェノキシカルボニル基あるいはフッ素原子、塩素原子、臭素原子またはヨウ素原子等のハロゲン原子等を挙げることができる。
【００３３】
本発明において「置換されてもよいアリール基」とは、アリール基の任意の位置が置換されてもよいアリール基を意味する。アリール基としては、フェニル基、ナフチル基、アントラセニル基、フルオレニル基またはフェナントレニル基等を挙げることができる。置換基としては、メチル基、tert-ブチル基またはベンジル基等のアルキル基、シクロプロパン、シクロペンタンまたはシクロヘキサン等のシクロアルキル基、フェニル基、水酸基、メトキシ基、ベンジルオキシ基またはメトキシエトキシ基等のアルコキシ基、フェノキシ基、ニトロ基、アミノ基、アミド基、カルボキシル基、アルコキシカルボニル基、フェノキシカルボニル基あるいはフッ素原子、塩素原子、臭素原子またはヨウ素原子等のハロゲン原子等を挙げることができる。
【００３４】
本発明において「置換されていてもよいヘテロ環」とは、ヘテロ環の任意の位置が置換されていてもよいヘテロ環を意味する。ヘテロ環としては、テトラヒドロピラニル基、テトラヒドロフラニル基、テトラヒドロチエニル基、ピペリジル基、モルホリニル基、ピペラジニル基、ピロリル基、フリル基、チエニル基、ピリジル基、フルフリル基、テニル基、ピリジルメチル基、ピリミジル基、ピラジル基、イミダゾイル基、イミダゾイルメチル基、インドリル基、インドリルメチル基、イソキノリル基、キノリル基またはチアゾリル基等が挙げられる。置換基としては、メチル基、tert-ブチル基またはベンジル基等のアルキル基、シクロプロパン、シクロペンタンまたはシクロヘキサン等のシクロアルキル基、フェニル基、水酸基、メトキシ基、ベンジルオキシ基またはメトキシエトキシ基等のアルコキシ基、フェノキシ基、ニトロ基、アミノ基、アミド基、カルボキシル基、アルコキシカルボニル基、フェノキシカルボニル基あるいはフッ素原子、塩素原子、臭素原子またはヨウ素原子等のハロゲン原子等を挙げることができる。
【００３５】
本発明において「水酸基の保護基としてのエーテル系の保護基」とは、水酸基を保護する目的でエーテル結合を有する保護基を意味し、メチル基、エチル基、tert-ブチル基、オクチル基、アリル基、ベンジル基、p-メトキシベンジル基、フルオレニル基、トリチル基、ベンズヒドリル基等を挙げることができる。
【００３６】
本発明において「アセタール系の保護基」とは、水酸基を保護する目的でアセタール結合を有する保護基を意味し、メトキシメチル基、メトキシエトキシメチル基、テトラヒドロピラン−２−イル基、テトラヒドロフラン−２−イル基等を挙げることができる。
【００３７】
本発明において「シリル系の保護基」とは、水酸基を保護する目的でシリルオキシ結合を有する保護基を意味し、トリメチルシリル基、トリエチルシリル基、tert-ブチルジメチルシリル基、tert-ブチルジフェニルシリル基等を挙げることができる。
【００３８】
本発明において「ハロゲン原子」としては、フッ素、塩素、臭素またはヨウ素等を挙げることができる。
【００３９】
本発明において「置換されていてもよいアシル基」とは、アシル基の任意の位置が置換されていてもよいアシル基を意味する。アシル基としては、ホルミル基、アセチル基、プロピオニル基、ピバロイル基、ベンゾイル基等を挙げることができる。置換基としては、メチル基、tert-ブチル基またはベンジル基等のアルキル基、シクロプロパン、シクロペンタンまたはシクロヘキサン等のシクロアルキル基、フェニル基、水酸基、メトキシ基、ベンジルオキシ基またはメトキシエトキシ基等のアルコキシ基、フェノキシ基、ニトロ基、アミノ基、アミド基、カルボキシル基、アルコキシカルボニル基、フェノキシカルボニル基あるいはフッ素原子、塩素原子、臭素原子またはヨウ素原子等のハロゲン原子等を挙げることができる。
【００４０】
本発明において「置換されていてもよいカーボネート基」とは、カーボネート基の任意の位置が置換されていてもよいカーボネート基を意味する。カーボネート基としては、メチルカーボネート基、エチルカーボネート基、イソプロピルカーボネート基、ベンジルカーボネート基等を挙げることができる。置換基としては、メチル基、tert-ブチル基またはベンジル基等のアルキル基、シクロプロパン、シクロペンタンまたはシクロヘキサン等のシクロアルキル基、フェニル基、水酸基、メトキシ基、ベンジルオキシ基またはメトキシエトキシ基等のアルコキシ基、フェノキシ基、ニトロ基、アミノ基、アミド基、カルボキシル基、アルコキシカルボニル基、フェノキシカルボニル基あるいはフッ素原子、塩素原子、臭素原子またはヨウ素原子等のハロゲン原子等を挙げることができる。
【００４１】
本発明において「置換されてもよいアルキルオキシ基」とは、アルキルオキシ基の任意の位置が置換されてもよいアルキルオキシ基を意味する。アルキルオキシ基としては、メトキシ基、エトキシ基、イソプロポキシ基、tert-ブトキシ基、ペンチルオキシ基、ヘキシルオキシ基、オクチルオキシ基、デシルオキシ基またはアリルオキシ基等を挙げることができる。置換基としては、水酸基、メトキシ基、ベンジルオキシ基またはメトキシエトキシ基等のアルコキシ基、フェノキシ基、ニトロ基、アミノ基、アミド基、カルボキシル基、アルコキシカルボニル基、フェノキシカルボニル基あるいはフッ素原子、塩素原子、臭素原子またはヨウ素原子等のハロゲン原子等を挙げることができる。
【００４２】
本発明において「置換されてもよいアラルキルオキシ基」とは、アラルキルオキシ基の任意の位置が置換されてもよいアラルキルオキシ基を意味する。アラルキルオキシ基としては、ベンジルオキシ基、ナフチルメチルオキシ基、フェニルエチルオキシ基または９−フルオレニルメチルオキシ基等が挙げられる。置換基としては、メチル基、tert-ブチル基またはベンジル基等のアルキル基、シクロプロパン、シクロペンタンまたはシクロヘキサン等のシクロアルキル基、フェニル基、水酸基、メトキシ基、ベンジルオキシ基またはメトキシエトキシ基等のアルコキシ基、フェノキシ基、ニトロ基、アミノ基、アミド基、カルボキシル基、アルコキシカルボニル基、フェノキシカルボニル基あるいはフッ素原子、塩素原子、臭素原子またはヨウ素原子等のハロゲン原子等を挙げることができる。
【００４３】
本発明において「置換されてもよいフェノキシ基」とは、フェノキシ基の任意の位置が置換されてもよいフェノキシ基を意味する。置換基としては、メチル基、tert-ブチル基またはベンジル基等のアルキル基、シクロプロパン、シクロペンタンまたはシクロヘキサン等のシクロアルキル基、フェニル基、水酸基、メトキシ基、ベンジルオキシ基またはメトキシエトキシ基等のアルコキシ基、フェノキシ基、ニトロ基、アミノ基、アミド基、カルボキシル基、アルコキシカルボニル基、フェノキシカルボニル基あるいはフッ素原子、塩素原子、臭素原子またはヨウ素原子等のハロゲン原子等を挙げることができる。
【００４４】
本発明において「置換されてもよいアミノ基」とは、アミノ基の任意の位置が置換されてもよいアミノ基を意味する。置換基としては、メチル基、tert-ブチル基またはベンジル基等のアルキル基、シクロプロパン、シクロペンタンまたはシクロヘキサン等のシクロアルキル基、フェニル基等を挙げることができる。
【００４５】
本発明において「アルカリ金属」とは、リチウム、ナトリウム、カリウム、ルビジウム、セシウム等を挙げることができる。
【００４６】
本発明において「アルカリ土類金属塩」とは、マグネシウム、カルシウム、ストロンチウム、バリウムベリリウム等の塩を意味し、ハロゲン化マグネシウム、アルコキシマグネシウム、ハロゲン化カルシウム、アルコキシカルシウム、ハロゲン化ストロンチウム、ハロゲン化バリウム、ハロゲン化ベリリウム等が挙げられる。さらに詳しくは−ＭｇＣｌ、−ＭｇＢｒ、−ＭｇＯＭｅ、−ＭｇＯＥｔ等のマグネシウム塩、−ＣａＣｌ、−ＣａＢｒ、−ＣａＯＭｅ、−ＣａＯＥｔ等のカルシウム塩、−ＢａＣｌ、−ＢａＢｒ、−ＢａＯＭｅ、−ＢａＯＥｔ等のバリウム塩を挙げることができる。また、アゾール酢酸誘導体２分子が１つのアルカリ土類金属塩を形成することもできる。
【００４７】
本発明において「アルキルオキシカルボニル基」としては、メトキシカルボニル基、エトキシカルボニル基、tert-ブトキシカルボニル基等を挙げることができる。
【００４８】
本発明において「アリールオキシカルボニル基」としては、フェノキシカルボニル、ナフチルオキシカルボニル基等を挙げることができる。
【００４９】
本発明において「置換されてもよいアミド基」とは、アミド基の任意の位置が置換されてもよいアミノ基を意味する。置換基としては、メチル基、tert-ブチル基またはベンジル基等のアルキル基、シクロプロパン、シクロペンタンまたはシクロヘキサン等のシクロアルキル基、フェニル基等を挙げることができる。
【００５０】
本発明において「置換されていてもよいヘテロ環オキシ基」とは、ヘテロ環オキシ基の任意の位置が置換されていてもよいヘテロ環オキシ基を意味する。ヘテロ環オキシ基としては、テトラヒドロピラニルオキシ基、テトラヒドロフラニルオキシ基、テトラヒドロチエニルオキシ基、ピペリジルオキシ基、モルホリニルオキシ基、ピペラジニルオキシ基、ピロリルオキシ基、フリルオキシ基、チエニルオキシ基、ピリジルオキシ基、フルフリルオキシ基、テニルオキシ基、ピリジルメチルオキシ基、ピリミジルオキシ基、ピラジルオキシ基、イミダゾイルオキシ基、イミダゾイルメチルオキシ基、インドリルオキシ基、インドリルメチルオキシ基、イソキノリルオキシ基、キノリルオキシ基またはチアゾリルオキシ基等が挙げられる。置換基としては、メチル基、tert-ブチル基またはベンジル基等のアルキル基、シクロプロパン、シクロペンタンまたはシクロヘキサン等のシクロアルキル基、フェニル基、水酸基、メトキシ基、ベンジルオキシ基またはメトキシエトキシ基等のアルコキシ基、フェノキシ基、ニトロ基、アミノ基、アミド基、カルボキシル基、アルコキシカルボニル基、フェノキシカルボニル基あるいはフッ素原子、塩素原子、臭素原子またはヨウ素原子等のハロゲン原子等を挙げることができる。
【００５１】
一般式（３）のハロメチルケトン誘導体から一般式（５）の光学活性ハロメチルアルコール誘導体あるいは（８）の光学活性エポキシド誘導体へのジアステレオ選択的に反応とは、一般式（３）のハロメチルケトン誘導体の不斉炭素の立体に対し選択的に新しい不斉炭素を生じることであり、アンチ選択的とは、ある面上に炭素鎖をジグザグに置いたときに、光学活性な炭素原子上のＲ２Ｏ−基に対して逆側に水酸基を生じるものであり、シン選択的とは同じ側に水酸基を生じる選択性を意味する。ジアステレオ選択的に反応し得られた一般式（５）の光学活性ハロメチルアルコール誘導体は反応条件下あるいは塩基や熱等の処理によりジアステレオ選択性を保ったまま一般式（８）で表される光学活性エポキシドに誘導することができる。すなわち、アンチ選択的とは一般式（９）[化１７]
【００５２】
【化１７】
に表されるようなジアステレオ選択性であり、（Ｓ）体から（Ｓ，Ｓ）体を生じ、（Ｒ）体から（Ｒ，Ｒ）体を生じる反応である。
また、シン選択性とは一般式（１０）［化１８］
【００５４】
【化１８】
に表されるようなジアステレオ選択性であり、（Ｓ）体から（Ｓ，Ｒ）体を生じ、（Ｒ）体から（Ｒ，Ｓ）体を生じる反応である。
【００５６】
以下に、本発明の代表的な製造法について説明する。
[１] 一般式（３）で表されるハロメチルケトン誘導体の製造法について述べる。
一般式（１）で表されるα−ヒドロキシカルボン酸誘導体に対し、一般式（２）で表されるハロ酢酸誘導体を塩基性条件下にて反応させることで一般式（３）で表されるハロメチルケトン誘導体を製造することができる。本反応は、炭素−炭素結合反応の後に、あるいは同時に脱炭酸反応を進行させることで、効率良くハロメチル基を導入することが可能である。また本反応において、出発原料に光学活性体を用いるが、反応による光学純度の低下はほとんど観察されない。
【００５７】
使用可能な塩基としては特に制限は無いが、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム等の無機塩基が挙げられる。また、トリエチルアミン、ピリジン、１，８−ジアザビシクロウンデセン等の有機アミン塩基が挙げられる。また、ナトリウムメトキシド、ナトリウムエトキシド、カリウムt-ブトキシド等のアルコキシドが挙げられる。また、水素化リチウム、水素化ナトリウム等の金属水素化物が挙げられる。また、アルキルリチウム、Grignard試薬等の有機金属塩基、中でもn-ブチルリチウム、エチルマグネシウムブロマイド、n-ブチルマグネシウムクロライド、tert-ブチルマグネシウムクロライド等が挙げられる。また、ナトリウムアミド、リチウムアミド、マグネシウムアミド等の金属アミド塩基、中でもリチウムジイソプロピルアミド、ハロゲン化マグネシウムジアルキルアミド、中でも塩化マグネシウムジイソプロピルアミド等の金属アミド塩基等を挙げることができる。これらの塩基は単独あるいは併用して用いることができる。
【００５８】
使用可能な溶媒としては、反応の進行を妨げないものであれば特に制限はないが、水、メタノール、エタノール、ブタノール等のアルコール系溶媒、ヘキサン、トルエン、キシレン等の炭化水素系溶媒、酢酸エチル、酢酸ブチル等のエステル系溶媒、ジエチルエーテル、ジオキサン、エチレングリコールジメチルエーテル、テトラヒドロフラン等のエーテル系溶媒、クロロホルム、ジクロロメタン等のハロゲン系溶媒、アセトニトリル、ジメチルホルムアミド、ジメチルスルホキシド、ジメチルイミダゾリジノン等を挙げることができる。またこれら溶媒は単独で、あるいは２種以上の任意の比率での混合溶媒として使用可能である。
【００５９】
反応温度に関しては、−７８℃から使用する溶媒の沸点まで実施可能であるが、好ましくは、−２０℃から溶媒の沸点の温度範囲である。反応時間は特に制限は無いが、数分間から２４時間、好ましくは３０分間から６時間の範囲である。
【００６０】
[２] 一般式（５）で表されるハロメチルアルコール誘導体の製造法または（８）で表されるエポキサイド誘導体の製造法について述べる。
一般式（３）で表されるハロメチルケトン誘導体に対し、一般式（４）で表されるフェニル金属試薬を反応させることで一般式（５）または（８）で表される誘導体を製造することができる。この反応において、Ｒ２で示される水酸基の保護基とＡで示される金属種の組み合わせにより、ジアステレオ選択性が変わり、適切な保護基と金属種を組み合わせることで、自由にシンあるいはアンチの立体を作り分けることができる。
【００６１】
概論すれば、Ｒ２Ｏ基における酸素原子と反応に関与するカルボニル基が金属の配位により立体が固定された、いわゆるキレーションモデルにしたがって有機金属試薬が反応することで、高いアンチのジアステレオ選択性で目的物を得ることができる。より具体的には、Ｓ配置の化合物からはＳ−Ｒ配置の化合物を、Ｒ配置の化合物からはＲ−Ｓ配置の化合物を選択的に製造することができる。保護基として具体的にはベンジル基、メトキシメチル基等を用い、有機金属試薬としてGrignard試薬を用いることで高いアンチ選択性（＞９：１）で目的の反応が行うことができる。
【００６２】
また、Ｒ２で示される水酸基の保護基を立体的に大きくし、適切な金属試薬を選択することで、高いシン選択性で目的物を得ることができる。より具体的には、Ｓ配置の化合物からはＳ−Ｓ配置の化合物を、Ｒ配置の化合物からはＲ−Ｒ配置の化合物を高いシン選択性（＞５：１）で製造することができる。具体的には、保護基としてシリル系の保護基を用いることで非常に高いシン選択性（＞７：１）で目的の反応が行うことができる。シリル系の保護基としては、トリメチルシリル基、ｔ−ブチルジメチルシリル基、ｔ−ブチルジフェニルシリル基、トリエチルシリル基等が挙げられる。
