CN105524111A - 手性亚膦酰胺单齿配体及其合成方法与应用 - Google Patents
手性亚膦酰胺单齿配体及其合成方法与应用 Download PDFInfo
- Publication number
- CN105524111A CN105524111A CN201610046961.5A CN201610046961A CN105524111A CN 105524111 A CN105524111 A CN 105524111A CN 201610046961 A CN201610046961 A CN 201610046961A CN 105524111 A CN105524111 A CN 105524111A
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- Prior art keywords
- phenyl
- acid
- phosphoramide
- chirality
- group
- Prior art date
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- 239000003446 ligand Substances 0.000 title claims abstract description 28
- 238000010189 synthetic method Methods 0.000 title claims abstract description 8
- 150000008300 phosphoramidites Chemical class 0.000 title abstract 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 229910052751 metal Inorganic materials 0.000 claims abstract description 11
- 239000002184 metal Substances 0.000 claims abstract description 11
- 229910052741 iridium Inorganic materials 0.000 claims abstract description 9
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229910052703 rhodium Inorganic materials 0.000 claims abstract description 7
- 239000010948 rhodium Substances 0.000 claims abstract description 7
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims abstract description 7
- -1 4-aminomethyl phenyl Chemical group 0.000 claims description 33
- DMSZORWOGDLWGN-UHFFFAOYSA-N ctk1a3526 Chemical compound NP(N)(N)=O DMSZORWOGDLWGN-UHFFFAOYSA-N 0.000 claims description 23
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 11
- 239000000654 additive Substances 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium(II) oxide Chemical compound [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 125000003368 amide group Chemical group 0.000 claims description 6
- 238000005576 amination reaction Methods 0.000 claims description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
- 125000004185 ester group Chemical group 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- LPNBBFKOUUSUDB-UHFFFAOYSA-N p-toluic acid Chemical compound CC1=CC=C(C(O)=O)C=C1 LPNBBFKOUUSUDB-UHFFFAOYSA-N 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 230000000996 additive effect Effects 0.000 claims description 5
- 239000007810 chemical reaction solvent Substances 0.000 claims description 5
