CN109020992B - Method for preparing beta-type mono/bis sweet wormwood alkyl ether amine maleate in stereoselective manner - Google Patents
Method for preparing beta-type mono/bis sweet wormwood alkyl ether amine maleate in stereoselective manner Download PDFInfo
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- CN109020992B CN109020992B CN201710433470.0A CN201710433470A CN109020992B CN 109020992 B CN109020992 B CN 109020992B CN 201710433470 A CN201710433470 A CN 201710433470A CN 109020992 B CN109020992 B CN 109020992B
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- Prior art keywords
- bis
- alkyl ether
- reaction
- ether amine
- amine
- Prior art date
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 title claims abstract description 29
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 title claims abstract description 27
- 238000000034 method Methods 0.000 title claims abstract description 22
- 150000001412 amines Chemical class 0.000 title claims abstract description 16
- 150000005215 alkyl ethers Chemical class 0.000 title claims abstract description 11
- 240000000011 Artemisia annua Species 0.000 title claims abstract description 7
- 235000001405 Artemisia annua Nutrition 0.000 title claims abstract description 6
- 230000000707 stereoselective effect Effects 0.000 title claims description 6
- -1 alkyl alcohol amine compound Chemical class 0.000 claims abstract description 96
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 17
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000011976 maleic acid Substances 0.000 claims abstract description 11
- 238000001953 recrystallisation Methods 0.000 claims abstract description 8
- 229960002521 artenimol Drugs 0.000 claims abstract description 6
- 229930016266 dihydroartemisinin Natural products 0.000 claims abstract description 6
- 239000003054 catalyst Substances 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 80
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 77
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 63
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 54
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 49
- 239000002904 solvent Substances 0.000 claims description 29
- 229960004191 artemisinin Drugs 0.000 claims description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 125000006239 protecting group Chemical group 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 238000010511 deprotection reaction Methods 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 8
- 229930191701 arteannuin Natural products 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 238000006482 condensation reaction Methods 0.000 claims description 5
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- 150000001414 amino alcohols Chemical class 0.000 claims description 4
- 239000003208 petroleum Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 239000003377 acid catalyst Substances 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 2
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical group C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 claims description 2
- 230000003287 optical effect Effects 0.000 claims 3
- 235000009051 Ambrosia paniculata var. peruviana Nutrition 0.000 claims 1
- 235000003097 Artemisia absinthium Nutrition 0.000 claims 1
- 240000001851 Artemisia dracunculus Species 0.000 claims 1
- 235000017731 Artemisia dracunculus ssp. dracunculus Nutrition 0.000 claims 1
- 235000003261 Artemisia vulgaris Nutrition 0.000 claims 1
- 239000001138 artemisia absinthium Substances 0.000 claims 1
- 239000002841 Lewis acid Substances 0.000 abstract description 4
- 150000007517 lewis acids Chemical class 0.000 abstract description 4
- 239000002253 acid Substances 0.000 abstract description 3
- 238000006555 catalytic reaction Methods 0.000 abstract description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
- 150000001875 compounds Chemical class 0.000 description 26
- 238000005481 NMR spectroscopy Methods 0.000 description 19
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 18
- 239000012074 organic phase Substances 0.000 description 18
- 239000000047 product Substances 0.000 description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 238000001914 filtration Methods 0.000 description 14
- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 description 13
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
- 229920006395 saturated elastomer Polymers 0.000 description 12
- 238000003756 stirring Methods 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 10
- 239000002274 desiccant Substances 0.000 description 10
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 10
- 239000008367 deionised water Substances 0.000 description 9
- 229910021641 deionized water Inorganic materials 0.000 description 9
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 8
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical group COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 8
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 8
- 229930101531 artemisinin Natural products 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 230000032798 delamination Effects 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- IRXSLJNXXZKURP-UHFFFAOYSA-N fluorenylmethyloxycarbonyl chloride Chemical compound C1=CC=C2C(COC(=O)Cl)C3=CC=CC=C3C2=C1 IRXSLJNXXZKURP-UHFFFAOYSA-N 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 description 3
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 3
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- BTEQQLFQAPLTLI-UHFFFAOYSA-N 2-trimethylsilylethyl carbonochloridate Chemical compound C[Si](C)(C)CCOC(Cl)=O BTEQQLFQAPLTLI-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- 230000000078 anti-malarial effect Effects 0.000 description 2
- 239000003430 antimalarial agent Substances 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 229960000981 artemether Drugs 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 2
- SXYIRMFQILZOAM-HVNFFKDJSA-N dihydroartemisinin methyl ether Chemical compound C1C[C@H]2[C@H](C)CC[C@H]3[C@@H](C)[C@@H](OC)O[C@H]4[C@]32OO[C@@]1(C)O4 SXYIRMFQILZOAM-HVNFFKDJSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000001506 immunosuppresive effect Effects 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000003223 protective agent Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- BQBRGOQCWAXXLR-UHFFFAOYSA-N 1-(chloromethyl)-2,4-dimethoxybenzene Chemical compound COC1=CC=C(CCl)C(OC)=C1 BQBRGOQCWAXXLR-UHFFFAOYSA-N 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 229930187998 Dihydroarteannuin Natural products 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000012445 acidic reagent Substances 0.000 description 1
- 150000001343 alkyl silanes Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- BJDCWCLMFKKGEE-ISOSDAIHSA-N artenimol Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C BJDCWCLMFKKGEE-ISOSDAIHSA-N 0.000 description 1
- FIHJKUPKCHIPAT-AHIGJZGOSA-N artesunate Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@@H](OC(=O)CCC(O)=O)[C@@H]4C FIHJKUPKCHIPAT-AHIGJZGOSA-N 0.000 description 1
- 229960004991 artesunate Drugs 0.000 description 1
- HKVFISRIUUGTIB-UHFFFAOYSA-O azanium;cerium;nitrate Chemical compound [NH4+].[Ce].[O-][N+]([O-])=O HKVFISRIUUGTIB-UHFFFAOYSA-O 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- FDJUMMKAFUMWBI-UHFFFAOYSA-N chloro carbonochloridate Chemical compound ClOC(Cl)=O FDJUMMKAFUMWBI-UHFFFAOYSA-N 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229910001882 dioxygen Inorganic materials 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- MOVBJUGHBJJKOW-UHFFFAOYSA-N methyl 2-amino-5-methoxybenzoate Chemical compound COC(=O)C1=CC(OC)=CC=C1N MOVBJUGHBJJKOW-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- ZVVSSOQAYNYNPP-UHFFFAOYSA-N olaflur Chemical compound F.F.CCCCCCCCCCCCCCCCCCN(CCO)CCCN(CCO)CCO ZVVSSOQAYNYNPP-UHFFFAOYSA-N 0.000 description 1
- 229960001245 olaflur Drugs 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- UAWABSHMGXMCRK-UHFFFAOYSA-L samarium(ii) iodide Chemical compound I[Sm]I UAWABSHMGXMCRK-UHFFFAOYSA-L 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- KSAVQLQVUXSOCR-UHFFFAOYSA-M sodium lauroyl sarcosinate Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CC([O-])=O KSAVQLQVUXSOCR-UHFFFAOYSA-M 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- QSUJAUYJBJRLKV-UHFFFAOYSA-M tetraethylazanium;fluoride Chemical compound [F-].CC[N+](CC)(CC)CC QSUJAUYJBJRLKV-UHFFFAOYSA-M 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/20—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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Abstract
The invention relates to the fields of organic synthesis and pharmaceutical intermediates, in particular to a method for preparing beta-type mono/bis sweet wormwood (symmetrical and asymmetrical) alkyl ether amine maleate by stereoselectivity, which comprises the following steps: under the catalysis of acid (including Lewis acid) catalyst, amino protected linear alkyl alcohol amine compound and acetyl dihydroartemisinin are used to produce alpha-type and beta-type mixed mono/bis (symmetrical and asymmetrical) alkyl ether amine with beta-type as main product, and through re-crystallization, beta-type mono/bis (symmetrical and asymmetrical) alkyl ether amine with high diastereoisomer is obtained, and after eliminating amino protection, the obtained beta-type mono/bis (symmetrical and asymmetrical) alkyl ether primary amine or secondary amine is salified with maleic acid to obtain corresponding optically pure beta-type mono/bis (symmetrical and asymmetrical) alkyl ether amine maleate, as shown in formulas (1) and (2). The method has high yield and high stereoselectivity.
