CN106008556B - Yi Dushaban and its isomers separation method - Google Patents
Yi Dushaban and its isomers separation method Download PDFInfo
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- CN106008556B CN106008556B CN201610354097.5A CN201610354097A CN106008556B CN 106008556 B CN106008556 B CN 106008556B CN 201610354097 A CN201610354097 A CN 201610354097A CN 106008556 B CN106008556 B CN 106008556B
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- dushaban
- ydb
- ethanol
- mixture
- isopropanol
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- 238000000926 separation method Methods 0.000 title claims abstract description 78
- 238000000034 method Methods 0.000 claims abstract description 27
- 238000013507 mapping Methods 0.000 claims abstract description 17
- 238000004587 chromatography analysis Methods 0.000 claims abstract description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000000945 filler Substances 0.000 claims abstract description 5
- 239000000741 silica gel Substances 0.000 claims abstract description 5
- 229910002027 silica gel Inorganic materials 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 57
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 55
- -1 n-hexane-ethanol-isopropanol-triethylamine Chemical compound 0.000 claims description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 32
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 28
- 238000001514 detection method Methods 0.000 claims description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 13
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 11
- 239000003208 petroleum Substances 0.000 claims description 11
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 8
- 238000012360 testing method Methods 0.000 claims description 8
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 5
- 238000010828 elution Methods 0.000 claims description 3
- SBTVLCPCSXMWIQ-UHFFFAOYSA-N (3,5-dimethylphenyl) carbamate Chemical group CC1=CC(C)=CC(OC(N)=O)=C1 SBTVLCPCSXMWIQ-UHFFFAOYSA-N 0.000 claims description 2
- XLGFSTGVRXACMF-UHFFFAOYSA-N C(C)NCC.C(C)(C)O.C(C)O.CCCCC Chemical compound C(C)NCC.C(C)(C)O.C(C)O.CCCCC XLGFSTGVRXACMF-UHFFFAOYSA-N 0.000 claims description 2
- HXWKNXRHIULQAV-UHFFFAOYSA-N ethanol N-ethylethanamine hexane propan-2-ol Chemical compound C(C)NCC.C(C)(C)O.C(C)O.CCCCCC HXWKNXRHIULQAV-UHFFFAOYSA-N 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000007689 inspection Methods 0.000 claims 1
- IJDIONYCFIJYLK-UHFFFAOYSA-N n,n-diethylethanamine;propan-2-ol Chemical compound CC(C)O.CCN(CC)CC IJDIONYCFIJYLK-UHFFFAOYSA-N 0.000 claims 1
- 239000011259 mixed solution Substances 0.000 abstract description 9
- 239000002798 polar solvent Substances 0.000 abstract description 6
- CMXPERZAMAQXSF-UHFFFAOYSA-M sodium;1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate;1,8-dihydroxyanthracene-9,10-dione Chemical compound [Na+].O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=CC=C2O.CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC CMXPERZAMAQXSF-UHFFFAOYSA-M 0.000 abstract description 3
- GOBGXRBYMHQOJI-UHFFFAOYSA-N (3,4-dimethylphenyl) carbamate Chemical group CC1=CC=C(OC(N)=O)C=C1C GOBGXRBYMHQOJI-UHFFFAOYSA-N 0.000 abstract 1
- 229920000856 Amylose Polymers 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 90
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 87
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 53
- 239000000243 solution Substances 0.000 description 44
- 239000007788 liquid Substances 0.000 description 41
- 239000012074 organic phase Substances 0.000 description 40
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 35
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 32
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 32
- 239000008346 aqueous phase Substances 0.000 description 31
- 238000006243 chemical reaction Methods 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 238000001035 drying Methods 0.000 description 26
- 239000012071 phase Substances 0.000 description 26
- 239000012535 impurity Substances 0.000 description 25
- 239000000047 product Substances 0.000 description 25
- 238000000605 extraction Methods 0.000 description 24
- 235000019441 ethanol Nutrition 0.000 description 22
- 238000003756 stirring Methods 0.000 description 22
- WJRKNLONLOMALV-UHFFFAOYSA-N 5-chloropyridine Chemical compound ClC1=C=NC=C[CH]1 WJRKNLONLOMALV-UHFFFAOYSA-N 0.000 description 21
- 238000005160 1H NMR spectroscopy Methods 0.000 description 20
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
- 238000004440 column chromatography Methods 0.000 description 19
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 18
- 238000003786 synthesis reaction Methods 0.000 description 18
- BFJMHTOBRRZELQ-UHFFFAOYSA-N 3-iodo-2h-pyrazolo[3,4-c]pyridine Chemical compound N1=CC=C2C(I)=NNC2=C1 BFJMHTOBRRZELQ-UHFFFAOYSA-N 0.000 description 17
- 230000015572 biosynthetic process Effects 0.000 description 17
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 16
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 16
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 16
- 239000012043 crude product Substances 0.000 description 16
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 16
- 238000010792 warming Methods 0.000 description 14
- 239000007787 solid Substances 0.000 description 13
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 12
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 12
- 239000012452 mother liquor Substances 0.000 description 12
- 238000010521 absorption reaction Methods 0.000 description 11
- 230000014759 maintenance of location Effects 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 9
- 229910052739 hydrogen Inorganic materials 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 8
- 239000012298 atmosphere Substances 0.000 description 8
- 239000012230 colorless oil Substances 0.000 description 8
- 238000005360 mashing Methods 0.000 description 8
- 238000001819 mass spectrum Methods 0.000 description 8
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 239000013558 reference substance Substances 0.000 description 7
- 229910052708 sodium Inorganic materials 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 6
- 230000006837 decompression Effects 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- SIOXPEMLGUPBBT-UHFFFAOYSA-N Picolinic acid Natural products OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 5
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000002027 dichloromethane extract Substances 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 0 *[C@@]1CC=CCC1 Chemical compound *[C@@]1CC=CCC1 0.000 description 4
- PWRBCZZQRRPXAB-UHFFFAOYSA-N 3-chloropyridine Chemical class ClC1=CC=CN=C1 PWRBCZZQRRPXAB-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 4
- OQQXGCLLMDQESN-UHFFFAOYSA-N cyclohexylcarbamic acid Chemical compound OC(=O)NC1CCCCC1 OQQXGCLLMDQESN-UHFFFAOYSA-N 0.000 description 4
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 4
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 4
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 235000019799 monosodium phosphate Nutrition 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical class [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 4
- 239000008247 solid mixture Substances 0.000 description 4
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- RABBMOYULJIAFU-UHFFFAOYSA-N 1h-pyrrole;thiophene Chemical class C=1C=CNC=1.C=1C=CSC=1 RABBMOYULJIAFU-UHFFFAOYSA-N 0.000 description 3
- HNNQYHFROJDYHQ-UHFFFAOYSA-N 3-(4-ethylcyclohexyl)propanoic acid 3-(3-ethylcyclopentyl)propanoic acid Chemical compound CCC1CCC(CCC(O)=O)C1.CCC1CCC(CCC(O)=O)CC1 HNNQYHFROJDYHQ-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical class CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 206010003658 Atrial Fibrillation Diseases 0.000 description 2
- HGVDHZBSSITLCT-JLJPHGGASA-N Edoxaban Chemical compound N([C@H]1CC[C@@H](C[C@H]1NC(=O)C=1SC=2CN(C)CCC=2N=1)C(=O)N(C)C)C(=O)C(=O)NC1=CC=C(Cl)C=N1 HGVDHZBSSITLCT-JLJPHGGASA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 239000005703 Trimethylamine hydrochloride Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical class [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
- SZYJELPVAFJOGJ-UHFFFAOYSA-N trimethylamine hydrochloride Chemical compound Cl.CN(C)C SZYJELPVAFJOGJ-UHFFFAOYSA-N 0.000 description 2
- KFINJSDRAOOEBN-UHFFFAOYSA-N C(C)N(CC)CC.C(C)(C)O.C(C)O.CCCCC Chemical compound C(C)N(CC)CC.C(C)(C)O.C(C)O.CCCCC KFINJSDRAOOEBN-UHFFFAOYSA-N 0.000 description 1
- QHIDLFOVHXQJFR-AXDLQRQNSA-N C=C/C(/Cl)=C\C=C(/N)\NC(C(NC1CCCCC1)=O)=O Chemical compound C=C/C(/Cl)=C\C=C(/N)\NC(C(NC1CCCCC1)=O)=O QHIDLFOVHXQJFR-AXDLQRQNSA-N 0.000 description 1
- HTUZEXXFHNZTOT-ACBHZAAOSA-N CC(C)(C)OC(N[C@@H](C1)C(CNC(OCc2ccccc2)=O)CCC1C(N(C)C)=N)=O Chemical compound CC(C)(C)OC(N[C@@H](C1)C(CNC(OCc2ccccc2)=O)CCC1C(N(C)C)=N)=O HTUZEXXFHNZTOT-ACBHZAAOSA-N 0.000 description 1
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N CCc1ccccc1 Chemical compound CCc1ccccc1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 1
- BFIQOLYZEGTFTE-LWOYVPTGSA-N CN(C)C([C@H](CC1)CC[C@@H]1NC(C(Nc(nc1)ccc1Cl)=O)O)=O Chemical compound CN(C)C([C@H](CC1)CC[C@@H]1NC(C(Nc(nc1)ccc1Cl)=O)O)=O BFIQOLYZEGTFTE-LWOYVPTGSA-N 0.000 description 1
- XFDYINWIFVDMOQ-LOWVWBTDSA-N C[C@@H](C[C@@H](CC1)C(N(C)C)=O)[C@H]1NC(C(Nc(cc1)ncc1Cl)=O)=O Chemical compound C[C@@H](C[C@@H](CC1)C(N(C)C)=O)[C@H]1NC(C(Nc(cc1)ncc1Cl)=O)=O XFDYINWIFVDMOQ-LOWVWBTDSA-N 0.000 description 1
- 102100029117 Coagulation factor X Human genes 0.000 description 1
- 108010014173 Factor X Proteins 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- YIKSCQDJHCMVMK-UHFFFAOYSA-N Oxamide Chemical class NC(=O)C(N)=O YIKSCQDJHCMVMK-UHFFFAOYSA-N 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 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
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229960000622 edoxaban Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000003073 embolic effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000010829 isocratic elution Methods 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- PUUZLWLFYQFYCF-UHFFFAOYSA-N n-ethylethanamine;hexane;propan-2-ol Chemical compound CC(C)O.CCNCC.CCCCCC PUUZLWLFYQFYCF-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 208000021090 palsy Diseases 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 229940011622 savaysa Drugs 0.000 description 1
- 150000003384 small molecules Chemical group 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
- G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
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Abstract
The present invention provides a kind of method that Yi Dushaban is isolated and purified using chromatography, and the separation method is chromatography, and its chromatographic condition includes：Filler is amylose three (3,5 xylyl carbamate) bonded silica gel, and mobile phase is selected from the mixed solution comprising non-polar solven and polar solvent.Yi Dushaban and its seven kinds of mappings, non-corresponding isomers can be separated from each other, be had the characteristics that quick, easy, efficient by the selection of chromatographic condition by the method for the present invention simultaneously.
