CN115215866B - 手性二胺类化合物和应用以及亚胺的不对称加成的方法 - Google Patents
手性二胺类化合物和应用以及亚胺的不对称加成的方法 Download PDFInfo
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- CN115215866B CN115215866B CN202110401309.1A CN202110401309A CN115215866B CN 115215866 B CN115215866 B CN 115215866B CN 202110401309 A CN202110401309 A CN 202110401309A CN 115215866 B CN115215866 B CN 115215866B
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- imine
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- 238000000034 method Methods 0.000 title claims abstract description 27
- -1 diamine compound Chemical class 0.000 title claims abstract description 26
- 150000002466 imines Chemical class 0.000 title claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 70
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 229910052723 transition metal Inorganic materials 0.000 claims description 8
- 150000003624 transition metals Chemical class 0.000 claims description 8
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 6
- 238000007294 asymmetric addition reaction Methods 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 3
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 13
- 229910052736 halogen Inorganic materials 0.000 abstract description 12
- 150000002367 halogens Chemical class 0.000 abstract description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 10
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 abstract description 10
- 125000003342 alkenyl group Chemical group 0.000 abstract description 8
- 125000000304 alkynyl group Chemical group 0.000 abstract description 8
- 125000003368 amide group Chemical group 0.000 abstract description 8
- 125000004093 cyano group Chemical group *C#N 0.000 abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 6
- 239000003446 ligand Substances 0.000 abstract description 6
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 125000006736 (C6-C20) aryl group Chemical group 0.000 abstract description 5
- 125000003860 C1-C20 alkoxy group Chemical group 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 150000003839 salts Chemical class 0.000 abstract description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 5
- 230000009257 reactivity Effects 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 100
- 239000000047 product Substances 0.000 description 46
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 21
- 238000004128 high performance liquid chromatography Methods 0.000 description 21
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 13
- 239000007787 solid Substances 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- ANJTVLIZGCUXLD-DTWKUNHWSA-N cytisine Chemical compound C1NC[C@H]2CN3C(=O)C=CC=C3[C@@H]1C2 ANJTVLIZGCUXLD-DTWKUNHWSA-N 0.000 description 10
- ANJTVLIZGCUXLD-BDAKNGLRSA-N (-)-Cytisine Natural products C1NC[C@@H]2CN3C(=O)C=CC=C3[C@H]1C2 ANJTVLIZGCUXLD-BDAKNGLRSA-N 0.000 description 9
- 150000004705 aldimines Chemical class 0.000 description 9
- 150000001543 aryl boronic acids Chemical class 0.000 description 9
- ANJTVLIZGCUXLD-UHFFFAOYSA-N ent-cytisine Natural products C1NCC2CN3C(=O)C=CC=C3C1C2 ANJTVLIZGCUXLD-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 229930014626 natural product Natural products 0.000 description 8
- WFOVEDJTASPCIR-UHFFFAOYSA-N 3-[(4-methyl-5-pyridin-4-yl-1,2,4-triazol-3-yl)methylamino]-n-[[2-(trifluoromethyl)phenyl]methyl]benzamide Chemical compound N=1N=C(C=2C=CN=CC=2)N(C)C=1CNC(C=1)=CC=CC=1C(=O)NCC1=CC=CC=C1C(F)(F)F WFOVEDJTASPCIR-UHFFFAOYSA-N 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- SLRCCWJSBJZJBV-AJNGGQMLSA-N sparteine Chemical compound C1N2CCCC[C@H]2[C@@H]2CN3CCCC[C@H]3[C@H]1C2 SLRCCWJSBJZJBV-AJNGGQMLSA-N 0.000 description 7
- 229960001945 sparteine Drugs 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- 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 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- SLRCCWJSBJZJBV-UHFFFAOYSA-N alpha-isosparteine Natural products C1N2CCCCC2C2CN3CCCCC3C1C2 SLRCCWJSBJZJBV-UHFFFAOYSA-N 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000004896 high resolution mass spectrometry Methods 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- PTPQJKANBKHDPM-UHFFFAOYSA-N 3,7-diazabicyclo[3.3.1]nonane Chemical class C1NCC2CNCC1C2 PTPQJKANBKHDPM-UHFFFAOYSA-N 0.000 description 4
- 229910010082 LiAlH Inorganic materials 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 238000006254 arylation reaction Methods 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229930008564 C01BA04 - Sparteine Natural products 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- JHRWWRDRBPCWTF-OLQVQODUSA-N captafol Chemical compound C1C=CC[C@H]2C(=O)N(SC(Cl)(Cl)C(Cl)Cl)C(=O)[C@H]21 JHRWWRDRBPCWTF-OLQVQODUSA-N 0.000 description 3
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 229940027564 cytisine Drugs 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- SLRCCWJSBJZJBV-TUVASFSCSA-N (+)-sparteine Chemical compound C1N2CCCC[C@@H]2[C@H]2CN3CCCC[C@H]3[C@@H]1C2 SLRCCWJSBJZJBV-TUVASFSCSA-N 0.000 description 2
- 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 2
- 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 2
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 description 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 2
