JP2008007488A - 脱ヒドロキシフッ素化剤 - Google Patents
脱ヒドロキシフッ素化剤 Download PDFInfo
- Publication number
- JP2008007488A JP2008007488A JP2006182235A JP2006182235A JP2008007488A JP 2008007488 A JP2008007488 A JP 2008007488A JP 2006182235 A JP2006182235 A JP 2006182235A JP 2006182235 A JP2006182235 A JP 2006182235A JP 2008007488 A JP2008007488 A JP 2008007488A
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- JP
- Japan
- Prior art keywords
- group
- derivative
- fluoride
- organic base
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000012025 fluorinating agent Substances 0.000 title claims abstract description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 73
- 150000007530 organic bases Chemical class 0.000 claims abstract description 49
- OBTWBSRJZRCYQV-UHFFFAOYSA-N sulfuryl difluoride Chemical compound FS(F)(=O)=O OBTWBSRJZRCYQV-UHFFFAOYSA-N 0.000 claims abstract description 46
- 239000005935 Sulfuryl fluoride Substances 0.000 claims abstract description 45
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 68
- 239000003795 chemical substances by application Substances 0.000 claims description 47
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 40
- 229910000040 hydrogen fluoride Inorganic materials 0.000 claims description 40
- 150000003839 salts Chemical class 0.000 claims description 26
- AUHZEENZYGFFBQ-UHFFFAOYSA-N 1,3,5-Me3C6H3 Natural products CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 claims description 13
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 12
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2,5-dimethylpyridine Chemical compound CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 9
- BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 claims description 8
- JYYNAJVZFGKDEQ-UHFFFAOYSA-N 2,4-Dimethylpyridine Chemical compound CC1=CC=NC(C)=C1 JYYNAJVZFGKDEQ-UHFFFAOYSA-N 0.000 claims description 8
- HWWYDZCSSYKIAD-UHFFFAOYSA-N 3,5-dimethylpyridine Chemical compound CC1=CN=CC(C)=C1 HWWYDZCSSYKIAD-UHFFFAOYSA-N 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- HOPRXXXSABQWAV-UHFFFAOYSA-N 2,3,4-trimethylpyridine Chemical compound CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 claims description 7
- HPYNZHMRTTWQTB-UHFFFAOYSA-N 2,3-dimethylpyridine Chemical compound CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 claims description 6
- MNDSSKADVGDFDF-UHFFFAOYSA-N 2,4,5-trimethylpyridine Chemical compound CC1=CC(C)=C(C)C=N1 MNDSSKADVGDFDF-UHFFFAOYSA-N 0.000 claims description 6
- NURQLCJSMXZBPC-UHFFFAOYSA-N 3,4-dimethylpyridine Chemical compound CC1=CC=NC=C1C NURQLCJSMXZBPC-UHFFFAOYSA-N 0.000 claims description 6
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical group CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 claims description 5
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 claims description 4
- VCMUWBCBVPWJPS-UHFFFAOYSA-N 3,4,5-Collidin Natural products CC1=CN=CC(C)=C1C VCMUWBCBVPWJPS-UHFFFAOYSA-N 0.000 claims description 3
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims description 3
- 238000005906 dihydroxylation reaction Methods 0.000 claims 1
- -1 monofluoromethyl Chemical class 0.000 abstract description 53
- 239000002253 acid Substances 0.000 abstract description 20
- 125000001153 fluoro group Chemical group F* 0.000 abstract description 18
- 230000003287 optical effect Effects 0.000 abstract description 12
- 150000002148 esters Chemical class 0.000 abstract description 11
- ZIWHMENIDGOELV-BKLSDQPFSA-N (2s)-4-fluoropyrrolidine-2-carboxylic acid Chemical class OC(=O)[C@@H]1CC(F)CN1 ZIWHMENIDGOELV-BKLSDQPFSA-N 0.000 abstract description 10
- 238000004519 manufacturing process Methods 0.000 abstract description 10
- UIYWFOZZIZEEKJ-XVFCMESISA-N 1-[(2r,3r,4r,5r)-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical class F[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 UIYWFOZZIZEEKJ-XVFCMESISA-N 0.000 abstract description 6
- 239000000463 material Substances 0.000 abstract description 4
- 239000003905 agrochemical Substances 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 59
- 125000000217 alkyl group Chemical group 0.000 description 39
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- 239000012043 crude product Substances 0.000 description 29
