CN110343117B - 青蒿素衍生物的制备方法 - Google Patents
青蒿素衍生物的制备方法 Download PDFInfo
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- CN110343117B CN110343117B CN201810301999.1A CN201810301999A CN110343117B CN 110343117 B CN110343117 B CN 110343117B CN 201810301999 A CN201810301999 A CN 201810301999A CN 110343117 B CN110343117 B CN 110343117B
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- Prior art keywords
- acid
- compound
- artemisinin derivative
- preparation
- coupling reaction
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- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical class 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 title claims abstract description 16
- 238000000034 method Methods 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 230000008569 process Effects 0.000 title claims description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- 238000005859 coupling reaction Methods 0.000 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims abstract description 10
- 125000006239 protecting group Chemical group 0.000 claims abstract description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 8
- 230000008878 coupling Effects 0.000 claims abstract description 6
- 238000010168 coupling process Methods 0.000 claims abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 5
- 230000009471 action Effects 0.000 claims abstract description 3
- -1 9-fluorenylmethoxycarbonyl Chemical group 0.000 claims description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000008025 crystallization Effects 0.000 claims description 8
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-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
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 4
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- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 4
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- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 3
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- 239000007787 solid Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 2
- NKDDWNXOKDWJAK-UHFFFAOYSA-N dimethoxymethane Chemical compound COCOC NKDDWNXOKDWJAK-UHFFFAOYSA-N 0.000 claims description 2
- KLKFAASOGCDTDT-UHFFFAOYSA-N ethoxymethoxyethane Chemical compound CCOCOCC KLKFAASOGCDTDT-UHFFFAOYSA-N 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 5
- 150000002148 esters Chemical class 0.000 abstract description 3
- 229910052736 halogen Inorganic materials 0.000 abstract description 3
- 150000002367 halogens Chemical class 0.000 abstract description 3
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 229960002521 artenimol Drugs 0.000 description 7
- 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 7