Description
Technical field
The present invention relates to a kind of method analyzed Yi Dushaban and its isomer impurities, and in particular to uses chromatography
The method separated to Yi Dushaban and its mapping and diastereoisomer, belongs to medicinal chemistry art.
Background technology
Yi Dushaban (edoxaban, trade name：Savaysa) it is small molecule mouth that Japanese Sankyo Co. develops
Anticoagulation is taken, is Stuart factor (FXa) retarding agent, January 8 in 2015, the approval of Nikkei U.S. FDA listed, for reducing non-valve
The palsy of property auricular fibrillation (atrial fibrillation) patient and systemic embolic risk.Entitled N- (5- chloropyridine -2- bases) N'- of its chemistry
[(1S, 2R, 4S) -4- (N, N- dimethylcarbamoyl)] -2- [(5- methyl -4,5,6,7- tetrahydrochysene -1,3- thiazoles simultaneously [5,4c] -
Pyridine-2-carboxamide base) cyclohexyl] oxamides.Yi Dushaban obtains through chemical synthesis, and its molecule has hand respectively at 1,2,4
Property center, 7 kinds of mappings and diastereoisomer can be formed in theory, its structural formula distinguishes (wherein Yi Dusha as shown in table 1 below
Class is SRS configuration of compound)：
The Yi Dushaban of table 1 and its seven kinds of isomer impurities
Yi Dushaban is as medicine, it is necessary to which there have accurate analysis method to be different to detect 7 kinds of mappings, diastereomeric in Yi Dushaban
The content of structure body.Have document report Yi Dushaban mappings, the synthetic method of diastereoisomer, such as United States Patent (USP) at present
Yi Dushaban and its 7 kinds of mappings, the synthetic method of diastereoisomer are reported in US2012/0053349A1, and discloses two
The method that kind uses high performance liquid chromatography separation Yi Dushaban and its impurity, but this method can only be such that impurity separates two-by-two, and
Yi Dushaban and its 7 kinds of isomer impurities can not be made disposably to be separated from each other.And the present invention is right for Yi Dushaban and its 7 kinds
Reflect, the mixture of diastereoisomer, have studied its separation method, can use a kind of chromatographic condition realize make Yi Dushaban and
Its 7 kinds of mappings, diastereoisomers separate simultaneously.
The content of the invention
It is an object of the invention to provide a kind of quick, easy, efficient Yi Dushaban and its mapping, diastereoisomer
Chromatography separating method.
To achieve the above object, the technical scheme is that：
A kind of Yi Dushaban and its isomers separation method, it is characterised in that：The separation method is chromatography, its color
Spectral condition includes：Filler is amylose-three (3,5- xylyl carbamate) bonded silica gel, mobile phase be selected from comprising
The mixed solution of non-polar solven and polar solvent.
According to the separation method of the present invention, the chromatogram is preferably high performance liquid chromatography, elution can be isocratic elution or
Gradient elution.
According to the separation method of the present invention, the non-polar solven can be in n-hexane, petroleum ether, pentane etc.
A kind of or its mixture.
According to the separation method of the present invention, the polar solvent can be in alcohols solvent, such as ethanol, isopropanol etc.
A kind of or its mixture.Preferably, the polar solvent can be the mixture of alcohols solvent, such as the mixing of ethanol and isopropanol
Thing.
According to the separation method of the present invention, organic amine can also be included in the mobile phase, the organic amine can be selected from
One kind or its mixture in diethylamine, triethylamine etc..
According to the separation method of the present invention, the mobile phase can be the mixed solution comprising n-hexane and polar solvent.
According to the separation method of the present invention, the mobile phase can be mixed comprising n-hexane, polar solvent and diethylamine
Close solution.
According to the separation method of the present invention, the mobile phase is also selected from such as A, B, C and D mixture, wherein A choosings
From n-hexane and/or petroleum ether and/or pentane, B is selected from ethanol, and C is selected from isopropanol, and D is selected from diethylamine and/or triethylamine.
As example, the mobile phase can be selected from n-hexane and/or petroleum ether and/or pentane -- and ethanol-isopropanol-
The mixture of diethylamine and/or triethylamine, it is selected from mixture, the n-hexane-second of n-hexane-ethanol-isopropanol-diethylamine
The mixture of alcohol-isopropanol-triethylamine, the mixture of petroleum ether-ethanol-isopropanol-diethylamine, petroleum ether-ethanol-isopropyl
The mixture of alcohol-triethylamine, the mixture of pentane-ethanol-isopropanol-diethylamine, pentane-ethanol-isopropanol-triethylamine
Mixture.
According to the separation method of the present invention, the volume ratio of A, B, C, D each component can be 40 in the flowing phase mixture
~70:10~50:1~40:0.1~0.5, preferably 50~65:10~45:1~35:0.1~0.3.As example, A, B, C, D
The volume ratio of each component can be 60：20：20：0.2；55：30：15：0.2；55：35：10：0.2；55：40：5：0.2；65：10：
30：0.2；Or 65：15：25：0.2.
According to the separation method of the present invention, it is preferable that the flow visualizing is anhydrous, such as A, B, C and D are anhydrous
's；Preferably, the ethanol is absolute ethyl alcohol, and the isopropanol is anhydrous isopropyl alcohol.
According to the separation method of the present invention, the detector used can be UV-detector, preferably Detection wavelength 290nm,
40 DEG C of column temperature, flow velocity 1.5ml/min；
Yi Dushaban isomers can be optionally from Yi Dushaban enantiomter, one kind of diastereoisomer or more
Kind (such as 2,3,4,5,6,7), wherein Yi Dushaban compounds are configured as SRS, the enantiomter, diastereoisomer
Respective configuration be selected from RSR, SRR, RSS, RRR, SSS, RRS, SSR.
The present invention also provides a kind of Yi Dushaban and its mapping, the detection method of content of diastereoisomer, including will be according to
Du Shaban and its isomers are separated using the separation method of the present invention, then test the content of each isolate.
The present invention also provide chromatographic condition as described above Yi Dushaban isolate and purify or Yi Dushaban purity analysis in
Purposes.