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 125000006239 protecting group Chemical group 0.000 description 24
- 125000000547 substituted alkyl group Chemical group 0.000 description 23
- 125000004432 carbon atom Chemical group C* 0.000 description 21
- 125000003118 aryl group Chemical group 0.000 description 19
- 229910052799 carbon Inorganic materials 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- 229910052731 fluorine Inorganic materials 0.000 description 17
- 239000011737 fluorine Substances 0.000 description 16
- 238000000034 method Methods 0.000 description 15
- 230000001012 protector Effects 0.000 description 15
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 14
- 238000004817 gas chromatography Methods 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 13
- 125000003545 alkoxy group Chemical group 0.000 description 13
- 125000003277 amino group Chemical group 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical class O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 125000001931 aliphatic group Chemical group 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 239000000758 substrate Substances 0.000 description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 11
- 150000001721 carbon Chemical group 0.000 description 11
- 239000012925 reference material Substances 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 10
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 10
- 150000003138 primary alcohols Chemical class 0.000 description 10
- 238000006467 substitution reaction Methods 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 9
- 229910052739 hydrogen Inorganic materials 0.000 description 9
- 239000012535 impurity Substances 0.000 description 9
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- 235000011181 potassium carbonates Nutrition 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 125000005843 halogen group Chemical group 0.000 description 8
- 239000002994 raw material Substances 0.000 description 8
- 229910001220 stainless steel Inorganic materials 0.000 description 8
- 239000010935 stainless steel Substances 0.000 description 8
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 7
- DRTQHJPVMGBUCF-CCXZUQQUSA-N arauridine Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-CCXZUQQUSA-N 0.000 description 7
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 125000003396 thiol group Chemical group [H]S* 0.000 description 7
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 125000003282 alkyl amino group Chemical group 0.000 description 6
- 125000004414 alkyl thio group Chemical group 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- 238000009835 boiling Methods 0.000 description 6
- 125000004093 cyano group Chemical group *C#N 0.000 description 6
- 125000004438 haloalkoxy group Chemical group 0.000 description 6
- 125000000623 heterocyclic group Chemical group 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 description 6
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 6
- 125000004430 oxygen atom Chemical group O* 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 0 Cc(nc1)c[n]1S(OC(*)(*)*)(=O)=O Chemical compound Cc(nc1)c[n]1S(OC(*)(*)*)(=O)=O 0.000 description 5
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical group C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- UQSQSQZYBQSBJZ-UHFFFAOYSA-M fluorosulfonate Chemical compound [O-]S(F)(=O)=O UQSQSQZYBQSBJZ-UHFFFAOYSA-M 0.000 description 5
- UQSQSQZYBQSBJZ-UHFFFAOYSA-N fluorosulfonic acid Chemical compound OS(F)(=O)=O UQSQSQZYBQSBJZ-UHFFFAOYSA-N 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- LUYQYZLEHLTPBH-UHFFFAOYSA-N perfluorobutanesulfonyl fluoride Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)S(F)(=O)=O LUYQYZLEHLTPBH-UHFFFAOYSA-N 0.000 description 5
- SLVAEVYIJHDKRO-UHFFFAOYSA-N trifluoromethanesulfonyl fluoride Chemical compound FC(F)(F)S(F)(=O)=O SLVAEVYIJHDKRO-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 4
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 4
- 239000007806 chemical reaction intermediate Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000003682 fluorination reaction Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 125000000686 lactone group Chemical group 0.000 description 3