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 229930017327 cytisine Natural products 0.000 description 2
- 229940104302 cytosine Drugs 0.000 description 2
- 150000004985 diamines Chemical class 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical class [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 2
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 230000005586 smoking cessation Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 239000011345 viscous material Substances 0.000 description 2
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 1
- OEQZLGCDEQVNGR-XVKVHKPRSA-N 4-amino-1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,3-diazinan-2-one Chemical compound O=C1NC(N)CCN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 OEQZLGCDEQVNGR-XVKVHKPRSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241000208125 Nicotiana Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 description 1
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000002921 anti-spasmodic effect Effects 0.000 description 1
- 230000000941 anti-staphylcoccal effect Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000005621 boronate group Chemical class 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 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
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000032798 delamination Effects 0.000 description 1
- 239000011903 deuterated solvents Substances 0.000 description 1
- BLEBFDYUDVZRFG-UHFFFAOYSA-N dichloromethane;propan-2-ol Chemical compound ClCCl.CC(C)O BLEBFDYUDVZRFG-UHFFFAOYSA-N 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 239000002895 emetic Substances 0.000 description 1
- 125000006437 ethyl cyclopropyl group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000006138 lithiation reaction Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- 125000006431 methyl cyclopropyl group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 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 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000033116 oxidation-reduction process Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 229940074439 potassium sodium tartrate Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000003169 respiratory stimulant agent Substances 0.000 description 1
- 229940066293 respiratory stimulants Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 125000005463 sulfonylimide group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 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
- 238000012360 testing method Methods 0.000 description 1
- ARYHTUPFQTUBBG-UHFFFAOYSA-N thiophen-2-ylboronic acid Chemical compound OB(O)C1=CC=CS1 ARYHTUPFQTUBBG-UHFFFAOYSA-N 0.000 description 1
- 229940043263 traditional drug Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/18—Bridged 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
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Abstract
本发明涉及手性配体的制备领域,公开了一种手性二胺类化合物和应用以及亚胺的不对称加成的方法。该化合物具有式(I)所示的通式结构或其盐,Q环为取代或未取代的六元环,X为‑CH2‑,或者X为碳氧双键或碳硫双键;R1‑R7各自独立地选自H、卤素、C1‑C20的烷基、C1‑C20的卤代烷基、C1‑C20的烷氧基、C6‑C20的芳基、C2‑C20的酯基、C2‑C20的羰基、C2‑C20的烷氧羰基、烯基、炔基、氨基、酰胺基、磺酰基、氰基、硝基、羧基、羟基或巯基。本发明提供的化合物在水相中能够实现高反应活性及高立体选择性,在绿色合成层面也属于一项新的挑战。此外,本发明还提供了一种亚胺的不对称加成的方法。
Description
技术领域
本发明涉及手性配体的制备领域,具体涉及一种手性二胺类化合物和应用以及亚胺的不对称加成的方法。
背景技术
天然产物(-)-Cytisine、(-)-Sparteine和(+)-Sparteine分子(Bispidine的相关天然衍生物)都是含有双哌啶的母核结构。手性双哌啶天然产物(-)-Cytisine自1865年被提分离出以来就受到了人们的广泛关注,随着天然产物(-)-Sparteine和(+)-Sparteine等的陆续发现,手性双哌啶家族在生物及化学领域掀起一股热潮。
早期美国的印第安人就把天然产物(-)-Cytisine当作传统药物用于催吐和导泻。在欧洲被用作呼吸兴奋剂、利尿剂或杀虫剂。在二战期间金链花的叶子被当作烟草的替代品。Cytisine是世界上最早的戒烟药,早在上世纪六十年代的东欧和中欧地区就开始用于戒烟。20世纪90年代末,(-)-Cytisine被证明与烟碱型乙酰胆碱受体的α4β2亚型具有高度亲和力,是低非特异性的部分激动剂。近期研究发现,Cytisine还具有止痛、抗高血压、抗痉挛、抗氧化和抗抑郁等多方面的药理作用。虽然(-)-Cytisine可从供应商处可得,但(-)-Cytisine仍然是一种相对昂贵的化学药物。
Sparteine具有抗心律失常和抗微生物感染的活性。此外,其它的Sparteine、Cytisine类似物,例如从苦参根中提取的双哌啶化合物a-c具有显著的抗金黄色葡萄球菌以及抗大肠杆菌活性;从苦豆草中提取的化合物d还具有抗乙肝型病毒的活性。
在(-)-Sparteine研究历程中的一个里程碑是1990年Hoppe等人在不对称碳锂化构建手性碳碳键反应中发现(-)-Sparteine能作为手性配体实现高度的立体选择性,这为高效构建手性中心提供了一个有效途径,开辟了手性bispidine配体的新领域。尽管近年来人们一致致力于上述天然产物及其衍生物研究与合成,例如以全合成或半合成的方式,但是上述天然产物及其衍生物的研究仍然存在很多挑战。
发明内容
本发明研究开发了一种天然产物sparteine类型的手性二胺类化合物和应用,该化合物在水相中能够实现高反应活性及高立体选择性,在绿色合成层面也属于一项新的挑战。此外,本发还提供了一种亚胺的不对称加成的方法。
为了实现上述目的,本发明第一方面提供一种手性二胺类化合物,该化合物具有式(I)所示的通式结构或其盐,
其中,式(I)中,
Q环为取代或未取代的六元环,X为-CH2-,或者X为碳氧双键或碳硫双键;
R1-R7各自独立地选自H、卤素、C1-C20的烷基、C1-C20的卤代烷基、C1-C20的烷氧基、C6-C20的芳基、C2-C20的酯基、C2-C20的羰基、C2-C20的烷氧羰基、烯基、炔基、氨基、酰胺基、磺酰基、氰基、硝基、羧基、羟基或巯基。
本发明中,R1-R7全部为H,且Q不含双键或者含有两个双键的未取代六元环除外。
本发明第二方面提供一种前述所述化合物在水相不对称反应中的应用,特别是在水相不对称加成反应中的应用。
本发明第三方面提供一种前述化合物在亚胺的不对称加成反应中的应用。
本发明第四方面提供一种亚胺的不对称加成的方法,该方法包括:在过渡金属催化剂与前述化合物的存在下,使亚胺与加成试剂接触。
与现有技术相比,本发明提供的技术方案至少具有以下优势:
(1)本发明提供的二胺类化合物(手性双哌啶类化合物),在分子层面,同时包含刚性和共价元素,既具有刚性的母核结构,同时还提供了共价连接的有利因素;
(2)本发明提供的二胺类化合物在作为手性配体应用时,相较于其它bispidine类化合物而言,具有能在水中实现高效手性催化的优势,可应用于环状磺酰胺(特别是六环磺酰亚胺)的不对称(芳基化)反应中,能够达到90%以上收率及对映选择性,为手性bispidine化合物的应用开拓了一个新领域。
具体实施方式
在本文中所披露的范围的端点和任何值都不限于该精确的范围或值,这些范围或值应当理解为包含接近这些范围或值的值。对于数值范围来说,各个范围的端点值之间、各个范围的端点值和单独的点值之间,以及单独的点值之间可以彼此组合而得到一个或多个新的数值范围,这些数值范围应被视为在本文中具体公开。
本发明中,“C1-20的烷基”包括碳原子总数为1-20的直链、支链、环状烷基,包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、正己基、环丙基、甲基环丙基、乙基环丙基、环戊基、甲基环戊基、环己基……等,“C1-C20的卤代烷基、C1-C20的烷氧基、C6-C20的芳基、C2-C20的酯基、C2-C20的羰基、C2-C20的烷氧羰基”亦然,也即具有有类似的含义。
如前所述,本发明第一方面提供一种手性二胺类化合物,该化合物具有式(I)所示的通式结构或其盐,