一般式（８）で表されるエポキサイド誘導体は、高いジアステレオ選択性で一般式（５）で表されるハロメチルアルコール誘導体が生成された後、反応条件下あるいは塩基や熱等の処理により環化反応が起こることで得ることができる。この場合、初めの反応で生じたジアステレオ選択性は失われることはない。
【００６３】
また、本反応において、出発原料を光学活性体とした場合、反応による光学純度の低下はほとんど観察されない。使用可能なフェニル金属化合物としては、フェニルリチウム誘導体、フェニルマグネシウム誘導体、フェニル亜鉛誘導体、フェニルチタン誘導体、フェニル銅誘導体またはフェニル銅リチウム誘導体等を挙げることができる。さらに、反応系に様々の添加物を加え、ジアステレオ選択性を変化させ、あるいは収率を向上させることができる。添加物として具体的には、ルイス酸、４級アンモニウム塩、等が挙げられる。さらに詳しくは、ＣｅＣｌ３、ＭｇＢｒ2、ＭｇＣｌ2、ＺｎＣｌ2、ＺｎＢｒ2、ＣｕＣｌ2、ＴｉＣｌ4、ＢＦ3、ＡｌＣｌ3、ＳｎＣｌ4、ＳｎＣｌ2等が挙げられる。
【００６４】
使用可能な溶媒としては、反応の進行を妨げないものであれば特に制限はないが、水、メタノール、エタノール、ブタノール等のアルコール系溶媒、ヘキサン、トルエン、キシレン等の炭化水素系溶媒、酢酸エチル、酢酸ブチル等のエステル系溶媒、ジエチルエーテル、ジオキサン、エチレングリコールジメチルエーテル、テトラヒドロフラン等のエーテル系溶媒、クロロホルム、ジクロロメタン等のハロゲン系溶媒、アセトニトリル、ジメチルホルムアミド、ジメチルスルホキシド、ジメチルイミダゾリジノン等を挙げることができる。またこれら溶媒は単独で、あるいは２種以上の任意の比率での混合溶媒として使用可能である。
【００６５】
反応温度に関しては、−７８℃から使用する溶媒の沸点まで実施可能であるが、好ましくは、−４０℃から室温の範囲である。反応時間は特に制限は無いが、数分間から２４時間、好ましくは３０分間から６時間の範囲である。
【００６６】
[３]一般式（６）で表されるアゾールメチルアルコール誘導体の製造法について述べる。
一般式（５）または（８）で表される誘導体に対し、トリアゾールまたはイミダゾールを反応させることで一般式（６）で表されるアゾールメチルアルコール誘導体を製造することができる。反応は、トリアゾールまたはイミダゾールを単独あるいは塩基共存下で実施することが可能である。使用可能な塩基としては特に制限は無いが、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム等の無機塩基、トリエチルアミン、ピリジン、１，８−ジアザビシクロウンデセン等の有機アミン塩基、水素化リチウム、水素化ナトリウム等の金属水素化物、n-ブチルリチウム、エチルマグネシウムブロマイド、n-ブチルマグネシウムクロライド、tert-ブチルマグネシウムクロライド等の有機金属塩基、またはナトリウムアミド、リチウムジイソプロピルアミド、塩化マグネシウムジイソプロピルアミド等の金属アミド塩基等を挙げることができる。
【００６７】
使用可能な溶媒としては、反応の進行を妨げないものであれば特に制限はないが、水、メタノール、エタノール、ブタノール等のアルコール系溶媒、ヘキサン、トルエン、キシレン等の炭化水素系溶媒、酢酸エチル、酢酸ブチル等のエステル系溶媒、ジエチルエーテル、ジオキサン、エチレングリコールジメチルエーテル、テトラヒドロフラン等のエーテル系溶媒、クロロホルム、ジクロロメタン等のハロゲン系溶媒、アセトニトリル、ジメチルホルムアミド、ジメチルスルホキシド等を挙げることができる。またこれら溶媒は単独で、あるいは２種以上の任意の比率での混合溶媒として使用可能である。
【００６８】
反応温度に関しては、−２０℃から使用する溶媒の沸点まで実施可能であるが、好ましくは、０℃から溶媒の沸点の温度範囲である。反応時間は特に制限は無いが、数分から７２時間、好ましくは３０分間から１２時間の範囲である。
【００６９】
[４]一般式（７）で表される光学活性２−フェニル−２，３−ジヒドロキシプロピルアゾール誘導体の製造法について述べる。
一般式（６）で表される光学活性アゾールメチルアルコール誘導体のＲ２で表される水酸基部分の保護基を選択的に脱保護化することで、一般式（７）で表される光学活性２−フェニル−２，３−ジヒドロキシプロピルアゾール誘導体を製造することができる。水酸基の脱保護方法は、脱保護される部分以外の構造に変化を与えない方法であれば特に制限はない。エーテル系の保護基の場合は、塩酸、硫酸、トリフルオロ酢酸、p-トルエンスルホン酸または酢酸等による酸処理、あるいはパラジウム−炭素等を触媒とする接触水素化分解処理等により実施可能である。また、アセタール系の保護基の場合は、塩酸、硫酸、トリフルオロ酢酸、p-トルエンスルホン酸、ピリジニウムp-トルエンスルホン酸または酢酸等による酸処理等を用いることができ、シリル系の保護基の場合は、塩酸、硫酸、トリフルオロ酢酸、p-トルエンスルホン酸、ピリジニウムp-トルエンスルホン酸または酢酸等による酸処理、またはテトラn-ブチルアンモニウムフルオライド等のフッ素アニオン処理によって実施可能である。
【００７０】
使用可能な溶媒としては、反応の進行を妨げないものであれば特に制限はないが、水、メタノール、エタノール、ブタノール等のアルコール系溶媒、ヘキサン、トルエン、キシレン等の炭化水素系溶媒、酢酸エチル、酢酸ブチル等のエステル系溶媒、ジエチルエーテル、ジオキサン、エチレングリコールジメチルエーテル、テトラヒドロフラン等のエーテル系溶媒、クロロホルム、ジクロロメタン等のハロゲン系溶媒、アセトニトリル、ジメチルホルムアミド、ジメチルスルホキシド等を挙げることができる。またこれら溶媒は単独で、あるいは２種以上の任意の比率での混合溶媒として使用可能である。
【００７１】
反応温度に関しては、−２０℃から使用する溶媒の沸点まで実施可能である。反応時間は特に制限は無いが、数分間から２４時間、好ましくは３０分間から６時間の範囲である。
【００７２】
なお、本発明の出発原料である一般式（１）で表される光学活性α−ヒドロキシカルボン酸誘導体は、市販で容易に入手可能であるか、または一般的に広く知られた方法で合成可能である。例えば、乳酸（Chem.Pharm.Bull., Vol.41(6), pp.1035-1042, 1993）、各種アミノ酸（Synthesis, 1987, p.479）、α−ハロカルボン酸誘導体（Tetrahedron Lett., 1985, Vol.26, p.5257）から既知の方法で合成可能である。また、製造方法として特に明記していない試薬および使用原料に関しては一般的に市販されており、いずれも入手は容易である。
【００７３】
【実施例】
以下に、本発明の実施例を記載するが、本発明はこれらによって制限されるものではない。
[実施例１] (3R)-1-クロロ-3-(3,4,5,6-テトラヒドロ-2H-ピラン-2-イルオキシ)-2-ブタノンの合成[化１９]
【００７４】
【化１９】
tret-ブチルマグネシウムクロライド（0.94Ｍ テトラヒドロフラン溶液）（200ｍｌ）に室温にてジイソプロピルアミン（19.4ｇ）を加え、70℃で1.5時間加熱還流後、室温まで冷却した（これを反応溶液Ａとした）。別の反応容器に(2R)-メチル-2-(3,4,5,6-テトラヒドロ-2H-ピラン-2-イルオキシ)プロピオネート(9.1ｇ)を入れ、テトラヒドロフラン（40ｍｌ）に溶解し、室温にてクロロ酢酸ナトリウム（11.3ｇ）を加えた。これを氷冷し、塩化マグネシウム(9.3ｇ)を少量ずつ加えてから室温で4時間攪拌した（これを反応溶液Ｂとした）。反応溶液Ｂを氷冷して反応溶液Ａを内温5℃以下で滴下し、これを70℃で2時間加熱還流後、室温まで冷却した。反応溶液を氷冷下で硫酸（18.0ｇ）/水（150ｍｌ）/酢酸エチル(225ｍｌ)の混合溶液に注加し、室温で40分間攪拌した。この溶液を分液し、有機層を飽和炭酸水素ナトリウム水溶液、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去して得られた残渣をシリカゲルカラムクロマトグラフィー(426ｇ，ヘキサン−酢酸エチル＝4：1)で単離精製し、目的化合物の保護基THPに由来する２種のジアステレオマーを黄色油状物質として得た。
【００７６】
収量＝9.2ｇ
収率＝92％
ジアステレオマーＡ
1H-NMR(400MHz, CDCl3) δ=4.65(dd, 1H, J=4.4, 2.8Hz), 4.45(quartet, 1H, J=6.8Hz), 4.42(d, 1H, J=16Hz), 4.36(d, 1H, J=16Hz), 3.91-3.82(m, 2H), 1.88-1.45(m, 6H), 1.41(d, 3H, J=6.8Hz)
ジアステレオマーＢ
1H-NMR(400MHz,CDCl3) δ=4.66(d,1H,J=17Hz), 4.55(dd,1H,J=6.4,2.4Hz), 4.42(d,1H,J=17Hz) 4.25(quartet, 1H, J=6.8Hz), 3.56-3.50(m, 1H), 3.47-3.41(m, 1H), 1.92-1.49(m, 6H), 1.35(d, 3H, J=6.8Hz)
IR(neat, diastereomixture) ν＝2946, 2870, 1741, 1433, 1398, 1327, 1203, 1130, 1078, 1035, 974, 892, 874, 816, 781cm-1
【００７７】
[実施例２] (2R,3R)-1-クロロ-2-(2,4-ジフルオロフェニル)-3-(3,4,5,6-テトラヒドロ-2H-ピラン-2-イルオキシ)-2-ブタノールの合成[化２０]
【００７８】
【化２０】
窒素雰囲気化でマグネシウム (1.5ｇ)をテトラヒドロフラン(25ｍｌ)に懸濁し、ヨウ素（50ｍｇ）を加えてから25℃〜30℃で2,4-ジフルオロブロモベンゼン（11.0ｇ）/テトラヒドロフラン（20ｍｌ）溶液を滴下した。室温で1.5時間攪拌しこれを溶液Ａ（49.2ｇ）とした。別の反応容器に実施例１で得られた化合物(2.0ｇ)を入れ、テトラヒドロフラン（20ｍｌ）に溶解して-20℃に冷却した。これに溶液Ａ（9.1g）を-5℃以下で滴下し、−10℃〜0℃で1時間、0℃〜10℃で2時間攪拌した。反応液を5℃に冷却し、1N塩酸（9ｍｌ）を加えてｐＨ8に調整した。5℃〜10℃で30分間攪拌した後酢酸エチル、水を加えて抽出し、有機層を飽和塩化ナトリウム水溶液で洗浄した。有機層を無水硫酸マグネシウムにて乾燥した後溶媒を減圧濃縮し、淡褐色残さを得た。
【００８０】
[反応のジアステレオ選択性]
アンチ誘導体(2R,3R)：シン誘導体(2S,3R)＝１０：１
ジアステレオ選択性は、シリカゲルカラムクロマトグラフィーによる精製を行なわず混合物のまま、実施例３および４に記載の方法を実施し、(2S,3R)-2-(2,4-ジフルオロフェニル)-1-(1H-1,2,4-トリアゾール-1-イル)-2,3-ブタンジオールおよび(2R,3R)-2-(2,4-ジフルオロフェニル)-1-(1H-1,2,4-トリアゾール-1-イル)-2,3-ブタンジオールに誘導した後、HPLCを用いて決定した（分析条件／YMC-PACK ODS A-303, 溶離液組成 メタノール：水：酢酸＝70：30：0.2, 検出法 UV 254ｎｍ）。
また、上記操作により得られた淡褐色残渣を、シリカゲルカラムクロマトグラフィー(68ｇ, ヘキサン−酢酸エチル＝4：1)にて単離精製して、（２Ｒ，３Ｒ）の立体配置を持つ主生成物のテトラヒドロピラン部位に由来する２種のジアステレオマー混合物を白色アモルファスとして得た。
【００８１】
収量＝2.0ｇ
収率＝64％
アンチ誘導体（２Ｒ，３Ｒ）のジアステレオマーＡ
1H-NMR(400MHz, CDCl3) δ=7.71(td, 1H, J=9.0,6.8Hz), 6.94-6.89(m, 1H), 6.83-6.76(m, 1H), 4.61(dd, 1H, J=4.8,2.4Hz), 4.38(d, 1H, J=11Hz), 4.21(d, 1H, J=11Hz), 4.12(quartet, 1H, J=6.8Hz), 4.00(s, 1H), 3.52-3.46(m, 2H), 1.86-1.32(m, 6H), 1.27(d, 3H, J=6.8Hz)
アンチ誘導体（２Ｒ，３Ｒ）のジアステレオマーＢ
1H-NMR(400MHz, CDCl3) δ=7.62(td, 1H, J=8.8, 6.4Hz), 6.94-6.89(m, 1H), 6.83-6.76(m, 1H), 4.29(m, 1H), 4.03(quartet, 1H, J=6.4Hz), 4.00(s, 1H), 3.95(dd, 1H, J=11, 2.4Hz), 3.91(dd, 1H, J=11, 2.4Hz), 3.46-3.37(m, 2H), 1.86-1.32(m, 6H), 1.13(dd, 3H, J=1.2, 6.4Hz)
IR(KBr-disk, diastereomixture) ν＝3437, 3079, 2943, 2873, 1736, 1616, 1502, 1469, 1421, 1356, 1273, 1201, 1121, 1084, 1025, 973, 927, 863, 815, 756, 726, 680, 632, 558, 543, 515cm-1
【００８２】
[実施例３] (2S,3R)-2-(2,4-ジフルオロフェニル)-3-(3,4,5,6-テトラヒドロ-2H-ピラン-2-イルオキシ)-1-(1H-1,2,4-トリアゾール-1-イル)-2-ブタノールの合成[化２１]
【００８３】
【化２１】
窒素雰囲気下、水素化ナトリウム（0.36ｇ）をN,N-ジメチルホルムアミド（6ｍｌ）に懸濁し、氷冷下で1,2,4-トリアゾールを少量ずつ加え、室温で40分間攪拌した。これに実施例２で得られたジアステレオマー混合物(0.71ｇ)/ N,N-ジメチルホルムアミド（5ｍｌ）溶液を滴下し、室温で4時間、70℃で6時間加熱攪拌した。反応液を室温まで冷却し、氷水中に注加して１Ｎ塩酸でｐＨ4に調整した。酢酸エチルを加えて抽出し、有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムにて乾燥した。溶媒を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー(32ｇ, クロロホルム−メタノール＝25：1)にて単離精製して、テトラヒドロピラン部位に由来する２種のジアステレオマー混合物を淡黄色アモルファスとして得た。
この反応では、不斉炭素の立体構造はアンチで変わらないが、塩素原子がトリアゾールに変わることで２位の立体表記が（Ｒ）から（Ｓ）に変化する。
【００８５】
収量＝0.68ｇ
収率＝86％
ジアステレオマーＡ
1H-NMR(400MHz, CDCl3) δ=8.12(s, 1H), 8.02(s, 1H), 7.73(d, 1H, J=11Hz), 7.55(td, 1H, J=9.0, 6.8Hz), 6.80-6.69(m, 1H), 5.15(dd, 1H, J=14,1.2Hz), 4.78(s, 1H), 4.62-4.61(m, 1H),4.56(dd, 1H, J=14, 1.2Hz), 4.10(quartet, 1H, J=6.4Hz), 3.45-3.41(m, 2H), 1.86-1.34(m, 6H), 1.17(dd, 3H, J=6.4,1.2Hz)
ジアステレオマーＢ
1H-NMR(400MHz, CDCl3) δ=8.05(s, 1H), 8.02(s, 1H), 7.73(d, 1H, J=11Hz), 7.44(td, 1H, J=9.0, 6.4Hz), 6.80-6.69(m, 1H), 4.98(dd, 1H, J=14,1.2Hz), 4.48(dd, 1H, J=14,0.8Hz), 4.41(s, 1H), 416(qd, 1H, J=6.0, 0.8Hz), 3.41-3.38(m, 2H), 1.86-1.34(m, 6H), 1.13(d, 3H, J=6.0Hz)
