JP2021109847A - アミノアルコール−ボロン−バイノール複合体及びこれを用いた光学活性アミノアルコール誘導体の製造方法 - Google Patents
アミノアルコール−ボロン−バイノール複合体及びこれを用いた光学活性アミノアルコール誘導体の製造方法 Download PDFInfo
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- JP2021109847A JP2021109847A JP2020002973A JP2020002973A JP2021109847A JP 2021109847 A JP2021109847 A JP 2021109847A JP 2020002973 A JP2020002973 A JP 2020002973A JP 2020002973 A JP2020002973 A JP 2020002973A JP 2021109847 A JP2021109847 A JP 2021109847A
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- Prior art keywords
- substituted
- alkyl
- unsubstituted
- compound
- heteroaryl
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- 238000000034 method Methods 0.000 title claims abstract description 38
- 150000001414 amino alcohols Chemical class 0.000 title claims abstract description 36
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 title abstract 2
- 150000001639 boron compounds Chemical class 0.000 claims abstract description 13
- 238000004519 manufacturing process Methods 0.000 claims description 62
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 50
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 43
- 150000001875 compounds Chemical class 0.000 claims description 37
- 125000001072 heteroaryl group Chemical group 0.000 claims description 33
- -1 hydroxy, amino Chemical group 0.000 claims description 32
- 125000001424 substituent group Chemical group 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- 239000001257 hydrogen Substances 0.000 claims description 28
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 28
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 24
- 125000003545 alkoxy group Chemical group 0.000 claims description 21
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 229910052736 halogen Inorganic materials 0.000 claims description 21
- 150000002367 halogens Chemical class 0.000 claims description 21
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 20
- 125000001188 haloalkyl group Chemical group 0.000 claims description 20
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 20
- 239000000126 substance Substances 0.000 claims description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 239000002244 precipitate Substances 0.000 claims description 14
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 9
- 125000000304 alkynyl group Chemical group 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 3
- 239000004327 boric acid Substances 0.000 claims description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- AJSTXXYNEIHPMD-UHFFFAOYSA-N triethyl borate Chemical compound CCOB(OCC)OCC AJSTXXYNEIHPMD-UHFFFAOYSA-N 0.000 claims description 2
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 claims description 2
- MDCWDBMBZLORER-UHFFFAOYSA-N triphenyl borate Chemical compound C=1C=CC=CC=1OB(OC=1C=CC=CC=1)OC1=CC=CC=C1 MDCWDBMBZLORER-UHFFFAOYSA-N 0.000 claims description 2
- LGQXXHMEBUOXRP-UHFFFAOYSA-N tributyl borate Chemical compound CCCCOB(OCCCC)OCCCC LGQXXHMEBUOXRP-UHFFFAOYSA-N 0.000 claims 1
- 230000003287 optical effect Effects 0.000 abstract description 27
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 116
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 63
- 229940125904 compound 1 Drugs 0.000 description 44
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 41
- 238000002360 preparation method Methods 0.000 description 41
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- ZFUPOFQRQNJDNS-UHFFFAOYSA-N (4-chlorophenyl)-pyridin-2-ylmethanol Chemical compound C=1C=CC=NC=1C(O)C1=CC=C(Cl)C=C1 ZFUPOFQRQNJDNS-UHFFFAOYSA-N 0.000 description 31
- 238000004128 high performance liquid chromatography Methods 0.000 description 30