- 238000004811 liquid chromatography Methods 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 230000002688 persistence Effects 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- 230000009257 reactivity Effects 0.000 description 3
- 230000000717 retained effect Effects 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 125000004434 sulfur atom Chemical group 0.000 description 3
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 239000002699 waste material 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
- WTKQMHWYSBWUBE-UHFFFAOYSA-N (3-nitropyridin-2-yl) thiohypochlorite Chemical group [O-][N+](=O)C1=CC=CN=C1SCl WTKQMHWYSBWUBE-UHFFFAOYSA-N 0.000 description 2
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 2
- SYTBZMRGLBWNTM-SNVBAGLBSA-N (R)-flurbiprofen Chemical compound FC1=CC([C@H](C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-SNVBAGLBSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical compound OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 239000002316 fumigant Substances 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 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 2
- GEMITLJMEMBDKW-UHFFFAOYSA-N hydrogen sulfate;1h-imidazol-3-ium Chemical compound C1=CNC=N1.OS(O)(=O)=O GEMITLJMEMBDKW-UHFFFAOYSA-N 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000010813 internal standard method Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 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 description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 150000003333 secondary alcohols Chemical class 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- WKXZJCKWUCBECD-GSVOUGTGSA-N (2r)-2-fluoropropan-1-ol Chemical compound C[C@@H](F)CO WKXZJCKWUCBECD-GSVOUGTGSA-N 0.000 description 1
- ZQXCQTAELHSNAT-UHFFFAOYSA-N 1-chloro-3-nitro-5-(trifluoromethyl)benzene Chemical compound [O-][N+](=O)C1=CC(Cl)=CC(C(F)(F)F)=C1 ZQXCQTAELHSNAT-UHFFFAOYSA-N 0.000 description 1
- ZRJYSDSGKGRTJF-UHFFFAOYSA-N 1-fluoro-3-methylbutan-2-amine Chemical compound CC(C)C(N)CF ZRJYSDSGKGRTJF-UHFFFAOYSA-N 0.000 description 1
- SIJBDWPVNAYVGY-UHFFFAOYSA-N 2,2-dimethyl-1,3-dioxolane Chemical compound CC1(C)OCCO1 SIJBDWPVNAYVGY-UHFFFAOYSA-N 0.000 description 1
- NWYYWIJOWOLJNR-UHFFFAOYSA-N 2-Amino-3-methyl-1-butanol Chemical compound CC(C)C(N)CO NWYYWIJOWOLJNR-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- SHOBGSRUFRALBO-UHFFFAOYSA-N 4-fluorobutan-1-ol Chemical compound OCCCCF SHOBGSRUFRALBO-UHFFFAOYSA-N 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical group O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 1
- 229910004261 CaF 2 Inorganic materials 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- BHFJBHMTEDLICO-UHFFFAOYSA-N Perfluorooctylsulfonyl fluoride Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)S(F)(=O)=O BHFJBHMTEDLICO-UHFFFAOYSA-N 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- ROYGRPOHMJLNAN-UHFFFAOYSA-N S(=O)(=O)(C(F)(F)F)OS(=O)(=O)C(F)(F)F.CCN(CC)CC Chemical compound S(=O)(=O)(C(F)(F)F)OS(=O)(=O)C(F)(F)F.CCN(CC)CC ROYGRPOHMJLNAN-UHFFFAOYSA-N 0.000 description 1
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical group O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 1
- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical group [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N adenyl group Chemical group N1=CN=C2N=CNC2=C1N GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 150000001371 alpha-amino acids Chemical class 0.000 description 1
- 235000008206 alpha-amino acids Nutrition 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000006015 bromomethoxy group Chemical group 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- WUKWITHWXAAZEY-UHFFFAOYSA-L calcium difluoride Chemical compound [F-].[F-].[Ca+2] WUKWITHWXAAZEY-UHFFFAOYSA-L 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000004651 chloromethoxy group Chemical group ClCO* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical group NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 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
