CN113214263B - Synthetic method of Rudesiwei key intermediate - Google Patents
Synthetic method of Rudesiwei key intermediate Download PDFInfo
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- CN113214263B CN113214263B CN202010101228.5A CN202010101228A CN113214263B CN 113214263 B CN113214263 B CN 113214263B CN 202010101228 A CN202010101228 A CN 202010101228A CN 113214263 B CN113214263 B CN 113214263B
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- 238000010189 synthetic method Methods 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 47
- 238000000034 method Methods 0.000 claims abstract description 24
- 125000006239 protecting group Chemical group 0.000 claims abstract description 7
- 150000002596 lactones Chemical class 0.000 claims abstract description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 4
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 3
- 238000007142 ring opening reaction Methods 0.000 claims abstract description 3
- -1 2-tetrahydropyranyl Chemical group 0.000 claims description 17
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical group [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 10
- IJOOHPMOJXWVHK-UHFFFAOYSA-N trimethylsilyl-trifluoromethansulfonate Natural products C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 10
- 239000007818 Grignard reagent Substances 0.000 claims description 8
- USZLCYNVCCDPLQ-UHFFFAOYSA-N hydron;n-methoxymethanamine;chloride Chemical compound Cl.CNOC USZLCYNVCCDPLQ-UHFFFAOYSA-N 0.000 claims description 8
- 150000007530 organic bases Chemical class 0.000 claims description 8
- 150000004795 grignard reagents Chemical class 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 239000002841 Lewis acid Substances 0.000 claims description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 6
- 150000007517 lewis acids Chemical class 0.000 claims description 6
- UGVPKMAWLOMPRS-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].CC[CH2-] UGVPKMAWLOMPRS-UHFFFAOYSA-M 0.000 claims description 6
- RYEXTBOQKFUPOE-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].CC[CH2-] RYEXTBOQKFUPOE-UHFFFAOYSA-M 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- LVKCSZQWLOVUGB-UHFFFAOYSA-M magnesium;propane;bromide Chemical group [Mg+2].[Br-].C[CH-]C LVKCSZQWLOVUGB-UHFFFAOYSA-M 0.000 claims description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 229960000583 acetic acid Drugs 0.000 claims description 4
- DQDWATOXYCARFV-UHFFFAOYSA-M magnesium;2-methanidylpropane;bromide Chemical compound [Mg+2].[Br-].CC(C)[CH2-] DQDWATOXYCARFV-UHFFFAOYSA-M 0.000 claims description 4
- YSMZEMQBSONIMJ-UHFFFAOYSA-M magnesium;2-methanidylpropane;chloride Chemical compound [Mg+2].[Cl-].CC(C)[CH2-] YSMZEMQBSONIMJ-UHFFFAOYSA-M 0.000 claims description 4
- IWCVDCOJSPWGRW-UHFFFAOYSA-M magnesium;benzene;chloride Chemical compound [Mg+2].[Cl-].C1=CC=[C-]C=C1 IWCVDCOJSPWGRW-UHFFFAOYSA-M 0.000 claims description 4
- LWLPYZUDBNFNAH-UHFFFAOYSA-M magnesium;butane;bromide Chemical compound [Mg+2].[Br-].CCC[CH2-] LWLPYZUDBNFNAH-UHFFFAOYSA-M 0.000 claims description 4
- QUXHCILOWRXCEO-UHFFFAOYSA-M magnesium;butane;chloride Chemical compound [Mg+2].[Cl-].CCC[CH2-] QUXHCILOWRXCEO-UHFFFAOYSA-M 0.000 claims description 4
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 claims description 4
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 claims description 4
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 claims description 4
- YCCXQARVHOPWFJ-UHFFFAOYSA-M magnesium;ethane;chloride Chemical compound [Mg+2].[Cl-].[CH2-]C YCCXQARVHOPWFJ-UHFFFAOYSA-M 0.000 claims description 4
- XWCQLLDGXBLGMD-UHFFFAOYSA-M magnesium;pentane;bromide Chemical compound [Mg+2].[Br-].CCCC[CH2-] XWCQLLDGXBLGMD-UHFFFAOYSA-M 0.000 claims description 4
- JFWWQYKSQVMLQU-UHFFFAOYSA-M magnesium;pentane;chloride Chemical compound [Mg+2].[Cl-].CCCC[CH2-] JFWWQYKSQVMLQU-UHFFFAOYSA-M 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- JGHYBJVUQGTEEB-UHFFFAOYSA-M dimethylalumanylium;chloride Chemical compound C[Al](C)Cl JGHYBJVUQGTEEB-UHFFFAOYSA-M 0.000 claims description 3
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 3
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 claims description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 239000012362 glacial acetic acid Substances 0.000 claims description 2
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims description 2
- 229910052740 iodine Chemical group 0.000 claims description 2
- 239000011630 iodine Chemical group 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 claims description 2
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 claims description 2
- SQBBHCOIQXKPHL-UHFFFAOYSA-N tributylalumane Chemical compound CCCC[Al](CCCC)CCCC SQBBHCOIQXKPHL-UHFFFAOYSA-N 0.000 claims description 2
- VOITXYVAKOUIBA-UHFFFAOYSA-N triethylaluminium Chemical compound CC[Al](CC)CC VOITXYVAKOUIBA-UHFFFAOYSA-N 0.000 claims description 2
- MCULRUJILOGHCJ-UHFFFAOYSA-N triisobutylaluminium Chemical compound CC(C)C[Al](CC(C)C)CC(C)C MCULRUJILOGHCJ-UHFFFAOYSA-N 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- CCZVEWRRAVASGL-UHFFFAOYSA-N lithium;2-methanidylpropane Chemical compound [Li+].CC(C)[CH2-] CCZVEWRRAVASGL-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 34
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000007858 starting material Substances 0.000 abstract description 4
- 230000008878 coupling Effects 0.000 abstract description 2
- 238000010168 coupling process Methods 0.000 abstract description 2
- 238000005859 coupling reaction Methods 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract 1