其中,式(I)中,
Q环为取代或未取代的六元环,X为-CH2-,或者X为碳氧双键或碳硫双键;
R1-R7各自独立地选自H、卤素、C1-C20的烷基、C1-C20的卤代烷基、C1-C20的烷氧基、C6-C20的芳基、C2-C20的酯基、C2-C20的羰基、C2-C20的烷氧羰基、烯基、炔基、氨基、酰胺基、磺酰基、氰基、硝基、羧基、羟基或巯基。
本发明中,R1-R7全部为H,且Q不含双键或者含有两个双键的未取代六元环除外。
本发明中,Q环上的虚线代表可以代表碳碳单键或碳碳双键。
根据本发明的一些实施方式,R1-R7各自独立地选自H、卤素、C1-C10的烷基、C1-C10的卤代烷基、C1-C10的烷氧基、C6-C10的芳基、C2-C10的酯基、C2-C10的羰基、C2-C10的烷氧羰基、烯基、炔基、氨基、酰胺基、磺酰基、氰基、硝基、羧基、羟基或巯基。
本发明中,优选地,R1-R7各自独立地选自H、卤素、C1-C4的烷基、C1-C4的卤代烷基、C1-C4的烷氧基、C6-C8的芳基、C2-C6的酯基、C2-C6的羰基、C2-C6的烷氧羰基、烯基、炔基、氨基、酰胺基或磺酰基。
根据本发明的一些实施方式,R3、R4、R5和R7全部为H,R1、R2和R6至少一个不为H。
根据本发明的一些实施方式,所述化合物选自式A-C所示结构中的一种,
式A-C中,R1、R2和R6与前述定义相同;
式A中R8-R10、式B中R11和R12、式C中R13和R14各自独立地选自H、卤素、C1-C20的烷基、C1-C20的卤代烷基、C1-C20的烷氧基、C6-C20的芳基、C2-C20的酯基、C2-C20的羰基、C1-C20的烷氧羰基、烯基、炔基、氨基、酰胺基、磺酰基、氰基、硝基、羧基、羟基或巯基;
式A中,Y为O或S;
式B中,Z为-CH2-,或者Z为碳氧双键或碳硫双键。
根据本发明的一些实施方式,式A中R8-R10、式B中R11和R12、式C中R13和R14各自独立地选自H、卤素、C1-C10的烷基、C1-C10的卤代烷基、C1-C10的烷氧基、C6-C10的芳基、C2-C10的酯基、C2-C10的羰基、C1-C10的烷氧羰基、烯基、炔基、氨基、酰胺基、磺酰基、氰基、硝基、羧基、羟基或巯基。
本发明中,优选地,式A中R8-R10、式B中R11和R12、式C中R13和R14各自独立地选自H、卤素、C1-C4的烷基、C1-C4的卤代烷基、C1-C4的烷氧基、C6-C8的芳基、C2-C6的酯基、C2-C6的羰基、C2-C6的烷氧羰基、烯基、炔基、氨基、酰胺基或磺酰基。
根据本发明的一些实施方式,式A-C中,R1、R2和R6各自独立地选自H、卤素、C1-C4的烷基、C1-C4的卤代烷基、C6-C8的芳基、C2-C6的烷氧羰基、氨基或磺酰基。
根据本发明的一些实施方式,式A中,R9为H,R8和R10各自独立地选自H、卤素、C1-C4的烷基或C6-C8的芳基。
根据本发明的一些实施方式,式B中,R11和R12各自独立地选自H、卤素、C1-C4的烷基、C6-C8的芳基或C1-C6的烷氧羰基。
根据本发明的一些实施方式,式C中,R13和R14各自独立地选自H、卤素、C1-C4的烷基、C6-C8的芳基、C2-C6的烷氧羰基、氨基或磺酰基。
根据本发明的一些实施方式,所述化合物选自以下具体化合物中的一种:
本发明中,本发明提供的式(I)所示结构的化合物的盐的形式(例如盐酸盐形式)也在本发明的保护范围内;这是考虑到某些化合物以盐形式存在结构比较稳定,且呈固体形式,容易储存和转移。
本发明对制备具有式(I)所示结构的手性二胺类化合物的方法没有特别的限定,可以参照本领域常规的方式进行。
示例性地,以化合物13、14、19、78的合成为例:首先,以(-)-Cytisine为起始原料与Boc2O酸酐进行取代反应,得到化合物101;然后将化合物101在PtO2和氢气的存在下进行还原反应,之后在HCl的作用下脱Boc得到化合物78;化合物78进一步在LiAlH4和NaBH4的作用下,得到化合物13;进一步地,化合物13中氮上的氢原子,可以被不同的取代基取代,例如甲基、苯基,分别得到化合物14和19;
示例性地,以化合物1、2、3、6、7、8的合成为例:首先,以化合物102为起始原料,在叔丁醇钾的存在下反应得到化合物103和104,然后化合物103和104与格式试剂RMgCl(例如R为甲基、异丙基、苯基)接触进行反应,得到化合物a和b,化合物a和b在PtO2和氢气的存在下进行还原反应,得到化合物c和d,化合物c和d进一步在LiAlH4和NaBH4的作用下,得到化合物e和f;
其中,化合物102可以通过本领域常规的方式获得,例如可以通过如下方法制备:使Cytisine与NCS(N-氯代丁二酰亚胺)进行反应得到;
示例性地,以化合物79和80的合成为例:首先以化合物101为起始原料,使化合物101与NBS(N-溴代琥珀酰亚胺)进行反应得到化合物105和106;之后化合物105和106与芳基硼在醋酸钯的存在下,得到偶联化合物107和108;化合物107和108在经两步还原,最终得到化合物79和80;
本发明中,可以先以手性天然产物(–)-Cytisine为起始原料进行化合物的制备,在有需要的情况下,再进一步拆分。其中,对所述拆分的方法没有特别的限定,可以参照本领域常规的方式。
本发明对以上制备过程中涉及的反应条件没有特别的限定,本领域技术人员可以根据有机合成领域内的公知常识以及本发明实施例部分提供的具体实例获得适宜的反应条件。
如前所述,本发明第二方面提供一种前述所述化合物在水相不对称反应中的应用,特别是在水相不对称加成反应中的应用。
本发明中,不对称反应可以指不对称偶联、加成、氧化还原和不对称拆分等。
如前所述,本发明第三方面提供一种前述化合物在亚胺的不对称加成反应中的应用。
如前所述,本发明第四方面提供一种亚胺的不对称加成的方法,该方法包括:在过渡金属催化剂与前述化合物的存在下,使亚胺与加成试剂接触。
根据本发明的一些实施方式,所述接触的条件包括:温度为50-120℃,优选为80-110℃;时间为5-30h,优选为10-24h。
本发明中,在前述亚胺的不对称加成的反应中,优选地,相对于1mmol的亚胺,过渡金属催化剂的用量可以为0.05-0.2mol,前述化合物的用量可以为0.05-0.2mol,加成试剂的用量可以为1.5-3mol。
根据本发明的一些实施方式,所述过渡金属催化剂包括过渡金属,选自Pd、Rh、Ru和Cu中的至少一种,优选为Pd。
根据本发明的一些实施方式,所述亚胺选自磺酰亚胺和/或酰基亚胺,优选为磺酰亚胺,更优选为环状磺酰亚胺。
根据本发明的一些实施方式,所述加成试剂选自芳基硼化合物,优选为芳基硼酸和/或硼酸酯,更优选为芳基硼酸。
本发明提供的手性二胺类化合物在亚胺的不对称加成中,产物的收率可达98%,ee值(对映体过量值)也可达98%。此外,本发明提供的化合物在前述其他的不对称反应中也能够获得中等的(ee值为30%-50%)对映选择性。
以下将通过实施例对本发明进行详细描述。
以下制备例和实施例中,所有商购获得的原料、试剂直接使用,不做进一步的处理。有机溶剂通过旋转蒸发器在减压下浓缩。除非另有说明,否则在硅胶(粒径50-75μm)上进行闪蒸柱层析。用薄层层析法(TLC)在玻璃背板上预涂二氧化硅(GF254)监测反应。用紫外光(254nm)或碘染色观察斑点。核磁共振谱在25℃的600MHz或400MHz Bruker Avance光谱仪上获得,并以残留的未氘溶剂作为内参照物进行校准。在手性相上用高效液相色谱(HPLC)测定对映体过量值。在Q-TOF Micro(Bruker Compass Data and Analysis 4.0)光谱仪或Q Exactive HF LC-MS(Thermo Fisher)上进行高分辨率质谱(HRMS)以进行精确的质谱分析。熔点记录在国家标准熔点测定仪上,不作校正。
制备例
化合物101的制备
将(-)-Cytisine(5.7克,30毫摩尔)和Boc2O(9.7毫升,1.4当量)溶于THF(116毫升)中,然后加入Na2CO3(3.20克,1.0当量)的水溶液(87mL);将上述混合物在40℃下搅拌反应24小时,用DCM(170毫升)和饱和NaCl水溶液(30毫升)稀释,待分层后,用DCM萃取水相3次。收集所有有机相用无水Na2SO4干燥,在减压下过滤和浓缩,得到化合物101(8.61克,收率99%)白色固体。1H NMR(400MHz,CDCl3)δ7.30–7.21(m,1H),6.42(br,1H),6.05(br,1H),4.45–4.01(m,3H),3.87–3.72(m,1H),3.13–2.86(m,3H),2.40(br,1H),1.94(dd,J=13.5,10.0Hz,2H),1.26(br,9H);13C NMR(101MHz,CDCl3)δ163.5,154.5(br),149.3-148.8(m),139.0-138.5(m),117.2,105.8-105.1(m),80.4-79.8(m),51.7,50.6,49.4,48.9,34.9,28.1,27.7,27.6,26.2。
化合物78的制备
将化合物101(N-Boc-Cytisine)(5克,17.2毫摩尔)、甲醇(250毫升)和PtO2(80%Pt)(0.5克,2毫摩尔)的混合液在室温下搅拌反应4天。反应后的混合物用过滤,滤饼用CH2Cl2/MeOH(9:1)彻底清洗。浓缩后的残渣用甲醇(40mL)溶解,然后加入HCl(Conc.)。甲醇在室温下搅拌24h后,蒸发成白色粘性物质,用饱和K2CO3水溶液碱化,然后用CH2Cl2萃取5次。所有收集的有机层在无水Na2SO4上干燥,过滤并在减压下浓缩,得到化合物78(4.6克,收率92%),白色固体。1H NMR(400MHz,CDCl3)δ4.68(dt,J=13.7,2.0Hz,1H),3.57–3.51(m,1H),3.36(d,J=14.1Hz,1H),3.12(d,J=13.4Hz,1H),3.03–2.97(m,1H),2.97–2.91(m,1H),2.91–2.85(m,1H),2.53–2.45(m,1H),2.42–2.31(m,1H),2.02(ddd,J=12.6,5.5,3.2Hz,1H),1.93(ddd,J=10.3,6.2,3.1Hz,1H),1.89–1.74(m,5H),1.74–1.63(m,1H),1.49(s,1H);13C NMR(101MHz,CDCl3)δ170.2,60.1,51.9,47.0,46.9,33.5,33.3,33.2,28.5,28.3,20.4。
化合物13的制备
在氩气气氛下用溶剂净化系统得到的LiAlH4(228毫克,1.0当量)和干四氢呋喃(15mL)充入圆底烧瓶。用注射器将1.16g的四氢胞苷(1.16克,6毫摩)加入干燥的四氢呋喃(15毫升)中,在氩气气氛下,温度为0℃。然后允许反应混合物在室温下搅拌30min,用饱和的罗谢尔盐(10毫升)熄灭。混合物在室温下搅拌15min,形成白色沉淀物,过滤除去。滤渣用乙醇彻底洗涤,滤液干燥浓缩成无色油,然后加入甲醇(30毫升)和硼氢化钠(227.0毫克,1.0当量)。将得到的溶液在室温下搅拌10min,然后用HCl(conc.)。通过蒸发除去溶剂,产生白色粘性物质,然后用CH2Cl2稀释,并在无水Na2SO4上干燥。不溶性物质被过滤掉了。滤液蒸发得到化合物13(0.97克,收率90%),白色固体。1H NMR(400MHz,CDCl3)δ11.04(br,1H),3.66(d,J=13.2Hz,1H),3.50(d,J=12.9Hz,1H),3.29(dt,J=12.8,2.7Hz,1H),3.14(d,J=13.2Hz,1H),2.97(dt,J=11.6,2.2Hz,1H),2.82(d,J=11.3Hz,1H),2.50(dt,J=11.7,2.5Hz,1H),2.28(d,J=10.5Hz,1H),2.11(br,1H),2.00–1.73(m,5H),1.70–1.44(m,4H),1.36–1.21(m,1H);13C NMR(101MHz,CDCl3)δ65.5,60.9,56.5,49.8,45.9,32.5,31.8,30.0,27.3,25.4,24.0.HRMS(ESI)calcd for C11H21N2(M+H)+181.17047,found 181.17051.m.p.:138-140℃.