- 230000000536 complexating effect Effects 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- XKTBBRQXDGKAFW-UHFFFAOYSA-N [Ti].C(C)(C)[O] Chemical compound [Ti].C(C)(C)[O] XKTBBRQXDGKAFW-UHFFFAOYSA-N 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 239000002808 molecular sieve Substances 0.000 claims description 4
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- XZXYQEHISUMZAT-UHFFFAOYSA-N 2-[(2-hydroxy-5-methylphenyl)methyl]-4-methylphenol Chemical compound CC1=CC=C(O)C(CC=2C(=CC=C(C)C=2)O)=C1 XZXYQEHISUMZAT-UHFFFAOYSA-N 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- 125000004861 4-isopropyl phenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 3
- RANNTKKBOMWKQB-UHFFFAOYSA-N [3,5-bis(trifluoromethyl)phenoxy]boronic acid silver Chemical compound [Ag].FC(C=1C=C(C=C(C1)C(F)(F)F)OB(O)O)(F)F RANNTKKBOMWKQB-UHFFFAOYSA-N 0.000 claims description 3
- 235000011054 acetic acid Nutrition 0.000 claims description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 229940107816 ammonium iodide Drugs 0.000 claims description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 3
- 125000002843 carboxylic acid group Chemical group 0.000 claims description 3
- 238000012512 characterization method Methods 0.000 claims description 3
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 3
- MBAKFIZHTUAVJN-UHFFFAOYSA-I hexafluoroantimony(1-);hydron Chemical compound F.F[Sb](F)(F)(F)F MBAKFIZHTUAVJN-UHFFFAOYSA-I 0.000 claims description 3
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 3
- 229940071870 hydroiodic acid Drugs 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 3
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 3
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 3
- 235000019260 propionic acid Nutrition 0.000 claims description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 3
- 229910052709 silver Inorganic materials 0.000 claims description 3
- 239000004332 silver Substances 0.000 claims description 3
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 3
- 239000010936 titanium Substances 0.000 claims description 3
- 229910052719 titanium Inorganic materials 0.000 claims description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 3
- WZCZNEGTXVXAAS-UHFFFAOYSA-N trifluoromethanol Chemical compound OC(F)(F)F WZCZNEGTXVXAAS-UHFFFAOYSA-N 0.000 claims description 3