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 230000002542 deteriorative effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 125000004914 dipropylamino group Chemical group C(CC)N(CCC)* 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- 125000003438 dodecyl 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])C([H])([H])C([H])([H])* 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- LZCLXQDLBQLTDK-BYPYZUCNSA-N ethyl (2S)-lactate Chemical compound CCOC(=O)[C@H](C)O LZCLXQDLBQLTDK-BYPYZUCNSA-N 0.000 description 1
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 1
- 150000002221 fluorine Chemical group 0.000 description 1
- 238000000806 fluorine-19 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000010436 fluorite Substances 0.000 description 1
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 238000004508 fractional distillation Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical group O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical group O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- KLGSHNXEUZOKHH-YKXIHYLHSA-N methyl (2s)-4-hydroxypyrrolidine-2-carboxylate;hydrochloride Chemical compound Cl.COC(=O)[C@@H]1CC(O)CN1 KLGSHNXEUZOKHH-YKXIHYLHSA-N 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000001400 nonyl 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])C([H])([H])[H] 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 125000005010 perfluoroalkyl group Chemical group 0.000 description 1
- JGTNAGYHADQMCM-UHFFFAOYSA-N perfluorobutanesulfonic acid Chemical compound OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F JGTNAGYHADQMCM-UHFFFAOYSA-N 0.000 description 1
- YFSUTJLHUFNCNZ-UHFFFAOYSA-N perfluorooctane-1-sulfonic acid Chemical class OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F YFSUTJLHUFNCNZ-UHFFFAOYSA-N 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- ZMRHBJQLCDZMAH-UHFFFAOYSA-M sodium chloride hydrate hydrochloride Chemical compound [OH-].[Na+].Cl.Cl ZMRHBJQLCDZMAH-UHFFFAOYSA-M 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical group CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000006000 trichloroethyl group Chemical group 0.000 description 1
- 125000002948 undecyl 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])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
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- C07B39/00—Halogenation
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- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/16—Preparation of halogenated hydrocarbons by replacement by halogens of hydroxyl groups
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- C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
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- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
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Abstract
【解決手段】スルフリルフルオリド(SO2F2)と、分子内に遊離のヒドロキシル基を有することのない有機塩基と、を含む、新規で有用な脱ヒドロキシフッ素化剤を見出した。本脱ヒドロキシフッ素化剤は、大量規模での使用が好ましくないパーフルオロアルカンスルホニルフルオリドを用いる必要がなく、医農薬および光学材料の重要中間体である、光学活性フルオロ誘導体、具体的には4−フルオロプロリン誘導体、2'−デオキシ−2'−フルオロウリジン誘導体および光学活性α−フルオロカルボン酸エステル誘導体、およびモノフルオロメチル誘導体等を大量規模でも有利に製造できる。
【選択図】なし
Description
[発明1]
脱ヒドロキシフッ素化剤であって、
スルフリルフルオリド(SO2F2)と、
分子内に遊離のヒドロキシル基を有することのない有機塩基と、
を含む、脱ヒドロキシフッ素化剤。
[発明2]
スルフリルフルオリドのモル数と、有機塩基のモル数の比が、5:1〜1:5の範囲である、発明1に記載の、脱ヒドロキシフッ素化剤。
[発明3]
系外から加えられたフッ化水素源(フッ化水素もしくは、フッ化水素が有機塩基との間に形成した、塩または錯体をいう。)を更に含む、発明1または発明2に記載の、脱ヒドロキシフッ素化剤。
[発明4]
スルフリルフルオリドのモル数と、系外から加えられたフッ化水素源のモル数(HF換算)の比が、3:1〜1:10の範囲である、発明3に記載の、脱ヒドロキシフッ素化剤。
[発明5]
有機塩基が、トリメチルアミン、トリエチルアミン、ジイソプロピルエチルアミン、トリn−プロピルアミン、ピリジン、2,3−ルチジン、2,4−ルチジン、2,5−ルチジン、2,6−ルチジン、3,4−ルチジン、3,5−ルチジン、2,3,4−コリジン、2,4,5−コリジン、2,5,6−コリジン、2,4,6−コリジン、3,4,5−コリジン、および3,5,6−コリジンからなる群より選ばれる、発明1乃至発明4の何れかに記載の、脱ヒドロキシフッ素化剤。
[発明6]
非プロトン性有機溶媒を更に含む、発明1乃至発明5の何れかに記載の、脱ヒドロキシフッ素化剤。
[ヒドロキシ誘導体について]
本発明の脱ヒドロキシフッ素化剤によれば、広範なヒドロキシ誘導体(分子内に少なくとも1つの遊離のヒドロキシル基を有する化合物をいう。)のOH基をF原子に置換することができる。以下、本発明の脱ヒドロキシフッ素化剤を適用できるヒドロキシ誘導体について、説明する。
[脱ヒドロキシフッ素化の反応条件]
本発明の脱ヒドロキシフッ素化剤中のスルフリルフルオリド(SO2F2)の、ヒドロキシ誘導体1モルに対する使用量としては、特に制限はないが、1モル以上を使用すればよく、通常は1〜10モルが好ましく、特に1〜5モルがより好ましい。
[実施例1]
ステンレス鋼(SUS)製耐圧反応容器に、下記式
1H−NMR(基準物質:Me4Si,重溶媒:CDCl3),δ ppm:1.43&1.49(s×2,トータル9H),1.95−2.55(トータル2H),3.51−3.94(トータル2H),3.75(S,3H),4.36−4.58(トータル1H),5.10−5.31(トータル1H).