化合物14的制备
在化合物13(0.6毫摩尔,108毫克)的甲醇(2毫升)溶液中加入37%的甲醛水溶液(2当量),然后在0℃缓慢加入NaBH4(1当量)。然后将反应升温至室温,并搅拌一夜。反应混合物在减压下浓缩。用盐酸(1M)调节pH值在7-8之间,然后用CH2Cl2(20毫升×3)提取。收集并浓缩结合的有机层,得到粗品。硅胶(甲醇/CH2Cl2,2:98-1:9)经闪蒸柱进一步纯化,得到化合物14(108.4毫克,93%),为淡黄色油。1H NMR(400MHz,CDCl3)δ3.84(d,J=11.7Hz,1H),3.73(d,J=10.9Hz,1H),3.55(d,J=11.3Hz,1H),3.25(d,J=11.9Hz,1H),2.95(d,J=11.7Hz,1H),2.86(d,J=11.7Hz,1H),2.51(d,J=8.0Hz,5H),2.47–2.37(m,1H),2.20–2.08(m,2H),1.94–1.73(m,6H),1.67(d,J=13.7Hz,1H),1.56–1.43(m,1H);13C NMR(101MHz,CDCl3)δ66.6,59.7,59.2,56.8,56.2,46.1,33.4,32.1,29.2,28.6,24.2,23.2.HRMS(ESI)calcd for C12H23N2(M+H)+195.18612,found 195.18636。
化合物19的制备
在密闭的试管中充入化合物13(0.3毫摩,54毫克)、溴苯(1当量)、tBuOK(5.0当量)和二甲基亚砜(1毫升)。然后在120℃下搅拌加热24h,冷却至室温后,将反应混合物转移到乙酸乙酯(EtOAc)(10毫升)的分离漏斗中,并用NaCl(AQ)(3×10毫升)洗涤。收集有机层,在无水Na2SO4上干燥,然后浓缩得到粗品。硅胶(甲醇/CH2Cl2,1:9)经闪蒸柱纯化,最终得到化合物19(61.5毫克,收率80%),黄油。1H NMR(400MHz,CDCl3)δ7.25(d,J=10.4Hz,2H),6.88(d,J=6.1Hz,2H),6.75(t,J=6.8Hz,1H),3.86(d,J=11.9Hz,1H),3.69(d,J=10.6Hz,1H),3.06(dd,J=11.2,4.3Hz,1H),2.90–2.84(m,1H),2.39(s,1H),2.12(s,1H),1.97–1.16(m,13H);13C NMR(101MHz,CDCl3)δ149.8,128.1,121.4,117.9,65.8,58.2,56.4,54.5,50.8,32.1,30.5,28.0,27.5,22.8,21.7.HRMS(ESI)calcd for C17H25N2(M+H)+257.20177,found 257.20203。
化合物1、2、3、6、7、8的制备
其中,R分别为甲基、异丙基和苯基,相应得到化合物1、2、3、6、7、8。
具体操作步骤如下:
将化合物102(Cl-cytisine)(1当量)溶解在四氢呋喃溶液中,加入叔丁醇钾的四氢呋喃溶液(0.2M,1.2当量)。反应在室温下搅拌3h,然后用乙醚洗涤2次,过滤后真空浓缩,得到化合物103和104。
氮气保护下,用烘箱烘干的250mL的Schlenck烧瓶,配以搅拌子,将化合物103和104的混合物(14.2g,21.8mmol,1当量)溶解在四氢呋喃(100mL)中。缓慢加入格氏试剂RMgCl(2M,38.15mL,3.5当量),在0℃搅拌过夜。
然后用甲醇和氨水淬灭反应液,浓缩反应液。二氯甲烷:甲醇(80:1)萃取3次,有机相经无水硫酸钠干燥后真空浓缩得到粗产物。用硅胶(10%v/v异丙醇-二氯甲烷+0.1%NH3·H2O)纯化得到35-40%收率的相应产品a和b(化合物1、2、3、6、7、8)。
1H NMR(400MHz,CDCl3)δ7.28(dd,J=9.0,6.9Hz,1H),6.44(dd,J=9.0,1.4Hz,1H),5.96(dd,J=6.9,1.2Hz,1H),3.99(dt,J=15.6,11.1Hz,2H),3.15(dd,J=11.9,2.5Hz,1H),2.81(s,1H),2.67(dt,J=11.9,2.4Hz,1H),2.44(d,J=1.9Hz,1H),2.32(d,J=10.2Hz,1H),2.16(ddt,J=13.1,10.3,6.5Hz,1H),2.04(dd,J=13.1,2.6Hz,1H),1.73(dt,J=5.4,4.6Hz,1H),0.94(dt,J=17.0,8.5Hz,6H).
13C NMR(101MHz,CDCl3)δ163.66(s),151.65(s),138.74(s),116.65(s),104.58(s),65.83(s),51.50(s),47.97(s),35.18(s),27.79(s),25.22(s),21.38(s),20.14(d,J=6.3Hz),-0.00(s).
1H NMR(400MHz,CDCl3)δ7.51(d,J=8.2Hz,2H),7.40(t,J=7.7Hz,2H),7.33(dd,J=9.0,6.9Hz,1H),7.29(d,J=7.6Hz,1H),6.50(dd,J=9.0,1.3Hz,1H),6.01(dd,J=6.9,1.2Hz,1H),4.36(d,J=15.7Hz,1H),4.19(s,1H),4.11(dd,J=15.8,6.7Hz,1H),3.28(dd,J=12.2,2.2Hz,1H),2.95(d,J=3.3Hz,1H),2.85–2.77(m,2H),1.95(d,J=12.9Hz,1H),1.80–1.76(m,1H).
13C NMR(101MHz,CDCl3)δ163.76(s),151.18(s),141.03(s),138.95(s),128.63(s),126.64(s),126.36(s),116.83(s),104.80(s),60.31(s),50.84(s),48.89(s),35.29(s),30.46(s),21.42(s).
1H NMR(400MHz,DMSO)δ8.70-8.30(br,2H),7.39(dd,J=9.2,6.8Hz,1H),6.37–6.29(dd,J=9.2,1.2Hz,1H),6.20(dd,J=6.8,1.0Hz,1H),3.94(d,J=15.9Hz,1H),3.79(dd,J=15.9,6.9Hz,1H),3.67(q,J=7.0Hz,1H),3.47(dd,J=12.9,2.8Hz,1H),3.21(s,1H),3.00(d,J=12.9Hz,1H),2.39(s,1H),2.18(d,J=13.7Hz,1H),1.75(d,J=13.0Hz,1H),1.41(d,J=7.0Hz,3H).
13C NMR(101MHz,DMSO)δ139.50(s),105.69(s),53.51(s),49.43(s),44.62(s),31.58(s),30.34(s),18.36(s),15.19(s).
1H NMR(400MHz,CDCl3)δ7.28(dd,J=9.0,7.0Hz,1H),6.42(t,J=9.0Hz,1H),5.96(d,J=7.0Hz,1H),4.09(d,J=15.5Hz,1H),3.92–3.83(m,1H),3.11(d,J=11.6Hz,1H),2.99(s,1H),2.77(d,J=12.3Hz,1H),2.32–2.23(m,2H),2.24–2.14(m,1H),2.07(d,J=13.1Hz,1H),1.71(dd,J=13.1,2.1Hz,1H),0.96(dt,J=14.4,7.2Hz,6H).
13C NMR(101MHz,CDCl3)δ163.69(s),153.05(s),138.75(s),116.42(s),104.87(s),66.71(s),50.10(s),47.07(s),35.78(s),27.46(s),25.07(s),20.87(s),20.17(s),20.12(s).
1H NMR(400MHz,CDCl3)δ7.51(d,J=8.2Hz,2H),7.40(t,J=8.0Hz,2H),7.33(dd,J=9.0,6.9Hz,1H),7.29(t,J=7.6Hz,1H),6.50(dd,J=9.0,1.3Hz,1H),6.01(dd,J=6.9,1.2Hz,1H),4.36(d,J=15.7Hz,1H),4.19(s,1H),4.11(dd,J=15.8,6.7Hz,1H),3.28(dd,J=12.2,2.2Hz,1H),2.95(d,J=3.3Hz,1H),2.85–2.77(m,2H),1.95(d,J=12.9Hz,1H),1.80–1.76(m,1H).
13C NMR(101MHz,CDCl3)δ151.81(s),140.30(s),138.87(s),128.75(s),126.81(s),126.46(s),117.02(s),105.29(s),61.43(s),49.97(s),47.68(s),38.21(s),27.53(s),20.94(s).
化合物21、22、23、27、28、29的制备:
其中,R分别为甲基、异丙基和苯基,相应得到化合物c和d(化合物21、22、23、27、28、29)。
具体操作如下:
使用烘干的100mL的Schlenck烧瓶,配以搅拌子,分别将起始原料化合物a和b(化合物1、2、3、6、7、8)(1当量)和二氧化铂(10%mmol)溶解于醋酸中,置换氢气,搅拌3天。
反应完全后在氮气保护下,真空过滤浓缩,得到相应的产品,收率达95%。
1H NMR(600MHz,CDCl3)δ7.45(d,J=11.8Hz,2H),7.35(t,J=7.7Hz,2H),7.24(t,J=7.3Hz,1H),4.80(d,J=13.6Hz,1H),3.93(s,1H),3.44(t,J=17.2Hz,1H),3.05(dd,J=13.9,6.0Hz,1H),2.98(d,J=13.8Hz,1H),2.89–2.84(m,1H),2.51(dd,J=16.2,2.9Hz,1H),2.43–2.29(m,2H),2.19(d,J=12.3Hz,1H),1.96–1.87(m,1H),1.86–1.78(m,1H),1.75–1.64(m,3H),1.60(d,J=13.1Hz,1H).
13C NMR(151MHz,CDCl3)δ175.86–172.55(m),170.92(s),142.03–141.79(m),128.59(s),127.08(s),126.84(s),60.45(s),60.17(s),47.38(s),42.12(s),33.18(s),32.97(s),31.65(s),27.85(s),27.44(s),19.93(s).
1H NMR(400MHz,CDCl3)δ7.44(d,J=7.5Hz,2H),7.35(t,J=6.9Hz,2H),7.23(dd,J=7.5,6.9Hz,1H),4.68(d,J=13.3Hz,1H),4.17(s,1H),3.67–3.59(m,1H),3.21(dd,J=13.2,5.2Hz,1H),2.85(t,J=12.4Hz,2H),2.53(d,J=17.3Hz,1H),2.44–2.33(m,1H),2.07(d,J=12.4Hz,2H),1.90(t,J=15.6Hz,5H),1.56(d,J=12.1Hz,1H).
13C NMR(101MHz,CDCl3)δ170.75(s),143.77(s),128.53(s),126.61(d,J=13.5Hz),60.92(s),55.17(s),47.24(d,J=18.5Hz),37.72(s),33.36(s),27.89(d,J=17.2Hz),27.49(s),20.16(s).