Brief description of the drawings
Fig. 1 is H-A08 1HNMR collection of illustrative plates
Fig. 2 is H-B08 1HNMR collection of illustrative plates
Fig. 3 is YDB-RSS 1HNMR collection of illustrative plates
Fig. 4 is YDB-RSR 1HNMR collection of illustrative plates
Fig. 5 is YDB-SSS 1HNMR collection of illustrative plates
Fig. 6 is YDB-SSR 1HNMR collection of illustrative plates
Fig. 7 is YDB-RRS 1HNMR collection of illustrative plates
Fig. 8 is YDB-RRR 1HNMR collection of illustrative plates
Fig. 9 is YDB-SRR 1HNMR collection of illustrative plates
Figure 10 is YDB-SRS 1HNMR collection of illustrative plates
Figure 11 is YDB-RSS high resolution mass spectrum
Figure 12 is YDB-RSR high resolution mass spectrum
Figure 13 is YDB-SSS high resolution mass spectrum
Figure 14 is YDB-RRR high resolution mass spectrum
Figure 15 is YDB-RRS high resolution mass spectrum
Figure 16 is YDB-SSR high resolution mass spectrum
Figure 17 is YDB-SRR high resolution mass spectrum
Figure 18 is YDB-SRS high resolution mass spectrum
Figure 19 is YDB-SSR UV absorption figure；
Figure 20 is YDB-SRS UV absorption figure；
Figure 21 is YDB-SRR UV absorption figure；
Figure 22 is the mixed solution of 8 kinds of impurity, with n-hexane-absolute ethyl alcohol-isopropanol-diethylamine (60：20：20：0.2)
For the chromatogram of mobile phase；
Figure 23 is the mixed solution of 8 kinds of impurity, with n-hexane-absolute ethyl alcohol-diethylamine (50：50：0.2) it is mobile phase
Chromatogram；
Figure 24 is the mixed solution of 8 kinds of impurity, with n-hexane-isopropanol-diethylamine (60：40：0.2) it is the color of mobile phase
Spectrogram；
Figure 25 is the mixed solution of 8 kinds of impurity, with n-hexane-absolute ethyl alcohol-diethylamine (60：40：0.2) it is mobile phase
Chromatogram；
Embodiment
The present invention is described in detail by following embodiments.But skilled in the art realises that following embodiments are not
Limiting the scope of the invention.Any improvement and change made on the basis of the present invention, all the protection model in the present invention
Within enclosing.Unless otherwise indicated, the raw material of the following example and reagent are known product, and those skilled in the art are commercially available to be obtained
Obtain or voluntarily prepare.
Synthetic method embodiment
Embodiment 1N1- (5- chloropyridine -2- bases)-N2- ((1R, 2S, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5-
Methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino cyclohexyl) ethylenediamine (YDB-RSS) conjunction
Into
1-1：The synthesis of iodo- 6- oxabicyclos [3.2.1] the octyl- 7- ketone (YDB-A02) of (1R, 4R, 5R) -4-
YDB-A001 (236g, 0.954mol) is added into ethyl acetate (1180ml), in 2M hydrochloric acid (1062ml), stirring
1h, liquid separation, aqueous phase are extracted with ethyl acetate, and merge organic phase, organic phase water, and saturated sodium-chloride is washed, and anhydrous sodium sulfate is done
Dry, mother liquor is concentrated under reduced pressure dry, obtains oily product (YDB-A01) 115g.
By YDB-A01 (115g, 0.911mol), KI (196.7g, 1.185mol), sodium acid carbonate (99.56,
1.185mol) add in dichloromethane (1150ml), water (1140ml), stir 10min.10 DEG C are cooled to, iodine is added portionwise
(300.8g, 1185mol), react at room temperature 2h.1N sodium thiosulfate solutions (1L) are added, liquid separation, aqueous phase is extracted with dichloromethane
Take, merge organic phase, washed, anhydrous sodium sulfate drying, be concentrated under reduced pressure into dry with saturated sodium-chloride.Gained faint yellow solid, adds
Enter petroleum ether and stirring 30min, filter, obtain off-white powder YDB-A02 (209g, 90.98%).
1-2：(1R, 3S, 4S) -3- [(tert-butoxycarbonyl) amino] -4- hydroxy cyclohexane carboxylics ethyl ester (YDB-A04)
Synthesis
YDB-A02 (208.5g, 0.827mol) is dissolved in ethanol (1877ml), is warming up to 90 DEG C, adds potassium carbonate
(137g, 0.99mol), flow back 2h, is cooled to room temperature.Filtrate concentrates, and adds water, dichloromethane, extraction, liquid separation, aqueous phase dichloro
Methane extracts, and merges organic phase, is washed, anhydrous sodium sulfate drying, be concentrated under reduced pressure with water (500ml), saturated sodium-chloride water solution
To doing, yellow oil (YDB-A03) 141g is obtained.
At room temperature, YDB-A03 (140.8g, 0.827mol) is dissolved in DMF (1L), adds ammonium chloride
(65.5g, 1.22mol) and sodium azide (79.5g, 1.22mol), 80 DEG C of reaction 2h.Room temperature is down to, adds ethyl acetate and ice
Water, extraction, liquid separation, ethyl acetate washing aqueous phase, merge organic phase, washed with water, saturated sodium-chloride water solution, anhydrous sodium sulfate
Dry.Under hydrogen atmosphere, (Boc) is added into gained ethyl acetate solution2O (198.5g, 0.91mol) and 10% palladium charcoal
(14g), is stirred overnight.Insoluble matter is filtered, filtrate is concentrated to dryness.Gained crude product column chromatography (n-hexane：Ethyl acetate=3:1~
1:1) purify.Precipitated again with n-hexane-dichloromethane, filter to obtain white solid YDB-A04 (89.4g, yield 37.5%).
1-3：(1R, 3S, 4R) -4- { [(benzyloxy) carbonyl] amino } -3- [(tert-butoxy) carbonyl] naphthenic acid second
Ester (YDB-A08) and (1R, 3S, 4S) -4- { [(benzyloxy) carbonyl] amino } -3- [(tert-butoxy) carbonyl] naphthenic acid second
The synthesis of ester (YDB-B08)
YDB-A04 (89.35g, 0.311mol) is dissolved in ethyl acetate (1787ml), 0 DEG C, adds trimethylamine hydrochloride
(29.7g, 0.311mol), methylsufonyl chloride (53.42g, 0.466mol), triethylamine (47.2g, 0.466mol), reaction is added dropwise
1h.After reaction completely, saturated aqueous ammonium chloride, liquid separation are added.Organic phase is washed with saturated sodium bicarbonate, saturated sodium-chloride,
Anhydrous sodium sulfate drying, filtering, mother liquor is concentrated under reduced pressure into dry, obtains white solid (YDB-A05) 113.66g.
By YDB-A05 (113.6g, 0.31mol), TBAB (30.06g, 0.09mol), Sodium azide (40.41g,
0.62mol) add in N- methyl piperidines (1136ml), be warming up to 80 DEG C of reaction 15h, be cooled to 0 DEG C, add water, ethyl acetate,
Extraction, liquid separation.Aqueous phase is extracted with ethyl acetate, and merges organic phase, is washed with water, saturated sodium-chloride, anhydrous sodium sulfate drying, mistake
Filter, is concentrated under reduced pressure into dry, obtains yellow oil (YDB-A06) (72.2g, 74.34%).
YDB-A06 (72.2g, 0.231mol) is dissolved in ethanol (850ml), under atmosphere of hydrogen, adds 10% palladium carbon
(8.5g), it is warming up to 50-60 DEG C of reaction 2h.Palladium carbon is filtered, filtrate decompression is concentrated to dryness, crude product column chromatography (PE:EA=1:1~
Acetone) purifying, obtain colorless oil product (YDB-A07) (61.4g, 93%).
YDB-A07 (61.4g, 0.214mol) is dissolved in ethyl acetate (600ml), add sodium acid carbonate (27g,
Water (300ml) solution 0.321mol), 0 DEG C is cooled to, benzyl chloroformate (40.1g, 0.235mol), room temperature reaction is added dropwise
30min.Water, ethyl acetate extraction are added, liquid separation, aqueous phase is extracted with ethyl acetate, and merges organic phase, with water, saturated sodium-chloride
Washing, anhydrous sodium sulfate drying, filtering, mother liquor is concentrated under reduced pressure into dry, obtains oily product 110g.Ethyl acetate (400ml) is added,
70 DEG C of dissolvings are warming up to, n-hexane (1.5L) is added, 30min is stirred at room temperature, 0 DEG C of stirring 30min is down to, filters, dry, obtain white
Color solid YDB-A08 (44.7g, 49.6%)；Mother liquor is concentrated under reduced pressure dry, column chromatography (PE:EA=5：1~10：1) purify, obtain nothing
Color oily product YDB-B08 (22.3g, 24.7%).
1-4：(1R, 2S, 4R) -2- [(tert-butoxycarbonyl) amino] -4- [(dimethylamino) carbonyl] Cyclohexylamino
Benzyl chloroformate and (1R, 2S, 4S) -2- [(tert-butoxycarbonyl) amino] -4- [(dimethylamino) carbonyl] Cyclohexylamino
The synthesis of benzyl chloroformate (YDB-A11)
Under argon gas protection, YDB-A08 (44g, 0.105mol) is dissolved in 440ml ethanol, 20% alcohol sodium solution is added dropwise
(48.9ml, 0.126mol), 20-30 DEG C of reaction 10h, ice bath cooling, adds 1mol/L sodium dihydrogen phosphates (880ml), acetic acid second
Ester (1L), extraction, liquid separation, aqueous phase are extracted with ethyl acetate, and merge organic phase, are washed with saturated sodium-chloride, anhydrous sodium sulfate is done
It is dry, it is concentrated under reduced pressure, obtains white solid mixture YDB-A09 (39g, 89%).
YDB-A09 (39g, 0.093mol) is dissolved in THF (780ml), adds lithium hydroxide (4.45g, 0.186mol)
Water (195ml) solution, it is warming up to 30-35 DEG C of reaction 3-4h.Ether (780ml) and 10% aqueous citric acid solution (780ml) are added,
Extraction, liquid separation, aqueous phase are extracted with ether, merge organic phase, anhydrous sodium sulfate drying, mother liquor is concentrated under reduced pressure into dry.Residue is molten
In dichloromethane (780ml), dimethylamine hydrochloride (15.17g, 0.186mol) is added at room temperature, HOBT (18.85g,
0.14mol), EDCI (26.8g, 0.14mol), triethylamine (32.9g, 0.326mol), 18h is reacted.Add saturated sodium bicarbonate
The aqueous solution (500ml), extraction, liquid separation, aqueous phase are extracted with dichloromethane, are merged organic phase, are washed with saturated sodium-chloride water solution,
Anhydrous sodium sulfate drying, filtering, it is concentrated under reduced pressure into dry crude product.By crude product column chromatography (DCM：MeOH=30：1) elute, obtain nothing
Color oily mixture YDB-A11 (30.2g, 77%).