- KOECRLKKXSXCPB-UHFFFAOYSA-K triiodobismuthane Chemical compound I[Bi](I)I KOECRLKKXSXCPB-UHFFFAOYSA-K 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 abstract description 8
- 239000003054 catalyst Substances 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 238000010668 complexation reaction Methods 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 238000006268 reductive amination reaction Methods 0.000 abstract 1
- 230000002829 reductive effect Effects 0.000 abstract 1
- 239000007788 liquid Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical group C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 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 1
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- BPZSYCZIITTYBL-YJYMSZOUSA-N R-Formoterol Chemical compound C1=CC(OC)=CC=C1C[C@@H](C)NC[C@H](O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-YJYMSZOUSA-N 0.000 description 1
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- DRHKJLXJIQTDTD-OAHLLOKOSA-N Tamsulosine Chemical compound CCOC1=CC=CC=C1OCCN[C@H](C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 DRHKJLXJIQTDTD-OAHLLOKOSA-N 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- CJBJHOAVZSMMDJ-HEXNFIEUSA-N darunavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1[C@@H]2CCO[C@@H]2OC1)C1=CC=CC=C1 CJBJHOAVZSMMDJ-HEXNFIEUSA-N 0.000 description 1
- 229960005107 darunavir Drugs 0.000 description 1
- 229960000632 dexamfetamine Drugs 0.000 description 1
- MGHPNCMVUAKAIE-UHFFFAOYSA-N diphenylmethanamine Chemical compound C=1C=CC=CC=1C(N)C1=CC=CC=C1 MGHPNCMVUAKAIE-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- VOBHXZCDAVEXEY-JSGCOSHPSA-N lisdexamfetamine Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](C)CC1=CC=CC=C1 VOBHXZCDAVEXEY-JSGCOSHPSA-N 0.000 description 1
- 229960001451 lisdexamfetamine Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 1
- 229960000311 ritonavir Drugs 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 150000003577 thiophenes Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/6574—Esters of oxyacids of phosphorus
- C07F9/65744—Esters of oxyacids of phosphorus condensed with carbocyclic or heterocyclic rings or ring systems
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1845—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing phosphorus