化合物36、37、38、41、42、43的制备
其中,当R分别为甲基、异丙基和苯基,相应得到化合物c和d(化合物36、37、38、41、42、43)。
具体操作步骤如下:
氮气保护下,分别将化合物c和d(化合物21、22、23、27、28、29)(1当量)和LiAlH4(1.2当量)置于装有搅拌子的干燥50mL的Schlenck烧瓶中,分别溶解于干燥的THF中,将LiAlH4溶液分别滴加到化合物c和d(化合物21、22、23、27、28、29)的溶液中,0℃下搅拌2h。
用酒石酸钾钠饱和溶液淬灭,直至无气泡出现。抽滤、洗涤有机相5次以上,合并有机相并旋干得到中间体。然后将中间体溶解在甲醇中,加入NaBH4(1当量),室温下搅拌3h。调整pH值6-7后,真空浓缩,然后溶解在二氯甲烷中并用无水Na2SO4干燥,再次浓缩得到相应的产物化合物36、37、38、41、42、43,收率分别为95%、92%、88%、90%、89和85%。
1H NMR(600MHz,CDCl3)δ7.32(t,J=7.9Hz,2H),7.27(d,J=6.9Hz,2H),6.99(t,J=7.2Hz,1H),4.28(d,J=9.9Hz,1H),4.01(dd,J=23.4,10.3Hz,2H),3.76(d,J=12.0Hz,1H),3.42(d,J=9.6Hz,1H),3.26(d,J=11.5Hz,1H),2.95(dd,J=25.2,11.2Hz,2H),2.83(t,J=11.6Hz,1H),2.32(d,J=13.4Hz,1H),2.09(d,J=15.5Hz,3H),1.90(ddd,J=35.4,23.9,13.0Hz,6H).
按照上述类似的方式,制备得到了以下一些具体化合物。
H NMR(400MHz,MeOD)δ4.14(d,J=69.3Hz,3H),3.12(ddd,J=92.4,42.3,32.2Hz,5H),1.86(t,J=59.2Hz,11H),1.49(s,9H)).
1H NMR(400MHz,CDCl3)δ4.71(dd,J=13.6,2.0Hz,1H),4.60(d,J=13.9Hz,1H),4.15(dd,J=13.3,1.5Hz,1H),3.44(d,J=11.3Hz,1H),3.04(dd,J=13.3,2.2Hz,1H),2.80(dd,J=22.8,8.3Hz,2H),2.35(dd,J=9.4,4.1Hz,2H),2.16(ddd,J=24.9,13.2,3.1Hz,1H),1.98–1.77(m,5H),1.71–1.58(m,2H),1.44(d,J=13.1Hz,9H).
1H NMR(400MHz,CDCl3)δ7.39–7.20(m,4H),7.02(dt,J=126.6,36.9Hz,2H),6.53(d,J=9.0Hz,1H),5.92(s,1H),4.80(s,1H),4.09(dd,J=33.5,26.6Hz,1H),3.96–3.51(m,2H),3.12(d,J=54.3Hz,3H),2.43(d,J=63.8Hz,1H),2.07–1.98(m,2H).
13C NMR(101MHz,CDCl3)δ171.27(s),163.30(s),135.27(s),129.56(s),126.58(s),117.65(s),117.62–117.53(m),48.81–48.71(m),34.78(s),27.62(s),26.26(s).
1H NMR(400MHz,CDCl3)δ5.45(d,J=143.5Hz,1H),3.16(s,2H),3.06(s,1H),2.94(s,1H),2.78–2.31(m,7H),2.23(d,J=15.9Hz,6H),1.96(s,1H),1.88–1.51(m,8H),1.50–1.26(m,3H).
1H NMR(400MHz,CDCl3)δ4.45–4.06(m,1H),3.07(dd,J=18.2,10.8Hz,2H),2.90(t,J=12.1Hz,1H),2.82(d,J=9.4Hz,1H),2.55–2.45(m,1H),2.43–2.26(m,4H),2.23(d,J=6.7Hz,6H),2.00(t,J=30.1Hz,2H),1.89–1.66(m,4H),1.64–1.47(m,5H),1.38–1.20(m,3H).
1H NMR(400MHz,CDCl3)δ7.32(d,J=9.6Hz,1H),6.45(d,J=9.6Hz,1H),4.12(d,J=15.6Hz,1H),3.95–3.89(m,1H),3.32(s,1H),3.23(dt,J=13.0,3.5Hz,2H),2.90(dt,J=12.5,2.4Hz,1H),2.26–2.20(m,1H),2.14(s,1H),1.76–1.71(m,1H),1.31(d,J=6.9Hz,3H).
13C NMR(101MHz,CDCl3)δ163.67(s),151.64(s),138.72(s),116.69(s),104.54(s),65.85(s),51.51(s),48.00(s),35.21(s),27.82(s),25.27(s),21.42(s),20.15(d,J=5.5Hz).
1H NMR(400MHz,CDCl3)δ7.31(d,J=9.6Hz,1H),6.43(d,J=9.6Hz,1H),4.05–3.92(m,2H),3.31(s,1H),3.07(dd,J=11.9,2.5Hz,1H),2.82(ddd,J=15.4,8.9,6.5Hz,1H),2.49–2.43(m,1H),2.32(d,J=10.2Hz,1H),2.18(ddt,J=13.1,10.2,6.5Hz,1H),2.09(dt,J=13.3,2.5Hz,1H),1.75–1.66(m,1H),1.00–0.91(m,6H).
13C NMR(101MHz,CDCl3)δ162.29(s),147.51(s),139.96(s),117.32(s),109.85(s),65.56(s),52.43(s),44.35(s),31.98(s),27.42(s),25.15(s),21.38(s),20.18(s),19.95(s).
1H NMR(400MHz,DMSO)δ9.80(br,1H),8.42(br,1H),7.49(s,1H),7.34(s,1H),6.83(s,1H),4.34(d,J=16.4Hz,1H),4.19(s,1H),3.48–3.42(m,1H),3.31(dd,J=30.4,11.8Hz,2H),3.23–3.14(m,2H),2.76(s,1H),2.05(d,J=12.2Hz,1H),1.92(d,J=13.2Hz,1H).
1H NMR(400MHz,CDCl3)δ7.59(d,J=8.3Hz,1H),7.17(s,3H),6.85(s,2H),6.64(t,J=7.8Hz,1H),5.28(d,J=7.1Hz,1H),4.90–4.81(m,2H),4.14(dd,J=16.1,5.1Hz,1H),4.01(dd,J=13.5,7.2Hz,1H),3.56(d,J=13.8Hz,1H),3.26(s,1H),2.93(s,1H),2.12(d,J=11.6Hz,1H),2.01(d,J=10.5Hz,1H),1.17(s,9H).
1H NMR(400MHz,CDCl3)δ7.66(dd,J=8.5,1.5Hz,1H),7.13(dd,J=8.5,7.2Hz,1H),6.48(dd,J=7.2,1.4Hz,1H),4.53(d,J=16.0Hz,1H),4.27(dd,J=16.0,6.8Hz,1H),3.04(d,J=2.5Hz,1H),2.93–2.87(m,1H),2.84–2.78(m,1H),2.52(dd,J=6.1,2.9Hz,1H),2.28(dt,J=7.3,3.6Hz,1H),2.22(d,J=11.1Hz,1H),2.09(s,3H),1.90–1.83(m,1H),1.81–1.75(m,1H).
1H NMR(400MHz,CDCl3)δ7.31(dd,J=9.1,6.8Hz,1H),6.50(dd,J=9.1,1.2Hz,1H),6.09–6.01(dd,J=6.8,0.8Hz,1H),4.19(d,J=15.9Hz,1H),4.02–3.83(m,3H),3.35(dd,J=11.8,6.6Hz,2H),3.15(s,1H),2.61(s,1H),2.09(d,J=13.3Hz,1H),1.97(d,J=13.2Hz,1H).
13C NMR(101MHz,CDCl3)δ163.29(s),146.76(s),138.80(s),118.35(s),105.65(s),53.60(s),52.74(s),48.30(s),34.05(s),26.96(s),25.03(s)).
19F NMR(376MHz,CDCl3)δ-74.62(s).
1H NMR(400MHz,CDCl3)δ7.32(dd,J=9.0,6.8Hz,1H),6.48(d,J=9.0Hz,1H),6.03(d,J=6.8Hz,1H),4.21(d,J=15.6Hz,1H),3.94(dd,J=15.7,6.5Hz,1H),3.45–3.33(m,2H),2.97(s,1H),2.88(d,J=11.7Hz,1H),2.72(s,1H),2.28(d,J=13.4Hz,1H),1.88(d,J=13.4Hz,1H).
19F NMR(376MHz,CDCl3)δ-71.27(s).
1H NMR(400MHz,CDCl3)δ7.79(s,1H),7.19–7.13(m,3H),6.96(dd,J=7.3,1.9Hz,2H),3.96–3.86(m,2H),3.35(d,J=2.8Hz,1H),3.07(d,J=10.9Hz,1H),2.91(d,J=10.8Hz,1H),2.62–2.57(m,2H),2.55–2.47(m,2H),2.40(s,1H),2.36(d,J=11.0Hz,1H),2.24(dd,J=10.9,2.1Hz,1H),1.82(d,J=2.2Hz,2H).
1H NMR(400MHz,CDCl3)δ7.28–7.22(m,1H),7.20–7.16(m,1H),6.90–6.84(m,2H),4.87(d,J=13.6Hz,1H),3.78(d,J=13.4Hz,1H),3.24(dd,J=13.6,2.6Hz,1H),3.03(dd,J=11.4,2.7Hz,1H),2.94–2.78(m,2H),2.33(dt,J=11.4,2.0Hz,1H),2.18(d,J=11.3Hz,1H),1.92–1.71(m,6H),1.64(ddt,J=17.5,10.1,3.6Hz,3H),1.49(d,J=11.1Hz,1H),1.35–1.29(m,1H).