Description
Technical Field
The invention relates to the fields of organic synthesis and pharmaceutical intermediates, in particular to a method for preparing beta-type arteannuin mono/bis (symmetrical and asymmetrical) alkyl ether amine maleate in a stereoselective manner.
Background
Artemisinin is an antimalarial drug isolated from the medicinal plant Artemisia annua in the 70 th century. So far, it is one of the medicines for effectively treating malaria worldwide and plays a great role clinically. Five antimalarial drugs (artemisinin, artesunate, artemether, dihydroartemisinin and compound artemether) 9 dosage forms exist up to now and are sold in various countries. The dioxygen bridge in the artemisinin structure is a key pharmacophore and is an essential important component for the artemisinin structure to play a role. Since artemisinin was discovered, the study of its antimalarial activity with its derivatives has been a major medical focus, and scientists have also desired to discover new artemisinin derivatives and explore their activity.
Artemisinin and its derivatives have immunosuppressive activity in addition to antimalarial activity. By structurally modifying artemisinin, the water-soluble derivative maleate thereof has better immunosuppressive activity, and is expected to become a candidate drug for treating lupus erythematosus. Meanwhile, when further activity research is carried out on the artemisinin compound, the artemisinin compound has potential anti-tumor activity, such as inhibition of tumor angiogenesis, blocking of invasion and metastasis of tumor cells, induction of cell cycle retardation, promotion of apoptosis and the like.
The activity research of the discovered novel water-soluble artemisinin derivative beta-type bis-artealkyl ether amine maleate shows that the water-soluble artemisinin derivative beta-type bis-artealkyl ether amine maleate can inhibit leukemia cell proliferation and induce cell apoptosis; has better clinical development value and is used for treating leukemia, in particular acute leukemia.
The stereochemical features of these active compounds require higher diastereoselectivity. The prior synthesis method has lower yield and low stereoselectivity.
Disclosure of Invention
In order to solve the problems, the invention provides a method for preparing beta-type mono/bis sweet wormwood (symmetrical and asymmetrical) alkyl ether amine maleate in stereoselectivity: under the catalysis of an acidic catalyst (including Lewis acid), an amino-protected linear alkyl alcohol amine compound and acetyl dihydroartemisinin are used for generating alpha-type and beta-type mixed mono/bis (symmetrical and asymmetrical) alkyl ether amine with beta-type as main products in a stereoselective manner, the beta-type mono/bis (symmetrical and asymmetrical) alkyl ether amine with high diastereoisomer is obtained through recrystallization, and after the amino protection is removed, the obtained beta-type mono/bis (symmetrical and asymmetrical) alkyl ether primary amine or secondary amine forms salts with maleic acid, so that the corresponding optically pure beta-type mono/bis (symmetrical and asymmetrical) alkyl ether amine maleate is obtained.
In a first aspect of the present invention, there is provided a process for the stereoselective preparation of β -type mono/bis (symmetrical and asymmetrical) alkyl ether amine maleates comprising the steps of:
(i) Amino protection of beta mono/bis arteannuin (symmetrical and asymmetrical) alkanolamines: different protecting groups (Protective groups, P) are selected to protect the alcohol amine compound, so as to obtain the amino alcohol containing the protecting groups, wherein the amino alcohol is shown in the following formulas (3) and (4):
when P 1 When=h, P 2 Amino protecting groups suitable for the reaction, such as benzyl (Bn), t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), trifluoroacetyl (Tfa), dimethoxycarbonyl (Fmoc), trimethylsilylethoxycarbonyl (Teoc), methyloxycarbonyl (or ethoxycarbonyl), 2, 4-Dimethoxybenzyl (DMB) and p-methoxybenzyl (PMB);
when P 1 、P 2 When not equal to H, P 1 、P 2 Is a combination of any two amino protecting groups suitable for the reaction, such as benzyl (Bn), t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), trifluoroacetyl (Tfa), dimethoxycarbonyl (Fmoc), trimethylsilylethoxycarbonyl (Teoc), methyloxycarbonyl (or ethoxycarbonyl), 2, 4-Dimethoxybenzyl (DMB) and P-methoxybenzyl (PMB), or P 1 -P 2 Is that
Wherein R is H, -NO 2 、-Cl、-F、-Br、-CF 3 -CN and-NHCOCH 3 Combinations of these groups include combinations in which one or more and the positions of the substituents are different;
wherein P is 3 Amino protecting groups suitable for the reaction, such as benzyl (Bn), t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), trifluoroacetyl (Tfa), dimethoxycarbonyl (Fmoc), trimethylsilylethoxycarbonyl (Teoc), methyloxycarbonyl (or ethoxycarbonyl), 2, 4-Dimethoxybenzyl (DMB) and p-methoxybenzyl (PMB);
(ii) Condensation reaction:
1) The alpha and beta type mixed single arteannuin alkyl ether amine with beta type as main product is produced by using the amine alcohol compound containing protecting group and acetyl dihydroarteannuin obtained in the (i) under the action of acid (including Lewis acid) catalyst, and the following formula (5) is shown as follows:
when P 1 When=h, P 2 Amino protecting groups suitable for the reaction, such as benzyl (Bn), t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), trifluoroacetyl (Tfa), dimethoxycarbonyl (Fmoc), trimethylsilylethoxycarbonyl (Teoc), methyloxycarbonyl (or ethoxycarbonyl), 2, 4-Dimethoxybenzyl (DMB) and p-methoxybenzyl (PMB);