- B01J31/185—Phosphites ((RO)3P), their isomeric phosphonates (R(RO)2P=O) and RO-substitution derivatives thereof
- B01J31/186—Mono- or diamide derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/44—Allylic alkylation, amination, alkoxylation or analogues
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Abstract
本发明涉及手性亚膦酰胺单齿配体及其合成方法与应用，该手性亚膦酰胺单齿配体可与一价金属铱或铑的盐络合制得催化剂，该催化剂用于β-芳基胺类化合物的合成反应，β-芳基胺类化合物是很多重要药物的药效基团。本发明提供的此类配体，能使得获取β-芳基胺类化合物的不对称还原胺化反应的催化剂用量降低到十万分之五，同时β-芳基胺产物的对映选择性可以达到98%；同时所用催化剂空气稳定，反应可以在有氧环境中操作，大大简化了生产操作。
Description
技术领域
本发明涉及手性配体，具体涉及一种手性亚膦酰胺单齿配体及其合成方法与应用。
背景技术
手性亚膦酰胺单齿配体因其结构简单、易于修饰、合成简便、原料低廉，在不对称催化反应中有广泛的应用。特别是在不对称氢化还原领域，手性亚膦酰胺单齿配体展示了良好的活性和立体选择性。前期发展的手性亚膦酰胺单齿配体主要侧重萘环骨架的修饰，氮原子所连的烷基取代基多为直链的烷烃、或者是简单的环状烷烃。
发明内容
本发明的目的是提供手性亚膦酰胺单齿配体及其合成方法与应用，可被应用于不对称还原胺化反应，在万分之一催化剂用量的条件下高效、高立体选择性地合成手性β-芳基胺。
本发明所采用的技术方案为：
手性亚膦酰胺单齿配体，其特征在于：
具有如下分子结构特征：
或
其中：
X为氧原子或者亚甲基；
R为氢原子、烷基、环烷基、链烯基、链炔基、不饱和的单环烃基、烷氧基、卤素、硝基、氰基、三氟甲基、二苯基膦、杂环取代基或者芳香取代基。
R为芳香取代基时，芳香取代基包括苯基、4-甲基苯基、4-甲氧基苯基、4-氯苯基、4-氟苯基、4-溴苯基、4-已基苯基、4-叔丁基苯基、4-异丙基苯基、4-三氟甲基苯基、3，5-二甲基苯基、3，5-二甲氧基苯基、3，5-二氟苯基、3，5-二氯苯基、3，5-二三氟甲基苯基、3，5-二溴苯基、3，5-二叔丁基苯基、3，5-二异丙基苯基、3，5-二叔丁基-4-甲氧基苯基。
手性亚膦酰胺单齿配体的合成方法，其特征在于：
具有以下合成路线：
手性亚膦酰胺单齿配体的应用，其特征在于：
所述手性亚膦酰胺单齿配体可与一价金属铱或铑的盐络合制得催化剂，该催化剂用于β-芳基胺类化合物的合成反应。
β-芳基胺类化合物的合成反应为不对称还原胺化反应：
其中：
Ir为一价金属铱的盐，也可为一价金属铑的盐；
Additives为添加剂组合；
Solvent为反应溶剂；
R6是烷基、芳基、酯基、酰胺基或羧酸基；
R1、R2、R3、R4、R5是相同或不同的氢、烷基、环烷基、链烯基、链炔基、不饱和的单环烃基、烷氧基、卤素、羟基、硝基、氰基、三氟甲基、杂环取代基、酯基、酰胺基、酰基、醛基或磺酰胺基；
Ar为苯基、2-甲苯基、4-甲苯基、4-甲氧基苯基、3，5-二甲氧基苯基或3，5-二甲苯基。
Additives为添加剂组合，包括以下一种化合物或者多种化合物的组合使用：
分子筛、四异丙基氧钛、四甲基氧钛、四已基氧钛、四丙基氧钛、四丁基氧钛、甲酸、乙酸、丙酸、苯甲酸、对甲基苯甲酸、苯磺酸、对甲基苯磺酸、三氟乙酸、三氟甲磺酸、氢氯酸、氢溴酸、氢碘酸、甲磺酸、六氟锑酸银、六氟磷酸银、四(3,5-二(三氟甲基)苯基)硼酸银、六氟锑酸纳、分子碘、碘化铵、四丁基碘化铵、碘化铋。
Solvent为反应溶剂，包括甲醇、乙醇、异丙醇、三氟甲醇、二氯甲烷、氯仿、1，2-二氯乙烷、氯苯、苯、甲苯、二甲苯、四氢呋喃、2-甲基四氢呋喃、乙醚、乙酸乙酯、甲酸乙酯、乙酸甲酯、1，4-二氧六环、乙腈、N,N-二甲基甲酰胺、己烷。
本发明具有以下优点：
本发明所涉及的手性亚膦酰胺单齿配体合成简便。其次氮原子所在的六元环上的两个甲基对反应的立体控制起着重要的作用。再次，该类配体的催化效率高，可以达到十万分之五的催化剂用量。此外，我们成功地将该类配体应用于不对称还原胺化这一绿色反应制备手性β-芳基胺。同时利用该配体制得的催化剂空气稳定，反应可以在有氧环境中操作。因此该类配体具有重要的潜在应用价值。
具体实施方式
下面结合具体实施方式对本发明进行详细的说明。
本发明涉及的手性亚膦酰胺单齿配体，具有如下分子结构特征：
或
其中：
X为氧原子或者亚甲基；
R为氢原子、烷基、环烷基、链烯基、链炔基、不饱和的单环烃基、烷氧基、卤素、硝基、氰基、三氟甲基、二苯基膦、杂环取代基或者芳香取代基。
R为芳香取代基时，芳香取代基包括但不局限于苯基、4-甲基苯基、4-甲氧基苯基、4-氯苯基、4-氟苯基、4-溴苯基、4-已基苯基、4-叔丁基苯基、4-异丙基苯基、4-三氟甲基苯基、3，5-二甲基苯基、3，5-二甲氧基苯基、3，5-二氟苯基、3，5-二氯苯基、3，5-二三氟甲基苯基、3，5-二溴苯基、3，5-二叔丁基苯基、3，5-二异丙基苯基、3，5-二叔丁基-4-甲氧基苯基。
上述手性亚膦酰胺单齿配体的合成方法，具有以下合成路线：
1、L1的制备：