IR(neat, diastereomixture) ν＝3392, 3128, 2945, 2872, 1669, 1616, 1502, 1419, 1387, 1274, 1203, 1137, 1078, 1033, 973, 872, 816, 729, 680, 660, 551cm-1
【００８６】
[実施例４] (2S,3R)-2-(2,4-ジフルオロフェニル)-1-(1H-1,2,4-トリアゾール-1-イル)-2,3-ブタンジオールの合成[化２２]
【００８７】
【化２２】
実施例３で得られた化合物(0.51ｇ)をエタノール(7ｍｌ)に溶解し、ピリジニウムパラトルエンスルホン酸(149ｍｇ)を加えて室温で1時間、55℃で2.5時間加熱攪拌した。反応溶液を室温まで冷却してから濃縮し、残渣に酢酸エチル、水を加えて抽出した。有機層を水洗後、無水硫酸マグネシウムにて乾燥した。溶媒を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー(32ｇ, クロロホルム−メタノール＝9：1)にて単離精製して、目的化合物を白色アモルファスとして得た。
【００８９】
収量＝0.22ｇ
収率＝57％
1H-NMR(400MHz, CDCl3) δ=8.03(d, 1H, J=1.2Hz), 7.76(s, 1H), 7.54(td, 1H, J=9.2, 6.4Hz), 6.83-6.78(m, 1H), 6.72(ddd, 1H, J=12,8.8,2.8Hz), 5.03(d, 1H, J=14,1.6Hz), 5.01(s, 1H),4.56(dd, 1H, J=14, 1.6Hz), 4.00(quartet, 1H, J=6.4Hz), 2.65(d, 1H, J=5.2Hz), 1.26(dd, 3H, J=6.4,1.2Hz)
IR(KBr-disk) ν＝3406, 3136, 2982, 2938, 1618, 1501, 1421, 1277, 1207, 1139, 1082, 1021, 967, 853, 815, 663, 633, 548cm-1
【００９０】
[実施例５] (3S)-1-クロロ-3-ベンジルオキシ-2-ブタノンの合成[化２３]
【００９１】
【化２３】
(2S)-メチル-2-ベンジルオキシプロピオネート(4.70ｇ, 24.2ｍｍｏｌ)をＴＨＦ(20ｍｌ)に溶解し、クロロ酢酸ナトリウム(5.63g)および塩化マグネシウム(4.61ｇ)を加え、窒素雰囲気下、室温にて１時間撹拌した（Ａ液）。市販の0.97Ｍ tert-ブチルマグネシウムクロライド−ＴＨＦ溶液(100ml)に、窒素雰囲気下、室温にて、ジイソプロピルアミン(9.90ｇ)を滴下し、65〜70℃に１時間加熱撹拌した（Ｂ液）。Ａ液を−15℃に冷却し、Ｂ液を滴下した（滴下時の内温は0℃以下を保った）。滴下終了後、反応液を65〜70℃に加温し、２時間撹拌した。反応液を冷却後、氷冷した酢酸エチル(100ｇ)-10％硫酸(90ｇ)の混合液に注加し、そのまま30分間撹拌した。有機層を分取し、５％−食塩水で洗浄し、無水硫酸マグネシウムにて乾燥した。有機層を減圧濃縮し、得られた残さをシリカゲルカラムクロマトグラフィー(C-300, 100ｇ, ヘキサン‐酢酸エチル＝10：1→8：1)で単離精製した。
【００９３】
収量＝4.06ｇ
収率＝79％
1H-N.M.R.(400MHz, CDCl3) δ＝7.40-7.30(m, 5H), 4.61(d, 1H, J=11.5Hz), 4.53(d, 1H, J=11.5Hz), 4.46(d, 1H, J=14.5Hz), 4.39(d, 1H, J=14.5Hz), 4.15(q, 1H), J=6.8Hz), 1.40(d, 3H, J=6.8Hz)
IR(neat)ν＝3033, 2986, 2939, 2870, 1742, 1497, 1455, 1396, 1308, 1115, 741, 699cm-1
【００９４】
[実施例６] (2S,3S)-1-クロロ-2-(2,4-ジフルオロフェニル)-3-ベンジルオキシ-2-ブタノールの合成[化２４]
【００９５】
【化２４】
実施例５で得られた化合物(3.19g, 15mmol)をTHF(15ml)に溶解し、-15℃に冷却した。予め2,4-ジフロロブロモベンゼン(3.47ｇ, 18ｍｍｏｌ)から調製したグリニヤ試薬(ＴＨＦ／20ｍｌ)を-5℃以下で滴下した。反応液を30分間撹拌の後、水(20ｍｌ)を5℃以下で滴下し、続いて1Ｎ-塩酸(30ml)を5℃以下で滴下した。酢酸エチル(50ｍｌ)で抽出し、２回水洗した。有機層を無水硫酸マグネシウムにて乾燥後、減圧濃縮し、淡褐色残さを得た。
【００９７】
[ジアステレオ選択性]
アンチ誘導体(2S,3S)：シン誘導体(2R,3S)＝１０：１
ジアステレオ選択性は、得られた淡褐色残さをシリカゲルカラムクロマトグラフィー精製することなく混合物のままで1H-N.M.R.(400MHz, CDCl3)を測定し、各ピークの積分比から決定した。
さらに、上記操作で得られた淡褐色残さをシリカゲルカラムクロマトグラフィー(C-300, 200g, ヘキサン‐酢酸エチル＝10：1→6：1)で単離精製し、標題化合物を得た。
【００９８】
アンチ誘導体(2S,3S)の収量＝2.50ｇ
アンチ誘導体(2S,3S)の収率＝51％
アンチ誘導体(2S,3S)
1H-N.M.R.(400MHz, CDCl3) δ＝7.67-7.60(m, 1H), 7.28-7.25(m, 3H), 7.08-7.05(m, 2H), 6.94-6.90(m, 1H), 6.77-6.72(m, 1H), 4.49(d, 1H, J=11.7Hz), 4.27(d, 1H, J=11.7Hz), 4.20(d, 1H, J=11.2Hz), 3.92-3.87(m, 2H), 3.17(s, 1H), 1.22(dd, 3H, J=0.7, 6.4Hz)
IR(neat) ν＝3538, 3066, 3032, 2978, 2938, 2873, 1616, 1501, 1420, 1271, 1131, 1091, 973, 852, 750, 698cm-1
シン誘導体(2R,3S)
1H-N.M.R.(400MHz, CDCl3) δ＝7.74-65(m, 1H), 7.38-7.31(m, 5H), 6.94-6.87(m, 1H), 6.79-6.71(m, 1H), 4.70(d, 1H, J=11.6Hz), 4.47(d, 1H, J=11.6Hz), 4.11-4.00(m, 3H), 2.99(s, 1H), 1.01(d, 3H, J=5.9Hz)
このとき、原料であるBCMKを1.33g回収した。BCMKの回収を考慮すると、換算収率は87％であった。
【００９９】
[実施例７] (2S,3S)-1-クロロ-2-(2,4-ジフルオロフェニル)-3-ベンジルオキシ-2-ブタノールの合成[化２５]
【０１００】
【化２５】
窒素雰囲気下、マグネシウム(6.0g, 46ｍｍｏｌ)をテトラヒドロフラン(120ｍｌ)に分散させ、よう素(5ｍｇ)加えて攪拌した。 2,4-ジフルオロブロモベンゼン(48ｇ, 248ｍｍｏｌ)のテトラヒドロフラン(120ｍｌ)溶液を、内温が３０〜35℃になるように滴下し、グリニヤ試薬Ａとした。別途、無水塩化セリウム(10ｇ, 40.8ｍｍｏｌ)を減圧下、１３０℃で１時間乾燥した。室温まで冷却した後、窒素雰囲気下にてテトラヒドロフラン(40ｍｌ)を加えて、懸濁の状態で30分間超音波処理を行ない懸濁溶液Ｂとした。続いて、 実施例５で得られた化合物(4.34ｇ, 20.4ｍｍｏｌ)のテトラヒドロフラン(10ｍｌ)溶液を、懸濁溶液Ｂに加え、さらに30分間超音波処理を行なった。テトラヒドロフラン(4ｍｌ)を懸濁溶液Ｂに追加した後、０℃から−５℃に保って、上記で調整したグリニヤ試薬Ａ(24ｍｌ, 24ｍｍｏｌ)を滴下した。滴下後更に12時間攪拌した。 氷冷下、1Ｎ塩酸(200ｍｌ)を滴下、酢酸エチル(400ｍｌ)で抽出した。有機層を飽和炭酸水素ナトリウム水溶液(400ｍｌ)、飽和食塩水(400ｍｌ)で洗浄し、硫酸マグネシウムで乾燥、ろ過、濃縮して、淡褐色残さを得た。
【０１０２】
[ジアステレオ選択性]
アンチ誘導体(2S,3S)：シン誘導体(2R,3S)＝１０：１
ジアステレオ選択性の決定は、実施例６と同様に行なった。
さらに、上記操作で得られた淡褐色残さをシリカゲルカラムクロマトグラフィー(C-300, 200g, ヘキサン‐酢酸エチル＝10：1→6：1)で単離精製し、標題化合物を得た。
アンチ誘導体(2S,3S)の収量＝6.13g
アンチ誘導体(2S,3S)の収率＝92％
1H-N.M.R.(400MHz, CDCl3)およびIR(neat)値は、実施例６と一致した。
【０１０３】
[実施例８] (2R,3S)-2-(2,4-ジフルオロフェニル)-3-ベンジルオキシ-1-(1H-1,2,4-トリアゾール-1-イル)-2-ブタノールの合成[化２６]
【０１０４】
【化２６】
60％-水素化ナトリウム(800ｇ, 20ｍｍｏｌ)をDMF（7ｇ）に懸濁し、窒素雰囲気下、氷冷にてトリアゾール(1.38ｇ, 20ｍｍｏｌ)を粉体装入した（内温は15℃以下を保持した）。氷冷下にて１時間撹拌し、ほぼ均一な淡褐色溶液を得た後に、実施例８で得られた化合物(1.63ｇ, 5ｍｍｏｌ)をＤＭＦ(7ｇ)に溶解した溶液を10℃以下で滴下装入した。反応液を70〜75℃に加温し、６時間撹拌した。反応液を冷却後、水(60ｇ)に注加し、酢酸エチル(100ｍｌ)で抽出した。水洗(60ｇで３回)をし、無水硫酸マグネシウムで乾燥後、有機層を減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(C-300, 100g, ヘキサン‐酢酸エチル＝1：2)で単離精製し、黄色シロップを得た。
この反応では、不斉炭素の立体構造はアンチで変わらないが、塩素原子がトリアゾールに変わることで２位の立体表記が（Ｓ）から（Ｒ）に変化する。
【０１０６】
収量＝1.33ｇ
収率＝80％
1H-N.M.R.(400MHz, CDCl3) δ＝7.99(s, 1H), 7.72(s, 1H), 7.49-7.43(m, 1H), 7.29-7.26(m, 3H), 7.10-7.08(m, 2H), 6.80-6.75(m, 1H), 6.71-6.65(m, 1H), 4.96(d, 1H, J=14.5Hz), 4.53(d, 1H, J=10.4Hz), 4.45(d, 1H, J=14.5Hz), 4.36(s, 1H), 4.27(d, 1H, J=10.4Hz), 3.90(q, 1H, J=6.1Hz), 1.25(d, 3H, J=6.1Hz)
IR(neat) ν＝3259, 3166, 3086, 1617, 1502, 1274, 1135, 1096, 966, 858, 747, 667cm-1
このシロップのうち1.1gから結晶化（ヘキサン−THF）し、乳白色結晶を得た。
収量＝960mg
【０１０７】
[実施例９] (2R,3S)-2-(2,4-ジフルオロフェニル)-1-(1H-1,2,4-トリアゾール-1-イル)-2,3-ブタンジオールの合成[化２７]
【０１０８】
【化２７】
実施例８で得られた化合物(719ｇ, 2ｍｍｏｌ)をメタノール(30ｍｌ)に溶解し、10％-パラジウム／炭素(0.3ｇ)を加え、オートグレーブ中、水素初期圧(1.0ＭＰａ)、50℃にて８時間撹拌した。反応液から触媒をろ別し、ろ液を減圧濃縮した。
【０１１０】
収量＝480ｍｇ
収率＝89％
1H-NMR(400MHz, CDCl3) δ=8.03(d, 1H, J=1.2Hz), 7.76(s, 1H), 7.54(td, 1H, J=9.2, 6.4Hz), 6.83-6.78(m, 1H), 6.72(ddd, 1H, J=12,8.8,2.8Hz), 5.03(d, 1H, J=14,1.6Hz), 5.01(s, 1H),4.56(dd, 1H, J=14, 1.6Hz), 4.00(quartet, 1H, J=6.4Hz), 2.65(d, 1H, J=5.2Hz), 1.26(dd, 3H, J=6.4,1.2Hz)
IR(KBr-disk) ν＝3406, 3136, 2982, 2938, 1618, 1501, 1421, 1277, 1207, 1139, 1082, 1021, 967, 853, 815, 663, 633, 548cm-1
【０１１１】
[実施例１０] (3R)-3-（tert-ブチルジフェニルシリルオキシ) -1-クロロ-2-ブタノンの合成[化２８]
【０１１２】
【化２８】
(2R)-メチル-2-（tert-ブチルジフェニルシリルオキシ）プロピオネート(6.83ｇ, 20ｍｍｏｌ)を用い、実施例１と同様に処理し、標題化合物を無色透明シロップとして得た。
【０１１４】
収量＝5.78ｇ
収率＝80％
1H-N.M.R.(400MHz, CDCl3) δ＝7.70-7.59(m, 4H), 7.49-7.32(m, 6H), 4.52(d, 1H, J=17.1Hz), 4.38(d, 1H, J=17.4Hz), 4.38(q, 1H, J=6.9Hz), 1.24(d, 3H, J=6.9Hz), 1.11(s, 9H)
【０１１５】
[実施例１１] (2R)-2-[(1'R)-1-(tert-ブチルジフェニルシリルオキシ)エチル]-2-(2,4-ジフルオロフェニル)オキシランおよび(2S)-2-[(1'R)-1-(tert-ブチルジフェニルシリルオキシ)エチル]-2-(2,4-ジフルオロフェニル)オキシランの合成[化２９]
【０１１６】
【化２９】
実施例１０で合成した化合物(3.61ｇ, 10ｍｍｏｌ)を用い実施例２と同様に処理し、標題化合物を無色透明シロップとして得た（ジアステレオマー混合物）。
【０１１８】
[ジアステレオ選択性]
アンチ誘導体（1'R,2S）：シン誘導体(1'R,2R)＝１：７．２５
ジアステレオ選択性は、1H-N.M.R.(400MHz, CDCl3)を測定し、各ピークの積分比から決定した。
収量＝2.20ｇ（ジアステレオマー混合物）
収率＝50％
アンチ誘導体（1'R,2S）
1H-N.M.R.(270MHz, CDCl3): δ=7.74-7.21(m, 11H), 6.90-6.71(m, 2H), 3.99(q, 1H, J=6.0HZ), 2.99(d, 1H, J=5.8Hz), 2.78(d, 1H, J=5.8Hz), 1.02(s, 9H), 1.02(d, 3H, J=6.0Hz)
シン誘導体(1'R,2R)
1H-N.M.R.(270MHz, CDCl3): δ=7.74-7.21(m, 11H), 6.90-6.71(m, 2H), 4.02(q, 1H, J=6.2Hz), 3.18(d, 1H, J=5.3Hz), 2.82(dd, 1H, J=1.0, 5.3Hz), 1.06(s, 9H), 0.95(dd, 3H, J=1.7, 6.2Hz)
【０１１９】
[実施例１２] (2R,3R)-2-(2,4-ジフルオロフェニル)-1-(1H-1,2,4-トリアゾール-1-イル)-2,3-ブタンジオールおよび(2S,3R)-2-(2,4-ジフルオロフェニル)-1-(1H-1,2,4-トリアゾール-1-イル)-2,3-ブタンジオールの合成[化３０]
【０１２０】
【化３０】