1H NMR(600MHz,CDCl3)δ8.58–8.49(m,1H),7.74(dtd,J=27.4,7.7,1.7Hz,1H),7.66–7.35(m,1H),7.30–7.21(m,1H),4.91(ddd,J=109.7,13.5,1.6Hz,1H),3.77(ddd,J=165.7,13.7,1.5Hz,1H),3.44–3.25(m,1H),3.08–2.94(m,1H),2.86–2.71(m,1H),2.66–2.50(m,1H),2.27–2.18(m,1H),1.98(dt,J=12.0,7.5Hz,1H),1.95–1.81(m,2H),1.81–1.68(m,2H),1.68–1.61(m,2H),1.61–1.50(m,2H),1.50–1.35(m,2H),1.18–1.02(m,1H).
1H NMR(600MHz,DMSO)δ7.76(s,1H),7.33–7.20(m,6H),6.53(s,1H),4.67(s,1H),4.57(d,J=14.0Hz,1H),4.12(d,J=13.2Hz,1H),3.63(d,J=10.6Hz,1H),3.38(t,J=10.0Hz,1H),3.25(s,1H),3.00(d,J=11.1Hz,1H),2.86(dd,J=13.3,7.7Hz,1H),2.76(d,J=7.8Hz,1H),2.47(d,J=14.3Hz,1H),2.40–2.35(m,1H),2.05(s,1H),1.94–1.69(m,8H),1.56–1.45(m,2H),1.38(s,9H).
1H NMR(600MHz,DMSO)δ7.76–6.53(m,8H),4.74–4.64(m,1H),4.54(dd,J=29.9,12.9Hz,1H),4.13(t,J=12.2Hz,1H),3.86(dd,J=63.3,17.1Hz,1H),3.69–3.59(m,1H),2.98(dd,J=50.5,16.9Hz,2H),2.89–2.83(m,1H),2.79–2.72(m,2H),2.37(dd,J=17.0,15.2Hz,1H),2.07–1.93(m,2H),1.91–1.70(m,6H),1.48(dd,J=53.4,11.3Hz,2H),1.36(d,J=26.1Hz,9H).
1H NMR(400MHz,DMSO)δ7.35–7.19(m,3H),7.02(s,1H),6.96(s,2H),6.90(s,1H),4.26–4.07(m,4H),3.79–3.73(m,1H),3.05(d,J=11.1Hz,1H),2.90(dd,J=11.7,8.2Hz,1H),2.41(s,1H),2.30(s,6H),2.26(d,J=4.6Hz,7H),1.95(t,J=12.0Hz,1H),1.86(d,J=12.8Hz,1H),1.24(d,J=22.5Hz,9H).
1H NMR(600MHz,CDCl3)δ7.37(d,J=7.1Hz,1H),7.22(s,2H),6.89(s,1H),6.10(s,1H),4.42–4.04(m,3H),3.82(dd,J=15.5,6.3Hz,1H),3.04(d,J=12.8Hz,1H),2.99–2.86(m,2H),2.38(d,J=18.3Hz,1H),1.94(d,J=12.9Hz,1H),1.88(d,J=13.0Hz,1H),1.37–1.14(m,9H).
1H NMR(400MHz,CDCl3)δ7.24(dd,J=9.1,7.3Hz,4H),7.18–7.12(m,1H),4.59(d,J=13.4Hz,1H),3.27(dd,J=9.7,5.4Hz,1H),2.99(t,J=10.6Hz,1H),2.67(d,J=2.2Hz,1H),2.52–2.27(m,4H),2.14–2.04(m,2H),1.92(d,J=8.4Hz,1H),1.89(s,3H),1.82–1.70(m,2H),1.64–1.48(m,2H),1.30–1.25(m,1H).
1H NMR(600MHz,CDCl3)δ4.60(d,J=13.7Hz,1H),4.52(d,J=13.8Hz,1H),4.05(d,J=13.0Hz,1H),3.41(d,J=11.2Hz,1H),3.00(d,J=13.1Hz,1H),2.79(t,J=15.6Hz,2H),2.18(dd,J=23.4,13.3Hz,1H),1.92(s,1H),1.83(dd,J=25.6,11.7Hz,2H),1.69–1.59(m,4H),1.41(d,J=19.6Hz,9H),1.17(d,J=25.6Hz,6H).
1H NMR(400MHz,DMSO)δ10.40-9.10(m,2H),7.74(br,1H),3.52(d,J=13.0Hz,1H),3.37(d,J=12.2Hz,1H),3.11(s,1H),2.99(s,1H),2.88(d,J=11.2Hz,1H),2.36(d,J=9.8Hz,1H),2.26(d,J=11.3Hz,1H),2.03(d,J=12.2Hz,2H),1.89(d,J=9.6Hz,2H),1.71(dd,J=15.0,12.2Hz,2H),1.68–1.61(m,1H),1.58(d,J=11.1Hz,1H),1.41(d,J=12.2Hz,1H),1.16(td,J=13.2,4.0Hz,1H),1.01(d,J=9.0Hz,3H),0.84(s,3H).
1H NMR(400MHz,CDCl3)δ4.70(d,J=13.5Hz,1H),4.62(dd,J=13.8,1.4Hz,1H),4.14(dd,J=16.3,4.4Hz,1H),3.45(d,J=11.4Hz,1H),3.03(dd,J=13.3,2.3Hz,1H),2.84–2.80(m,1H),2.79–2.76(m,1H),2.35(td,J=12.8,6.5Hz,1H),2.23(ddd,J=25.3,13.3,3.1Hz,1H),2.01–1.73(m,6H),1.59(d,J=20.4Hz,1H),1.41(s,9H),1.13(d,J=7.0Hz,3H).
1H NMR(400MHz,CDCl3)δ7.26(s,5H),7.18–7.11(m,3H),7.06–7.01(m,2H),4.72(d,J=13.8Hz,1H),4.57(d,J=13.7Hz,1H),4.13(dd,J=9.9,6.9Hz,1H),3.52(d,J=12.8Hz,1H),3.16(d,J=13.7Hz,1H),3.07(s,1H),3.03–2.96(m,2H),2.72(dd,J=27.5,13.1Hz,2H),2.33(dd,J=24.8,11.9Hz,1H),2.21(d,J=12.8Hz,1H),1.89(s,1H),1.83–1.76(m,1H),1.68(d,J=12.6Hz,1H),1.56(s,2H),1.50(dd,J=13.3,2.8Hz,1H),1.41(s,9H),1.36(s,1H).
1H NMR(400MHz,CDCl3)δ7.23(d,J=7.5Hz,2H),7.17(d,J=7.2Hz,1H),7.12(t,J=7.1Hz,2H),4.76(d,J=13.6Hz,1H),4.57(d,J=13.8Hz,1H),4.16(d,J=13.4Hz,1H),3.48(dd,J=12.6,2.5Hz,1H),3.41(d,J=11.6Hz,1H),3.03(dd,J=13.2,2.2Hz,1H),2.82(d,J=13.7Hz,1H),2.76(dd,J=13.9,1.9Hz,1H),2.56–2.40(m,2H),2.10(td,J=15.1,3.6Hz,1H),1.94–1.80(m,3H),1.78–1.68(m,2H),1.59(s,1H),1.45(s,9H),1.36–1.24(m,1H).
1H NMR(400MHz,CDCl3)δ10.94(br,1H),7.30-7.24(m,2H),7.18(t,J=7.3Hz,1H),7.12(d,J=7.0Hz,2H),3.62(d,J=13.2Hz,1H),3.43(d,J=10.2Hz,2H),3.28(d,J=12.8Hz,1H),3.13(d,J=13.0Hz,1H),2.91(d,J=11.6Hz,1H),2.72(d,J=10.2Hz,1H),2.53–2.40(m,3H),2.23(d,J=10.7Hz,1H),2.08(s,1H),2.00–1.89(m,2H),1.81(d,J=12.4Hz,3H),1.64–1.49(m,3H),1.02(qd,J=12.4,4.3Hz,1H).
1H NMR(600MHz,CDCl3)δ11.24(br,1H),7.85(br,1H),7.32(t,J=7.4Hz,2H),7.27(d,J=6.4Hz,1H),7.23(dd,J=13.2,6.3Hz,2H),7.21–7.18(m,1H),7.15(d,J=7.1Hz,2H),6.98(d,J=6.9Hz,2H),3.66(d,J=13.3Hz,1H),3.53(d,J=12.8Hz,1H),3.33(s,1H),3.20(s,1H),2.92(dd,J=12.6,6.8Hz,2H),2.80(d,J=13.7Hz,1H),2.60–2.54(m,1H),2.51–2.45(m,2H),2.35(t,J=12.5Hz,1H),2.07(s,1H),2.01(d,J=11.8Hz,1H),1.92(ddd,J=15.1,12.8,3.0Hz,2H),1.75(d,J=11.6Hz,2H),1.69(d,J=12.9Hz,1H),1.59(d,J=13.1Hz,1H),1.42–1.30(m,2H).