通用制备方法：在5mL反应瓶中，加入286mg（1mmol）的BINOL和3mLPCl3，加热至90oC搅拌2小时，减压下除去多余的PCl3得粘稠的无色液体。向该液体中加入10mL甲苯和相应1mmol胺，搅拌3小时，过滤除去固体杂质，滤液浓缩后经柱色谱纯化得到最终的产物。
以下是采用上述方法合成的L1A的产率、颜色、物态、核磁数据和质谱数据。
L1A：两步产率85%；白色粉末；;1HNMR(500MHz,CD3OD):δ7.94-8.06(4H,m),7.28-7.60(8H,m),3.36(2H,m)),2.26(1H,M),2.10(1H,m),1.60(2H,m),0.92(1H,d,J=6.8Hz)),0.86(1H,d,J=6.8Hz),0.76(6H,m)；ESI-MSm/z:427.17[M]+。
2、L2的制备：
通用制备方法：在5mL反应瓶中，加入295mg（1mmol）的H8-BINOL和3mLPCl3，加热至90oC搅拌2小时，减压下除去多余的PCl3得粘稠的无色液体。向该液体中加入10mL甲苯和相应1mmol胺，搅拌3小时，过滤除去固体杂质，滤液浓缩后经柱色谱纯化得到最终的产物。
以下是采用上述方法合成的L2A的产率、颜色、物态、核磁数据和质谱数据。
L2A：两步产率86%；白色粉末；;1HNMR(500MHz,CDCl3):δ7.11(1H,d,J=8.7Hz),7.04(2H,m),6.90(1H,d,J=8.2Hz),3.14(2H,m),2.86(4H,m),2.66(2H,m),2.26-2.44(2H,m),2.14(1H,m),1.96(1H,m),1.84(8H,m),1.60(2H,m),1.50(2H,m),0.74(6H,dd,J=2.4Hz,J=6.6Hz)；ESI-MSm/z:427.17[M]+。
上述手性亚膦酰胺单齿配体可与一价金属铱或铑的盐络合制得催化剂，该催化剂用于β-芳基胺类化合物的合成反应。β-芳基胺类化合物是很多重要药物的药效基团，如Dextroamphetamine、Lisdexamfetamine、(R,R)-Formoterol、(R)-Tamsulosin、Ritonavir或Darunavir，其中芳基包括但不局限于取代苯、取代萘、取代吡啶、取代呋喃、取代噻吩或者取代吡咯。在手性亚膦酰胺单齿配体与一价金属铱的盐络合制得的催化剂的作用下，利用á-芳基酮与二芳基甲胺合成β-芳基胺类化合物，反应原料简单廉价，反应简便易操作，该类配体的活性和对映选择性很高，催化剂活性和立体选择性都很高。
β-芳基胺类化合物的合成反应为不对称还原胺化反应：
其中：
Ir为一价金属铱的盐，也可为一价金属铑的盐；
Additives为添加剂组合，包括以下一种化合物或者多种化合物的组合使用：
分子筛、四异丙基氧钛、四甲基氧钛、四已基氧钛、四丙基氧钛、四丁基氧钛、甲酸、乙酸、丙酸、苯甲酸、对甲基苯甲酸、苯磺酸、对甲基苯磺酸、三氟乙酸、三氟甲磺酸、氢氯酸、氢溴酸、氢碘酸、甲磺酸、六氟锑酸银、六氟磷酸银、四(3,5-二(三氟甲基)苯基)硼酸银、六氟锑酸纳、分子碘、碘化铵、四丁基碘化铵、碘化铋；
Solvent为反应溶剂，包括甲醇、乙醇、异丙醇、三氟甲醇、二氯甲烷、氯仿、1，2-二氯乙烷、氯苯、苯、甲苯、二甲苯、四氢呋喃、2-甲基四氢呋喃、乙醚、乙酸乙酯、甲酸乙酯、乙酸甲酯、1，4-二氧六环、乙腈、N,N-二甲基甲酰胺、己烷；
R6是烷基、芳基、酯基、酰胺基或羧酸基；
R1、R2、R3、R4、R5是相同或不同的氢、烷基、环烷基、链烯基、链炔基、不饱和的单环烃基、烷氧基、卤素、羟基、硝基、氰基、三氟甲基、杂环取代基、酯基、酰胺基、酰基、醛基或磺酰胺基；
Ar为苯基、2-甲苯基、4-甲苯基、4-甲氧基苯基、3，5-二甲氧基苯基或3，5-二甲苯基。
L2A催化的不对称还原胺化这一绿色反应制备手性β-芳基胺：
N-二苯甲基-1-（4-甲氧基苯基）丙-2-胺的制备：
通用制备方法：在5mL反应瓶中，加入32.8mg（0.2mmol）的1-（4-甲氧基苯基）-丙-2-酮、0.2mmol二苯甲胺、2mL二氯甲烷、0.1g4A分子筛、56mg（0.04mmol）四异丙基氧钛、5.5mg（0.05mmol）三氟乙酸和万分之一的铱与L2A络合制得的催化剂。将反应瓶置于高压反应釜，并用氢气置换2次后，将氢气加压至50大气压反应14小时，TLC显示反应完全。加入饱和碳酸氢钠水溶液，分离有机相。有机相减压蒸馏后得到粗产品N-二苯甲基-1-（4-甲氧基苯基）丙-2-胺的制备。产品经手性高效液相色谱分析，其立体选择性为98%。
以下是采用上述方法合成的3个N-二苯甲基-1-芳基丙-2-胺的名称、编号、产率、立体选择性、颜色、物态、核磁数据和质谱数据。
N-二苯甲基-1-（4-甲氧基苯基）丙-2-胺（1-1）：产率93%；对映选择性98%；淡黄色粉末；;1HNMR(500MHz,CDCl3):δ7.28-7.48(10H,m),7.16(2H,d,J=8.6Hz),6.92(2H,d,J=8.6Hz)),5.08(1H,s),3.88(3H,s),2.92(1H,m),2.68-2.88(2H,m),1.68(1H,bs)，1.18(3H,d,J=6.2Hz)；ESI-MSm/z:331.19[M]+。
5-（2-（二苯甲胺基）丙级）-2-甲氧基-苯磺酰胺（1-2）：产率78%；对映选择性85%；白色粉末；1HNMR(500MHz,CDCl3):δ7.74(1H,s),7.20-7.7.40(11H,m),7.00(1H,d,J=8.5Hz),5.34(1H,s),4.04(3H,s),2.88(1H,m),2.62-2.84(2H,m),1.50(1H,bs)，1.10(3H,d,J=6.3Hz)；ESI-MSm/z:410.17[M]+。