- 238000000825 ultraviolet detection Methods 0.000 description 29
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 26
- 230000000052 comparative effect Effects 0.000 description 18
- ZFUPOFQRQNJDNS-LBPRGKRZSA-N (s)-(4-chlorophenyl)-pyridin-2-ylmethanol Chemical compound C1([C@H](O)C=2N=CC=CC=2)=CC=C(Cl)C=C1 ZFUPOFQRQNJDNS-LBPRGKRZSA-N 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 9
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 229930014626 natural product Natural products 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 5
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 5
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 5
- 229910052796 boron Inorganic materials 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 229940125833 compound 23 Drugs 0.000 description 5
- 229940126214 compound 3 Drugs 0.000 description 5
- 229940125898 compound 5 Drugs 0.000 description 5
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 4
- PPTXVXKCQZKFBN-UHFFFAOYSA-N (S)-(-)-1,1'-Bi-2-naphthol Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=C(O)C=CC2=C1 PPTXVXKCQZKFBN-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 3
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 3
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 3
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 3
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 3
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 3
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 3
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 3
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 0 C(C1)C2*1CCN**2 Chemical compound C(C1)C2*1CCN**2 0.000 description 3
- 229940126657 Compound 17 Drugs 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 3
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 3
- WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 0.000 description 3
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- 102000005969 steroid hormone receptors Human genes 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 229910001868 water Inorganic materials 0.000 description 1
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract
Description
(2工程)上記の1工程の沈殿物を加水分解して、光学活性を有するアミノアルコール誘導体を得る段階;を含む。
XはC又はNであり;
R1は水素又はC1〜C10アルキル置換基で置換され;
XはC又はNであり;
R1は水素又はC1〜C10アルキル置換基で置換され;
また、本発明における下記用語は、特に指示されない限り、下記の意味を有する。定義されていない任意の用語は、当該分野で理解される意味を有する。
用語“アルケニル”又は“アルキニル”はそれぞれ、1つ又はそれ以上の二重結合又は三重結合を有する直鎖又は側鎖が含まれた炭化水素ラジカルを意味する。
用語“アリール”は、共有パイ電子系を有している少なくとも1つの環を有する芳香族置換体を意味し、例えば、フェニル、ベンジルなどがある。
1.化合物1:(S)−(4−クロロフェニル)(ピリジン−2−イル)メタノールの製造
[α]D = + 90.5 (c 0.5, EtOH).
[α]D = - 90.1 (c 0.21, EtOH).
[α]D = + 21.6 (c 0.5, EtOH).
[α]D = - 24.6 (c 0.5, EtOH).
[α]D = - 3.8 (c 0.5, CHCl3).
[α]D = + 20.5 (c 0.5, EtOH).
[α]D = + 28.9 (c 0.5, EtOH).
[α]D = + 60.0 (c 0.5, EtOH).
HRMS (EI) calculated for C33H24BNO3 [M]+: 493.1849, found: 493.1847;
[α]D = + 10.2 (c 0.5, EtOH).
[α]D = + 32.3 (c 0.5, EtOH).
[α]D = + 24.2 (c 0.5, EtOH).
[α]D = + 64.1 (c 0.5, EtOH).
[α]D = - 10.8 (c 0.75, CHCl3).
[α]D = - 23.2 (c 0.5, EtOH).
[α]D = + 32.4 (c 0.5, EtOH).
[α]D = - 3.6 (c 0.5, EtOH).
[α]D = + 64.3 (c 0.75, CHCl3).
[α]D = - 121.2 (c 0.1, CHCl3).
[α]D = - 15.4 (c 1.0, CHCl3).
[α]D = - 21.6 (c 1.25, CHCl3).
[α]D = - 83.0 (c 0.5, EtOH).
[α]D = + 21.6 (c 1.5, CHCl3).
[α]D = + 12.4 (c 1.5, CHCl3).
[α]D = + 28.6 (c 0.5, EtOH).
[α]D = - 14.8 (c 1.5, CHCl3).
[α]D = - 18.9 (c 1.0, CHCl3).
[α]D = + 30.4 (c 1.25, EtOH).
[α]D = + 45.3 (c 0.9, EtOH).
[α]D = - 69.8 (c 1.5, CHCl3).
[α]D = - 102.4 (c 1.25, CHCl3).
[α]D = - 4.6 (c 0.5, MeOH).
[α]D = - 25.6 (c 0.5, MeOH).
[α]D = + 38.5 (c 1.0, CHCl3).