60％-水素化ナトリウム(400ｇ, 10ｍｍｏｌ)をＤＭＦ（7ｇ）に懸濁し、窒素雰囲気下、氷冷にてトリアゾール(690ｍｇ, 10ｍｍｏｌ)を粉体装入した（内温は15℃以下を保持した）。氷冷下にて１時間撹拌し、ほぼ均一な淡褐色溶液を得た後に、実施例１１で得られたジアステレオマー混合物(1.10ｇ, 2.5ｍｍｏｌ)をＤＭＦ(7ｇ)に溶解した溶液を10℃以下で滴下装入した。反応液を70〜75℃に加温し、６時間撹拌した。反応液を冷却後、水(30ｇ)に注加し、酢酸エチル(50ｍｌ)で抽出した。水洗(30ｇで３回)をし、無水硫酸マグネシウムで乾燥後、有機層を減圧濃縮した。得られた残さをテトラヒドロフラン(10ｇ)に溶解し、テトラ-n-ブチルアンモニウムフロリド(980ｍｇ,3.75ｍｍｏｌ)を加え、室温にて30分間撹拌した。反応液に水(10ｇ)および酢酸エチル(20ｇ)を加え、10分間撹拌の後、有機層を分取した。有機層を無水硫酸マグネシウムで乾燥し、乾燥剤をろ別後、ろ液を減圧濃縮し、標題化合物をジアステレオマー混合物の淡黄色シロップとして得た。
【０１２２】
[ジアステレオマー比]
アンチ誘導体（1'R,2S）：シン誘導体(1'R,2R)＝１：７．２５
ジアステレオ比は、HPLCによる分析によって決定した。分析条件／YMC-PACK ODS A-303, 溶離液組成 メタノール：水：酢酸＝70:30:0.2, 検出法 UV 254nmさらに、上記操作によって得られたジアステレオマー混合物である淡黄色シロップからトルエンを用いて結晶化させ、(2R,3R)-2-(2,4-ジフルオロフェニル)-1-(1H-1,2,4-トリアゾール-1-イル)-2,3-ブタンジオール(498mg, 74％)を優先的に白色結晶として得た。
【０１２３】
融点：116-117℃
ジアステレオマー過剰率＝96％de
分析条件／YMC-PACK ODS A-303, 溶離液組成 メタノール：水：酢酸＝70：30：0.2, 検出法 UV 254ｎｍ
光学純度＝99％ee
【０１２４】
光学純度の測定は、(2R,3R)-2-(2,4-ジフルオロフェニル)-1-(1H-1,2,4-トリアゾール-1-イル)-2,3-ブタンジオールをChem.Phram.Bull.41(6)1035-1042(1993)に記載の方法に準じて既知化合物である(2S,3R)-2-(2,4-ジフルオロフェニル)-3-メチル-2-(1H-1,2,4-トリアゾール-1-イル)メチルオキシランに誘導し、HPLC分析によって決定した。分析条件／DAICEL CHIRALCEL OF, 溶離液組成 ヘキサン：２−プロパノール：ジエチルアミン＝60：40：0.1, 検出法 UV 254ｎｍ
(2R,3R)体
1H-N.M.R.(270MHz, CDCl3): δ=7.84(s, 1H), 7.82(s, 1H), 7.46-7.37(m., 1H), 6.80-6.72(m, 2H), 4.87-4.77(m, 3H ), 4.36-4.29(m, 1H), 2.63(d, 1H, J=9.2Hz), 0.97(d, 3H, J=6.5Hz)
(2S,3R)体
1H-N.M.R. (270MHz, CDCl3)は、実施例４と一致した。
【０１２５】
【発明の効果】
医農薬の非常に重要な中間体である、光学活性ハロメチルアルコール誘導体および光学活性エポキシド誘導体の高立体選択的製造法を見出し、工業的な観点から光学活性２−フェニル−２，３−ジヒドロキシプロピルアゾール誘導体が短工程で安価にかつ安定的に製造することが可能となった。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a novel process for producing an optically active 2-phenyl-2,3-dihydroxypropylazole derivative, which is an important compound for production in various fields including medical and agrochemical fields, in a short process.
[0002]
[Prior art]
In recent years, fungal infections typified by so-called opportunistic infections have become a problem due to an increase in immunodeficiency patients due to infections such as AIDS, an increase in patients with reduced immunity due to advancement of advanced medical care or an increase in the elderly. In particular, for those who are immunocompromised, deep fungal infections such as candidiasis and aspergillosis are often serious and life-threatening, and are one of the infections to be noted in the medical field. Conventionally, azole antifungal agents typified by fluconazole have been frequently used for these infectious diseases, but in recent years, the emergence of resistant bacteria and the lack of basic action have been pointed out. Development of more effective therapeutic agents effective against bacterial species is desired (Pharmaceutical Journal, vol37 (7), pp.115-119).
[0003]
On the other hand, the azole antifungal agents currently under development tend to be more complex in structure, especially how to efficiently construct the asymmetric carbon to which the azolemethyl group is bonded and the asymmetric carbon moiety present continuously. Is a major technical problem (J. Med. Chem., Vol. 41, pp. 1869-1882, 1998). However, until now, an inexpensive and stable production method has not been established from an industrial viewpoint.
[0004]
The conventional manufacturing technique will be described below.
As a method for constructing a continuous asymmetric site, in any case, it is constructed by carrying out diastereoselective carbon increase epoxidation to a ketone group via an α-hydroxyphenyl ketone derivative (Chem. Pharm. Bull., Vol.41 (6), pp.1035-1042, 1993). However, the conventional production method has (1) poor diastereoselectivity of about 4: 1, (2) low yield when trying to isolate only the desired isomer, and (3) a long number of steps, The isolation and purification steps were extremely complicated, and (4) the production method was extremely problematic from an industrial point of view, such as racemization depending on the reaction conditions. In addition, the α-hydroxyphenyl ketone derivative itself is produced by a multi-step process (Bioorg. Med. Chem. Lett., Vol1 (7), pp.349-352, 1991) or an expensive reaction reagent such as an asymmetric catalyst. (Tetrahedron Letters, vol37 (36), pp.6531-6534, 1996) was required, and it was not fully satisfactory as an industrial production method. In recent years, a new production method using L-alanine as a starting material, which has improved these existing methods, has been reported (US6300522), but in order to solve the fundamental problem in that it passes through an α-hydroxyphenyl ketone derivative. However, it was not always an industrially satisfactory production method.
[0005]
As described above, since it is an optically active compound having two asymmetric carbons even though the development of a more useful novel azole antifungal agent is desired, the conventional production technique is industrially effective. From the viewpoint, an inexpensive and stable production method has not been established, and rapid development of a more efficient new production method is desired for these intermediate compounds.
[0006]
[Patent Document 1]
U.S. Pat.No. 6300522
[0007]
[Non-Patent Document 1]
Pharmaceutical Journal, vol.37 (7), pp.115-119
[0008]
[Non-Patent Document 2]
J.Med.Chem., Vol.41, pp.1869-1882, 1998
[0009]
[Non-Patent Document 3]
Chem. Pharm. Bull., Vol. 41 (6), pp.1035-1042, 1993
[0010]
[Non-Patent Document 4]
Tetrahedron Letters, vol.37 (36), pp.6531-6534, 1996
[0011]
[Problems to be solved by the invention]
An object of the present invention is an optically active 2-phenyl-2,3-dihydroxypropyl which is a useful compound in the field of medicine and agricultural chemicals, and is an especially important intermediate in the production process of an optically active azole antifungal agent. With respect to the production of azole derivatives, from an industrial point of view, it is to provide a method for producing inexpensively and stably in a short process and a novel intermediate.
[0012]
[Means for Solving the Problems]
As a result of intensive studies in order to solve the above-mentioned problems, the present inventors made an optically active α-hydroxycarboxylic acid derivative as a starting material, reacted with a haloacetic acid derivative, and a very important intermediate for medical and agricultural chemicals. In addition, an optically active halomethyl ketone derivative is produced, and further, a high diastereoselective reaction that allows the alkylation reaction to be freely anti- or syn-configured depending on the selection of the protecting group and the reaction conditions has been found. By producing an optically active halomethyl alcohol derivative, which is a very important intermediate, and further reacting with triazole or imidazole to produce an optically active azolemethyl alcohol derivative, and further selectively deprotecting it, medical and agricultural chemicals A completely new intermediate for obtaining optically active 2-phenyl-2,3-dihydroxypropyl azole derivatives We found a manufacturing route.