when P 1 、P 2 When not equal to H, P 1 、P 2 Is a combination of any two amino protecting groups suitable for the reaction, such as benzyl (Bn), t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), trifluoroacetyl (Tfa), dimethoxycarbonyl (Fmoc), trimethylsilylethoxycarbonyl (Teoc), methyloxycarbonyl (or ethoxycarbonyl), 2, 4-Dimethoxybenzyl (DMB) and P-methoxybenzyl (PMB), or P 1 -P 2 Is that
Wherein R is H, -NO 2 、-Cl、-F、-Br、-CF 3 -CN and-NHCOCH 3 Combinations of these groups include combinations in which one or more and the positions of the substituents are different;
2) The alpha and beta type mixed bis (symmetrical and asymmetrical) alkyl ether amine with beta type as main product is produced by using the amine alcohol compound containing protecting group and acetyl dihydroartemisinin in the presence of acid catalyst, and the beta type mixed bis (symmetrical and asymmetrical) alkyl ether amine is shown in the following formula (6):
wherein P is 3 Amino protecting groups suitable for the reaction, such as benzyl (Bn), t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), trifluoroacetyl (Tfa), dimethoxycarbonyl (Fmoc), trimethylsilylethoxycarbonyl (Teoc), methyloxycarbonyl (or ethoxycarbonyl), 2, 4-Dimethoxybenzyl (DMB) and p-methoxybenzyl (PMB);
the alpha and beta type mixed arteannuin alkyl ether amine is recrystallized to obtain optically pure beta type arteannuin alkyl ether amine;
(iii) Deprotection reaction:
1) Deprotection reaction is carried out on the optically pure beta-type mono-arteannuin alkyl ether amine obtained in the step (ii) to obtain the optically pure beta-type mono-arteannuin alkyl ether amine, wherein the optically pure beta-type mono-arteannuin alkyl ether amine is shown in the following formula (7):
when P 1 When=h, P 2 Amino protecting groups suitable for the reaction, such as benzyl (Bn), t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), trifluoroacetyl (Tfa), dimethoxycarbonyl (Fmoc), trimethylsilylethoxycarbonyl (Teoc), methyloxycarbonyl (or ethoxycarbonyl), 2, 4-Dimethoxybenzyl (DMB) and p-methoxybenzyl (PMB);
when P 1 、P 2 When not equal to H, P 1 、P 2 Is benzyl (Bn), t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), trifluoroacetyl (Tfa), fluorenylmethoxycarbonyl (Fmoc), trimethylsiloxyAny two combinations of amino protecting groups suitable for the reaction, such as carbonyl (Teoc), methoxy (or ethoxy) carbonyl, 2, 4-Dimethoxybenzyl (DMB) and P-methoxybenzyl (PMB), or P 1 -P 2 Is that
Wherein R is H, -NO 2 、-Cl、-F、-Br、-CF 3 -CN and-NHCOCH 3 Combinations of these groups include combinations in which one or more and the positions of the substituents are different;
2) Deprotection reaction is carried out on the optically pure beta-type bis (symmetrical and asymmetrical) alkyl ether amine obtained in the step (ii) to obtain the optically pure beta-type bis (symmetrical and asymmetrical) alkyl ether amine, wherein the optically pure beta-type bis (symmetrical and asymmetrical) alkyl ether amine is shown in the following formula (8):
wherein P is 3 Amino protecting groups suitable for the reaction, such as benzyl (Bn), t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), trifluoroacetyl (Tfa), dimethoxycarbonyl (Fmoc), trimethylsilylethoxycarbonyl (Teoc), methyloxycarbonyl (or ethoxycarbonyl), 2, 4-Dimethoxybenzyl (DMB) and p-methoxybenzyl (PMB);
(iv) Salt forming reaction:
1) Salifying the optically pure beta-type monoalkenyl ether amine without a protecting group obtained in the step (vi) with maleic acid to obtain optically pure beta-type monoalkenyl ether amine maleate, wherein the optically pure beta-type monoalkenyl ether amine maleate is shown in the following formula (9):
2) Salifying the optically pure beta-type bis (symmetrical and asymmetrical) alkylamine without protective group obtained in the step (vi) with maleic acid to obtain optically pure beta-type bis (symmetrical and asymmetrical) alkylamine maleate, wherein the optically pure beta-type bis (symmetrical and asymmetrical) alkylamine maleate is shown in the following formula (10):
and recrystallizing the beta-type arteannuin alkyl ether amine maleate to obtain a pure compound.
In the preferred embodiment process, in step (i), the amino protection of the alcohol amine compound is carried out in the presence of a solvent and a base to give mono/bis (symmetrical and unsymmetrical) alkylamines containing protecting groups.
In the preferred embodiment process, in step (i), the protecting agent used is benzyl bromide (BnBr), di-tert-butyl dicarbonate ((Boc)) 2 O), benzyl chloroformate (CbzCl), trifluoroacetic anhydride (TFAA), p-methoxybenzyl chloride (PMBCl), 9-fluorenylmethyl chloroformate (FmocCl), trimethylsilyl ethoxycarbonyl chloride (TeocCl), 2, 4-dimethoxybenzyl chloride (DMBCl), methyl (or ethyl) oxycarbonyl chloride, phthalic anhydride, and the like.
In a preferred embodiment process, in step (i), the base used comprises: sodium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, triethylamine, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, and the like are suitable as organic or inorganic bases for the reaction.
In the method of the preferred embodiment, in the step (i), the molar ratio of the alcohol amine compound to the alkali to the amino protecting agent is 1:2.0-10:2-5, and the reaction temperature is-10-50 ℃.
In a preferred embodiment of the method, in step (i), the solvent for the reaction is an organic solvent suitable for the reaction, such as tetrahydrofuran, chloroform, methylene chloride, ethanol, diethyl ether, 1, 4-dioxane, methanol, N-dimethylformamide, ethyl acetate, toluene and acetonitrile.