1-5：(1S, 2R, 5R) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -5- [(first
Base amino) carbonyl] Cyclohexylamino carboxylate (YDB-AC-RSS) and (1S, 2R, 5S) -2- (2- [(5- chloropyridines -
2- yls) amino] -2- oxoacetyls } amino) -5- [(methylamino) carbonyl] Cyclohexylamino carboxylate (YDB-
AC-RSR synthesis)
YDB-A11 (30g, 0.072mol) is dissolved in methanol (300ml), 10% palladium carbon (3g), room are added under hydrogen atmosphere
Warm stirring reaction 5h, palladium carbon is filtered, filtrate decompression is concentrated to dryness, and obtains colorless oil product YDB-A12 about 37g.
Oily product is dissolved in DMF (300ml), adds 2- [(5- chloropyridine -2- bases) amino] -2-
Ethyl hydrochloride (24.7g, 0.094mol), HOBT (12.7g, 0.094mol) and EDCI (20.7g,
0.108mol), it is warming up to 65-70 DEG C of reaction 4-5h.Add water, dichloromethane extraction, liquid separation.Organic phase saturated sodium bicarbonate
The aqueous solution (500ml) and saturated sodium-chloride water solution (500ml) washing, anhydrous sodium sulfate drying, are concentrated under reduced pressure.Crude product column chromatography
(PE:EA=1:1~2:1) purify, obtain YDB-AC-RSS (5.5g, 16.4%), YDB-AC-RSR (11.9g, 35.5%).
1-6：N1- (5- chloropyridine -2- bases)-N2- ((1R, 2S, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- first
Base -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino cyclohexyl) ethylenediamine (YDB-RSS) synthesis
YDB-AC-RSS (5.5g, 0.012mol) is dissolved in ethanol (300ml), adds saturation hydrochloric acid-ethanol solution
(60ml), react at room temperature 18h.Reaction solution is concentrated under reduced pressure.Product is dissolved in DMF (300ml), sequentially add triethylamine (7.9g,
0.078mol), EDCI (2.76g, 0.014mol), HOBT (8.8g, 0.065mol), 5- methyl -4,5,6,7- tetrahydrochysenes [1,3] thiophene
Azoles simultaneously [5,4-c] pyridine -2- carboxylic acid hydrochlorides (3.38g, 0.014mol), 12h is reacted under room temperature condition.Add water 300ml, two
Chloromethanes 300ml, extraction, liquid separation, aqueous phase are extracted with dichloromethane, are merged organic phase, are washed with saturated sodium-chloride, anhydrous slufuric acid
Sodium is dried, and is concentrated under reduced pressure into dry, column chromatography (PE:EA=1:2) purify, obtain solid 3.7g, add n-hexane 35ml mashing, obtain
YDB-RSS (1.9g, 29.5%).1HNMR(400MHz,CDCl3)δ：1.84-2.02 (6H, m), 2.51 (3H, s), 2.81-2.98
(8H, m), 3.09 (3H, s), 3.69-3.79 (2H, dd, J=15.6,24.8Hz), 4.39 (2H, m), 7.73 (1H, d, J=
8.8Hz), 8.00 (1H, d, J=8Hz), 8.22 (1H, d, J=8.8Hz), 8.30 (1H, s), 8.55 (1H, s), 9.70 (1H,
s).HRMS (ESI+) m/z=548.1858 [M+H]+。
Embodiment 2N1- (5- chloropyridine -2- bases)-N2- ((1R, 2S, 4R) -4- [(dimethylamino) carbonyl] -2- { [(5-
Methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino cyclohexyl) ethylenediamine (YDB-RSR) conjunction
Into
2-1:
YDB-AC-RSR (11.9g, 0.025mol) is dissolved in ethanol (600ml), adds saturation hydrochloric acid-ethanol solution
(130ml), react at room temperature 18h.Reaction solution is concentrated under reduced pressure.Product is dissolved in DMF (600ml), sequentially add triethylamine (16.4g,
0.163mol), EDCI (5.75g, 0.03mol), HOBT (18.3g, 0.136mol), 5- methyl -4,5,6,7- tetrahydrochysenes [1,3] thiophene
Azoles simultaneously [5,4-c] pyridine -2- carboxylic acid hydrochlorides (7.04g, 0.03mol), 12h is reacted under room temperature condition.Add water, dichloromethane
Alkane, extraction, liquid separation, aqueous phase are extracted with dichloromethane, are merged organic phase, are washed, anhydrous sodium sulfate drying, subtracted with saturated sodium-chloride
Pressure is concentrated to dryness, column chromatography (PE:EA=1:2) purify, obtain solid (6.8g), add n-hexane mashing, obtain YDB-RSR (4g,
28.8%).1HNMR(400MHz,CDCl3)δ：1.69-2.13 (6H, m), 2.54 (3H, s), 2.82-2.95 (8H, m), 3.06
(3H, s), 3.74-3.76 (2H, dd, J=15.2,23.6Hz), 4.12 (1H, m), 4.70 (1H, m), 7.39 (1H, d, J=
8Hz), 7.67 (1H, d, J=8.4Hz), 8.04 (1H, d, J=7.2Hz), 8.17 (1H, d, J=8.8Hz), 8.30 (1H, s),
9.73(1H,s)。
HRMS (ESI+) m/z=548.1603 [M+H]+, m/z=570.1417 [M+Na]+。
Embodiment 3N1- (5- chloropyridine -2- bases)-N2- ((1S, 2S, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5-
Methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino cyclohexyl) ethylenediamine (YDB-SSS) conjunction
Into
3-1:(1S, 2S, 4R) -2- [(tert-butoxycarbonyl) amino] -4- [(dimethylamino) carbonyl] Cyclohexylamino
Benzyl chloroformate and (1S, 2S, 4S) -2- [(tert-butoxycarbonyl) amino] -4- [(dimethylamino) carbonyl] Cyclohexylamino
The synthesis of benzyl chloroformate (YDB-B11)
Under argon gas protection, YDB-B08 (22g, 0.052mol) is dissolved in 220ml ethanol, 20% alcohol sodium solution is added dropwise
(24.5ml, 0.063mol), 20-30 DEG C of reaction 10h, ice bath cooling, adds 1mol/L sodium dihydrogen phosphates (440ml), acetic acid second
Ester (500ml), extraction, liquid separation, aqueous phase are extracted with ethyl acetate, and merge organic phase, are washed with saturated sodium-chloride, anhydrous sodium sulfate
Dry, be concentrated under reduced pressure, obtain white solid mixture YDB-B09 (20g, 91%).
YDB-B09 (20g, 0.047mol) is dissolved in THF (400ml), adds lithium hydroxide (2.25g, 0.094mol)
Water (100ml) solution, it is warming up to 30-35 DEG C of reaction 3-4h.Ether (400ml) and 10% aqueous citric acid solution (400ml) are added,
Extraction, liquid separation, aqueous phase are extracted with ether, merge organic phase, anhydrous sodium sulfate drying, mother liquor is concentrated under reduced pressure into dry.Residue is molten
In dichloromethane (400ml), dimethylamine hydrochloride (7.66g, 0.094mol) is added at room temperature, HOBT (9.53g,
0.071mol), EDCI (13.5g, 0.071mol), triethylamine (16.6g, 0.165mol), 18h is reacted.Add unsaturated carbonate hydrogen
Sodium water solution, extraction, liquid separation, aqueous phase are extracted with dichloromethane, are merged organic phase, are washed with saturated sodium-chloride water solution, anhydrous
Sodium sulphate is dried, and filtering, is concentrated under reduced pressure into dry crude product.Crude product column chromatography is eluted, obtains colorless oil mixture YDB-B11
(15.1g, 75%).
3-2:(1S, 2S, 5R) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -5- [(first
Base amino) carbonyl] Cyclohexylamino carboxylate (YDB-AC-SSR) and (1S, 2S, 5S) -2- (2- [(5- chloropyridines -
2- yls) amino] -2- oxoacetyls } amino) -5- [(methylamino) carbonyl] Cyclohexylamino carboxylate (YDB-
AC-SSS synthesis)
YDB-B11 (15g, 0.036mol) is dissolved in methanol (150ml), 10% palladium carbon (1.5g) is added under hydrogen atmosphere,
Reaction 5h is stirred at room temperature, filters palladium carbon, filtrate decompression is concentrated to dryness, and obtains colorless oil product YDB-B12 about 16g.By YDB-B12
DMF (150ml) is dissolved in, adds 2- [(5- chloropyridine -2- bases) amino] -2- ethyl hydrochlorides
(12.4g, 0.047mol), HOBT (6.3g, 0.047mol) and EDCI (10.4g, 0.054mol), it is warming up to 65 DEG C of reaction 5h.