[0013]
It has been found that in the above reaction route, there is almost no racemization accompanying the reaction, and a compound having a desired configuration can be selectively produced with high optical purity. In particular, an inexpensive lactic acid derivative is used as the optically active α-hydroxycarboxylic acid derivative, a silyl-based protective group is used as a protective group, and a very high syn selectivity is obtained via a novel optically active silyloxy-haloalkylketone derivative. And found that novel optically active silyloxy-halomethyl alcohol derivatives and optically active silyloxy-epoxide derivatives, which are extremely important intermediates for the production of optically active azole antifungal agents, can be obtained. I found it. As a result, the production of 2-phenyl-2,3-dihydroxypropyl azole derivatives, which are extremely important intermediates for the production of optically active azole antifungal agents and have the desired configuration with high optical purity, From a general viewpoint, it has become possible to carry out the process stably and inexpensively with a short process, and the present invention has been completed.
[0014]
That is, the present invention is as described in [1] to [9] below.
[1] General formula (1)
[0015]
[Chemical 9]
(Wherein R1 represents an alkyl group which may be substituted, an aralkyl group which may be substituted, an aryl group which may be substituted or a heterocyclic ring which may be substituted; R2 represents an ether group as a hydroxyl-protecting group; A protecting group, an acetal protecting group or a silyl protecting group, wherein R3 is a hydroxyl group, a halogen atom, an optionally substituted acyl group, an optionally substituted carbonate group, an optionally substituted alkyloxy group, An aralkyloxy group that may be substituted, a phenoxy group that may be substituted, or an amino group that may be substituted is shown, * on the carbon atom means an asymmetric carbon, and can take R configuration or S configuration .) And an α-hydroxycarboxylic acid derivative represented by the general formula (2)
[0017]
[Chemical Formula 10]
(In the formula, R 4 represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aralkyl group, an optionally substituted aryl group, an alkali metal or an alkaline earth metal, and X represents a halogen atom. The haloacetic acid derivative represented by the general formula (3)
[0019]
Embedded image
(Wherein R1, R2, X and * are as defined above), and the halomethyl ketone derivative is further represented by the general formula (4) [Chemical Formula 12]
[0021]
Embedded image
(Wherein R5 and R6 are each independently a halogen atom, an alkyloxycarbonyl group, an aryloxycarbonyl group, an amino group that may be substituted, an amide group that may be substituted, an alkyl group that may be substituted, An optionally substituted alkyloxy group, an optionally substituted aralkyl group, an optionally substituted aralkyloxy group, an optionally substituted phenyl group, an optionally substituted phenyloxy group, an optionally substituted heterocycle or substituted Represents a heterocyclic oxy group which may be substituted, and A represents Li, MgX, ZnX, TiXThree, Ti (OR7)Three, CuX or CuLi. However, X shows a halogen atom and R7 shows a lower alkyl group. And a phenyl metal reagent represented by the following formula (5):
[0023]
Embedded image
(Wherein R1, R2, R5, R6, X and * are as defined above), and the optically active halomethyl alcohol derivative is further reacted with triazole or imidazole. General formula (6)
[0025]
Embedded image
(Wherein R 1, R 2, R 5, R 6 and * are as defined above. Y represents a carbon atom or a nitrogen atom), and an optically active azole methyl derivative is produced. By selectively deprotecting the alcohol derivative, the general formula (7)
[0027]
Embedded image
(Wherein R 1, R 5, R 6, Y and * are as defined above), an optically active 2-phenyl-2,3-dihydroxypropyl azole derivative represented by
[2] An α-hydroxycarboxylic acid derivative represented by the general formula (1) (wherein R1, R2, and R3 * are as defined above) and the general formula (2) (wherein R4 and X are The haloacetic acid derivative represented by the general formula (3) is reacted under basic conditions, and the halo represented by the general formula (3) (wherein R1, R2, X and * are as defined above). A methyl ketone derivative is produced, and a phenyl metal reagent represented by the general formula (4) (wherein R5, R6, A, X and R7 are as defined above) is diastereoselectively selected for the halomethyl ketone derivative. Reaction is carried out to give a general formula (8)
[0029]
Embedded image
(Wherein R1, R2, R5, R6, and * are as defined above), and the optically active epoxide derivative is further reacted with triazole or imidazole to give a general formula ( 6) (wherein R1, R2, R5, R6, Y and * are as defined above) are produced, and the optically active azole methyl alcohol derivative is selectively selected. By deprotecting, an optically active 2-phenyl-2,3-dihydroxypropylazole derivative represented by the general formula (7) (wherein R1, R5, R6, Y and * are as defined above) is produced. And how to
[3] A halomethyl ketone derivative represented by the general formula (3) (wherein R1, R2, X and * are as defined above) and the general formula (4) (wherein R5, R6 and A are And a general formula (5) (wherein R1, R2, R5, R6, X and * are as defined above). A method for producing an optically active halomethyl alcohol derivative represented by:
[4] A halomethyl ketone derivative represented by the general formula (3) (wherein R1, R2, X and * are as defined above) and the general formula (4) (wherein R5, R6 and A are And a phenyl metal reagent represented by the general formula (8) (wherein R1, R2, R5, R6, X and * are as defined above). A method for producing an optically active epoxide derivative represented by:
[5] An optically active halomethyl alcohol derivative represented by the general formula (5) (wherein R1, R2, R5, R6, X and * are as defined above), or a general formula (8) (wherein R 1, R 2, R 5, R 6, X and * are as defined above) and a triazole or imidazole to react with general formula (6) (wherein R 1, R 2, R 5, R6, Y and * are as defined above.), An optically active azole methyl alcohol derivative represented by
[6] An optically active azole methyl alcohol derivative represented by the general formula (6) (wherein R1, R2, R5, R6, Y and * are as defined above) is deprotected to give the general formula (7) (Wherein R 1, R 5, R 6, Y and * are as defined above), an optically active 2-phenyl-2,3-dihydroxypropyl azole derivative represented by
[7] The production method according to any one of [1] to [6], wherein R1 is a methyl group;
[8] The production method according to any one of [1] to [6], wherein R1 is a methyl group, and R5 and R6 are halogen atoms.
[9] An optically active halomethyl alcohol derivative in which R1 is a methyl group and R5 and R6 are halogen atoms in the general formula (5).
[0031]
DETAILED DESCRIPTION OF THE INVENTION
Next, the compound of the present invention will be described in more detail.
In the present invention, the “alkyl group that may be substituted” means an alkyl group that may be substituted at any position of the alkyl group. Examples of the alkyl group include a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a pentyl group, a hexyl group, an octyl group, a decyl group, and an allyl group. Substituents include alkoxy groups such as hydroxyl group, methoxy group, benzyloxy group or methoxyethoxy group, phenoxy group, nitro group, amino group, amide group, carboxyl group, alkoxycarbonyl group, phenoxycarbonyl group or fluorine atom, chlorine atom And halogen atoms such as bromine atom or iodine atom.
[0032]
In the present invention, the “aralkyl group which may be substituted” means an aralkyl group in which any position of the aralkyl group may be substituted. Examples of the aralkyl group include a benzyl group, a naphthylmethyl group, a phenylethyl group, and a 9-fluorenylmethyl group. Examples of the substituent include an alkyl group such as a methyl group, tert-butyl group or benzyl group, a cycloalkyl group such as cyclopropane, cyclopentane or cyclohexane, a phenyl group, a hydroxyl group, a methoxy group, a benzyloxy group or a methoxyethoxy group. Examples thereof include an alkoxy group, a phenoxy group, a nitro group, an amino group, an amide group, a carboxyl group, an alkoxycarbonyl group, a phenoxycarbonyl group, or a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
[0033]
In the present invention, the “aryl group that may be substituted” means an aryl group that may be substituted at any position of the aryl group. Examples of the aryl group include a phenyl group, a naphthyl group, an anthracenyl group, a fluorenyl group, and a phenanthrenyl group. Examples of the substituent include an alkyl group such as a methyl group, tert-butyl group or benzyl group, a cycloalkyl group such as cyclopropane, cyclopentane or cyclohexane, a phenyl group, a hydroxyl group, a methoxy group, a benzyloxy group or a methoxyethoxy group. Examples thereof include an alkoxy group, a phenoxy group, a nitro group, an amino group, an amide group, a carboxyl group, an alkoxycarbonyl group, a phenoxycarbonyl group, or a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
[0034]
In the present invention, the “optionally substituted heterocycle” means a heterocycle in which any position of the heterocycle may be substituted. Heterocycles include tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, piperidyl, morpholinyl, piperazinyl, pyrrolyl, furyl, thienyl, pyridyl, furfuryl, tenenyl, pyridylmethyl, pyrimidyl Group, pyrazyl group, imidazolyl group, imidazolylmethyl group, indolyl group, indolylmethyl group, isoquinolyl group, quinolyl group or thiazolyl group. Examples of the substituent include an alkyl group such as a methyl group, tert-butyl group or benzyl group, a cycloalkyl group such as cyclopropane, cyclopentane or cyclohexane, a phenyl group, a hydroxyl group, a methoxy group, a benzyloxy group or a methoxyethoxy group. Examples thereof include an alkoxy group, a phenoxy group, a nitro group, an amino group, an amide group, a carboxyl group, an alkoxycarbonyl group, a phenoxycarbonyl group, or a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
[0035]
In the present invention, the “ether-based protecting group as a hydroxyl-protecting group” means a protecting group having an ether bond for the purpose of protecting the hydroxyl group, and includes a methyl group, an ethyl group, a tert-butyl group, an octyl group, an allyl group. Group, benzyl group, p-methoxybenzyl group, fluorenyl group, trityl group, benzhydryl group and the like.
[0036]
In the present invention, the “acetal protecting group” means a protecting group having an acetal bond for the purpose of protecting a hydroxyl group,, MeToxiethoxymethyl group, tetrahydropyraN-2-ylGroup, tetrahydrofuraN-2-ylGroups and the like.
[0037]
In the present invention, the “silyl protecting group” means a protecting group having a silyloxy bond for the purpose of protecting a hydroxyl group, such as a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, etc. Can be mentioned.
[0038]
In the present invention, examples of the “halogen atom” include fluorine, chlorine, bromine and iodine.
[0039]
In the present invention, the “optionally substituted acyl group” means an acyl group in which any position of the acyl group may be substituted. Examples of the acyl group include formyl group, acetyl group, propionyl group, pivaloyl group, benzoyl group and the like. Examples of the substituent include an alkyl group such as a methyl group, tert-butyl group or benzyl group, a cycloalkyl group such as cyclopropane, cyclopentane or cyclohexane, a phenyl group, a hydroxyl group, a methoxy group, a benzyloxy group or a methoxyethoxy group. Examples thereof include an alkoxy group, a phenoxy group, a nitro group, an amino group, an amide group, a carboxyl group, an alkoxycarbonyl group, a phenoxycarbonyl group, or a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
[0040]
In the present invention, the “optionally substituted carbonate group” means a carbonate group in which any position of the carbonate group may be substituted. Examples of the carbonate group include a methyl carbonate group, an ethyl carbonate group, an isopropyl carbonate group, and a benzyl carbonate group. Examples of the substituent include an alkyl group such as a methyl group, tert-butyl group or benzyl group, a cycloalkyl group such as cyclopropane, cyclopentane or cyclohexane, a phenyl group, a hydroxyl group, a methoxy group, a benzyloxy group or a methoxyethoxy group. Examples thereof include an alkoxy group, a phenoxy group, a nitro group, an amino group, an amide group, a carboxyl group, an alkoxycarbonyl group, a phenoxycarbonyl group, or a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
[0041]
In the present invention, the “optionally substituted alkyloxy group” means an alkyloxy group in which any position of the alkyloxy group may be substituted. Examples of the alkyloxy group include methoxy group, ethoxy group, isopropoxy group, tert-butoxy group, pentyloxy group, hexyloxy group, octyloxy group, decyloxy group and allyloxy group. Substituents include alkoxy groups such as hydroxyl group, methoxy group, benzyloxy group or methoxyethoxy group, phenoxy group, nitro group, amino group, amide group, carboxyl group, alkoxycarbonyl group, phenoxycarbonyl group or fluorine atom, chlorine atom And halogen atoms such as bromine atom or iodine atom.
[0042]
In the present invention, “optionally substituted aralkyloxy group” means an aralkyloxy group in which any position of the aralkyloxy group may be substituted. Examples of the aralkyloxy group include a benzyloxy group, a naphthylmethyloxy group, a phenylethyloxy group, and a 9-fluorenylmethyloxy group. Examples of the substituent include an alkyl group such as a methyl group, a tert-butyl group or a benzyl group, a cycloalkyl group such as cyclopropane, cyclopentane or cyclohexane, a phenyl group, a hydroxyl group, a methoxy group, a benzyloxy group or a methoxyethoxy group. Examples thereof include an alkoxy group, a phenoxy group, a nitro group, an amino group, an amide group, a carboxyl group, an alkoxycarbonyl group, a phenoxycarbonyl group, or a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
[0043]
In the present invention, “optionally substituted phenoxy group” means a phenoxy group in which any position of the phenoxy group may be substituted. Examples of the substituent include an alkyl group such as a methyl group, tert-butyl group or benzyl group, a cycloalkyl group such as cyclopropane, cyclopentane or cyclohexane, a phenyl group, a hydroxyl group, a methoxy group, a benzyloxy group or a methoxyethoxy group. Examples thereof include an alkoxy group, a phenoxy group, a nitro group, an amino group, an amide group, a carboxyl group, an alkoxycarbonyl group, a phenoxycarbonyl group, or a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
[0044]
In the present invention, the “amino group which may be substituted” means an amino group which may be substituted at any position of the amino group. Examples of the substituent include an alkyl group such as a methyl group, tert-butyl group or benzyl group, a cycloalkyl group such as cyclopropane, cyclopentane or cyclohexane, and a phenyl group.
[0045]
In the present invention, examples of the “alkali metal” include lithium, sodium, potassium, rubidium, cesium and the like.