- 229930016266 dihydroartemisinin Natural products 0.000 description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
- HPGHCIXRRLNXRN-XQLAAWPRSA-N beta-aminoarteether 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](OCCN)[C@@H]4C HPGHCIXRRLNXRN-XQLAAWPRSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 150000001540 azides Chemical class 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
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- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- NWMRUUDFNUPLHU-UHFFFAOYSA-N 9h-fluoren-1-ylmethyl n-(2-hydroxyethyl)carbamate Chemical compound C1C2=CC=CC=C2C2=C1C(COC(=O)NCCO)=CC=C2 NWMRUUDFNUPLHU-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
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- SAGINAGERRNGGV-UHFFFAOYSA-N benzyl n-(2-hydroxyethyl)carbamate Chemical compound OCCNC(=O)OCC1=CC=CC=C1 SAGINAGERRNGGV-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
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- 125000004185 ester group Chemical group 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical group CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000003041 laboratory chemical Substances 0.000 description 1
- 150000007527 lewis bases Chemical class 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical group CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- RMIODHQZRUFFFF-UHFFFAOYSA-N methoxyacetic acid Chemical group COCC(O)=O RMIODHQZRUFFFF-UHFFFAOYSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229960002446 octanoic acid Drugs 0.000 description 1
- NIXKBAZVOQAHGC-UHFFFAOYSA-N phenylmethanesulfonic acid Chemical group OS(=O)(=O)CC1=CC=CC=C1 NIXKBAZVOQAHGC-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000005547 pivalate group Chemical group 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- MBYLVOKEDDQJDY-UHFFFAOYSA-N tris(2-aminoethyl)amine Chemical compound NCCN(CCN)CCN MBYLVOKEDDQJDY-UHFFFAOYSA-N 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 238000005406 washing Methods 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种制备青蒿素衍生物的方法，所述方法为：化合物(I)与(II)在偶联试剂的作用下于溶剂中发生偶联反应得到化合物(III)；其中，R1为羟基、酯基、磺酸酯基或卤素；R2、R3均为H；或R2、R3中一个为H，另一个为N的保护基；或R2、R3共同构成N的保护基。本发明的制备方法具有原料易得，操作安全简单，产品纯度高，成本低等优点。
Description
技术领域
本发明涉及药物化学领域，具体涉及青蒿素衍生物SM934的制备方法。SM934是正在进行临床试验，用于治疗红斑狼疮的候选药物。
背景技术
青蒿素衍生物SM934除了具有抗疟活性外，还可用于红斑狼疮的治疗。
专利CN102153564公开了其制备方法(制备方法一)。该方法以二氢青蒿素为原料，在三氟化硼乙醚催化条件下与乙二醇反应，经过柱层析分离得到化合物中间体V。中间体V与对甲苯磺酰氯反应得到化合物VI，进一步的与氨水反应直接得到化合物SM934。但是，此反应过程中会生成副产物SM1044，使得分离纯化SM934比较困难。
SM934制备方法一
专利CN102010422也公开了以双氢青蒿素为原料的另外一种制备方法(制备方法二)，该方法以双氢青蒿素IV为原料，通过与溴乙醇反应得到化合物VII后，再与NaN3和NaI反应得到叠氮化合物VIII，最后用PPh3还原叠氮化合物，得到SM934。
SM934制备方法二
上述两种方法路线较长，且收率低，纯化困难；方法二还用到了容易爆炸的叠氮化物，不利于大规模制备。
因此，寻找原材料价廉易得，操作安全简单，产品纯度高，低成本的适于大规模制备青蒿素衍生物SM934的新方法，对加快相关新药的研究进程，降低相关新药的生产成本具有重要意义。
发明内容
本发明所要解决的技术问题是克服现有技术的不足，提供青蒿素衍生物SM934制备的新方法。