In a preferred embodiment process, the acidic (including lewis acid) catalyst used in step (ii) includes, but is not limited to, boron trifluoride etherate and trifluoroacetic acid; the mol ratio of the acetyl dihydroartemisinin, alcohol amine containing a protecting group and the acid catalyst in the reaction is 1.0:1.0-5.0:0.4-1, and the reaction temperature is-10-30 ℃; the solvent for the reaction is an organic solvent suitable for the reaction, such as tetrahydrofuran, chloroform, dichloromethane, 1, 2-dichloroethane or diethyl ether, the solvent for recrystallization is a solvent suitable for the step of recrystallization, such as n-hexane, petroleum ether, cyclohexane, n-heptane, diethyl ether, dichloromethane, ethyl acetate, ethanol and methanol, and the beta-type product in the mixture of alpha and beta usually accounts for 90% or more.
In a preferred embodiment method, in step (iii), the reagent for removing amine group protection comprises: (1) tetraalkyl amine fluoride: such as tetramethyl ammonium fluoride, tetraethyl ammonium fluoride, tetrabutyl ammonium fluoride and the like, which can be used for removing the groups such as the fluorenyl methoxycarbonyl, the trimethylsilylethoxycarbonyl and the like; (2) organic amines: such as piperidine, ethanolamine, cyclohexylamine, morpholine, pyrrolidone, DBU, triethylamine and the like, can be used for removing the fluorenyl methoxycarbonyl and trifluoroacetyl; (3) Alkylsilanes such as trimethyliodosilane which can be used for the removal of carbomethoxy, carbotrimethylsiloxy and t-butoxycarbonyl; (4) acidic reagent: such as p-toluenesulfonic acid, methanesulfonic acid and the like, can be used for removing groups such as 2, 4-dimethoxy benzyl, trimethyl silicon ethoxycarbonyl and the like; (5) oxidizing agent: reagents such as Ceric Ammonium Nitrate (CAN), DDQ, samarium diiodide and the like CAN be used for removing groups such as p-methoxybenzyl, 2, 4-dimethoxybenzyl, benzyl and the like; (6) Other deprotection reagents, hydrazine hydrate, methamidol solution, sodium borohydride, etc. can be used to remove the o-arylbenzoyl group.
In the preferred embodiment process, in step (iii), the molar ratio of beta-form mono/bis (symmetrical and asymmetrical) alkyl ether amine to deprotection reagent is 1.0:1.0-10.0, the reaction temperature is 0-30 ℃, and the reaction solvent is 1, 4-dioxane, chloroform, acetonitrile, dichloromethane, ethanol, dichloromethane, tetrahydrofuran, diethyl ether, isopropanol, etc. organic solvents suitable for the reaction.
In a preferred embodiment of the process, in step (iv), the acid used is maleic acid, the molar ratio of β -type mono/bis (symmetrical and asymmetrical) alkyl ether amine to maleic acid is 1.0:1.0-10.0, the reaction temperature is-10-15 ℃, and the solvents used for the reaction include, but are not limited to, ethyl acetate, diethyl ether, and the like suitable solvents for the reaction; the solvents used for recrystallization were: ethanol/n-hexane, ethanol/n-heptane, ethanol/cyclohexane, ethanol/petroleum ether and the like are suitable solvents for the recrystallization in this step.
The invention has the advantages that:
the invention provides a method for preparing beta-type mono/bis sweet wormwood (symmetrical and asymmetrical) alkyl ether amine maleate with high stereoselectivity.
Drawings
FIG. 1 shows nuclear magnetic resonance hydrogen spectrum of bis-arteether amine dimaleate.
Detailed Description
The following provides a detailed description of embodiments of the present invention with reference to examples.
Example 1: amino protection reaction
(1) The reaction equation:
experimental operation: ethanolamine (5.0 mL,82.8 mmol) was taken in a 100mL round bottom flask and dissolved in 50mL dichloromethane and triethylamine (23 mL,165.7 mmol) was added. The ice bath was cooled to 0deg.C and di-tert-butyl dicarbonate (28.5 mL,124.2 mmol) was slowly added dropwise to the solution. After the addition, the reaction was warmed to room temperature and stirred continuously. The reaction was followed by TLC, after complete consumption of starting material, quenched by deionized water (30 mL), and allowed to stand for delamination. The organic phase was washed twice with saturated brine (30 mL) and dried over anhydrous sodium sulfate. After the drying agent was removed by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 12.7g of a pure compound in a yield of 95%.
1 H NMR(400MHz,CDCl 3 ):δ1.37(s,9H),3.18-3.6(m,4H),3.93(s,1H),5.42(s,1H). 13 C NMR(100MHz,CDCl 3 ):δ28.6,48.7,79.5,116.3,134.0,155.4.
(2) The reaction equation:
experimental operation: diethanolamine (3.1 mL,0.05 mol) was taken in a 100mL round bottom flask and dissolved in 50mL dichloromethane and N, N-diisopropylethylamine (16.5 mL,0.1 mol) was added. The ice bath was cooled to 0deg.C and a solution of p-methoxybenzyl chloride (10.2 mL,0.075 mol) in methylene chloride (20 mL) was slowly added dropwise to the solution. After the addition, the reaction was warmed to room temperature and stirred continuously. The reaction was followed by TLC, after complete consumption of starting material, quenched by deionized water (20 mL), and allowed to stand for delamination. The organic phase was washed twice with saturated brine (30 mL) and dried over anhydrous sodium sulfate. After the drying agent was removed by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 8.3g of a pure compound in 92% yield.
1 H NMR(400MHz,CDCl 3 ):δ2.73-2.76(m,4H),3.62-3.65(m,2H),3.70(s,2H),3.78(s,3H),6.86-6.84(m,2H),7.21-7.20(m,2H).
(3) The reaction equation:
experimental operation: ethanolamine (2.5 mL,41.4 mmol) was taken in a 100mL round bottom flask and dissolved in 50mL dichloromethane and sodium bicarbonate (13.8 g,0.17 mol) was added. The ice bath was cooled to 0℃and 9-fluorenylmethacrylate chloroformate (9.6 g,37.3 mmol) was slowly added dropwise to the solution. After the addition, the reaction was warmed to room temperature and stirred continuously. The reaction was followed by TLC, after complete consumption of starting material, quenched by deionized water (30 mL), and allowed to stand for delamination. The organic phase was washed twice with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 9.5g of a pure compound in a yield of 90%.
1 H NMR(400MHz,CDCl 3 ):δ2.06(t,J＝4.8Hz,1H),3.40-3.30(m,2H),3.77-3.67(m,2H),4.22(t,J＝6.5Hz,1H),4.43(d,J＝6.7Hz,2H),5.15(s,1H),7.32(t,J＝7.4Hz,2H),7.41(t,J＝7.4Hz,2H),7.59(d,J＝7.5Hz,2H),7.77(d,J＝7.5Hz,2H). 13 C NMR(100MHz,CDCl 3 ,):δ43.45,47.24,62.36,66.76,125.00,1127.05,127.70,141.33,143.86,157.14,19.98.