[0046]
In the present invention, “alkaline earth metal salt” means a salt such as magnesium, calcium, strontium, barium beryllium, etc., magnesium halide, alkoxymagnesium, calcium halide, alkoxycalcium, strontium halide, barium halide, Examples include beryllium halide. More specifically, magnesium salts such as -MgCl, -MgBr, -MgOMe, and -MgOEt, calcium salts such as -CaCl, -CaBr, -CaOMe, and -CaOEt, and barium salts such as -BaCl, -BaBr, -BaOMe, and -BaOEt Can be mentioned. Also, two molecules of azole acetic acid derivative can form one alkaline earth metal salt.
[0047]
In the present invention, examples of the “alkyloxycarbonyl group” include methoxycarbonyl group, ethoxycarbonyl group, tert-butoxycarbonyl group and the like.
[0048]
In the present invention, examples of the “aryloxycarbonyl group” include phenoxycarbonyl and naphthyloxycarbonyl groups.
[0049]
In the present invention, the “amide group that may be substituted” means an amino group that may be substituted at any position of the amide group. Examples of the substituent include an alkyl group such as a methyl group, tert-butyl group or benzyl group, a cycloalkyl group such as cyclopropane, cyclopentane or cyclohexane, and a phenyl group.
[0050]
In the present invention, the “optionally substituted heterocyclic oxy group” means a heterocyclic oxy group in which any position of the heterocyclic oxy group may be substituted. Examples of the heterocyclic oxy group include tetrahydropyranyloxy group, tetrahydrofuranyloxy group, tetrahydrothienyloxy group, piperidyloxy group, morpholinyloxy group, piperazinyloxy group, pyrrolyloxy group, furyloxy group, thienyloxy group, Pyridyloxy group, furfuryloxy group, tenyloxy group, pyridylmethyloxy group, pyrimidyloxy group, pyrazyloxy group, imidazolyloxy group, imidazolylmethyloxy group, indolyloxy group, indolylmethyloxy group, isoquinolyloxy group Quinolyloxy group or thiazolyloxy group. Examples of the substituent include an alkyl group such as a methyl group, tert-butyl group or benzyl group, a cycloalkyl group such as cyclopropane, cyclopentane or cyclohexane, a phenyl group, a hydroxyl group, a methoxy group, a benzyloxy group or a methoxyethoxy group. Examples thereof include an alkoxy group, a phenoxy group, a nitro group, an amino group, an amide group, a carboxyl group, an alkoxycarbonyl group, a phenoxycarbonyl group, or a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
[0051]
The diastereoselective reaction from the halomethyl ketone derivative of the general formula (3) to the optically active halomethyl alcohol derivative of the general formula (5) or the optically active epoxide derivative of (8) is a halo of the general formula (3). A new asymmetric carbon is generated selectively with respect to the asymmetric carbon steric structure of the methyl ketone derivative. Anti-selective means that an optically active carbon atom is formed when a carbon chain is zigzag on a certain surface. A hydroxyl group is formed on the opposite side of the R 2 O— group, and syn-selective means selectivity for generating a hydroxyl group on the same side. The optically active halomethyl alcohol derivative of the general formula (5) obtained by diastereoselective reaction is represented by the general formula (8) while maintaining diastereoselectivity under the reaction conditions or by treatment with a base or heat. An optically active epoxide can be derived. That is, anti-selective means that the general formula (9)
[0052]
Embedded image
In this reaction, a (S, S) form is generated from the (S) form, and a (R, R) form is formed from the (R) form.
The syn selectivity is the general formula (10)
[0054]
Embedded image
In this reaction, the (S) form is generated from the (S) form and the (R, S) form is produced from the (R) form.
[0056]
Below, the typical manufacturing method of this invention is demonstrated.
[1] A method for producing a halomethyl ketone derivative represented by the general formula (3) will be described.
The α-hydroxycarboxylic acid derivative represented by the general formula (1) is represented by the general formula (3) by reacting the haloacetic acid derivative represented by the general formula (2) under basic conditions. Halomethyl ketone derivatives can be produced. In this reaction, a halomethyl group can be efficiently introduced by allowing the decarboxylation reaction to proceed after or simultaneously with the carbon-carbon bond reaction. In this reaction, an optically active substance is used as a starting material, but almost no decrease in optical purity due to the reaction is observed.
[0057]
Although there is no restriction | limiting in particular as a base which can be used, Inorganic bases, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, are mentioned. Moreover, organic amine bases, such as a triethylamine, a pyridine, and a 1, 8- diazabicycloundecene, are mentioned. Moreover, alkoxides, such as sodium methoxide, sodium ethoxide, potassium t-butoxide, are mentioned. Moreover, metal hydrides, such as lithium hydride and sodium hydride, are mentioned. Further, organic metal bases such as alkyl lithium and Grignard reagent, among them, n-butyl lithium, ethyl magnesium bromide, n-butyl magnesium chloride, tert-butyl magnesium chloride and the like can be mentioned. In addition, metal amide bases such as sodium amide, lithium amide, and magnesium amide, among them, lithium diisopropylamide, halogenated magnesium dialkylamide, and particularly metal amide bases such as magnesium chloride diisopropylamide can be used. These bases can be used alone or in combination.
[0058]
Solvents that can be used are not particularly limited as long as they do not interfere with the progress of the reaction, but water, alcohol solvents such as methanol, ethanol, and butanol, hydrocarbon solvents such as hexane, toluene, xylene, and ethyl acetate. , Ester solvents such as butyl acetate, ether solvents such as diethyl ether, dioxane, ethylene glycol dimethyl ether and tetrahydrofuran, halogen solvents such as chloroform and dichloromethane, acetonitrile, dimethylformamide, dimethyl sulfoxide, dimethylimidazolidinone, etc. Can do. These solvents can be used alone or as a mixed solvent in any ratio of two or more.
[0059]
Regarding the reaction temperature, the reaction can be carried out from −78 ° C. to the boiling point of the solvent to be used, but preferably in the temperature range from −20 ° C. to the boiling point of the solvent. The reaction time is not particularly limited, but is in the range of several minutes to 24 hours, preferably 30 minutes to 6 hours.
[0060]
[2] A method for producing a halomethyl alcohol derivative represented by the general formula (5) or a method for producing an epoxide derivative represented by (8) will be described.
The derivative represented by the general formula (5) or (8) is produced by reacting the halomethyl ketone derivative represented by the general formula (3) with the phenyl metal reagent represented by the general formula (4). be able to. In this reaction, the diastereoselectivity changes depending on the combination of the protective group for the hydroxyl group represented by R2 and the metal species represented by A. Can be made separately.
[0061]
In general, the organometallic reagent reacts according to the so-called chelation model in which the carbonyl group involved in the reaction with the oxygen atom in the R2O group is fixed by the coordination of the metal. The object can be obtained. More specifically, it is possible to selectively produce an S—R configuration compound from an S configuration compound and an R—S configuration compound from an R configuration compound. By specifically using a benzyl group, a methoxymethyl group or the like as the protecting group and using a Grignard reagent as the organometallic reagent, the desired reaction can be performed with high anti-selectivity (> 9: 1).
[0062]
Further, the target product can be obtained with high syn selectivity by sterically increasing the hydroxyl protecting group represented by R2 and selecting an appropriate metal reagent. More specifically, an SS configuration compound can be produced from an S configuration compound, and an RR configuration compound from an R configuration compound can be produced with high syn selectivity (> 5: 1). Specifically, the target reaction can be performed with very high syn selectivity (> 7: 1) by using a silyl protecting group as the protecting group. Examples of the silyl-based protecting group include a trimethylsilyl group, a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group, and a triethylsilyl group.
The epoxide derivative represented by the general formula (8) is produced under the reaction conditions or treatment with a base or heat after the halomethyl alcohol derivative represented by the general formula (5) is formed with high diastereoselectivity. It can be obtained when the chemical reaction occurs. In this case, the diastereoselectivity generated in the first reaction is not lost.
[0063]
In this reaction, when the starting material is an optically active substance, a decrease in optical purity due to the reaction is hardly observed. Examples of phenyl metal compounds that can be used include phenyl lithium derivatives, phenyl magnesium derivatives, phenyl zinc derivatives, phenyl titanium derivatives, phenyl copper derivatives, and phenyl copper lithium derivatives. Furthermore, various additives can be added to the reaction system to change the diastereoselectivity or to improve the yield. Specific examples of the additive include a Lewis acid and a quaternary ammonium salt. More specifically, CeCl3, MgBr2MgCl2ZnCl2ZnBr2, CuCl2TiClFour, BFThreeAlClThree, SnClFour, SnCl2Etc.
[0064]
Solvents that can be used are not particularly limited as long as they do not interfere with the progress of the reaction, but water, alcohol solvents such as methanol, ethanol, and butanol, hydrocarbon solvents such as hexane, toluene, xylene, and ethyl acetate. , Ester solvents such as butyl acetate, ether solvents such as diethyl ether, dioxane, ethylene glycol dimethyl ether and tetrahydrofuran, halogen solvents such as chloroform and dichloromethane, acetonitrile, dimethylformamide, dimethyl sulfoxide, dimethylimidazolidinone, etc. Can do. These solvents can be used alone or as a mixed solvent in any ratio of two or more.
[0065]
Regarding the reaction temperature, it can be carried out from −78 ° C. to the boiling point of the solvent used, and is preferably in the range of −40 ° C. to room temperature. The reaction time is not particularly limited, but is in the range of several minutes to 24 hours, preferably 30 minutes to 6 hours.
[0066]
[3] A method for producing an azolemethyl alcohol derivative represented by the general formula (6) will be described.
The azole methyl alcohol derivative represented by the general formula (6) can be produced by reacting the derivative represented by the general formula (5) or (8) with triazole or imidazole. The reaction can be carried out with triazole or imidazole alone or in the presence of a base. Although there is no restriction | limiting in particular as a base which can be used, Inorganic bases, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, a triethylamine, a pyridine, 1, 8- diazabicycloun Organic amine bases such as decene, metal hydrides such as lithium hydride and sodium hydride, organometallic bases such as n-butyllithium, ethylmagnesium bromide, n-butylmagnesium chloride, tert-butylmagnesium chloride, or sodium amide, Examples thereof include metal amide bases such as lithium diisopropylamide and magnesium chloride diisopropylamide.
[0067]
Solvents that can be used are not particularly limited as long as they do not interfere with the progress of the reaction, but water, alcohol solvents such as methanol, ethanol, and butanol, hydrocarbon solvents such as hexane, toluene, xylene, and ethyl acetate. And ester solvents such as butyl acetate, ether solvents such as diethyl ether, dioxane, ethylene glycol dimethyl ether and tetrahydrofuran, halogen solvents such as chloroform and dichloromethane, acetonitrile, dimethylformamide and dimethyl sulfoxide. These solvents can be used alone or as a mixed solvent in any ratio of two or more.
[0068]
Regarding the reaction temperature, the reaction can be carried out from −20 ° C. to the boiling point of the solvent to be used, and preferably in the temperature range from 0 ° C. to the boiling point of the solvent. The reaction time is not particularly limited, but is in the range of several minutes to 72 hours, preferably 30 minutes to 12 hours.
[0069]
[4] A method for producing the optically active 2-phenyl-2,3-dihydroxypropylazole derivative represented by the general formula (7) will be described.
By selectively deprotecting the protecting group of the hydroxyl moiety represented by R2 of the optically active azole methyl alcohol derivative represented by the general formula (6), the optical activity 2- Phenyl-2,3-dihydroxypropyl azole derivatives can be produced. The method for deprotecting the hydroxyl group is not particularly limited as long as it does not change the structure other than the portion to be deprotected. In the case of an ether-based protecting group, it can be carried out by acid treatment with hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid or acetic acid, or catalytic hydrogenolysis treatment using palladium-carbon or the like as a catalyst. In the case of an acetal type protective group, acid treatment with hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonic acid or acetic acid, etc. can be used. In this case, it can be carried out by acid treatment with hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonic acid or acetic acid, or fluorine anion treatment such as tetra n-butylammonium fluoride.
[0070]
Solvents that can be used are not particularly limited as long as they do not interfere with the progress of the reaction, but water, alcohol solvents such as methanol, ethanol, and butanol, hydrocarbon solvents such as hexane, toluene, xylene, and ethyl acetate. And ester solvents such as butyl acetate, ether solvents such as diethyl ether, dioxane, ethylene glycol dimethyl ether and tetrahydrofuran, halogen solvents such as chloroform and dichloromethane, acetonitrile, dimethylformamide and dimethyl sulfoxide. These solvents can be used alone or as a mixed solvent in any ratio of two or more.
[0071]
Regarding the reaction temperature, it can be carried out from −20 ° C. to the boiling point of the solvent used. The reaction time is not particularly limited, but is in the range of several minutes to 24 hours, preferably 30 minutes to 6 hours.
[0072]
The optically active α-hydroxycarboxylic acid derivative represented by the general formula (1), which is a starting material of the present invention, can be easily obtained commercially or synthesized by a generally well-known method. It is. For example, lactic acid (Chem. Pharm. Bull., Vol.41 (6), pp.1035-1042, 1993), various amino acids (Synthesis, 1987, p.479), α-halocarboxylic acid derivatives (Tetrahedron Lett., 1985) , Vol.26, p.5257). In addition, reagents and raw materials used that are not particularly specified as production methods are generally commercially available, and both are easily available.
[0073]
【Example】
Examples of the present invention will be described below, but the present invention is not limited by these.
[Example 1] Synthesis of (3R) -1-chloro-3- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy) -2-butanone
[0074]
Embedded image
Diisopropylamine (19.4 g) was added to tret-butylmagnesium chloride (0.94 M tetrahydrofuran solution) (200 ml) at room temperature, heated to reflux at 70 ° C. for 1.5 hours, and then cooled to room temperature (this was designated as reaction solution A). In a separate reaction vessel, (2R) -methyl-2- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy) propionate (9.1 g) was added and dissolved in tetrahydrofuran (40 ml) at room temperature. Sodium chloroacetate (11.3 g) was added. This was ice-cooled, magnesium chloride (9.3 g) was added in small portions, and the mixture was stirred at room temperature for 4 hours (this was designated as reaction solution B). The reaction solution B was ice-cooled, and the reaction solution A was added dropwise at an internal temperature of 5 ° C. or lower, and this was heated to reflux at 70 ° C. for 2 hours and then cooled to room temperature. The reaction solution was poured into a mixed solution of sulfuric acid (18.0 g) / water (150 ml) / ethyl acetate (225 ml) under ice-cooling and stirred at room temperature for 40 minutes. This solution was separated, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was isolated and purified by silica gel column chromatography (426 g, hexane-ethyl acetate = 4: 1), and two kinds of diastereomers derived from the protecting group THP of the target compound were obtained. Obtained as a yellow oil.