本发明提供了一种制备青蒿素衍生物的新方法，所述方法为：
化合物(I)与(II)于溶剂中在偶联试剂的作用下发生偶联反应得到化合物(III)；
其中，
R1为羟基、酯基、磺酸酯基或卤素；
R2、R3均为H；或R2、R3中一个为H，另一个为N的保护基；或R2、R3共同构成N的保护基。
优选地，所述N的保护基选自甲氧羰基、乙氧羰基、2-三甲硅基乙氧羰基、2-氯乙氧羰基、1,1-二甲基-2-卤乙氧羰基、1,1-二甲基-2,2,2-三氯乙氧羰基、1-甲基-1-(4-联苯基)乙氧羰基、叔丁氧羰基、乙烯氧羰基、烯丙基氧羰基、苄氧羰基、对甲氧基苄氧羰基、对硝基苄氧羰基、2,4-二氯苄氧羰基、2-二苯基异丙氧羰基、9-芴基甲氧羰基、1-金刚烷氧羰基、烯丙基氧羰基、甲酰基、乙酰基、三氯乙酰基、三氟乙酰基。
优选地，所述偶联试剂选自路易斯酸，路易斯碱；
优选地，所述溶剂选自二氯甲烷、二氯乙烷、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、环丁砜、N-甲基吡咯烷酮、甲苯、二甲苯、氯苯、四氢呋喃、甲基四氢呋喃、乙二醇二甲醚、二乙二醇二甲醚、甲基叔丁基醚、二乙氧基甲烷、二甲氧基甲烷、乙腈、苯腈、正己烷、正庚烷、环己烷中的一种或多种。
优选地，所述偶联试剂的用量相对于化合物(I)为0.0001～5摩尔当量，更优选为0.001～1摩尔当量；
所述偶联反应的温度不限，优选为0℃～100℃，更优选为0～50℃；
所述偶联反应的时间优选为0.5～24小时，更优选1～12小时；
所述偶联反应可在任何压力下进行，通常在常压下反应。
当R2、R3中一个为H，另一个为N的保护基；或R2、R3共同构成N的保护基时，化合物(III)经进一步脱保护反应得到青蒿素衍生物SM934。
所述脱保护反应在有机酸、有机碱、无机酸或无机碱存在下进行。
所述有机酸选自甲酸、乙酸、丙酸、丁酸、辛酸、己二酸、乙二酸、丙二酸、丁二酸、马来酸、酒石酸、苯甲酸、苯乙酸、邻苯二甲酸、对苯二甲酸、戊酸、己酸、癸酸、硬脂酸、软脂酸、丙烯酸、酒石酸、草酸、苹果酸、苯甲酸、三氟醋酸、甲磺酸、乙磺酸、对甲苯磺酸；所述有机碱选自吡啶、哌啶、吗啉、二环己胺、对二甲氨基吡啶、三乙胺、三(2-氨乙基)胺、四丁基氟化铵、二异丙基乙基胺、氨水、甲胺、乙胺、二乙胺、三乙烯二胺、叔丁醇钾、叔丁醇钠、硼氢化钠、三乙基硼氢化钠、硼氢化钾、三乙基硼氢化钾、硼氢化锂、三乙基硼氢化锂；所述无机酸选自硫酸、盐酸、硝酸；所述无机碱选自碳酸钾、碳酸铯、氢氧化钾、氢氧化钠、氢氧化锂。
所述偶联反应的反应产物(SM934)还可以进一步在结晶溶剂中通过结晶得到固体形态的化合物(SM934)。
所述结晶溶剂选自正戊烷，正己烷，正庚烷，正辛烷，环己烷，石油醚，甲苯，氯苯，甲醇，乙醇，异丙醇，正丁醇中的一种或多种。
所述结晶温度为-20℃～100℃，优选为-10℃～50℃，更优选为0℃～20℃。
采用本发明方法制备得到的青蒿素衍生物SM934可直接用于疟疾、病毒、肿瘤及免疫相关疾病的治疗。
本发明中，
所述酯基，为双氢青蒿素上的羟基和羧酸、酰氯、酸酐或酯反应生成的基团，包括脂肪酸酯基和芳香酸酯基，如甲酸酯基、乙酸酯基、三氟乙酸酯基、2-甲氧基乙酸酯基、丙酸酯基、丁酸酯基、新戊酸酯基、苯甲酸酯基、对苯基苯甲酸酯基、巴豆酸酯基、4-甲氧基巴豆酸酯基等；
所述磺酸酯基，为双氢青蒿素上的羟基和磺酸、磺酰氯或磺酸酐反应生成的基团，包括脂肪酸酯基和芳香酸酯基，如甲磺酸酯基、三氟甲磺酸酯基、乙磺酸酯基、三氟乙磺酸酯基、对甲苯磺酸酯基、苄基磺酸酯基等；
所述卤素包括氟、氯、溴、碘。
有益效果
由于以上技术方案的实施，本发明与现有技术相比具有如下优点：
本发明方案中采用的原料例如乙二醇胺廉价易得，合成路线短、收率高、选择性好，适于大规模制备。
具体实施方式
通过下列实施例说明本发明的实施方案。然而，本发明的实施方案不受限于下列实施例中的特定细节，因为鉴于本发明的公开内容，其他变化对本领域普通技术人员是已知和显而易见的。
样品数据由以下仪器测定：核磁共振氢谱(1H-NMR)用BrukerAvance III 400核磁共振仪；显色使用的精科WFH-203B三用紫外分析仪，波长为254nm和365nm。柱层析硅胶(100-200目，300-400目)为青岛海洋化工厂生产；TLC硅胶板为烟台化工厂生产的HSGF-254型薄层层析硅胶板，薄层层析使用的层析板厚度为0.2±0.03mm；乙腈，甲基叔丁基醚，正庚烷，四氢呋喃均为分析纯，由国药集团化学试剂有限公司提供。所用试剂和溶剂除特别说明外，均未经特别处理。所有温度以℃(摄氏度)表示，室温或环境温度是指20～25℃，温度计未经校正。
实施例1 Cbz保护的蒿乙醚胺
化合物III-1的合成：将双氢青蒿素(0.4g，1eq)溶解于二氯甲烷中，加入化合物2-苄氧羰基氨基-1-乙醇(0.55g，2eq)后，冰浴条件下慢慢滴加三氟化硼乙醚络合物(0.02mL，0.2eq)，然后让反应液慢慢升至室温，过夜搅拌反应基本完全。将反应液依次用水、饱和碳酸氢钠水溶液洗涤，再用水洗至中性(测定洗涤水的pH值近中性)，最后用饱和食盐水洗涤。有机相用无水硫酸钠干燥。浓缩柱分离得产物(531mg，产率为81.8％)。1HNMR(400MHz,Chloroform-d)δ7.45–7.30(m,1H),5.43–5.31(m,1H),5.20–5.05(m,2H),5.01(s,1H),4.82(d,J＝3.5Hz,1H),4.00–3.80(m,1H),3.59–3.34(m,0H),2.74–2.57(m,1H),2.51–2.29(m,1H),2.13–1.51(m,6H),1.45(s,3H),1.41–1.18(m,4H),1.00–0.88(m,6H).
实施例2 蒿乙醚胺
青蒿素衍生物SM934的合成：将化合物III-1(20mg)溶于THF(0.2mL)中，滴加三乙基硼氢化锂(0.2mL)室温搅拌过夜，次日TLC显示，原料转化约30％不再进行，浓缩，加乙酸乙酯，水洗2次，饱和食盐水洗2次，无水硫酸钠干燥，浓缩柱分离得产物(5mg，产率为35.2％)。1H NMR(400MHz,Chloroform-d)δ8.18(s,2H),6.25(s,2H),5.47(s,1H),4.87(d,J＝3.5Hz,1H),4.21–4.03(m,1H),3.84–3.68(m,1H),3.32(t,J＝5.2Hz,2H),2.76–2.57(m,1H),2.46–2.30(m,1H),2.22–1.55(m,5H),1.54–1.31(m,5H),1.31–1.17(m,1H),1.05–0.81(m,6H).