[α]D = + 28.4 (c 1.05, EtOH).
1.比較化合物1:(S)−(4−クロロフェニル)(ピリジン−2−イル)メタノールの製造
前記実施例1及び比較例1で製造された化合物1に対するアミノアルコール誘導体の光学純度を比較すると、下記表1の通りである。
Claims (6)
- (1工程)下記の化学式1:
XはC又はNであり;
R1は水素又はC1〜C10アルキル置換基で置換され;
R2は、置換又は非置換されたC1〜C10アルキル、置換又は非置換されたC1〜C10アルケニル、置換又は非置換されたC1〜C10アルキニル、置換又は非置換されたC4〜C12シクロアルキル、置換又は非置換されたC4〜C12ヘテロシクロアルキル、置換又は非置換されたC4〜C12アリール又は置換又は非置換されたC4〜C12ヘテロアリールからなる群から選ばれる置換基で置換され、
このとき、前記置換されたアルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、アリール又はヘテロアリールは、水素、ハロゲン、ヒドロキシ、アミノ、シアノ、ニトロ、−S−(C1〜C10アルキル)、C1〜C10ハロアルキル、C1〜C10アルキル又はC1〜C10アルコキシからなる群から選ばれる1種以上の置換基で置換され;
R3は、置換又は非置換されたC4〜C12アリール又は置換又は非置換されたC4〜C12ヘテロアリールで置換され、
このとき、前記置換されたアリール又はヘテロアリールは、水素、ハロゲン、ヒドロキシ、アミノ、シアノ、ニトロ、−S−(C1〜C10アルキル)、C1〜C10ハロアルキル、C1〜C10アルキル又はC1〜C10アルコキシからなる群から選ばれる1種以上の置換基で置換され;
R4及びR5は、置換又は非置換されたC1〜C10アルキル、置換又は非置換されたC4〜C12ヘテロシクロアルキル又は置換又は非置換されたC4〜C12ヘテロアリールからなる群から選ばれる置換基で置換され、
このとき、前記置換されたアルキル、ヘテロシクロアルキル又はヘテロアリールは、水素、ハロゲン、ヒドロキシ、アミノ、シアノ、ニトロ、−S−(C1〜C10アルキル)、C1〜C10ハロアルキル、C1〜C10アルキル又はC1〜C10アルコキシからなる群から選ばれる1種以上の置換基で置換されるか、
又は、R4及びR5は共に、置換又は非置換されたC4〜C12ヘテロシクロアルキル又は置換又は非置換されたC4〜C12ヘテロアリールを形成可能であり、
このとき、前記置換されたヘテロシクロアルキル又はヘテロアリールは、水素、ハロゲン、ヒドロキシ、アミノ、シアノ、ニトロ、−S−(C1〜C10アルキル)、C1〜C10ハロアルキル、C1〜C10アルキル又はC1〜C10アルコキシからなる群から選ばれる1種以上の置換基で置換され、
R6は、水素、置換又は非置換されたC1〜C10アルキル又は置換又は非置換されたC4〜C12アリール置換基で置換され;
このとき、前記置換されたアルキル又はアリールは、水素、ハロゲン、ヒドロキシ、アミノ、シアノ、ニトロ、−S−(C1〜C10アルキル)、C1〜C10ハロアルキル、C1〜C10アルキル又はC1〜C10アルコキシからなる群から選ばれる1種以上の置換基で置換される。)
で表示されるラセミック化合物にホウ素化合物、(R)又は(S)−バイノール及び溶媒を加えてアミノアルコール−ボロン−バイノール複合体を沈殿物として得る段階;
(2工程)上記の1工程の沈殿物を加水分解して光学活性を有するアミノアルコール誘導体を得る段階;を含む
ことを特徴とするラセミックアミノアルコールから光学活性を有するアミノアルコール誘導体を製造する方法。 - 上記の1工程のホウ素化合物は、ホウ酸、トリメチルホウ酸、トリエチルホウ酸、トリイソプロピルホウ酸、トリブチルホウ酸及びトリフェニルホウ酸からなる群から選ばれる