Add water, dichloromethane extraction, liquid separation.Organic phase is washed with saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution, nothing
Aqueous sodium persulfate is dried, and is concentrated under reduced pressure.Crude product column chromatography (PE:EA=1:1~2:1) purify, obtain YDB-AC-SSS (1.8g),
YDB-AC-SSR(3.7g)。
3-3：N1- (5- chloropyridine -2- bases)-N2- ((1S, 2S, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- first
Base -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino cyclohexyl) ethylenediamine (YDB-SSS) synthesis
YDB-AC-SSS (1.8g, 3.85mmol) is dissolved in ethanol (180ml), adds saturation hydrochloric acid-ethanol solution
(17ml), react at room temperature 18h.Reaction solution is concentrated under reduced pressure.Product is dissolved in DMF (180ml), sequentially add triethylamine (2.5g,
0.025mol), EDCI (0.89g, 4.62mmol), HOBT (2.8g, 0.021mol), 5- methyl -4,5,6,7- tetrahydrochysenes [1,3] thiophene
Azoles simultaneously [5,4-c] pyridine -2- carboxylic acid hydrochlorides (1.1g, 4.62mmol), 12h is reacted under room temperature condition.Add water, dichloromethane
Alkane, extraction, liquid separation, aqueous phase are extracted with dichloromethane, are merged organic phase, are washed, anhydrous sodium sulfate drying, subtracted with saturated sodium-chloride
Pressure is concentrated to dryness, column chromatography (PE:EA=1:2) purify, obtain solid (1.18g), add n-hexane mashing, obtain YDB-SSS
(0.74g, 35.2%).1HNMR(400MHz,CDCl3)δ：1.71 (2H, m), 2.03 (3H, m), 2.31 (1H, m), 2.54 (3H,
S), 2.85-2.96 (7H, m), 2.96-3.04 (4H, m), 3.67-3.88 (3H, m), 4.68 (1H, m), 7.21 (1H, d, J=
8.8Hz), 7.69 (1H, d, J=8.8Hz), 8.01 (1H, d, J=8.8Hz), 8.22 (1H, d, J=8.8Hz), 8.26 (1H,
S), 9.63 (1H, s).HRMS (ESI+) m/z=548.1854 [M+H]+。
Embodiment 4N1- (5- chloropyridine -2- bases)-N2- ((1S, 2S, 4R) -4- [(dimethylamino) carbonyl] -2- { [(5-
Methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino cyclohexyl) ethylenediamine (YDB-SSR) conjunction
Into
4-1：
YDB-AC-SSR (3.7g, 7.9mmol) is dissolved in ethanol (300ml), adds saturation hydrochloric acid-ethanol solution
(40ml), react at room temperature 18h.Reaction solution is concentrated under reduced pressure.Product is dissolved in DMF (300ml), sequentially add triethylamine (5.2g,
0.051mol), EDCI (1.82g, 9.48mmol), HOBT (5.87g, 0.043mol), 5- methyl -4,5,6,7- tetrahydrochysenes [1,3]
Thiazole simultaneously [5,4-c] pyridine -2- carboxylic acid hydrochlorides (2.22g, 9.48mmol), 12h is reacted under room temperature condition.Add water, dichloro
Methane, extraction, liquid separation, aqueous phase are extracted with dichloromethane, are merged organic phase, are washed with saturated sodium-chloride, anhydrous sodium sulfate drying,
It is concentrated under reduced pressure into dry, column chromatography (PE:EA=1:2) purify, obtain solid (2.5g), add n-hexane mashing, filter to obtain YDB-SSR
(1.34g, 31%).1HNMR(400MHz,CDCl3)δ：1.54 (1H, m), 1.72-1.76 (1H, m), 1.88 (2H, m), 2.14
(1H, m), 2.27 (1H, m), 2.54 (3H, s), 2.76 (1H, m), 2.93 (7H, m), 3.08 (3H, s), 3.73-3.89 (3H,
M), 4.13 (1H, m), 7.41 (1H, d, J=9.2Hz), 7.69 (1H, d, J=8Hz), 7.94 (1H, d, J=7.6Hz), 8.17
(1H, d, J=8.8Hz), 8.27 (1H, s), 9.63 (1H, s).
HRMS (ESI+) m/z=548.18314 [M+H]+。
Embodiment 5N1- (5- chloropyridine -2- bases)-N2- ((1R, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5-
Methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino cyclohexyl) ethylenediamine (YDB-RRS) conjunction
Into
5-1：The synthesis of iodo- 6- oxabicyclos [3.2.1] the octyl- 7- ketone (H-A02) of (1S, 4S, 5S) -4-
H-A001 (440g, 1.78mol) is added into ethyl acetate (2.2L), in 2M hydrochloric acid (2L), stirs 1h, liquid separation, water
Mutually extracted with ethyl acetate (500ml × 2), merge organic phase, organic phase water, saturated sodium-chloride is washed, and anhydrous sodium sulfate is done
Dry, mother liquor is concentrated under reduced pressure dry, obtains oily product (H-A01) 233g.By H-A01 (233g, 1.85mol), KI (398.4g,
2.4mol), sodium acid carbonate (201.6,2.4mol) is added in dichloromethane (2L), water (2L), stirs 10min.10 DEG C are cooled to,
Iodine (609.1g, 2.4mol) is added portionwise, reacts at room temperature 2h.1N sodium thiosulfate solutions (1.5L), liquid separation are added, aqueous phase is used
Dichloromethane extracts, and merges organic phase, is washed, anhydrous sodium sulfate drying, be concentrated under reduced pressure into dry with saturated sodium-chloride.Gained is yellowish
Color solid, petroleum ether and stirring 30min is added, filtering, obtains faint yellow solid H-A02 (400g, 90%).
5-2：The conjunction of (1S, 3R, 4R) -3- [(tert-butoxycarbonyl) amino] -4- hydroxy cyclohexane carboxylics ethyl ester (H-A04)
Into
H-A02 (400g, 1.59mol) is dissolved in ethanol (2L), is warming up to 90 DEG C, add potassium carbonate (263.7g,
1.91mol), flow back 2h, is cooled to room temperature.Filtrate concentrates, and adds water (1L), dichloromethane (1L), extraction, liquid separation, and aqueous phase is with two
Chloromethanes extract, merge organic phase, washed with water, saturated sodium-chloride water solution, anhydrous sodium sulfate drying, be concentrated under reduced pressure into it is dry,
Obtain pale yellow oil (H-A03) 272g.
At room temperature, H-A03 (270g, 1.59mol) is dissolved in DMF (2L), adds ammonium chloride
(127.6g, 2.39mol) and sodium azide (155g, 2.39mol), 80 DEG C of reaction 2h.Room temperature is down to, adds ethyl acetate (1L)
With frozen water (1L), extraction, liquid separation, ethyl acetate washing aqueous phase, merge organic phase, washed with water, saturated sodium-chloride water solution, nothing
Aqueous sodium persulfate is dried.Under hydrogen atmosphere, (Boc) is added into gained ethyl acetate solution2O (381.7g, 1.75mol) and 10%
Palladium charcoal (27g), is stirred overnight.Insoluble matter is filtered, filtrate is concentrated to dryness.Add petroleum ether (1L) and 2h, ice bath cooling is stirred at room temperature
1h is stirred, filters to obtain white solid H-A04 (192g, 42%).
5-3：(1S, 3R, 4R) -4- { [(benzyloxy) carbonyl] amino } -3- [(tert-butoxy) carbonyl] naphthenic acid second
Ester (H-A08) and (1S, 3R, 4S) -4- { [(benzyloxy) carbonyl] amino } -3- [(tert-butoxy) carbonyl] naphthenic acid ethyl ester
(H-B08) synthesis
H-A04 (192g, 0.668mol) is dissolved in ethyl acetate (3L), 0 DEG C, add trimethylamine hydrochloride (63.8g,
0.668mol), methylsufonyl chloride (114.6g, 1mol), triethylamine (101.2g, 1mol) is added dropwise, reacts 1h.After reaction completely,
Add saturated aqueous ammonium chloride (3L), liquid separation.Organic phase is washed with saturated sodium bicarbonate, saturated sodium-chloride, anhydrous sodium sulfate
Dry, filtering, mother liquor is concentrated under reduced pressure into dry, obtains white solid (H-A05) 243g.
By H-A05 (243g, 0.665mol), TBAB (64.3g, 0.2mol), sodium azide (86.5g,
1.33mol) add in N- methyl piperidines (2L), be warming up to 80 DEG C of reaction 15h, be cooled to 0 DEG C, add water (1L), ethyl acetate,
Extraction, liquid separation.Aqueous phase is extracted with ethyl acetate, and merges organic phase, is washed with water, saturated sodium-chloride, anhydrous sodium sulfate drying, mistake
Filter, is concentrated under reduced pressure into dry, obtains pale tan oil (H-A06) (155.8g, 75%).
H-A06 (155.8g, 0.5mol) is dissolved in ethanol (1L), under atmosphere of hydrogen, 10% palladium carbon (15.6g) is added, rises
Warm to 50-60 DEG C reaction 2h.Palladium carbon is filtered, filtrate decompression is concentrated to dryness, and obtains yellow oily product H-A07 (142.3g).