(4) The reaction equation:
experimental operation: ethanolamine (5.0 mL,82.8 mmol) was taken in a 100mL round bottom flask and dissolved in 50mL dichloromethane and triethylamine (23 mL,165.7 mmol) was added. The ice bath was cooled to 0deg.C and ethyl chloroformate (17.3 mL,124.2 mmol) was slowly added dropwise to the solution. After the addition, the reaction was warmed to room temperature and stirred continuously. The reaction was followed by TLC, after complete consumption of starting material, quenched by deionized water (30 mL), and allowed to stand for delamination. The organic phase was washed twice with saturated brine (30 mL) and dried over anhydrous sodium sulfate. After the drying agent was removed by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 10.1g of a pure compound in 92% yield.
1 H NMR(400MHz,CDCl 3 ):δ1.24(t,J＝7.1Hz,3H),3.49(t,J＝6.6Hz,2H),3.48(t,J＝6.6,2H),4.23(q,J＝7.1Hz,2H).
Experimental operation: ethanolamine derivative (5.0 g,37.6 mmol) and sodium carbonate (5.18 g,48.9 mmol) were weighed into a 250mL round bottom flask, 1, 4-dioxane/water (90 mL, 1:1) was added and stirred at room temperature to form a suspension. Another 9-fluorenylmethyl chloroformate (8.7 g,33.8 mmol) was dissolved in 30ml of toluene, and was slowly added dropwise to the above reaction mixture using a dropping funnel (the internal temperature was controlled to be not more than 25 ℃ C. During the addition), and after the addition, stirring was continued overnight. TLC followed the reaction, after complete consumption of starting material, concentrated hydrochloric acid was used to adjust pH to 3 and extracted twice with ethyl acetate (50 mL), the organic phase was separated, washed twice with saturated brine (50 mL), dried over anhydrous sodium sulfate (20 g) and concentrated to give crude 10.8g in 90% yield.
(5) The reaction equation:
experimental operation: diethanolamine (5.0 g,47.56 mmol) and sodium carbonate (6.55 g,61.83 mmol) were weighed into a 250mL round bottom flask, 1, 4-dioxane/water (90 mL, 1:1) was added and stirred at room temperature to form a suspension. Another 9-fluorenylmethyl chloroformate (11.07 g,42.80 mmol) was dissolved in 30ml of toluene, and was slowly added dropwise to the above reaction mixture using a dropping funnel (the internal temperature was controlled to be not more than 25 ℃ C. During the addition), and after the addition, stirring was continued overnight. TLC followed the reaction, after complete consumption of starting material, concentrated hydrochloric acid was used to adjust pH to 3 and extracted twice with ethyl acetate (50 mL), the organic phase was separated, washed twice with saturated brine (50 mL), dried over anhydrous sodium sulfate (20 g) and concentrated to give 12g of crude product in 95.5% yield.
1 H NMR(400MHz,CDCl 3 ):3.19(d,J＝3.6Hz,2H),3.40(m,J＝4.0Hz,4H),3.77(d,J＝8.0Hz,2H),4.23(t,J＝5.2Hz,1H),4.56-4.58(m,1H),7.30-7.34(m,2H),7.36-7.41(m,2H),7.56(d,J＝7.6Hz,2H),7.76(d,J＝7.6Hz,2H).
Example 2: condensation reaction
(1) The reaction equation:
experimental operation: the compound acetyldihydroartemisinin (3.3 g,10.0 mmol) was weighed into 20mL of dichloromethane, and to this solution was added the alcohol amine compound (1.6 g,10.0 mmol). Cooling to 0-5deg.C in ice bath, and dropwise adding BF under stirring 3 .Et 2 A solution of O (0.5 mL,4.0 mmol) in dichloromethane (2 mL) was then warmed slowly to 20-25℃and the reaction was followed by TLC in time, after approximately 4 hours the reaction reached equilibrium. The reaction solution was washed with water (the pH of the wash water was measured), saturated aqueous sodium bicarbonate solution, then water was washed to neutrality, and finally with saturated foodThe organic phase was washed with brine solution and dried over anhydrous sodium sulfate. Filtering, concentrating, and column chromatography to obtain 2.2g of pure product with a yield of 51%.
1 H NMR(400MHz,CDCl 3 ):δ0.93-0.97(m,7H),1.25-1.36(m,2H),1.38(s,9H),1.43(s,3H),1.48-1.56(m,2H),1.62-1.67(m,1H),1.73-1.79(m,2H),1.81-1.92(m,1H),2.03-2.07(m,1H),2.21-2.24(m,1H),2.34-2.42(m,1H),2.67-2.69(m,1H),3.63-3.91(m,4H),4.85(d,J＝3.2Hz,1H),5.44(s,1H).
(2) The reaction equation:
experimental operation: the compound acetyldihydroartemisinin (1.6 g,5.0 mmol) was weighed into 20mL of dichloromethane, and to this solution was added the alcohol amine compound (0.9 g,5.0 mmol). Cooling to 0-5deg.C in ice bath, and dropwise adding BF under stirring 3 .Et 2 O (0.25 mL,2.0 mmol) was then slowly warmed to 20-25℃and the reaction was followed by TLC in time, after approximately 4 hours the reaction reached equilibrium. The reaction solution was washed successively with water (note to measure the pH of the washing water), saturated aqueous sodium hydrogencarbonate solution, then water was washed to neutrality, finally washed with saturated aqueous sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate. Filtration, concentration and column chromatography give 940mg of product with a yield of 42%.
1 H NMR(400MHz,CDCl 3 ):δ0.89-0.95(m,7H),1.22-1.31(m,2H),1.43(s,3H),1.45-1.52(m,2H),1.58-1.63(m,1H),1.69-1.75(m,2H),1.79-2.05(m,2H),2.13-2.20(m,1H),2.30-2.65(m,2H),3.62-3.65(m,1H),3.69-3.72(m,2H),3.76-3.79(m,2H),3.83(s,3H),3.85-3.91(m,1H),4.82(d,J＝3.2Hz,1H),5.50(s,1H),6.84-6.86(m,2H),7.20-7.24(m,2H).