19F−NMR(基準物質:C6F6,重溶媒:CDCl3),δ ppm:−11.27(トータル1F).
[実施例2]
ステンレス鋼(SUS)製耐圧反応容器に、下記式
[実施例3]
ステンレス鋼(SUS)製耐圧反応容器に、下記式
19F−NMR(基準物質:C6F6,重溶媒:CDCl3),δ ppm:−43.13(dt,51.9Hz,15.4Hz),−42.50(dt,51.5Hz,15.4Hz),−37.62(dt,51.5Hz,15.0Hz),−37.55(dt,51.9Hz,15.0Hz)/トータル1F.
[実施例4]
ステンレス鋼(SUS)製耐圧反応容器に、下記式
光学純度97.7%ee(テトラヒドロフラン中、過剰の水素化リチウムアルミニウムを用いてヒドリド還元し、得られた(R)−2−フルオロ−1−プロパノールをMosher酸エステルに誘導し、ガスクロマトグラフィーにより決定した。不斉転写率は99.3%であった).
1H−NMR(基準物質:Me4Si,重溶媒:CDCl3),δ ppm:1.32(t,7.2Hz,3H),1.58(dd,23.6Hz,6.9Hz,3H),4.26(q,7.2Hz,2H),5.00(dq,49.0Hz,6.9Hz,1H).
19F−NMR(基準物質:C6F6,重溶媒:CDCl3),δ ppm:−21.88(dq,48.9Hz,24.4Hz,1F).
[実施例5]
ステンレス鋼(SUS)製耐圧反応容器に、下記式
1H−NMR(基準物質:Me4Si,重溶媒:CDCl3),δ ppm:0.90(d,6.8Hz,3H),1.08(d,6.8Hz,3H),2.44(m,1H),4.24(m,1H),4.76(ddd,46.6Hz,9.5Hz,4.8Hz,1H),5.01(dt,46.6Hz,9.5Hz,1H),7.74(Ar−H,2H),7.86(Ar−H,2H).
19F−NMR(基準物質:C6F6,重溶媒:CDCl3),δ ppm:−62.12(dt,13.3Hz,46.6Hz,1F).
原料基質の第一級アルコール誘導体は、Protective Groups in Organic Synthesis,Third Edition,1999,John Wiley & Sons,Inc.を参考にして、市販されている光学活性バリノールから製造することができる。また得られたモノフルオロメチル誘導体は、同図書を参考にして、光学純度を損なうことなく光学活性1−イソプロピル−2−フルオロエチルアミンに変換することができる。
[実施例6]
ステンレス鋼(SUS)製耐圧反応容器に、下記式
1H−NMR(基準物質:Me4Si,重溶媒:CDCl3),δ ppm:1.42−1.88(m,10H),3.35−3.52(m,2H),3.70−3.88(m,2H),4.45(dt,46.8Hz,6.1Hz,2H),4.56(m,1H).
19F−NMR(基準物質:C6F6,重溶媒:CDCl3),δ ppm:−56.37(septet,23.4Hz,1F).
原料基質の第一級アルコール誘導体は、Protective Groups in Organic Synthesis,Third Edition,1999,John Wiley & Sons,Inc.を参考にして、市販されている1,4−ブタンジオールから製造することができる。また得られたモノフルオロメチル誘導体は、同図書を参考にして、4−フルオロ−1−ブタノールに変換することができる。
[実施例7]
ステンレス鋼(SUS)製耐圧反応容器に、下記式
1H−NMR(基準物質:Me4Si,重溶媒:CDCl3),δ ppm:0.89(t,6.8Hz,3H),1.20−1.45(m,14H),1.60−1.70(m,2H),4.44(dt,47.6Hz,6.2Hz,2H).