[0076]
Yield = 9.2g
Yield = 92%
Diastereomer A
1H-NMR (400MHz, CDClThree) δ = 4.65 (dd, 1H, J = 4.4, 2.8Hz), 4.45 (quartet, 1H, J = 6.8Hz), 4.42 (d, 1H, J = 16Hz), 4.36 (d, 1H, J = 16Hz) , 3.91-3.82 (m, 2H), 1.88-1.45 (m, 6H), 1.41 (d, 3H, J = 6.8Hz)
Diastereomer B
1H-NMR (400MHz, CDClThree) δ = 4.66 (d, 1H, J = 17Hz), 4.55 (dd, 1H, J = 6.4,2.4Hz), 4.42 (d, 1H, J = 17Hz) 4.25 (quartet, 1H, J = 6.8Hz), 3.56-3.50 (m, 1H), 3.47-3.41 (m, 1H), 1.92-1.49 (m, 6H), 1.35 (d, 3H, J = 6.8Hz)
IR (neat, diastereomixture) ν = 2946, 2870, 1741, 1433, 1398, 1327, 1203, 1130, 1078, 1035, 974, 892, 874, 816, 781cm-1
[0077]
Example 2 (2R, 3R) -1-Chloro-2- (2,4-difluorophenyl) -3- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy) -2- Synthesis of butanol [Chemical Formula 20]
[0078]
Embedded image
Magnesium (1.5 g) was suspended in tetrahydrofuran (25 ml) under a nitrogen atmosphere, iodine (50 mg) was added, and a solution of 2,4-difluorobromobenzene (11.0 g) / tetrahydrofuran (20 ml) was added at 25-30 ° C. It was dripped. The mixture was stirred at room temperature for 1.5 hours to obtain a solution A (49.2 g). In a separate reaction vessel, the compound (2.0 g) obtained in Example 1 was placed, dissolved in tetrahydrofuran (20 ml), and cooled to -20 ° C. Solution A (9.1 g) was added dropwise thereto at −5 ° C. or lower, and the mixture was stirred at −10 ° C. to 0 ° C. for 1 hour and at 0 ° C. to 10 ° C. for 2 hours. The reaction solution was cooled to 5 ° C., and adjusted to pH 8 by adding 1N hydrochloric acid (9 ml). After stirring at 5 ° C. to 10 ° C. for 30 minutes, ethyl acetate and water were added for extraction, and the organic layer was washed with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was concentrated under reduced pressure to obtain a light brown residue.
[0080]
[Diastereoselectivity of reaction]
Anti-derivative (2R, 3R): Sin derivative (2S, 3R) = 10: 1
The diastereoselectivity was determined by carrying out the method described in Examples 3 and 4 while maintaining the mixture without purification by silica gel column chromatography, and (2S, 3R) -2- (2,4-difluorophenyl) -1 -(1H-1,2,4-triazol-1-yl) -2,3-butanediol and (2R, 3R) -2- (2,4-difluorophenyl) -1- (1H-1,2, After derivatization to 4-triazol-1-yl) -2,3-butanediol, it was determined using HPLC (analysis conditions / YMC-PACK ODS A-303, eluent composition methanol: water: acetic acid = 70: 30 : 0.2, detection method UV 254 nm).
The pale brown residue obtained by the above operation is isolated and purified by silica gel column chromatography (68 g, hexane-ethyl acetate = 4: 1), and the main product having the configuration of (2R, 3R). Two diastereomeric mixtures derived from the tetrahydropyran moiety were obtained as white amorphous.
[0081]
Yield = 2.0g
Yield = 64%
Diastereomer A of anti-derivative (2R, 3R)
1H-NMR (400MHz, CDClThree) δ = 7.71 (td, 1H, J = 9.0, 6.8Hz), 6.94-6.89 (m, 1H), 6.83-6.76 (m, 1H), 4.61 (dd, 1H, J = 4.8, 2.4Hz), 4.38 (d, 1H, J = 11Hz), 4.21 (d, 1H, J = 11Hz), 4.12 (quartet, 1H, J = 6.8Hz), 4.00 (s, 1H), 3.52-3.46 (m, 2H), 1.86 -1.32 (m, 6H), 1.27 (d, 3H, J = 6.8Hz)
Diastereomer B of anti-derivative (2R, 3R)
1H-NMR (400MHz, CDClThree) δ = 7.62 (td, 1H, J = 8.8, 6.4Hz), 6.94-6.89 (m, 1H), 6.83-6.76 (m, 1H), 4.29 (m, 1H), 4.03 (quartet, 1H, J = 6.4Hz), 4.00 (s, 1H), 3.95 (dd, 1H, J = 11, 2.4Hz), 3.91 (dd, 1H, J = 11, 2.4Hz), 3.46-3.37 (m, 2H), 1.86- 1.32 (m, 6H), 1.13 (dd, 3H, J = 1.2, 6.4Hz)
IR (KBr-disk, diastereomixture) ν = 3437, 3079, 2943, 2873, 1736, 1616, 1502, 1469, 1421, 1356, 1273, 1201, 1121, 1084, 1025, 973, 927, 863, 815, 756, 726, 680, 632, 558, 543, 515cm-1
[0082]
[Example 3] (2S, 3R) -2- (2,4-difluorophenyl) -3- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy) -1- (1H-1 , 2,4-Triazol-1-yl) -2-butanol
[0083]
Embedded image
Under a nitrogen atmosphere, sodium hydride (0.36 g) was suspended in N, N-dimethylformamide (6 ml), 1,2,4-triazole was added little by little under ice cooling, and the mixture was stirred at room temperature for 40 minutes. To this was added dropwise the diastereomer mixture (0.71 g) / N, N-dimethylformamide (5 ml) solution obtained in Example 2, and the mixture was stirred with heating at room temperature for 4 hours and at 70 ° C. for 6 hours. The reaction solution was cooled to room temperature, poured into ice water, and adjusted to pH 4 with 1N hydrochloric acid. Ethyl acetate was added for extraction, and the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the resulting residue was isolated and purified by silica gel column chromatography (32 g, chloroform-methanol = 25: 1), and a mixture of two diastereomers derived from the tetrahydropyran site was pale yellow. Obtained as amorphous.
In this reaction, the steric structure of the asymmetric carbon is not changed by anti, but the two-dimensional steric notation is changed from (R) to (S) by changing the chlorine atom to triazole.
[0085]
Yield = 0.68g
Yield = 86%
Diastereomer A
1H-NMR (400MHz, CDClThree) δ = 8.12 (s, 1H), 8.02 (s, 1H), 7.73 (d, 1H, J = 11Hz), 7.55 (td, 1H, J = 9.0, 6.8Hz), 6.80-6.69 (m, 1H) , 5.15 (dd, 1H, J = 14,1.2Hz), 4.78 (s, 1H), 4.62-4.61 (m, 1H), 4.56 (dd, 1H, J = 14, 1.2Hz), 4.10 (quartet, 1H , J = 6.4Hz), 3.45-3.41 (m, 2H), 1.86-1.34 (m, 6H), 1.17 (dd, 3H, J = 6.4, 1.2Hz)
Diastereomer B
1H-NMR (400MHz, CDClThree) δ = 8.05 (s, 1H), 8.02 (s, 1H), 7.73 (d, 1H, J = 11Hz), 7.44 (td, 1H, J = 9.0, 6.4Hz), 6.80-6.69 (m, 1H) , 4.98 (dd, 1H, J = 14,1.2Hz), 4.48 (dd, 1H, J = 14,0.8Hz), 4.41 (s, 1H), 416 (qd, 1H, J = 6.0, 0.8Hz), 3.41-3.38 (m, 2H), 1.86-1.34 (m, 6H), 1.13 (d, 3H, J = 6.0Hz)
IR (neat, diastereomixture) ν = 3392, 3128, 2945, 2872, 1669, 1616, 1502, 1419, 1387, 1274, 1203, 1137, 1078, 1033, 973, 872, 816, 729, 680, 660, 551cm-1
[0086]
Example 4 Synthesis of (2S, 3R) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2,3-butanediol 22]
[0087]
Embedded image
The compound (0.51 g) obtained in Example 3 was dissolved in ethanol (7 ml), pyridinium paratoluenesulfonic acid (149 mg) was added, and the mixture was heated and stirred at room temperature for 1 hour and at 55 ° C. for 2.5 hours. The reaction solution was cooled to room temperature and concentrated, and the residue was extracted with ethyl acetate and water. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the resulting residue was isolated and purified by silica gel column chromatography (32 g, chloroform-methanol = 9: 1) to obtain the target compound as a white amorphous.
[0089]
Yield = 0.22g
Yield = 57%
1H-NMR (400MHz, CDClThree) δ = 8.03 (d, 1H, J = 1.2Hz), 7.76 (s, 1H), 7.54 (td, 1H, J = 9.2, 6.4Hz), 6.83-6.78 (m, 1H), 6.72 (ddd, 1H , J = 12,8.8,2.8Hz), 5.03 (d, 1H, J = 14,1.6Hz), 5.01 (s, 1H), 4.56 (dd, 1H, J = 14, 1.6Hz), 4.00 (quartet, 1H, J = 6.4Hz), 2.65 (d, 1H, J = 5.2Hz), 1.26 (dd, 3H, J = 6.4, 1.2Hz)
IR (KBr-disk) ν = 3406, 3136, 2982, 2938, 1618, 1501, 1421, 1277, 1207, 1139, 1082, 1021, 967, 853, 815, 663, 633, 548cm-1
[0090]
[Example 5] Synthesis of (3S) -1-chloro-3-benzyloxy-2-butanone
[0091]
Embedded image
(2S) -Methyl-2-benzyloxypropionate (4.70 g, 24.2 mmol) was dissolved in THF (20 ml), sodium chloroacetate (5.63 g) and magnesium chloride (4.61 g) were added, and under a nitrogen atmosphere, The mixture was stirred at room temperature for 1 hour (solution A). To a commercially available 0.97M tert-butylmagnesium chloride-THF solution (100 ml), diisopropylamine (9.90 g) was added dropwise at room temperature under a nitrogen atmosphere, and the mixture was heated and stirred at 65 to 70 ° C. for 1 hour (solution B). Liquid A was cooled to −15 ° C., and liquid B was added dropwise (the internal temperature during the addition was kept at 0 ° C. or lower). After completion of dropping, the reaction solution was heated to 65 to 70 ° C. and stirred for 2 hours. The reaction mixture was cooled, poured into a mixture of ice-cooled ethyl acetate (100 g) -10% sulfuric acid (90 g), and stirred as it was for 30 minutes. The organic layer was separated, washed with 5% -saline solution and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was isolated and purified by silica gel column chromatography (C-300, 100 g, hexane-ethyl acetate = 10: 1 → 8: 1).
[0093]
Yield = 4.06g
Yield = 79%
1H-N.M.R. (400MHz, CDClThree) δ = 7.40-7.30 (m, 5H), 4.61 (d, 1H, J = 11.5Hz), 4.53 (d, 1H, J = 11.5Hz), 4.46 (d, 1H, J = 14.5Hz), 4.39 ( d, 1H, J = 14.5Hz), 4.15 (q, 1H), J = 6.8Hz), 1.40 (d, 3H, J = 6.8Hz)
IR (neat) ν = 3033, 2986, 2939, 2870, 1742, 1497, 1455, 1396, 1308, 1115, 741, 699cm-1
[0094]
[Example 6] Synthesis of (2S, 3S) -1-chloro-2- (2,4-difluorophenyl) -3-benzyloxy-2-butanol
[0095]
Embedded image
The compound (3.19 g, 15 mmol) obtained in Example 5 was dissolved in THF (15 ml) and cooled to −15 ° C. A Grignard reagent (THF / 20 ml) prepared in advance from 2,4-difluorobromobenzene (3.47 g, 18 mmol) was added dropwise at -5 ° C. or lower. After stirring the reaction solution for 30 minutes, water (20 ml) was added dropwise at 5 ° C. or lower, and 1N hydrochloric acid (30 ml) was added dropwise at 5 ° C. or lower. Extracted with ethyl acetate (50 ml) and washed twice with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a light brown residue.
[0097]
[Diastereoselectivity]
Anti-derivative (2S, 3S): Thin derivative (2R, 3S) = 10: 1
Diastereoselectivity means that the resulting light brown residue remains as a mixture without purification by silica gel column chromatography.1H-N.M.R. (400MHz, CDClThree) Was measured and determined from the integration ratio of each peak.
Further, the pale brown residue obtained by the above operation was isolated and purified by silica gel column chromatography (C-300, 200 g, hexane-ethyl acetate = 10: 1 → 6: 1) to obtain the title compound.
[0098]
Yield of anti-derivative (2S, 3S) = 2.50g
Yield of anti-derivative (2S, 3S) = 51%
Anti-derivative (2S, 3S)
1H-N.M.R. (400MHz, CDClThree) δ = 7.67-7.60 (m, 1H), 7.28-7.25 (m, 3H), 7.08-7.05 (m, 2H), 6.94-6.90 (m, 1H), 6.77-6.72 (m, 1H), 4.49 ( d, 1H, J = 11.7Hz), 4.27 (d, 1H, J = 11.7Hz), 4.20 (d, 1H, J = 11.2Hz), 3.92-3.87 (m, 2H), 3.17 (s, 1H), 1.22 (dd, 3H, J = 0.7, 6.4Hz)
IR (neat) ν = 3538, 3066, 3032, 2978, 2938, 2873, 1616, 1501, 1420, 1271, 1131, 1091, 973, 852, 750, 698cm-1
Thin derivatives (2R, 3S)
1H-N.M.R. (400MHz, CDClThree) δ = 7.74-65 (m, 1H), 7.38-7.31 (m, 5H), 6.94-6.87 (m, 1H), 6.79-6.71 (m, 1H), 4.70 (d, 1H, J = 11.6Hz) , 4.47 (d, 1H, J = 11.6Hz), 4.11-4.00 (m, 3H), 2.99 (s, 1H), 1.01 (d, 3H, J = 5.9Hz)
At this time, 1.33 g of the raw material BCMK was recovered. Considering the recovery of BCMK, the conversion yield was 87%.