(3) The reaction equation:
experimental operation: the compound acetyldihydroartemisinin (1.6 g,5.0 mmol) was weighed into 20mL of dichloromethane, and to this solution was added the alcohol amine compound (0.9 g,5.0 mmol). Ice bath cooled to 0-5℃, stirring dropwise with trifluoroacetic acid (0.15 mL,2.0 mmol) in dichloromethane (2 mL), then slowly heating to 20-25℃, TLC followed by reaction in time, after about 4 hours the reaction reached equilibrium. The reaction solution was washed successively with water (note to measure the pH of the washing water), saturated aqueous sodium hydrogencarbonate solution, then water was washed to neutrality, finally washed with saturated aqueous sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate. Filtration, concentration and column chromatography give 890mg of product with a yield of 40%.
Nuclear magnetic data were as in experimental run (3).
(4) The reaction equation:
experimental operation: the compound acetyldihydroartemisinin (3.3 g,10.0 mmol) was weighed into 20mL dichloromethane and to this solution was added the alcohol amine compound (2.8 g,10.0 mmol). Cooling to 0-5deg.C in ice bath, and dropwise adding BF under stirring 3 .Et 2 A solution of O (0.5 mL,4.0 mmol) in dichloromethane (2 mL) was then warmed slowly to 20-25℃and the reaction was followed by TLC in time, after approximately 4 hours the reaction reached equilibrium. The reaction solution was washed successively with water (note to measure the pH of the washing water), saturated aqueous sodium hydrogencarbonate solution, then water was washed to neutrality, finally washed with saturated aqueous sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate. Filtering, concentrating, and column chromatography to obtain 2.75g of pure product with the yield of 50%.
1 H NMR(400MHz,CDCl 3 ):δ0.85-0.90(m,7H),1.21-1.31(m,2H),1.38(s,3H),1.42-1.50(m,2H),1.56-1.62(m,1H),1.67-1.73(m,2H),1.75-2.01(m,2H),2.10-2.21(m,1H),2.32-2.63(m,2H),3.60-3.62(m,1H),3.68-3.70(m,2H),3.84-3.90(m,1H),4.22(t,J＝6.5Hz,1H),4.43(d,J＝6.7Hz,2H),4.85(d,J＝3.2Hz,1H),5.52(s,1H),7.30(t,J＝7.4Hz,2H),7.36(t,J＝7.4Hz,2H),7.59(d,J＝7.5Hz,2H),7.75(d,J＝7.5Hz,2H).
(5) The reaction equation:
experimental operation: the compound acetyldihydroartemisinin (3.2 g,10.0 mmol) was weighed into 20mL dichloromethane and to this solution was added the alcohol amine compound (3.6 g,10.0 mmol). Cooling to 0-5deg.C in ice bath, and dropwise adding BF under stirring 3 .Et 2 A solution of O (0.5 mL,2.0 mmol) in dichloromethane (2 mL) was then warmed slowly to 20-25℃and the reaction was followed by TLC in time, after approximately 4 hours the reaction reached equilibrium. The reaction solution was washed successively with water (note to measure the pH of the washing water), saturated aqueous sodium hydrogencarbonate solution, then water was washed to neutrality, finally washed with saturated aqueous sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate. Filtering, concentrating, and column chromatography to obtain 2.7g of pure product with the yield of 44%.
1 H NMR(400MHz,CDCl 3 ):δ0.79-0.85(m,7H),1.15-1.27(m,2H),1.30(t,J＝3.8Hz,3H),1.39(s,3H),1.39-1.47(m,2H),1.53-1.60(m,1H),1.65-1.71(m,2H),1.73-1.98(m,2H),2.08-2.17(m,1H),2.31-2.60(m,2H),3.58-3.60(m,1H),3.65-3.69(m,2H),3.85-3.92(m,1H),4.12-4.15(m,2H),4.20(t,J＝6.5Hz,1H),4.39(d,J＝6.7Hz,2H),4.82(d,J＝3.2Hz,1H),5.50(s,1H),7.31(t,J＝7.4Hz,2H),7.39(t,J＝7.4Hz,2H),7.61(d,J＝7.5Hz,2H),7.79(d,J＝7.5Hz,2H).
(6) The reaction equation:
experimental operation: compound 105 (8.2 g,25.0 mmol) was weighed and dissolved in 20mL of methylene chloride, and to this solution was added an alcohol amine compound (1.6 g,5.0 mmol). Cooling to 0-5deg.C in ice bath, and dropwise adding BF under stirring 3 .Et 2 O (0.5 mL,4.0 mmol) was then slowly warmed to 20-25℃and the reaction was followed by TLC in time, after approximately 4 hours the reaction reached equilibrium. The reaction solution was washed successively with water (note to measure the pH of the washing water), saturated aqueous sodium hydrogencarbonate solution, then water was washed to neutrality, finally washed with saturated aqueous sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate. Filtering, concentrating, column chromatography to obtain 2.1g of product,the yield thereof was found to be 50%.
1 H NMR(400MHz,CD 2 Cl 2 ):0.80-0.97(m,14H),1.16-1.28(m,5H),1.42-1.58(m,9H),1.49-1.59(m,2H),1.65-1.70(m,4H),1.83-2.03(m,3H),2.31-2.39(m,2H),2.60-2.63(m,1H),3.29-3.94(m,5H),3.84-3.94(m,1H),4.21-4.25(m,1H),4.40-4.48(m,2H),4.68-4.77(m,1H),5.31-5.37(m,2H),7.29-7.33(m,2H),7.38-7.41(m,2H),7.56-7.58(m,2H),7.75-7.70(m,2H).
Example 3: deprotection reaction
(1) The reaction equation:
experimental operation: the compound (1.7 g,4 mmol) was weighed into a 50mL round bottom flask and 15mL acetonitrile was added. To this solution was then added trimethyliodinated alkane (5.1 mL,36 mmol) and stirred overnight at room temperature. After the consumption of the raw materials was completed, methanol was added and the solvent was distilled off under reduced pressure. To the residue was added 1mol/LNaOH solution (20 mL) and diluted and extracted with ethyl acetate (30 mL, TLC detection, confirming that the aqueous phase no longer contains product), the combined organic phases were washed twice with saturated brine (30 mL), dried over anhydrous sodium sulfate (10 g), the desiccant was filtered off, and the solvent was distilled off under reduced pressure to give a yellow oil in 85% yield.
(2) The reaction equation:
experimental operation: the compound (890 mg,2 mmol) was weighed into a 50mL round bottom flask and 15mL acetonitrile and 3mL deionized water were added. Ammonium cerium nitrate (3.3 g,6 mmol) was then added to the solution. The reaction was followed by TLC, and after complete consumption of starting material, the solvent was distilled off under reduced pressure. Deionized water (20 mL) was added to the residue, diluted and extracted with ethyl acetate (30 mL, tlc detection, confirming that the aqueous phase no longer contains product), the combined organic phases were washed twice with saturated brine (30 mL), dried over anhydrous sodium sulfate (10 g), and after the drying agent was filtered off, the solvent was distilled off under reduced pressure to give a yellow oil in 87% yield.