19F−NMR(基準物質:C6F6,重溶媒:CDCl3),δ ppm:−55.97(septet,23.8Hz,1F).
原料基質の第一級アルコール誘導体は市販品を利用した。
Claims (6)
- 脱ヒドロキシフッ素化剤であって、
スルフリルフルオリド(SO2F2)と、
分子内に遊離のヒドロキシル基を有することのない有機塩基と、
を含む、脱ヒドロキシフッ素化剤。 - スルフリルフルオリドのモル数と、有機塩基のモル数の比が、5:1〜1:5の範囲である、請求項1に記載の、脱ヒドロキシフッ素化剤。
- 系外から加えられたフッ化水素源(フッ化水素もしくは、フッ化水素が有機塩基との間に形成した、塩または錯体をいう。)を更に含む、請求項1または請求項2に記載の、脱ヒドロキシフッ素化剤。
- スルフリルフルオリドのモル数と、系外から加えられたフッ化水素源のモル数(HF換算)の比が、3:1〜1:10の範囲である、請求項3に記載の、脱ヒドロキシフッ素化剤。
- 有機塩基が、トリメチルアミン、トリエチルアミン、ジイソプロピルエチルアミン、トリn−プロピルアミン、ピリジン、2,3−ルチジン、2,4−ルチジン、2,5−ルチジン、2,6−ルチジン、3,4−ルチジン、3,5−ルチジン、2,3,4−コリジン、2,4,5−コリジン、2,5,6−コリジン、2,4,6−コリジン、3,4,5−コリジン、および3,5,6−コリジンからなる群より選ばれる、請求項1乃至請求項4の何れかに記載の、脱ヒドロキシフッ素化剤。
- 非プロトン性有機溶媒を更に含む、請求項1乃至請求項5の何れかに記載の、脱ヒドロキシフッ素化剤。
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Cited By (6)
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JP2006290870A (ja) * | 2005-03-18 | 2006-10-26 | Central Glass Co Ltd | スルフリルフルオリドを用いるフッ素化反応 |
JP2008037781A (ja) * | 2006-08-04 | 2008-02-21 | Central Glass Co Ltd | 2’−デオキシ−2’−フルオロウリジンの製造方法 |
WO2009116320A1 (ja) * | 2008-03-21 | 2009-09-24 | セントラル硝子株式会社 | 光学活性フルオロアミン類の製造方法 |
WO2009122834A1 (ja) * | 2008-03-31 | 2009-10-08 | セントラル硝子株式会社 | 4-パーフルオロイソプロピルアニリン類の製造方法 |
JP2010507604A (ja) * | 2006-10-27 | 2010-03-11 | バイエル・クロツプサイエンス・アクチエンゲゼルシヤフト | 2−フルオロプロピオネートの製造のための立体選択的一段階フッ素化法 |
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002531426A (ja) * | 1998-11-30 | 2002-09-24 | ゾルファイ フルーオル ウント デリヴァーテ ゲゼルシャフト ミット ベシュレンクテル ハフツング | 酸塩化物から酸弗化物を製造するための方法 |
JP2005126386A (ja) * | 2003-10-27 | 2005-05-19 | Kyorin Pharmaceut Co Ltd | フルオロピロリジン誘導体の製造方法 |
JP2006083163A (ja) * | 2004-08-18 | 2006-03-30 | Central Glass Co Ltd | 光学活性α−フルオロカルボン酸エステル誘導体の製造方法 |
JP2006290870A (ja) * | 2005-03-18 | 2006-10-26 | Central Glass Co Ltd | スルフリルフルオリドを用いるフッ素化反応 |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4439488C1 (de) * | 1994-10-26 | 1996-03-21 | Schering Ag | Verfahren zur Umwandlung von Hydroxylgruppen in die entsprechenden Fluorverbindungen |
US6248889B1 (en) | 1998-11-20 | 2001-06-19 | 3M Innovative Properties Company | Process for converting an alcohol to the corresponding fluoride |
DE10104663A1 (de) * | 2001-02-02 | 2002-08-08 | Solvay Fluor & Derivate | Herstellung von Fluorverbindungen |
JP4774676B2 (ja) | 2003-04-10 | 2011-09-14 | セントラル硝子株式会社 | 2’−デオキシ−2’−フルオロウリジンの製造方法 |
CN1795200B (zh) | 2003-04-10 | 2010-05-12 | 中央硝子株式会社 | 制备2′-脱氧-2′-氟尿苷的方法 |