[0099]
[Example 7] Synthesis of (2S, 3S) -1-chloro-2- (2,4-difluorophenyl) -3-benzyloxy-2-butanol
[0100]
Embedded image
Under a nitrogen atmosphere, magnesium (6.0 g, 46 mmol) was dispersed in tetrahydrofuran (120 ml), and iodine (5 mg) was added and stirred. A solution of 2,4-difluorobromobenzene (48 g, 248 mmol) in tetrahydrofuran (120 ml) was added dropwise so that the internal temperature was 30 to 35 ° C., and Grignard reagent A was obtained. Separately, anhydrous cerium chloride (10 g, 40.8 mmol) was dried under reduced pressure at 130 ° C. for 1 hour. After cooling to room temperature, tetrahydrofuran (40 ml) was added under a nitrogen atmosphere, and sonication was performed for 30 minutes in a suspended state to obtain a suspension solution B. Subsequently, a solution of the compound (4.34 g, 20.4 mmol) obtained in Example 5 in tetrahydrofuran (10 ml) was added to the suspension solution B, and sonication was further performed for 30 minutes. Tetrahydrofuran (4 ml) was added to the suspension solution B, and then maintained at 0 ° C. to −5 ° C., the Grignard reagent A (24 ml, 24 mmol) prepared above was added dropwise. After dropping, the mixture was further stirred for 12 hours. Under ice cooling, 1N hydrochloric acid (200 ml) was added dropwise, and the mixture was extracted with ethyl acetate (400 ml). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (400 ml) and saturated brine (400 ml), dried over magnesium sulfate, filtered and concentrated to give a light brown residue.
[0102]
[Diastereoselectivity]
Anti-derivative (2S, 3S): Thin derivative (2R, 3S) = 10: 1
Determination of diastereoselectivity was performed in the same manner as in Example 6.
Further, the pale brown residue obtained by the above operation was isolated and purified by silica gel column chromatography (C-300, 200 g, hexane-ethyl acetate = 10: 1 → 6: 1) to obtain the title compound.
Yield of anti-derivative (2S, 3S) = 6.13g
Yield of anti-derivative (2S, 3S) = 92%
1H-N.M.R. (400MHz, CDClThree) And IR (neat) values were consistent with Example 6.
[0103]
[Example 8] Synthesis of (2R, 3S) -2- (2,4-difluorophenyl) -3-benzyloxy-1- (1H-1,2,4-triazol-1-yl) -2-butanol [Chemical 26]
[0104]
Embedded image
60% -sodium hydride (800 g, 20 mmol) was suspended in DMF (7 g), and triazole (1.38 g, 20 mmol) was charged in ice-cooled nitrogen atmosphere (internal temperature kept at 15 ° C. or lower) did). After stirring for 1 hour under ice-cooling to obtain an almost uniform light brown solution, a solution obtained by dissolving the compound (1.63 g, 5 mmol) obtained in Example 8 in DMF (7 g) was added dropwise at 10 ° C. or lower. I was charged. The reaction was warmed to 70-75 ° C. and stirred for 6 hours. The reaction mixture was cooled, poured into water (60 g), and extracted with ethyl acetate (100 ml). After washing with water (3 times at 60 g) and drying over anhydrous magnesium sulfate, the organic layer was concentrated under reduced pressure. The obtained residue was isolated and purified by silica gel column chromatography (C-300, 100 g, hexane-ethyl acetate = 1: 2) to obtain a yellow syrup.
In this reaction, the steric structure of the asymmetric carbon is not changed by anti, but the steric notation at the 2-position is changed from (S) to (R) by changing the chlorine atom to triazole.
[0106]
Yield = 1.33g
Yield = 80%
1H-N.M.R. (400MHz, CDClThree) δ = 7.99 (s, 1H), 7.72 (s, 1H), 7.49-7.43 (m, 1H), 7.29-7.26 (m, 3H), 7.10-7.08 (m, 2H), 6.80-6.75 (m, 1H), 6.71-6.65 (m, 1H), 4.96 (d, 1H, J = 14.5Hz), 4.53 (d, 1H, J = 10.4Hz), 4.45 (d, 1H, J = 14.5Hz), 4.36 ( s, 1H), 4.27 (d, 1H, J = 10.4Hz), 3.90 (q, 1H, J = 6.1Hz), 1.25 (d, 3H, J = 6.1Hz)
IR (neat) ν = 3259, 3166, 3086, 1617, 1502, 1274, 1135, 1096, 966, 858, 747, 667cm-1
Crystallization (hexane-THF) from 1.1 g of the syrup gave milky white crystals.
Yield = 960mg
[0107]
Example 9 Synthesis of (2R, 3S) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2,3-butanediol 27]
[0108]
Embedded image
The compound (719 g, 2 mmol) obtained in Example 8 was dissolved in methanol (30 ml), 10% -palladium / carbon (0.3 g) was added, and the hydrogen initial pressure (1.0 MPa) was adjusted to 50 ° C. in an autograve. And stirred for 8 hours. The catalyst was filtered off from the reaction solution, and the filtrate was concentrated under reduced pressure.
[0110]
Yield = 480mg
Yield = 89%
1H-NMR (400MHz, CDClThree) δ = 8.03 (d, 1H, J = 1.2Hz), 7.76 (s, 1H), 7.54 (td, 1H, J = 9.2, 6.4Hz), 6.83-6.78 (m, 1H), 6.72 (ddd, 1H , J = 12,8.8,2.8Hz), 5.03 (d, 1H, J = 14,1.6Hz), 5.01 (s, 1H), 4.56 (dd, 1H, J = 14, 1.6Hz), 4.00 (quartet, 1H, J = 6.4Hz), 2.65 (d, 1H, J = 5.2Hz), 1.26 (dd, 3H, J = 6.4, 1.2Hz)
IR (KBr-disk) ν = 3406, 3136, 2982, 2938, 1618, 1501, 1421, 1277, 1207, 1139, 1082, 1021, 967, 853, 815, 663, 633, 548cm-1
[0111]
[Example 10] Synthesis of (3R) -3- (tert-butyldiphenylsilyloxy) -1-chloro-2-butanone
[0112]
Embedded image
(2R) -Methyl-2- (tert-butyldiphenylsilyloxy) propionate (6.83 g, 20 mmol) was used in the same manner as in Example 1 to obtain the title compound as a colorless transparent syrup.
[0114]
Yield = 5.78g
Yield = 80%
1H-N.M.R. (400MHz, CDClThree) δ = 7.70-7.59 (m, 4H), 7.49-7.32 (m, 6H), 4.52 (d, 1H, J = 17.1Hz), 4.38 (d, 1H, J = 17.4Hz), 4.38 (q, 1H , J = 6.9Hz), 1.24 (d, 3H, J = 6.9Hz), 1.11 (s, 9H)
[0115]
Example 11 (2R) -2-[(1′R) -1- (tert-butyldiphenylsilyloxy) ethyl] -2- (2,4-difluorophenyl) oxirane and (2S) -2- [ Synthesis of (1'R) -1- (tert-butyldiphenylsilyloxy) ethyl] -2- (2,4-difluorophenyl) oxirane
[0116]
Embedded image
The compound synthesized in Example 10 (3.61 g, 10 mmol) was treated in the same manner as in Example 2 to obtain the title compound as a colorless transparent syrup (diastereomer mixture).
[0118]
[Diastereoselectivity]
Anti-derivative (1′R, 2S): Sin derivative (1′R, 2R) = 1: 7.25
Diastereoselectivity is1H-N.M.R. (400MHz, CDClThree) Was measured and determined from the integration ratio of each peak.
Yield = 2.20 g (diastereomeric mixture)
Yield = 50%
Anti-derivative (1'R, 2S)
1H-N.M.R. (270MHz, CDClThree): δ = 7.74-7.21 (m, 11H), 6.90-6.71 (m, 2H), 3.99 (q, 1H, J = 6.0HZ), 2.99 (d, 1H, J = 5.8Hz), 2.78 (d, 1H, J = 5.8Hz), 1.02 (s, 9H), 1.02 (d, 3H, J = 6.0Hz)
Thin derivatives (1'R, 2R)
1H-N.M.R. (270MHz, CDClThree): δ = 7.74-7.21 (m, 11H), 6.90-6.71 (m, 2H), 4.02 (q, 1H, J = 6.2Hz), 3.18 (d, 1H, J = 5.3Hz), 2.82 (dd, 1H, J = 1.0, 5.3Hz), 1.06 (s, 9H), 0.95 (dd, 3H, J = 1.7, 6.2Hz)
[0119]
Example 12 (2R, 3R) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2,3-butanediol and (2S, Synthesis of 3R) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2,3-butanediol
[0120]
Embedded image
60% -sodium hydride (400 g, 10 mmol) was suspended in DMF (7 g), and triazole (690 mg, 10 mmol) was charged in a nitrogen atmosphere under ice-cooling (the internal temperature was kept at 15 ° C. or lower). ). After stirring for 1 hour under ice-cooling to obtain an almost uniform light brown solution, a solution of the diastereomeric mixture (1.10 g, 2.5 mmol) obtained in Example 11 in DMF (7 g) was dissolved in 10 ml. The dripping was carried out at a temperature below 0 ° C. The reaction was warmed to 70-75 ° C. and stirred for 6 hours. The reaction mixture was cooled, poured into water (30 g), and extracted with ethyl acetate (50 ml). The organic layer was concentrated under reduced pressure after washing with water (3 times with 30 g) and drying over anhydrous magnesium sulfate. The obtained residue was dissolved in tetrahydrofuran (10 g), tetra-n-butylammonium fluoride (980 mg, 3.75 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Water (10 g) and ethyl acetate (20 g) were added to the reaction solution, and after stirring for 10 minutes, the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound as a pale yellow syrup of a diastereomeric mixture.
[0122]
[Diastereomer ratio]
Anti-derivative (1′R, 2S): Sin derivative (1′R, 2R) = 1: 7.25
The diastereo ratio was determined by analysis by HPLC. Analytical conditions / YMC-PACK ODS A-303, eluent composition Methanol: water: acetic acid = 70: 30: 0.2, detection method UV 254 nm Further, toluene was removed from the pale yellow syrup, which is a diastereomeric mixture obtained by the above operation. (2R, 3R) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2,3-butanediol (498 mg, 74%) was preferentially obtained as white crystals.
[0123]
Melting point: 116-117 ℃
Diastereomeric excess = 96% de
Analysis conditions / YMC-PACK ODS A-303, eluent composition Methanol: water: acetic acid = 70: 30: 0.2, detection method UV 254 nm
Optical purity = 99% ee
[0124]
The optical purity was measured using (2R, 3R) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2,3-butanediol in Chem. (2S, 3R) -2- (2,4-difluorophenyl) -3-methyl-2- (1H) which is a known compound according to the method described in Phram.Bull.41 (6) 1035-1042 (1993) Derived to -1,2,4-triazol-1-yl) methyloxirane and determined by HPLC analysis. Analysis conditions / DAICEL CHIRALCEL OF, eluent composition hexane: 2-propanol: diethylamine = 60: 40: 0.1, detection method UV 254 nm
(2R, 3R) body
1H-N.M.R. (270MHz, CDClThree): δ = 7.84 (s, 1H), 7.82 (s, 1H), 7.46-7.37 (m., 1H), 6.80-6.72 (m, 2H), 4.87-4.77 (m, 3H), 4.36-4.29 ( m, 1H), 2.63 (d, 1H, J = 9.2Hz), 0.97 (d, 3H, J = 6.5Hz)
(2S, 3R) body
1H-N.M.R. (270MHz, CDClThree) Was consistent with Example 4.
[0125]
【The invention's effect】
A highly stereoselective production method of optically active halomethyl alcohol derivatives and optically active epoxide derivatives, which are very important intermediates for pharmaceuticals and agricultural chemicals, has been found, and optically active 2-phenyl-2,3-dihydroxypropyl from an industrial viewpoint An azole derivative can be produced quickly and stably in a short process.
Claims (25)
で表されるα−ヒドロキシカルボン酸誘導体と、一般式（２）
で表されるハロ酢酸誘導体を塩基性条件下反応させ、一般式（３）
で表されるハロメチルケトン誘導体を製造し、さらに該ハロメチルケトン誘導体に一般式（４）
で表されるフェニル金属試薬をジアステレオ選択的に反応させ、一般式（８）[化８]
An α-hydroxycarboxylic acid derivative represented by the general formula (2)
A haloacetic acid derivative represented by the general formula (3)
The halomethyl ketone derivative represented by the general formula (4)
A phenyl metal reagent represented by general formula (8) [Chemical 8]
で表されるハロメチルケトン誘導体と、一般式（４）
で表されるフェニル金属試薬をジアステレオ選択的に反応させ、一般式（５）
A halomethyl ketone derivative represented by general formula (4):
A diastereoselective reaction of a phenyl metal reagent represented by general formula (5):
で表されるハロメチルケトン誘導体と、一般式（４）
で表されるフェニル金属試薬をジアステレオ選択的に反応させ、一般式（８）
A halomethyl ketone derivative represented by general formula (4):
A diastereoselective reaction of a phenyl metal reagent represented by general formula (8):
一般式（５）
で表される光学活性ハロメチルアルコール誘導体と、トリアゾールまたはイミダゾールと反応させ、一般式（６）
で表される光学活性アゾールメチルアルコール誘導体を製造する方法。Embedded image
General formula (5)
And an optically active halomethyl alcohol derivative represented by general formula (6)
A process for producing an optically active azolemethyl alcohol derivative represented by the formula:
で表される光学活性エポキシド誘導体を製造し、さらに該光学活性エポキシド誘導体と、トリアゾールまたはイミダゾールと反応させ、一般式（６）
で表される光学活性アゾールメチルアルコール誘導体を製造する方法。 One Ri by the method of claim 4 general formula (8)
In to produce an optical active epoxide derivative represented, and further reacted with the optically active epoxide derivative, a triazole or imidazole of the general formula (6)
A process for producing an optically active azolemethyl alcohol derivative represented by the formula:
で表される光学活性アゾールメチルアルコール誘導体を製造し、さらに、該光学活性アゾールメチルアルコール誘導体を脱保護し、一般式（７）
In formula to produce an optically active azole-methyl alcohol derivative, further the optically active azole-methyl alcohol derivative was deprotected formula (7)
で表される光学活性アゾールメチルアルコール誘導体を製造し、さらに、該光学活性アゾールメチルアルコール誘導体を脱保護し、一般式（７）And further deprotecting the optically active azole methyl alcohol derivative represented by the general formula (7):
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