H-A07 (142g, 0.496mol) is dissolved in ethyl acetate (1.3L), adds sodium acid carbonate (62.5g, 0.744mol)
Water (700ml) solution, be cooled to 0 DEG C, benzyl chloroformate (93.1g, 0.546mol) be added dropwise, react at room temperature 30min.Add
Water, ethyl acetate extraction, liquid separation, aqueous phase are extracted with ethyl acetate, merge organic phase, washed with water, saturated sodium-chloride, anhydrous sulphur
Sour sodium is dried, and filtering, mother liquor is concentrated under reduced pressure into dry.Ethyl acetate is added, petroleum ether (3L), 2h is stirred at room temperature, is down to 0 DEG C of stirring
2h, filter, dry, obtain white solid H-B08 (112.6g, 54%)；1HNMR(400MHz,CDCl3)δ：1.22-1.26(3H,t,
J=7.2Hz), 1.43 (10H, m), 1.55-2.04 (5H, m), 2.39 (1H, m), 3.69 (1H, m), 4.09-4.16 (3H, m),
4.70 (1H, m), 5.05-5.13 (2H, m), 5.30 (1H, s), 7.27-7.34 (5H, m).
Mother liquor is concentrated under reduced pressure dry, column chromatography (PE:EA=5：1~10：1) purify, obtain faint yellow oily product H-A08
(72.5,34.8%)；1HNMR(400MHz,CDCl3)δ：1.25-1.28 (3H, t, J=7.2Hz), 1.40 (11H, m), 1.55
(1H, m), 1.97 (1H, m), 2.12 (1H, m), 2.41 (1H, m), 2.73 (1H, m), 3.33 (1H, m), 3.61 (1H, m),
4.14-4.19 (2H, q, J=7.2Hz), 4.59 (1H, m), 5.07 (2H, s), 5.36 (1H, s), 7.32 (5H, m).
5-4：(1R, 2R, 4S) -2- [(tert-butoxycarbonyl) amino] -4- [(dimethylamino) carbonyl] Cyclohexylamino
Benzyl chloroformate and (1R, 2R, 4R) -2- [(tert-butoxycarbonyl) amino] -4- [(dimethylamino) carbonyl] Cyclohexylamino
The synthesis of benzyl chloroformate (H-A11)
Under argon gas protection, H-A08 (72.5g, 0.172mol) is dissolved in 800ml ethanol, 20% alcohol sodium solution is added dropwise
(80ml, 0.206mol), 20-30 DEG C of reaction 10h, ice bath cooling, adds 1mol/L sodium dihydrogen phosphates (800ml), ethyl acetate
(800ml), extraction, liquid separation, aqueous phase are extracted with ethyl acetate, and merge organic phase, are washed with saturated sodium-chloride, anhydrous sodium sulfate is done
It is dry, it is concentrated under reduced pressure, obtains white solid mixture H-A09 (67.4g, 93%).
H-A09 (67.4g, 0.16mol) is dissolved in THF (800ml), adds the water of lithium hydroxide (7.66g, 0.32mol)
(337ml) solution, it is warming up to 30-35 DEG C of reaction 3-4h.Add ether (800ml) and 10% aqueous citric acid solution (800ml), extraction
Take, liquid separation, aqueous phase is extracted with ether, merges organic phase, anhydrous sodium sulfate drying, mother liquor is concentrated under reduced pressure into dry.Residue is dissolved in
Dichloromethane, at room temperature add dimethylamine hydrochloride (26.1g, 0.32mol), HOBT (32.4g, 0.24mol), EDCI (46g,
0.24mol), triethylamine (56.7g, 0.56mol), 18h is reacted.Add saturated sodium bicarbonate aqueous solution, extraction, liquid separation, aqueous phase
Extracted with dichloromethane, merge organic phase, washed with saturated sodium-chloride water solution, anhydrous sodium sulfate drying, filtered, be concentrated under reduced pressure
It is extremely dry to obtain crude product.By crude product column chromatography (DCM：MeOH=30：1) elute, obtain colorless oil mixture H-A11 (49g, 73%).
5-5：(1R, 2R, 5R) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -5- [(first
Base amino) carbonyl] Cyclohexylamino carboxylate (YDB-AC-RRR) and (1R, 2R, 5S) -2- (2- [(5- chloropyridines -
2- yls) amino] -2- oxoacetyls } amino) -5- [(methylamino) carbonyl] Cyclohexylamino carboxylate (YDB-
AC-RRS synthesis)
H-A11 (49g, 0.117mol) is dissolved in methanol (500ml), 10% palladium carbon (4.9g), room are added under hydrogen atmosphere
Warm stirring reaction 5h, palladium carbon is filtered, filtrate decompression is concentrated to dryness, and obtains colorless oil product H-A12 about 48.7g.
Oily product H-A12 is dissolved in DMF (500ml), adds 2- [(5- chloropyridine -2- bases) ammonia
Base] -2- ethyls hydrochloride (40.16g, 0.152mol), HOBT (20.56g, 0.152mol) and EDCI (33.6g,
0.176mol), 70 DEG C of reaction 4h are warming up to.Add water, dichloromethane extraction, liquid separation.Organic phase saturated sodium bicarbonate water is molten
Liquid and saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying, are concentrated under reduced pressure.Crude product column chromatography purifies, and obtains YDB-AC-
RRR (12.5g, 23%), YDB-AC-RRS (23g, 46%).
5-6：N1- (5- chloropyridine -2- bases)-N2- ((1R, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- first
Base -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino cyclohexyl) ethylenediamine (YDB-RRS) synthesis
YDB-AC-RRS (23g, 0.049mol) is dissolved in 460ml acetonitriles, addition pyrovinic acid (23.5g,
0.245mol), stir, be cooled to 0 DEG C, triethylamine (32.2g, 0.318mol) is added dropwise, is warmed to room temperature, sequentially adds EDCI
(11.3g, 0.059mol), HOBT (6.9g, 0.051mol), 5- methyl -4,5,6,7- tetrahydrochysenes [1,3] thiazole simultaneously [5,4-c] pyrrole
Pyridine -2- carboxylic acid hydrochlorides (13.8g, 0.059mol), stir 3h at room temperature.Add water, dichloromethane, stirring, liquid separation, aqueous phase use
Dichloromethane extracts, and merges organic phase, is washed with saturated sodium-chloride, anhydrous sodium sulfate drying, filters, is concentrated under reduced pressure slightly dry
Product, column chromatography (DCM：MeOH=30:1) purify to obtain product 12.1g, add n-hexane mashing, filter YDB-RRS (7.5g,
27.8%).1HNMR(400MHz,CDCl3)δ：1.54 (1H, m), 1.72 (1H, m), 1.88 (2H, m), 2.15 (1H, m), 2.27
(1H, m), 2.49 (3H, s), 2.76-2.90 (5H, m), 2.95 (3H, s), 3.07 (3H, s), 3.65-3.70 (2H, dd, J=
15.6,37.2Hz), 3.89 (1H, m), 4.14 (1H, m), 7.44 (1H, d, J=8.8Hz), 7.68 (1H, d, J=8.8Hz),
7.96 (1H, d, J=8.4Hz), 8.17 (1H, d, J=8.8Hz), 8.27 (1H, s), 9.65 (1H, s).
HRMS (ESI+) m/z=548.18359 [M+H]+, m/z=570.16527 [M+Na]+.
Embodiment 6N1- (5- chloropyridine -2- bases)-N2- ((1R, 2R, 4R) -4- [(dimethylamino) carbonyl] -2- { [(5-
Methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino cyclohexyl) ethylenediamine (YDB-RRR) conjunction
Into
6-1：
YDB-AC-RRR (12.5g, 0.027mol) is dissolved in 250ml acetonitriles, addition pyrovinic acid (12.8g,
0.134mol), stir, be cooled to 0 DEG C, triethylamine (17.7g, 0.175mol) is added dropwise, is warmed to room temperature, sequentially adds EDCI
(6.2g, 0.032mol), HOBT (3.8g, 0.028mol), 5- methyl -4,5,6,7- tetrahydrochysenes [1,3] thiazole simultaneously [5,4-c] pyrrole
Pyridine -2- carboxylic acid hydrochlorides (7.6g, 0.032mol), stir 3h at room temperature.Add water, dichloromethane, stirring, liquid separation, aqueous phase use
Dichloromethane extracts, and merges organic phase, is washed with saturated sodium-chloride, anhydrous sodium sulfate drying, filters, is concentrated under reduced pressure slightly dry
Product, column chromatography (DCM：MeOH=30:1) purify to obtain product 6.6g, add n-hexane mashing, filter YDB-RRR (4.3g,
29.4%).1HNMR(400MHz,CDCl3)δ：1.72 (2H, m), 2.01 (3H, m), 2.31 (1H, m), 2.54 (3H, s), 2.85-
2.96 (7H, m), 3.04-3.07 (4H, m), 3.68-3.88 (3H, m), 4.68 (1H, m), 7.20 (1H, d, J=7.6Hz),
7.67 (1H, d, J=9.2Hz), 8.01 (1H, d, J=8.4Hz), 8.21 (1H, d, J=8.4Hz), 8.26 (1H, s), 9.63
(1H,s)。
HRMS (ESI+) m/z=548.1855 [M+H]+。
Embodiment 7N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4R) -4- [(dimethylamino) carbonyl] -2- { [(5-
Methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino cyclohexyl) ethylenediamine (YDB-SRR) conjunction
Into
7-1：(1S, 2R, 4R) -2- [(tert-butoxycarbonyl) amino] -4- [(dimethylamino) carbonyl] Cyclohexylamino
Benzyl chloroformate and (1S, 2R, 4S) -2- [(tert-butoxycarbonyl) amino] -4- [(dimethylamino) carbonyl] Cyclohexylamino
The synthesis of benzyl chloroformate (H-B11)
Under argon gas protection, H-B08 (112g, 0.266mol) is dissolved in 1L ethanol, be added dropwise 20% alcohol sodium solution (125ml,
0.32mol), 20-30 DEG C of reaction 10h, ice bath cooling, 1mol/L sodium dihydrogen phosphates (1L) is added, ethyl acetate (1L), are extracted,
Liquid separation, aqueous phase are extracted with ethyl acetate, and merge organic phase, are washed, anhydrous sodium sulfate drying, be concentrated under reduced pressure with saturated sodium-chloride,
Obtain white solid mixture H-B09 (97.4g, 87%).