JP2005008534A (ja) | 2003-06-17 | 2005-01-13 | Soc De Conseils De Recherches & D'applications Scientifiques (Scras) | 抗癌剤及び癌の治療方法 |
JP4109592B2 (ja) | 2003-09-11 | 2008-07-02 | 文化シヤッター株式会社 | 開閉装置 |
JP4610252B2 (ja) | 2004-04-26 | 2011-01-12 | セントラル硝子株式会社 | 4−フルオロプロリン誘導体の製造方法 |
JP4675065B2 (ja) | 2004-06-22 | 2011-04-20 | セントラル硝子株式会社 | 4−フルオロプロリン誘導体の製造方法 |
CN1976891B (zh) * | 2004-08-18 | 2011-05-25 | 中央硝子株式会社 | 光学活性α-氟代羧酸酯衍生物的制造方法 |
-
2006
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2007
- 2007-06-25 WO PCT/JP2007/062687 patent/WO2008001718A1/ja active Application Filing
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- 2007-06-25 EP EP07767494A patent/EP2020402A4/en not_active Withdrawn
- 2007-06-25 CN CN2007800248325A patent/CN101484405B/zh active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002531426A (ja) * | 1998-11-30 | 2002-09-24 | ゾルファイ フルーオル ウント デリヴァーテ ゲゼルシャフト ミット ベシュレンクテル ハフツング | 酸塩化物から酸弗化物を製造するための方法 |
JP2005126386A (ja) * | 2003-10-27 | 2005-05-19 | Kyorin Pharmaceut Co Ltd | フルオロピロリジン誘導体の製造方法 |
JP2006083163A (ja) * | 2004-08-18 | 2006-03-30 | Central Glass Co Ltd | 光学活性α−フルオロカルボン酸エステル誘導体の製造方法 |
JP2006290870A (ja) * | 2005-03-18 | 2006-10-26 | Central Glass Co Ltd | スルフリルフルオリドを用いるフッ素化反応 |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2006290870A (ja) * | 2005-03-18 | 2006-10-26 | Central Glass Co Ltd | スルフリルフルオリドを用いるフッ素化反応 |
JP2008037781A (ja) * | 2006-08-04 | 2008-02-21 | Central Glass Co Ltd | 2’−デオキシ−2’−フルオロウリジンの製造方法 |
JP2010507604A (ja) * | 2006-10-27 | 2010-03-11 | バイエル・クロツプサイエンス・アクチエンゲゼルシヤフト | 2−フルオロプロピオネートの製造のための立体選択的一段階フッ素化法 |
WO2009116320A1 (ja) * | 2008-03-21 | 2009-09-24 | セントラル硝子株式会社 | 光学活性フルオロアミン類の製造方法 |
JP2009227596A (ja) * | 2008-03-21 | 2009-10-08 | Central Glass Co Ltd | 光学活性フルオロアミン類の製造方法 |
CN101977890A (zh) * | 2008-03-21 | 2011-02-16 | 中央硝子株式会社 | 光学活性氟胺类的制造方法 |
US8426645B2 (en) | 2008-03-21 | 2013-04-23 | Central Glass Company, Limited | Process for production of optically active fluoroamine |
CN101977890B (zh) * | 2008-03-21 | 2014-01-01 | 中央硝子株式会社 | 光学活性氟胺类的制造方法 |
WO2009122834A1 (ja) * | 2008-03-31 | 2009-10-08 | セントラル硝子株式会社 | 4-パーフルオロイソプロピルアニリン類の製造方法 |
JP2009242270A (ja) * | 2008-03-31 | 2009-10-22 | Central Glass Co Ltd | 4−パーフルオロイソプロピルアニリン類の製造方法 |
JP2012144511A (ja) * | 2010-06-03 | 2012-08-02 | Central Glass Co Ltd | (2R)−2−フルオロ−2−C−メチル−D−リボノ−γ−ラクトン類前駆体の製造方法 |
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