实施例3 Fmoc保护的蒿乙醚胺
化合物III-2的合成：将2-(N-芴甲氧羰基氨基)乙醇(0.5g，1.76mmol)溶解于二氯甲烷中，加入双氢青蒿素(0.753g，2.65mmol)后，冰浴条件下慢慢滴加三氟化硼乙醚络合物(0.25mL，0.88mmol)，然后让反应液慢慢升至室温，3h后TLC显示反应基本完全。加水，用乙酸乙酯萃取三次，合并有机相，饱和食盐水洗2次，无水硫酸钠干燥，浓缩，柱层析得产物(0.842mg，收率86.8％)。1H NMR(400MHz,Chloroform-d)δ7.79(dd,J＝7.6,3.4Hz,5H),7.63(dd,J＝14.2,7.2Hz,2H),7.50–7.38(m,2H),7.38–7.30(m,4H),5.42(d,J＝17.2Hz,1H),4.83(d,J＝3.5Hz,1H),4.57–4.33(m,2H),4.31–4.19(m,1H),4.02–3.32(m,4H),2.77–2.59(m,1H),2.57–2.23(m,2H),2.11–2.00(m,2H),1.98–1.18(m,13H),1.02–0.89(m,6H).
实施例4 Fmoc保护的蒿乙醚胺
化合物III-2的合成：将2-(N-芴甲氧羰基氨基)乙醇(0.5g，1.76mmol)溶于二氯甲烷，加入双氢青蒿素(0.864g，2.65mmol)后，冰浴条件下慢慢滴加三氟化硼乙醚络合物(0.25mL，0.88mmol)，然后让反应液慢慢升至室温，3h后TLC显示反应基本完全。加水，用乙酸乙酯萃取三次，合并有机相，饱和食盐水洗2次，无水硫酸钠干燥，浓缩，柱层析得产物(0.662mg，收率68％)。
实施例5 蒿乙醚胺
青蒿素衍生物SM934的合成：将化合物III-2(50mg)溶于DMF(0.5mL)中，加入哌啶(0.05mL)，室温搅拌20min反应完全，加乙酸乙酯，水洗3次，饱和食盐水洗2次，无水硫酸钠干燥，浓缩得粗产物，加少量乙酸乙酯直至溶解，边搅拌边加入马来酸/乙酸乙酯溶液(1mL，浓度为0.29mol/L)，有固体析出，在冰浴中静置，过滤得产物(25mg，收率83.9％)。1H NMR(400MHz,Chloroform-d)δ8.18(s,2H),6.25(s,2H),5.47(s,1H),4.87(d,J＝3.5Hz,1H),4.21–4.03(m,1H),3.84–3.68(m,1H),3.32(t,J＝5.2Hz,2H),2.76–2.57(m,1H),2.46–2.30(m,1H),2.22–1.55(m,5H),1.54–1.31(m,5H),1.31–1.17(m,1H),1.05–0.81(m,6H).
Claims (7)
1.一种制备青蒿素衍生物的方法，其特征在于，所述方法为：
化合物(I)与(II)于溶剂中在偶联试剂的作用下发生偶联反应得到化合物(III)；
其中，
R1为羟基；
R2、R3中一个为H，另一个为N的保护基；所述N的保护基选自苄氧羰基、9-芴基甲氧羰基；
所述偶联试剂选自路易斯酸，所述路易斯酸为三氟化硼乙醚络合物；
所述溶剂选自二氯甲烷、二氯乙烷、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、环丁砜、N-甲基吡咯烷酮、甲苯、二甲苯、氯苯、四氢呋喃、甲基四氢呋喃、乙二醇二甲醚、二乙二醇二甲醚、甲基叔丁基醚、二乙氧基甲烷、二甲氧基甲烷、乙腈、苯腈、正己烷、正庚烷、环己烷中的一种或多种；
所述偶联试剂的用量相对于化合物(I)为0.001～1摩尔当量；
所述偶联反应的温度为0℃～50℃，所述偶联反应的时间为0.5～12小时。
2.根据权利要求1所述的制备方法，其特征在于：化合物(III)经进一步脱保护反应得到青蒿素衍生物SM934：
3.根据权利要求2所述的制备方法，其特征在于：所述脱保护反应在有机酸、有机碱、无机酸或无机碱存在下进行。
4.根据权利要求2或3中所述的制备方法，其特征在于：所述偶联反应的青蒿素衍生物SM934进一步在结晶溶剂中通过结晶得到固体形态的青蒿素衍生物SM934。
5.根据权利要求4所述的制备方法，其特征在于：所述结晶溶剂选自正戊烷、正己烷、正庚烷、正辛烷、环己烷、石油醚、甲苯、氯苯、甲醇、乙醇、异丙醇、正丁醇中的一种或多种；
所述结晶温度为-20℃～100℃。
6.根据权利要求5所述的制备方法，其特征在于：所述结晶温度为-10℃～50℃。
7.根据权利要求6所述的制备方法，其特征在于：所述结晶温度为0℃～20℃。
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