13C NMR(151MHz,CDCl3)δ138.11(s),137.18(s),131.01(s),130.62(s),128.25(s),127.82(s),126.56(s),126.24(s),65.37(s),64.02(s),60.77(s),49.86(s),45.98(s),45.27(s),42.81(s),37.34(s),32.17(s),31.33(s),30.50(s),27.21(s),25.92(s).
1H NMR(400MHz,CDCl3)δ7.23(dt,J=4.4,2.1Hz,3H),7.03(dd,J=6.6,2.6Hz,2H),6.91(dd,J=9.0,6.9Hz,1H),6.39(dd,J=9.0,1.3Hz,1H),4.83(dd,J=6.9,1.2Hz,1H),4.18(d,J=15.4Hz,1H),4.12(q,J=6.9Hz,1H),4.06(d,J=2.0Hz,1H),3.93(dd,J=15.1,7.1Hz,1H),3.31–3.25(m,1H),3.16(dd,J=11.2,1.0Hz,1H),2.89(s,1H),2.45(s,1H),2.17–2.08(m,2H).
测试例
环状N-磺酰亚胺不对称芳基化的一般步骤:
用亚胺(0.2毫摩尔)、芳基硼酸(2当量)、Pd(TFA)2(10mol%)和二胺配体(手性二胺类化合物)(10mol%)充入密封管,然后用水(1.6毫升)。反应用搅拌加热24小时,冷却至室温后,将反应混合物转移到乙酸乙酯(EtOAc)15毫升的分离漏斗中。有机层用氯化钠水溶液洗涤、干燥和浓缩。残留物用闪蒸柱(石油醚/乙酸乙酯,5:1)纯化。表1列出了醛亚胺(143a)与不同的芳基硼酸反应的结果,同时,也以相同的方式得到了化合物144aa。
表1
由表1可以看出,在大多数情况下,24h后都能获得较高的产率和较好的ee值,尤其是含给电子基的芳基硼酸。更多的缺电子芳基硼酸(如噻吩硼酸)提供了较低的ee值,也收集到了醛亚胺的水解产物(143a)。此外,间位或对位含取代基的芳基硼酸的ee值明显高于邻位含取代基的芳基硼酸。
对不同位置具有不同取代基的醛亚胺进行了考察。如下表2所示。
表2
[a]反应分别在100℃,90℃和80℃下进行。
由表2可以看出,含给电子基的醛亚胺,特别是位于143b的6位的醛亚胺(单取代的亚胺)具有较高的产率和较好的对映选择性,而含吸电子基团的醛亚胺更有可能发生水解反应生成相应的水杨醛。因此,在亚胺加成之前,应增加芳基硼酸用量或醛亚胺容易发生环状裂解。而6-硝基取代醛亚胺在较低温度下水解容易,不能进行芳基化反应,也不能生成芳基化产物。
对以下手性二胺类化合物进行了效果测试,得到了对应上述反应(以化合物143a和PhB(OH)2作为原料)的反应立体选择性,如表3所示。
表3
1H NMR(400MHz,CDCl3)δ7.33(t,J=7.8Hz,1H),7.25(d,J=8.2Hz,2H),7.09(t,J=7.9Hz,2H),6.94(d,J=8.6Hz,2H),6.84(d,J=7.8Hz,1H),5.87(d,J=8.4Hz,1H),4.56(d,J=8.5Hz,1H),3.84(s,3H);13C NMR(101MHz,CDCl3)δ160.6,151.6,130.2,130.1,129.9,128.8,125.4,122.4,119.0,114.9,61.7,55.6.HPLC[Daicel Chiralpak IC,正己烷/i-PrOH=90/10,220nm,1.5mL/min.tR1=18.38min(主产物),tR2=31.82min(次产物)];ee=91%.
1H NMR(400MHz,CDCl3)δ7.48–7.41(m,3H),7.37–7.30(m,3H),7.11-7.08(m,2H),6.83(d,J=7.6Hz,1H),5.91(d,J=8.7Hz,1H),4.67(d,J=8.5Hz,1H);13C NMR(101MHz,CDCl3)δ151.6,137.9,129.8,129.6,129.5,128.8,128.6,125.3,122.0,118.9,62.0.HPLC[Daicel Chiralpak IC,正己烷/i-PrOH=90/10,220nm,1.0mL/min.tR1=15.18min(主产物),tR2=17.68min(次产物)];ee=76%.
1H NMR(400MHz,CDCl3)δ7.46–7.40(m,1H),7.35(dd,J=7.5,1.6Hz,1H),7.28(ddd,J=8.8,4.8,0.7Hz,1H),7.04(dtd,J=16.9,7.6,1.0Hz,3H),6.97(d,J=8.2Hz,1H),6.68(d,J=7.8Hz,1H),5.91(d,J=10.2Hz,1H),5.70(d,J=10.2Hz,1H),3.68(s,3H);13CNMR(101MHz,CDCl3)δ157.3,151.2,131.3,131.0,129.3,126.9,125.0,124.6,122.8,121.4,118.4,112.1,60.4,55.7.HPLC[Daicel Chiralpak IC,正己烷/i-PrOH=90/10,220nm,1.0mL/min.tR1=19.77min(主产物),tR2=28.66min(次产物)];ee=76%.
1H NMR(400MHz,CDCl3)δ7.37–7.29(m,2H),7.12–7.06(m,1H),7.03(dd,J=8.3,1.0Hz,1H),6.98–6.94(m,1H),6.91(d,J=7.6Hz,1H),6.85(dd,J=7.7,5.5Hz,2H),5.85(d,J=8.7Hz,1H),4.91(d,J=8.7Hz,1H),3.80(s,3H);13C NMR(101MHz,CDCl3)δ160.3,151.4,139.2,130.6,129.7,128.6,125.3,122.0,121.0,118.8,115.0,114.5,61.9,55.4.HPLC[Daicel Chiralpak IC,正己烷/i-PrOH=90/10,220nm,1.0mL/min.tR1=23.05min(主产物),tR2=27.09min(次产物)];ee=93%.
1H NMR(400MHz,CDCl3)δ7.35(ddd,J=8.2,7.5,0.7Hz,1H),7.29–7.22(m,4H),7.17–7.04(m,2H),6.86(d,J=7.8Hz,1H),5.89(d,J=8.7Hz,1H),4.80(d,J=8.7Hz,1H),2.42(s,3H);13C NMR(101MHz,CDCl3)δ151.6,139.7,135.0,130.2,129.8,128.8,128.7,125.3,122.4,118.9,61.9,21.4.HPLC[Daicel Chiralpak IC,正己烷/i-PrOH=90/10,220nm,1.5mL/min.tR1=15.76min(主产物),tR2=17.50min(次产物)];ee=91%.
1H NMR(400MHz,CDCl3)δ7.35(ddd,J=8.7,5.5,1.5Hz,3H),7.18–7.06(m,4H),6.82(d,J=7.8Hz,1H),5.91(d,J=8.5Hz,1H),4.71(d,J=8.4Hz,1H);13C NMR(101MHz,CDCl3)δ163.3(d,J=249.7Hz),151.6,133.9(d,J=3.4Hz),130.9(d,J=8.5Hz),130.1,128.6,125.5,121.8,119.1,116.7(d,J=21.8Hz),61.4.HPLC[Daicel Chiralpak IC,正己烷/i-PrOH=90/10,220nm,1.5mL/min.tR1=13.27min(主产物),tR2=17.71min(次产物)];ee=96%.
1H NMR(400MHz,CDCl3)δ7.51–7.45(m,1H),7.39(ddd,J=7.9,6.5,2.7Hz,1H),7.37–7.29(m,3H),7.12–7.08(m,2H),6.81–6.75(m,1H),6.30(d,J=9.2Hz,1H),5.07(d,J=9.1Hz,1H);13C NMR(101MHz,CDCl3)δ151.5,135.0,134.1,131.3,130.9,130.7,129.8,127.8,127.7,125.4,121.2,118.9,59.5.HPLC[Daicel Chiralpak IC,正己烷/i-PrOH=90/10,220nm,1.0mL/min.tR1=11.76min(次产物),tR2=12.28min(主产物)];ee=78%.
1H NMR(400MHz,CDCl3)δ7.45–7.31(m,4H),7.25(d,J=7.7Hz,1H),7.13(t,J=7.4Hz,1H),7.06(d,J=8.3Hz,1H),6.83(d,J=7.8Hz,1H),5.86(d,J=8.5Hz,1H),4.93(d,J=8.5Hz,1H);13C NMR(101MHz,CDCl3)δ151.5,139.7,135.3,130.8,130.0,129.8,129.1,128.4,127.1,125.5,121.3,119.0,61.4.HPLC[Daicel Chiralpak IC,正己烷/i-PrOH=90/10,220nm,1.0mL/min.tR1=16.79min(次产物),tR2=23.09min(主产物)];ee=90%.
1H NMR(400MHz,CDCl3)δ7.45–7.39(m,2H),7.38–7.32(m,1H),7.32–7.27(m,2H),7.15–7.07(m,2H),6.81(d,J=7.8Hz,1H),5.90(d,J=8.5Hz,1H),4.68(d,J=8.4Hz,1H);13C NMR(101MHz,CDCl3)δ151.4,136.3,135.6,130.3,130.0,129.7,128.5,125.4,121.5,119.0,61.2.HPLC[Daicel Chiralpak IC,正己烷/i-PrOH=90/10,220nm,1.0mL/min.tR1=13.82min(主产物),tR2=22.08min(次产物)];ee=94%.