(3) The reaction equation:
/>
experimental operation: the compound (1.2 g,3.33 mmol) was weighed into a 100mL round bottom flask and was dissolved in 25mL THF. Tetrabutylammonium fluoride (1.4 mL,0.5 mol) was then added to the solution and stirring was continued at 25 ℃. TLC was followed up to completion, after the starting material was consumed, deionized water (20 mL) was added to dilute and extracted with ethyl acetate (30 mL, TLC detection, confirming that the aqueous phase no longer contains product), the combined organic phases were washed twice with saturated brine (30 mL), dried over anhydrous sodium sulfate (10 g), the desiccant was filtered off, and the solvent was distilled off under reduced pressure to give a yellow oil in 90% yield
(4) The reaction equation:
experimental operation: the compound (1.83 g,3.33 mmol) was weighed into a 50mL round bottom flask and added with 30mL of dichloromethane and stirred at room temperature to dissolve all, and DBU (1.5 mL,10 mmol) was added to the solution and stirring continued at room temperature overnight. Deionized water (20 mL) was added until the consumption of the material was complete, and the mixture was allowed to stand for delamination. The organic phase was washed with saturated brine (20 mL) and filtered over anhydrous sodium sulfate. The drying agent was filtered off and the solvent was distilled off under reduced pressure to give a yellow oil in 92% yield.
(5) The reaction equation:
experimental operation: the compound (3.1 g,5 mmol) was weighed into a 50mL round bottom flask and 15mL acetonitrile was added. To the solution was then added trimethyliodinated alkane (5.7 mL,40 mmol) and stirred overnight at room temperature. After the consumption of the raw materials was completed, methanol was added and the solvent was distilled off under reduced pressure. To the residue was added 1mol/LNaOH solution (20 mL) and diluted and extracted with ethyl acetate (30 mL, TLC detection, confirming that the aqueous phase no longer contains product), the combined organic phases were washed twice with saturated brine (30 mL), dried over anhydrous sodium sulfate (10 g), the desiccant was filtered off, and the solvent was distilled off under reduced pressure to give a yellow oil in 85% yield.
(6) The reaction equation:
experimental operation: the compound (800 mg,0.94 mmol) was weighed into a 50mL round bottom flask and dissolved in total by the addition of 8mL THF. Tetrabutylammonium fluoride (0.64 mL,1.34 mmol) was then added to the solution and stirring continued at 25 ℃. After complete consumption of the starting material, TLC followed by dilution with deionized water (20 mL) and extraction with ethyl acetate (30 mL, TLC detection, confirming no more product in the aqueous phase), the combined organic phases were washed twice with saturated brine (30 mL), dried over anhydrous sodium sulfate (10 g), filtered off the drying agent and the solvent was evaporated under reduced pressure to give a yellow oil with a yield of 88%.
Example 4: salt formation reaction
(1) The reaction equation:
experimental operation: artemisininyl etheramine (1.09 g,3.3 mmol) was weighed, maleic acid (306 mg,2.64 mmol) was weighed and dissolved in ethyl acetate (10.0 mL), and slowly added dropwise to an ethyl acetate solution of the above-obtained compound. After the dripping is finished, standing for 15min at 0 ℃, filtering, drying a filter cake, and recrystallizing with ethanol/n-hexane to obtain a pure compound with the yield of 30%.
1 H NMR(400MHz,CD 2 Cl 2 ):δ0.87-0.94(m,7H),1.21-1.38(m,2H),1.42(s,3H),1.45-1.48(m,2H),1.59-1.69(m,2H),1.71-1.77(m,1H),1.85-1.90(m,1H),2.00-2.05(m,1H),2.32-2.40(m,1H),2.65-2.67(m,1H),3.30-3.32(m,2H),3.73-3.78(m,1H),4.08-4.14(m,1H),4.86(d,J＝3.2Hz,1H),5.45(s,1H),6.23(s,2H),8.14-8.16(m,2H).
13 C NMR(100MHz,CDCl 3 ):δ12.83,20.31,24.49,24.67,26.09,30.75,34.54,36.33,37.23,39.92,44.15,52.41,65.03,80.96,88.03,102.69,104.26,135.90,170.06.
(2) The reaction equation:
experimental operation: artemisininyl alkyl diethyl ether amine (1.09 g,3.3 mmol) was weighed, cooled to below room temperature, maleic acid (770 mg,6.6 mmol) was weighed and dissolved in ethyl acetate (20.0 mL) and added slowly dropwise to an ethyl acetate solution of the above-obtained compound. After the dripping is finished, standing for 15min at 0 ℃, filtering, drying a filter cake, and recrystallizing with ethanol/n-hexane to obtain a pure compound with the yield of 25%.
1 H NMR(400MHz,CD 2 Cl 2 ):δ0.92-0.96(m,7H),1.21-1.38(m,2H),1.42(s,3H),1.45-1.48(m,2H),1.59-1.69(m,2H),1.71-1.77(m,1H),1.85-1.90(m,1H),2.00-2.05(m,1H),2.32-2.40(m,1H),2.65-2.67(m,1H),3.30-3.32(m,2H),3.73-3.78(m,1H),4.08-4.14(m,1H),4.86(d,J＝3.2Hz,1H),5.45(s,1H),6.23(s,4H),8.14-8.16(m,4H).
(3) The reaction equation:
experimental operation: diarteannuin alkyl ether amine (640 mg,1 mmol) was weighed, cooled to below room temperature, maleic acid (90 mg,0.8 mmol) was weighed and dissolved with ethyl acetate (5 mL) and slowly added dropwise to an ethyl acetate solution of the above-obtained compound. After the dripping is finished, standing for 15min at 0 ℃, filtering, drying a filter cake, and recrystallizing with ethanol/n-hexane to obtain 300mg of pure compound with the yield of 40%.
1 H NMR(400MHz,CD 2 Cl 2 ):0.92-0.96(m,14H),1.24-1.37(m,11H),1.43-1.51(m,4H),1.60-1.64(m,4H),1.74-1.79(m,2H),1.87-1.92(m,2H),2.01-2.07(m,2H),2.29-1.37(m,2H),2.62-2.65(m,2H),3.40(s,4H),3.83-3.86(m,2H),4.10-4.15(m,2H),4.82(d,J＝3.2Hz,2H),5.14(s,2H),6.37(s,4H).