H-B09 (97.4g, 0.23mol) is dissolved in THF (800ml), adds the water of lithium hydroxide (11g, 0.46mol)
(500ml) solution, it is warming up to 30-35 DEG C of reaction 4h.Add ether (800ml) and 10% aqueous citric acid solution (800ml), extraction
Take, liquid separation, aqueous phase is extracted with ether, merges organic phase, anhydrous sodium sulfate drying, mother liquor is concentrated under reduced pressure into dry.Residue is dissolved in
Dichloromethane, dimethylamine hydrochloride (37.5g, 0.46mol), HOBT (46.6g, 0.345mol), EDCI are added at room temperature
(66.1g, 0.345mol), triethylamine (81.4g, 0.805mol), react 18h.Saturated sodium bicarbonate aqueous solution is added, is extracted,
Liquid separation, aqueous phase are extracted with dichloromethane, are merged organic phase, are washed with saturated sodium-chloride water solution, anhydrous sodium sulfate drying, mistake
Filter, it is concentrated under reduced pressure into dry crude product.Crude product column chromatography is eluted, obtains colorless oil mixture H-B11 (69.6g, 71.6%).
7-2：(1R, 2S, 5S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -5- [(first
Base amino) carbonyl] Cyclohexylamino carboxylate (YDB-AC-SRS) and (1R, 2S, 5R) -2- (2- [(5- chloropyridines -
2- yls) amino] -2- oxoacetyls } amino) -5- [(methylamino) carbonyl] Cyclohexylamino carboxylate (YDB-
AC-SRR synthesis)
H-B11 (69.5g, 0.166mol) is dissolved in methanol (700ml), 10% palladium carbon (6.95g) is added under hydrogen atmosphere,
Reaction 5h is stirred at room temperature, filters palladium carbon, filtrate decompression is concentrated to dryness, and obtains colorless oil product H-B12 about 62g.
Oily product H-B12 is dissolved in DMF (700ml), adds 2- [(5- chloropyridine -2- bases) ammonia
Base] -2- ethyls hydrochloride (57g, 0.216mol), HOBT (29.2g, 0.216mol) and EDCI (47.7g,
0.249mol), 70 DEG C of reaction 5h are warming up to.Add water, dichloromethane extraction, liquid separation.Organic phase saturated sodium bicarbonate water is molten
Liquid and saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying, are concentrated under reduced pressure.Crude product column chromatography purifies, and obtains YDB-AC-
SRR (13.2g, 17%), YDB-AC-SRS (15.7g, 20.3%).
7-3：N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4R) -4- [(dimethylamino) carbonyl] -2- { [(5- first
Base -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino cyclohexyl) ethylenediamine (YDB-SRR) synthesis
YDB-AC-SRR (13g, 0.028mol) is dissolved in 260ml acetonitriles, addition pyrovinic acid (13.3g,
0.139mol), stir, be cooled to 0 DEG C, triethylamine (18.4g, 0.182mol) is added dropwise, is warmed to room temperature, sequentially adds EDCI
(6.44g, 0.034mol), HOBT (4g, 0.029mol), 5- methyl -4,5,6,7- tetrahydrochysenes [1,3] thiazole simultaneously [5,4-c] pyridine -
2- carboxylic acid hydrochlorides (7.9g, 0.034mol), stir 3h at room temperature.Add water, dichloromethane, stirring, liquid separation, aqueous phase dichloro
Methane extracts, and merges organic phase, is washed with saturated sodium-chloride, anhydrous sodium sulfate drying, filters, and be concentrated under reduced pressure dry crude product, post
Chromatographic purifying obtains product 7.2g, adds n-hexane mashing, filters to obtain YDB-SRR (4.5g, 29.5%).
1HNMR(400MHz,CDCl3)δ：1.83 (3H, m), 1.98 (3H, m), 2.53 (3H, s), 2.86-2.98 (8H, m),
3.09 (3H, s), 3.75 (2H, dd, J=15.6,24.4Hz), 4.38 (2H, m), 7.70 (1H, d, J=8Hz), 8.01 (1H, d,
J=7.2Hz), 8.21 (1H, d, J=8.4Hz), 8.29 (1H, s), 8.56 (1H, s), 9.70 (1H, s).
HRMS (ESI+) m/z=548.1845 [M+H]+。
Embodiment 8N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5-
Methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino cyclohexyl) ethylenediamine (YDB-SRS) conjunction
Into
8-1：
YDB-AC-SRS (15.5g, 0.033mol) is dissolved in 310ml acetonitriles, addition pyrovinic acid (15.9g,
0.165mol), stir, be cooled to 0 DEG C, triethylamine (21.7g, 0.214mol) is added dropwise, is warmed to room temperature, sequentially adds EDCI
(7.6g, 0.04mol), HOBT (4.68g, 0.035mol), 5- methyl -4,5,6,7- tetrahydrochysenes [1,3] thiazole simultaneously [5,4-c] pyrrole
Pyridine -2- carboxylic acid hydrochlorides (9.3g, 0.04mol), stir 3h at room temperature.Water is added, dichloromethane, stirring, liquid separation, aqueous phase is with two
Chloromethanes extracts, and merges organic phase, is washed with saturated sodium-chloride, anhydrous sodium sulfate drying, filters, and be concentrated under reduced pressure dry crude product,
Column chromatography purifies to obtain product 8.4g, adds n-hexane mashing, filters to obtain YDB-SRS (4.9g, 27%).
1HNMR(400MHz,CDCl3)δ：1.69-2.06 (6H, m), 2.55 (3H, s), 2.86-2.88 (3H, m), 2.95
(5H, m), 3.06 (3H, s), 3.74 (2H, dd, J=15.6,24.4Hz), 4.12 (1H, m), 4.70 (1H, m), 7.42 (1H, d,
J=8Hz), 7.69 (1H, d, J=8.8Hz), 8.04 (1H, d, J=7.2Hz), 8.17 (1H, d, J=8.8Hz), 8.30 (1H,
S), 9.73 (1H, s)
HRMS (ESI+) m/z=548.1841 [M+H]+。
The high performance liquid chromatography separation of embodiment 9
1. the initial option of Detection wavelength
The present invention has investigated the UV absorption of Yi Dushaban and its mapping, diastereoisomer in water, and specific method is：
Take each impurity reference substance appropriate, be dissolved in water the solution being made containing each μ g of reference substance 20 in every 1ml respectively, using ultraviolet-visible
AAS (two annex IV A of China's coastal port) determines, and the results are shown in Table 2 and accompanying drawing 19-21.Due to general different
The absorption of structure body is close, so the present invention only determines the UV absorption of 3 groups of isomers.
The Yi Dushaban of table 2 and its isomers UV absorption wavelength
| Sample ID | UV absorption |
| YDB-SSR | Ultraviolet absorption maximum 258nm, 288nm； |
| YDB-SRS | Ultraviolet absorption maximum 288nm； |
| YDB-SRR | Ultraviolet absorption maximum 288nm； |
Conclusion：There is maximum suction at about 290nm wavelength from Figure 19,20 and 21 and table 2, Yi Dushaban and its isomers
Receive, so selected Detection wavelength is 290nm.
2. the selection and optimization of mobile phase
Inventor uses following chromatographic condition：Amylose-three (3,5- xylyls carbamate) bonded silica gel is
The chromatographic column of filler；N-hexane-absolute ethyl alcohol-isopropanol-diethylamine (60：20：20：0.2) it is mobile phase；Detection wavelength
290nm；Column temperature is 40 DEG C, and the separation condition of Yi Dushaban and its impurity is groped, and part of test results is shown in Table 3 and attached
Figure 22.
The selection of the mobile phase of table 3
From Figure 22 and table 3, Yi Dushaban and its mapping, the mixture of diastereoisomer are in n-hexane-anhydrous second
Alcohol-isopropanol-diethylamine (60：20：20：0.2) under the chromatographic condition of mobile phase, Yi Dushaban and its mapping, diastereomeric are different
The separating degree of structure body is preferable, and retention time is moderate.Therefore the mobile phase condition is adapted to different to Yi Dushaban and its mapping, diastereomeric
The high performance liquid chromatography separation of structure body.