N-二苯甲基-1-苯基-丙-2-胺（1-3）：产率93%；对映选择性96%；无色液体;1HNMR(500MHz,CDCl3):δ7.17-7.44(m,15H),5.05(s,1H),2.84-2.92(m,2H),2.72(dd,J=6.2Hz,6.2Hz,1H),1.68(bs,1H),1.18(d,J=6.2Hz,3H);ESI-MSm/z:301.17[M]+。
本发明的内容不限于实施例所列举，本领域普通技术人员通过阅读本发明说明书而对本发明技术方案采取的任何等效的变换，均为本发明的权利要求所涵盖。
Claims (7)
1.手性亚膦酰胺单齿配体，其特征在于：
具有如下分子结构特征：
或
其中：
X为氧原子或者亚甲基；
R为氢原子、烷基、环烷基、链烯基、链炔基、不饱和的单环烃基、烷氧基、卤素、硝基、氰基、三氟甲基、二苯基膦、杂环取代基或者芳香取代基。
2.根据权利要求1所述的手性亚膦酰胺单齿配体，其特征在于：
R为芳香取代基时，芳香取代基包括苯基、4-甲基苯基、4-甲氧基苯基、4-氯苯基、4-氟苯基、4-溴苯基、4-已基苯基、4-叔丁基苯基、4-异丙基苯基、4-三氟甲基苯基、3，5-二甲基苯基、3，5-二甲氧基苯基、3，5-二氟苯基、3，5-二氯苯基、3，5-二三氟甲基苯基、3，5-二溴苯基、3，5-二叔丁基苯基、3，5-二异丙基苯基、3，5-二叔丁基-4-甲氧基苯基。
3.手性亚膦酰胺单齿配体的合成方法，其特征在于：
具有以下合成路线：
。
4.手性亚膦酰胺单齿配体的应用，其特征在于：
所述手性亚膦酰胺单齿配体可与一价金属铱或铑的盐络合制得催化剂，该催化剂用于β-芳基胺类化合物的合成反应。
5.根据权利要求4所述的手性亚膦酰胺单齿配体的应用，其特征在于：
β-芳基胺类化合物的合成反应为不对称还原胺化反应：
其中：
Ir为一价金属铱的盐，也可为一价金属铑的盐；
Additives为添加剂组合；
Solvent为反应溶剂；
R6是烷基、芳基、酯基、酰胺基或羧酸基；
R1、R2、R3、R4、R5是相同或不同的氢、烷基、环烷基、链烯基、链炔基、不饱和的单环烃基、烷氧基、卤素、羟基、硝基、氰基、三氟甲基、杂环取代基、酯基、酰胺基、酰基、醛基或磺酰胺基；
Ar为苯基、2-甲苯基、4-甲苯基、4-甲氧基苯基、3，5-二甲氧基苯基或3，5-二甲苯基。
6.根据权利要求5所述的手性亚膦酰胺单齿配体的应用，其特征在于：
Additives为添加剂组合，包括以下一种化合物或者多种化合物的组合使用：
分子筛、四异丙基氧钛、四甲基氧钛、四已基氧钛、四丙基氧钛、四丁基氧钛、甲酸、乙酸、丙酸、苯甲酸、对甲基苯甲酸、苯磺酸、对甲基苯磺酸、三氟乙酸、三氟甲磺酸、氢氯酸、氢溴酸、氢碘酸、甲磺酸、六氟锑酸银、六氟磷酸银、四(3,5-二(三氟甲基)苯基)硼酸银、六氟锑酸纳、分子碘、碘化铵、四丁基碘化铵、碘化铋。
7.根据权利要求5所述的手性亚膦酰胺单齿配体的应用，其特征在于：
Solvent为反应溶剂，包括甲醇、乙醇、异丙醇、三氟甲醇、二氯甲烷、氯仿、1，2-二氯乙烷、氯苯、苯、甲苯、二甲苯、四氢呋喃、2-甲基四氢呋喃、乙醚、乙酸乙酯、甲酸乙酯、乙酸甲酯、1，4-二氧六环、乙腈、N,N-二甲基甲酰胺、己烷。
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| CN109734611A (zh) * | 2019-01-23 | 2019-05-10 | 西北农林科技大学 | 一种手性三级胺类化合物的合成方法及其用途 |
| CN111032047A (zh) * | 2017-05-30 | 2020-04-17 | 千年制药公司 | 用于生产光学活性化合物的方法 |
| CN113444125A (zh) * | 2020-03-26 | 2021-09-28 | 西北大学 | 新型亚磷酰胺配体及其制备方法和在不对称羰基化反应中的应用 |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111032047A (zh) * | 2017-05-30 | 2020-04-17 | 千年制药公司 | 用于生产光学活性化合物的方法 |
| CN111032047B (zh) * | 2017-05-30 | 2023-10-27 | 多特疗法-1公司 | 用于生产光学活性化合物的方法 |
| CN109734611A (zh) * | 2019-01-23 | 2019-05-10 | 西北农林科技大学 | 一种手性三级胺类化合物的合成方法及其用途 |
| CN109734611B (zh) * | 2019-01-23 | 2021-12-07 | 西北农林科技大学 | 一种手性三级胺类化合物的合成方法及其用途 |
| CN113444125A (zh) * | 2020-03-26 | 2021-09-28 | 西北大学 | 新型亚磷酰胺配体及其制备方法和在不对称羰基化反应中的应用 |
| CN113444125B (zh) * | 2020-03-26 | 2024-01-26 | 西北大学 | 亚磷酰胺配体及其制备方法和在不对称羰基化反应中的应用 |
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