1H NMR(400MHz,CDCl3)δ7.61–7.53(m,2H),7.39–7.30(m,1H),7.25–7.21(m,2H),7.11(td,J=7.7,1.1Hz,1H),7.07(dd,J=8.3,0.9Hz,1H),6.81(d,J=7.8Hz,1H),5.87(d,J=8.6Hz,1H),4.82(d,J=8.5Hz,1H);13C NMR(101MHz,CDCl3)δ151.5,136.8,132.6,130.6,130.0,128.5,125.4,123.8,121.4,119.0,61.3.HPLC[Daicel Chiralpak IC,正己烷/i-PrOH=90/10,220nm,1.0mL/min.tR1=14.61min(主产物),tR2=23.80min(次产物)];ee=85%.
1H NMR(400MHz,CDCl3)δ7.65(d,J=8.2Hz,2H),7.60(d,J=7.3Hz,2H),7.47(t,J=7.5Hz,2H),7.43–7.39(m,3H),7.38–7.32(m,1H),7.11(dd,J=16.4,8.0Hz,2H),6.90(d,J=7.8Hz,1H),5.96(d,J=8.6Hz,1H),4.81(t,J=7.8Hz,1H);13C NMR(101MHz,CDCl3)δ151.6,142.5,140.1,136.7,129.8,129.3,129.0,128.7,128.1,127.9,127.2,125.3,122.0,118.9,61.7.HPLC[Daicel Chiralpak IC,正己烷/i-PrOH=90/10,220nm,1.0mL/min.tR1=22.87min(主产物),tR2=28.14min(次产物)];ee=76%.
1H NMR(400MHz,CDCl3)δ7.41(dd,J=5.1,0.8Hz,1H),7.35(t,J=7.7Hz,1H),7.19–7.11(m,2H),7.09–7.01(m,3H),6.21(d,J=8.6Hz,1H),4.88(d,J=8.5Hz,1H);13CNMR(101MHz,CDCl3)δ151.0,140.1,130.3,129.0,128.6,127.7,127.4,125.4,121.7,119.0,57.0.HPLC[Daicel Chiralpak IC,正己烷/i-PrOH=90/10,220nm,1.5mL/min.tR1=15.91min(主产物),tR2=17.32min(次产物)];ee=66%.
1H NMR(400MHz,CDCl3)δ7.88(ddd,J=10.0,9.3,6.5Hz,4H),7.61–7.52(m,2H),7.35(ddd,J=8.1,3.5,1.6Hz,2H),7.15–7.05(m,2H),6.85(d,J=7.8Hz,1H),6.08(d,J=8.5Hz,1H),4.79(d,J=8.5Hz,1H);13C NMR(101MHz,CDCl3)δ151.7,135.0,133.7,133.3,123.0,129.9,129.0,128.8,128.3,128.0,127.4,127.2,125.5,125.3,122.1,119.1,62.4.HPLC[Daicel Chiralpak IC,正己烷/i-PrOH=90/10,220nm,1.5mL/min.tR1=20.58min(主产物),tR2=39.2min(次产物)];白色固体,ee=86%.
1H NMR(400MHz,CDCl3)δ7.49–7.40(m,3H),7.38–7.30(m,2H),7.11(ddd,J=8.4,1.4,0.6Hz,1H),6.96(d,J=8.4Hz,1H),6.59(s,1H),5.85(d,J=8.6Hz,1H),4.62(d,J=8.5Hz,1H),2.20(s,3H);13C NMR(101MHz,CDCl3)δ144.8,133.3,130.4,125.7,124.8,124.8,124.1,123.9,116.8,113.9,57.3,16.0.HPLC[Daicel Chiralpak IC,正己烷/i-PrOH=90/10,220nm,1mL/min.tR1=19.10min(主产物),tR2=21.45min(次产物)];白色固体,ee=94%.
1H NMR(400MHz,CDCl3)δ7.47–7.40(m,3H),7.39–7.32(m,2H),7.17(dd,J=6.8,0.6Hz,1H),6.97(t,J=7.6Hz,1H),6.63(d,J=7.8Hz,1H),5.87(d,J=8.7Hz,1H),5.00(d,J=8.6Hz,1H),2.25(s,3H);13C NMR(101MHz,CDCl3)δ150.0,138.1,131.1,129.5,129.4,128.9,128.1,126.1,124.6,121.9,62.0,15.5.HPLC[Daicel Chiralpak IC,正己烷/i-PrOH=90/10,220nm,1mL/min.tR1=13.94min(主产物),tR2=15.69min(次产物)];白色固体,ee=79%.
1H NMR(600MHz,CDCl3)δ7.46–7.39(m,3H),7.33(dd,J=6.7,2.9Hz,2H),6.90(d,J=8.0Hz,1H),6.88(s,1H),6.69(d,J=8.0Hz,1H),5.86(d,J=8.6Hz,1H),4.67(d,J=8.6Hz,1H);13C NMR(151MHz,CDCl3)δ151.4,140.3,138.1,129.5,129.4,128.8,128.3,126.2,119.1,119.0,61.9,21.0.HPLC[Daicel Chiralpak IC,正己烷/i-PrOH=90/10,220nm,1mL/min.tR1=19.16min(主产物),tR2=20.16min(次产物)];白色固体,ee=80%.
1H NMR(400MHz,CDCl3)δ7.51–7.42(m,4H),7.37–7.30(m,2H),6.99–6.93(m,2H),5.86(d,J=8.7Hz,1H),4.76(d,J=8.6Hz,1H);13C NMR(101MHz,CDCl3)δ156.7,145.5,137.9,129.8,129.7,128.9,122.9,120.0,115.4,113.4,62.3,55.8.HPLC[DaicelChiralpak IC,正己烷/i-PrOH=90/10,220nm,1.5mL/min.tR1=27.4min(主产物),tR2=30.75min(次产物)];白色固体,ee=82%.
1H NMR(400MHz,CDCl3)δ7.56–7.40(m,4H),7.37–7.29(m,2H),6.95(d,J=8.8Hz,2H),5.85(d,J=8.7Hz,1H),4.87(d,J=8.7Hz,1H);13C NMR(101MHz,CDCl3)δ150.6,137.0,132.9,131.2,130.0,129.8,128.8,124.0,120.7,118.0,61.7.HPLC[Daicel ChiralpakIC,正己烷/i-PrOH=90/10,220nm,1.5mL/min.tR1=19.69min(主产物),tR2=22.5min(次产物)];白色固体,ee=86%.
1H NMR(400MHz,CDCl3)δ7.50–7.44(m,3H),7.37–7.28(m,3H),7.05(d,J=8.8Hz,1H),6.81(d,J=1.7Hz,1H),5.87(d,J=8.6Hz,1H),4.65(d,J=8.5Hz,1H);13C NMR(101MHz,CDCl3)δ150.0,137.0,130.6,129.9,129.9,129.7,128.8,128.3,123.7,120.3,61.8.HPLC[Daicel Chiralpak IC,正己烷/i-PrOH=90/10,220nm,1mL/min.tR1=11.16min(主产物),tR2=12.65min(次产物)];白色固体,ee=85%.
1H NMR(400MHz,DMSO-d6)δ9.20(d,J=6.0Hz,1H),8.09(d,J=9.0Hz,1H),8.00(d,J=7.9Hz,1H),7.50–7.37(m,4H),7.33–7.24(m,3H),7.17(dd,J=7.0,2.1Hz,2H),6.49(d,J=5.8Hz,1H);13C NMR(101MHz,DMSO-d6)δ150.2,139.4,131.5,131.0,130.4,129.2,128.6,128.3,127.9,126.0,124.7,118.8,114.5,58.4.HPLC[Daicel Chiralpak IC,正己烷/i-PrOH=90/10,220nm,1mL/min.tR1=20.34min(次产物),tR2=22.7min(主产物)];ee=98%。
以上详细描述了本发明的优选实施方式,但是,本发明并不限于此。在本发明的技术构思范围内,可以对本发明的技术方案进行多种简单变型,包括各个技术特征以任何其它的合适方式进行组合,这些简单变型和组合同样应当视为本发明所公开的内容,均属于本发明的保护范围。
Claims (6)
1.一种手性二胺类化合物,其特征在于,该化合物具有式C所示结构,
,
式C中,R1为H;
R2和R6均为H;
R13为H;
R14选自C1-C20的烷基或C1-C20的卤代烷基。
2.根据权利要求1所述的化合物,其中,式C中,R14为C1-C4的烷基。
3.一种手性二胺类化合物,其特征在于,所述化合物选自以下具体化合物中的一种:
。
4.一种亚胺不对称加成的方法,其特征在于,该方法包括:在过渡金属催化剂与权利要求1-3中任意一项所述的化合物的存在下,使所述亚胺与加成试剂接触;
其中,所述过渡金属催化剂包括过渡金属,所述过渡金属选自Pd、Rh、Ru和Cu中的至少一种;所述加成试剂选自芳基硼化合物ArB(OH)2;所述亚胺如式D所示;所述不对称加成的反应的产物如式E所示:
式D;式E:
其中,所述式E选自以下化学结构:
。
5.根据权利要求4所述的方法,其中,所述接触的条件包括:温度为50-120℃;时间为5-30h。
6.根据权利要求5所述的方法,其中,所述接触的条件包括:温度为80-110℃;时间为10-24h。
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