請求項1に記載のアミノアルコール誘導体の製造方法。 - 上記の1工程の溶媒は、アセトニトリル、ジクロロメタン、トルエン及びイソプロパノールからなる群から選ばれる
請求項1に記載のアミノアルコール誘導体の製造方法。 - 上記の1工程は、化学式1で表示されるラセミック化合物1モル当量基準でホウ素化合物1モル当量、(R)−バイノール又は(S)−バイノール0.45〜0.6モル当量を使用する
請求項1に記載のアミノアルコール誘導体の製造方法。 - 請求項1ないし5のいずれかに記載の方法で製造され、下記の化学式3:
XはC又はNであり;
R1は水素又はC1〜C10アルキル置換基で置換され;
R2は、置換又は非置換されたC1〜C10アルキル、置換又は非置換されたC1〜C10アルケニル、置換又は非置換されたC1〜C10アルキニル、置換又は非置換されたC4〜C12シクロアルキル、置換又は非置換されたC4〜C12ヘテロシクロアルキル、置換又は非置換されたC4〜C12アリール又は置換又は非置換されたC4〜C12ヘテロアリールからなる群から選ばれる置換基で置換され、
このとき、前記置換されたアルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、アリール又はヘテロアリールは、水素、ハロゲン、ヒドロキシ、アミノ、シアノ、ニトロ、−S−(C1〜C10アルキル)、C1〜C10ハロアルキル、C1〜C10アルキル又はC1〜C10アルコキシからなる群から選ばれる1種以上の置換基で置換され;
R3は、置換又は非置換されたC4〜C12アリール又は置換又は非置換されたC4〜C12ヘテロアリールで置換され、
このとき、前記置換されたアリール又はヘテロアリールは、水素、ハロゲン、ヒドロキシ、アミノ、シアノ、ニトロ、−S−(C1〜C10アルキル)、C1〜C10ハロアルキル、C1〜C10アルキル又はC1〜C10アルコキシからなる群から選ばれる1種以上の置換基で置換され;
R4及びR5は、置換又は非置換されたC1〜C10アルキル、置換又は非置換されたC4〜C12ヘテロシクロアルキル又は置換又は非置換されたC4〜C12ヘテロアリールからなる群から選ばれる置換基で置換され、
このとき、前記置換されたアルキル、ヘテロシクロアルキル又はヘテロアリールは、水素、ハロゲン、ヒドロキシ、アミノ、シアノ、ニトロ、−S−(C1〜C10アルキル)、C1〜C10ハロアルキル、C1〜C10アルキル又はC1〜C10アルコキシからなる群から選ばれる1種以上の置換基で置換されるか、
又は、R4及びR5は共に、置換又は非置換されたC4〜C12ヘテロシクロアルキル又は置換又は非置換されたC4〜C12ヘテロアリールを形成可能であり、
このとき、前記置換されたヘテロシクロアルキル又はヘテロアリールは、水素、ハロゲン、ヒドロキシ、アミノ、シアノ、ニトロ、−S−(C1〜C10アルキル)、C1〜C10ハロアルキル、C1〜C10アルキル又はC1〜C10アルコキシからなる群から選ばれる1種以上の置換基で置換され;
R6は、水素、置換又は非置換されたC1〜C10アルキル又は置換又は非置換されたC4〜C12アリール置換基で置換され、
このとき、前記置換されたアルキル又はアリールは、水素、ハロゲン、ヒドロキシ、アミノ、シアノ、ニトロ、−S−(C1〜C10アルキル)、C1〜C10ハロアルキル、C1〜C10アルキル又はC1〜C10アルコキシからなる群から選ばれる1種以上の置換基で置換される。)
で示される
ことを特徴とするアミノアルコール−ボロン−バイノール複合体。
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