Specific chromatographic condition and method are as follows：
Chromatographic condition：Amylose-three (3,5- xylyls carbamate) bonded silica gel is the chromatographic column of filler
(manufacturer：Welch, brand：CHIRALPAK (Chinese names:Daicel), model：IA, specification：4.0mm × 10ml, 5 μm, numbering：
80311)；N-hexane-absolute ethyl alcohol-isopropanol-diethylamine (volume ratio 60：20：20：0.2) it is mobile phase；Detection wavelength
290nm；Column temperature is 40 DEG C.
Yi Dushaban and its mapping, the preparation of diastereoisomer reference substance solution：Take respectively SRS, RSR, SRR, RSS,
RRR, SSS, RRS and SSR reference substance are appropriate, take a small amount of methanol to dissolve respectively and are diluted with absolute ethyl alcohol, are made in every 1ml respectively
The solution of the μ g containing SRS, RSR, SRR, RSS, RRR, SSS, RRS, SSR impurity about 100.
Yi Dushaban and its impurity reference substance mixed solution preparation：Take respectively SRS, RSR, SRR, RSS, RRR, SSS,
RRS and SSR each 1ml of impurity reference substance solution, are placed in 10ml measuring bottles, add absolute ethyl alcohol to be settled to scale, shake up, produce.
Assay method：Take the μ l of impurity reference substance mixed solution 20 to inject high performance liquid chromatograph, and record chromatogram.
Testing result shows that Yi Dushaban SRS and configuration are respectively the different of RSR, SRR, RSS, RRR, SSS, RRS, SSR
The mutual separating degree of structure body is preferable.
The high performance liquid chromatography separation of embodiment 10
Separation detection is carried out using the identical condition of embodiment 9 and method, mobile phase is only replaced with into n-hexane-anhydrous second
Alcohol-isopropanol-diethylamine (volume ratio 55：30：15：0.2).
The high performance liquid chromatography separation of embodiment 11
Separation detection is carried out using the identical condition of embodiment 9 and method, mobile phase is only replaced with into n-hexane-anhydrous second
Alcohol-isopropanol-diethylamine (volume ratio 55：35：10：0.2).
The high performance liquid chromatography separation of embodiment 12
Separation detection is carried out using the identical condition of embodiment 9 and method, mobile phase is only replaced with into n-hexane-anhydrous second
Alcohol-isopropanol-diethylamine (volume ratio 55：40：5：0.2).
The high performance liquid chromatography separation of embodiment 13
Separation detection is carried out using the identical condition of embodiment 9 and method, mobile phase is only replaced with into n-hexane-anhydrous second
Alcohol-isopropanol-diethylamine (volume ratio 65：10：30：0.2).
The high performance liquid chromatography separation of embodiment 14
Separation detection is carried out using the identical condition of embodiment 9 and method, mobile phase is only replaced with into n-hexane-anhydrous second
Alcohol-isopropanol-diethylamine (volume ratio 65：15：25：0.2).
The high performance liquid chromatography separation of embodiment 15
Separation detection is carried out using the identical condition of embodiment 9 and method, mobile phase is only replaced with into n-hexane-anhydrous second
Alcohol-isopropanol-triethylamine (volume ratio 60：20：20：0.2).
Comparative example 1：
Separation detection is carried out using the identical condition of embodiment 9 and method, mobile phase is only replaced with into n-hexane-anhydrous second
Alcohol-diethylamine (volume ratio 50：50：0.2).Testing result is shown in Figure 23.
Comparative example 2：
Separation detection is carried out using the identical condition of embodiment 9 and method, mobile phase is only replaced with into n-hexane-isopropyl
Alcohol-diethylamine (volume ratio 60：40：0.2).Testing result is shown in Figure 24.
Comparative example 3：
Separation detection is carried out using the identical condition of embodiment 9 and method, mobile phase is only replaced with into n-hexane-anhydrous second
Alcohol-diethylamine (volume ratio 60：40：0.2).Testing result is shown in Figure 25.
Embodiment 9-15 and comparative example 1-3 testing result
Table 4 give it is identical in other conditions, in the case of only changing flow visualizing, according to comprising Yi Dushaban and
The result that its mapping, the blend sample separation spectrogram of diastereoisomer collect：
The separating effect of 4 different flow visualizings of table
| Flow visualizing (numbering) | As a result |
| Embodiment 9 | Main peak retention time is moderate, and main peak is good with impurity separating degree |
| Embodiment 10 | Main peak retention time is moderate, and main peak is good with impurity separating degree |
| Embodiment 11 | Main peak retention time is moderate, and main peak is good with impurity separating degree |
| Embodiment 12 | Main peak retention time is moderate, and main peak is good with impurity separating degree |
| Embodiment 13 | Main peak retention time is moderate, and main peak is good with impurity separating degree |
| Embodiment 14 | Main peak retention time is moderate, and main peak is good with impurity separating degree |
| Embodiment 15 | Main peak retention time is moderate, and main peak is good with impurity separating degree |
| Comparative example 1 | Main peak retention time is too short, and main peak does not separate with impurity |
| Comparative example 2 | Main peak retention time is too short, and main peak does not separate with impurity |
| Comparative example 3 | Main peak retention time is too short, and main peak does not separate with impurity |
Result above shows, under the chromatographic condition of the present invention, Yi Dushaban and its mapping, diastereoisomer can be compared with
Good separation.
Claims (9)
1. a kind of Yi Dushaban and its isomers separation method, it is characterised in that：Methods described is chromatography, its chromatographic condition
For：Filler is selected from amylose-three (3,5- xylyl carbamate) bonded silica gel, and mobile phase is selected from A, B, C and D
Mixture, wherein A are selected from n-hexane and/or petroleum ether and/or pentane, and B is selected from ethanol, and C is selected from isopropanol, and D is selected from diethyl
Amine and/or triethylamine；
The volume ratio for flowing A, B, C, D each component in phase mixture is 50~65:10~45:1~35:0.1~0.3.
2. the method as described in claim 1, wherein the mobile phase is selected from the mixing of n-hexane-ethanol-isopropanol-diethylamine
Thing, the mixture of n-hexane-ethanol-isopropanol-triethylamine, mixture, the oil of petroleum ether-ethanol-isopropanol-diethylamine
The mixture of ether-ethanol-isopropanol-triethylamine, the mixture of pentane-ethanol-isopropanol-diethylamine, pentane-ethanol-
The mixture of isopropanol-triethylamine.
3. method as claimed in claim 2, wherein the volume ratio of A, B, C, D each component is 60 in the mobile phase mixture：
20：20：0.2；55：30：15：0.2；55：35：10：0.2；55：40：5：0.2；65：10：30：0.2；Or 65：15：25：0.2.
4. the method as described in claim any one of 1-3, wherein the flow visualizing is anhydrous.
5. method as claimed in claim 4, it is characterised in that：The chromatogram is high performance liquid chromatography, and elution is washed selected from isocratic
It is de-.
6. method as claimed in claim 5, it is characterised in that chromatographic condition be the detector used for UV-detector, inspection
Survey wavelength 290nm, 40 DEG C of column temperature, flow velocity 1.5ml/min.
7. a kind of Yi Dushaban and its mapping, the detection method of content of diastereoisomer, including by Yi Dushaban and its isomery
Body usage right requires any one of 1-6 method separation, then tests the content of each isolate.
8. the method as described in any one of claim 1-3,5-7, it is characterised in that：Contain in the Yi Dushaban and its isomers
Have Yi Dushaban one or more isomers, and the configuration of the isomers include RSR, SRR, RSS, RRR, SSS, RRS,
SSR。
9. method as claimed in claim 4, it is characterised in that：Contain Yi Dushaban's in the Yi Dushaban and its isomers
One or more isomers, and the configuration of the isomers includes RSR, SRR, RSS, RRR, SSS, RRS, SSR.
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| CN111606826B (en) * | 2020-07-02 | 2022-02-22 | 沧州那瑞化学科技有限公司 | Preparation method of edoxaban intermediate |
| CN111848647B (en) * | 2020-08-03 | 2021-11-23 | 珠海市海瑞德新材料科技有限公司 | Methyl tetrahydropyridine benzothiazole active compound and preparation method and application thereof |
| CN111763222B (en) * | 2020-08-03 | 2021-05-25 | 珠海市海瑞德新材料科技有限公司 | Intermediate for preparing edoxaban free base and preparation method and application thereof |
| CN112062714A (en) * | 2020-08-28 | 2020-12-11 | 浙江苏泊尔制药有限公司 | Analysis and purification method of edoxaban tosylate hydrate and preparation method of main impurities of edoxaban tosylate hydrate |
| CN112321613B (en) * | 2020-11-06 | 2022-04-12 | 江苏华阳制药有限公司 | Preparation method of idoxaban tosylate and isomer thereof |
| CN113884601A (en) * | 2021-10-29 | 2022-01-04 | 哈药集团技术中心 | Method for detecting idoxaban tosylate isomer |
| CN115728414B (en) * | 2022-11-10 | 2025-03-28 | 武汉海特生物创新医药研究有限公司 | A method for detecting the enantiomer of edosapan intermediate 2 |
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