(4) The reaction equation:
experimental operation: diarteannuin alkyl ether amine (640 mg,1 mmol) was weighed, cooled to below room temperature, maleic acid (90 mg,0.75 mmol) was weighed and dissolved with ethyl acetate (5 mL) and slowly added dropwise to an ethyl acetate solution of the above-obtained compound. After the dripping is finished, standing for 15min at 0 ℃, filtering, drying a filter cake, and recrystallizing with ethanol/n-hexane to obtain 260mg of pure compound with the yield of 35%. The nuclear magnetic resonance hydrogen spectrum of the bis-arteether amine bis-maleate is shown in figure 1.
1 H NMR(400MHz,CD 2 Cl 2 ):0.89-0.96(m,14H),1.21-1.4(m,12H),1.42-1.58(m,3H),1.69-1.79(m,4H),1.86-1.91(m,2H),1.99-2.05(m,2H),2.32-2.41(m,4H),3.22-3.34(m,4H),4.05-4.07(m,4H),4.53(d,J＝9.2Hz,2H),5.42(s,2H),6.26(s,4H).
While the preferred embodiments of the present invention have been illustrated and described, the present invention is not limited to the embodiments, and various equivalent modifications and substitutions can be made by one skilled in the art without departing from the spirit of the present invention, and these equivalent modifications and substitutions are intended to be included in the scope of the present invention as defined in the appended claims.
Claims (5)
1. Stereoselective preparationβA method of bis-arteannuin alkyl ether amine maleate form comprising the steps of:
(i) Amino protection reaction:
selection of protecting group P 3 Protecting the alcohol amine compound to obtain amino alcohol containing a protecting group, wherein the amino alcohol is shown as a formula (4):
(ii) Condensation reaction:
stereoselectively generating the amino alcohol compound containing the protecting group obtained in the step (i) and acetyl dihydroartemisinin under the action of an acid catalystβOf the type of main productsα、βA mixed bis-artemisinin alkyl ether amine of the type shown in formula (6):
the obtained productα、βRecrystallizing the mixed bis-arteannuin alkyl ether amine to obtain the corresponding optical purityβBis arteannuin alkyl ether amine of the type;
(iii) Deprotection reaction:
for the optically pure product obtained in step (ii)βDeprotection reaction is carried out on the double-sweet wormwood alkyl ether amine within the temperature range of 0-30 ℃ to obtain corresponding optical purityβBis-artemisinin alkyl ether amine of the type shown in formula (8):
the deprotecting reagent is selected from trimethyl iodosilane, CAN, tetrabutylammonium fluoride and DBU;
(iv) Salt forming reaction:
for the optically pure product obtained in step (iii)βSalifying the bis-arteannuin alkyl ether amine with maleic acid to obtain optically pure productβBis-arteannuin alkyl ether amine maleate of the type shown in the following formula (10):
wherein m is 1,2,3 or 4; n is 1,2,3 or 4; x is 1/2,1 or 2; p (P) 3 Is fluorenylmethoxycarbonyl;
the obtained optical purityβAnd recrystallizing the double sweet wormwood alkyl ether amine maleate to obtain a pure product.
2. The process according to claim 1, wherein in step (i) the amino protection reaction is carried out in the presence of a solvent and a base;
the alkali of the amino protection reaction is selected from sodium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, triethylamine, sodium bis (trimethylsilyl) amide or potassium bis (trimethylsilyl) amide;
the solvent for the amino protection reaction is selected from tetrahydrofuran, chloroform, dichloromethane, ethanol, diethyl ether, 1, 4-dioxane, methanol, N, N-dimethylformamide, ethyl acetate, toluene or acetonitrile.
3. The process according to claim 1, wherein in step (ii), the acidic catalyst of the condensation reaction is boron trifluoride etherate or trifluoroacetic acid; the solvent for the condensation reaction is selected from tetrahydrofuran, chloroform, methylene dichloride, 1, 2-dichloroethane or diethyl ether; the solvent for recrystallization is selected from n-hexane, petroleum ether, cyclohexane, n-heptane, diethyl ether, dichloromethane, ethyl acetate, ethanol or methanol.
4. The process according to claim 1, wherein in step (iii), the solvent for the deprotection reaction is selected from 1, 4-dioxane, chloroform, acetonitrile, dichloromethane, ethanol, dichloromethane, tetrahydrofuran, diethyl ether or isopropanol.
5. The process according to claim 1, wherein in step (iv), the solvent of the salification reaction is ethyl acetate or diethyl ether;
the solvent used for recrystallization is selected from the following combinations: ethanol and n-hexane; ethanol and n-heptane; ethanol and cyclohexane; or ethanol and petroleum ether.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1900081A (en) * | 2005-07-22 | 2007-01-24 | 中国科学院上海药物研究所 | Water soluble artemisine derivative and its preparing method, medicinal composition and use |
| CN102153564A (en) * | 2011-01-31 | 2011-08-17 | 中国科学院上海药物研究所 | Nitrogen-atom-containing arteannuin dimers, and preparation method and application thereof |
| CN103664985A (en) * | 2013-12-12 | 2014-03-26 | 华东理工大学 | Stereoselectivity preparation method of beta-hydroxy sweet wormwood herb alkyl ether |
| WO2015152577A2 (en) * | 2014-04-02 | 2015-10-08 | 연세대학교 산학협력단 | Composition for preventing and treating bone disease |
-
2017
- 2017-06-09 CN CN201710433470.0A patent/CN109020992B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1900081A (en) * | 2005-07-22 | 2007-01-24 | 中国科学院上海药物研究所 | Water soluble artemisine derivative and its preparing method, medicinal composition and use |
| CN102153564A (en) * | 2011-01-31 | 2011-08-17 | 中国科学院上海药物研究所 | Nitrogen-atom-containing arteannuin dimers, and preparation method and application thereof |
| CN103664985A (en) * | 2013-12-12 | 2014-03-26 | 华东理工大学 | Stereoselectivity preparation method of beta-hydroxy sweet wormwood herb alkyl ether |
| WO2015152577A2 (en) * | 2014-04-02 | 2015-10-08 | 연세대학교 산학협력단 | Composition for preventing and treating bone disease |
Non-Patent Citations (4)
| Title |
|---|
| Synthesis and Cytotoxicity of Novel 10-Substituted Dihydroartemisinin Derivatives Containing N-Arylphenyl-ethenesulfonamide Groups;Yajing Liu et al.;《Molecules》;20130304;第18卷;第2864-2877页 * |
| 姚其正.氨基保护基.《药物合成反应》.中国国药科技出版社,2012,第491、494-496页. * |
| 李丕高.氨基保护.《现代有机合成化学》.陕西科学技术出版社,2006,第301-302页. * |
| 青蒿素二聚体的合成及生物活性研究进展;陈娇;《化工中间体》;20151231(第02期);第31-32页 * |
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