- 238000005580 one pot reaction Methods 0.000 abstract 1
- 238000007363 ring formation reaction Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 239000012043 crude product Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000010791 quenching Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000005051 trimethylchlorosilane Substances 0.000 description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- JNODDICFTDYODH-UHFFFAOYSA-N 2-hydroxytetrahydrofuran Chemical compound OC1CCCO1 JNODDICFTDYODH-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 208000025370 Middle East respiratory syndrome Diseases 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 125000005234 alkyl aluminium group Chemical group 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 210000001503 joint Anatomy 0.000 description 2
- 229910003002 lithium salt Inorganic materials 0.000 description 2
- 159000000002 lithium salts Chemical class 0.000 description 2
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical group [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 description 2
- UNYNVICDCJHOPO-UHFFFAOYSA-N quabalactone III Natural products CC1OC(=O)C(O)=C1C UNYNVICDCJHOPO-UHFFFAOYSA-N 0.000 description 2
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- MTJGVAJYTOXFJH-UHFFFAOYSA-N 3-aminonaphthalene-1,5-disulfonic acid Chemical compound C1=CC=C(S(O)(=O)=O)C2=CC(N)=CC(S(O)(=O)=O)=C21 MTJGVAJYTOXFJH-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- DQBQKQNQGKIWKQ-WXFUMESZSA-N CN(C([C@@H]([C@@H]([C@@H](COC1=CC=CC=C1)O)OC1=CC=CC=C1)OC1=CC=CC=C1)=O)OC Chemical compound CN(C([C@@H]([C@@H]([C@@H](COC1=CC=CC=C1)O)OC1=CC=CC=C1)OC1=CC=CC=C1)=O)OC DQBQKQNQGKIWKQ-WXFUMESZSA-N 0.000 description 1
- 241001678559 COVID-19 virus Species 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 201000011001 Ebola Hemorrhagic Fever Diseases 0.000 description 1
- 206010023927 Lassa fever Diseases 0.000 description 1
- 208000030156 Marburg disease Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 241000725643 Respiratory syncytial virus Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- ANUZKYYBDVLEEI-UHFFFAOYSA-N butane;hexane;lithium Chemical compound [Li]CCCC.CCCCCC ANUZKYYBDVLEEI-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 150000002681 magnesium compounds Chemical class 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940087646 methanolamine Drugs 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- RZZIKHSWRWWPAN-UHFFFAOYSA-N oxolane-2-carbonitrile Chemical compound N#CC1CCCO1 RZZIKHSWRWWPAN-UHFFFAOYSA-N 0.000 description 1
- IPWFJLQDVFKJDU-UHFFFAOYSA-N pentanamide Chemical compound CCCCC(N)=O IPWFJLQDVFKJDU-UHFFFAOYSA-N 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical compound [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-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)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention provides a method for preparing a key intermediate of ridiflower shown in a formula (VII). The compound shown in the formula (II) is obtained by ring opening by using benzyl fully-protected lactone shown in the formula (I) as an initial material. Protecting the hydroxyl of the compound (II) by a proper protecting group to obtain the compound shown as the formula (III). The intermediate shown in the formula (V) can be obtained by coupling, deprotection and cyclization of the compound (III) and the compound (IV) in a one-pot method. The intermediate (V) can be converted in two steps to obtain a key intermediate (VII) of the Reidesciclovir. The method provided by the invention uses the commercially available compound (I) as a starting material, and obtains the key intermediate compound (VII) for preparing the Reidesciclovir through five-step reaction in high yield, thereby greatly reducing the cost and being suitable for industrial mass production.
Description
Technical Field
The invention relates to a method for synthesizing and purifying a key intermediate of Rudexiluwei, belonging to the field of medicines.
Background
Rudeciclovir (CAS number: 1809249-37-3) an antiviral drug developed by Gilidex corporation and having the formula:
redysivir was used initially for the treatment of ebola virus disease and marburg virus infection and was later found to exhibit reasonable antiviral activity against more distantly related viruses such as respiratory syncytial virus, hunin virus, lassa fever virus and MERS. Recently, a laboratory test by Jilidide on Redexilvir with 2019-nCoV demonstrated "show activity on SARS and MERS" in non-human animals.
At present, the synthesis method of the Reidesciclovir is mainly a small-scale synthesis route reported by literature (Nature (London, United Kingdom), 531(7594), 381-3852016), which takes a sugar lactone fragment 01 and a base fragment 02 as starting materials, and carries out butt joint under a strong alkaline condition to obtain an intermediate 03, then carries out reaction with TMSCN under an acidic condition to replace a hydroxyl group with a cyano group to obtain a compound 04, then removes benzyl protection to obtain a compound 05, further protects an adjacent dihydroxy with propylidene to obtain a compound 06, then carries out butt joint with a phosphate fragment 07 to obtain a compound 08, and removes propylidene protection to obtain a final product Reidesciclovir. The detailed reaction route is shown as the following formula.
From the above routes, it can be seen that in the whole synthesis process route, the compounds 01 and 02 in the key step 1 are butted to construct the main fragment, but the yield is the lowest (only 40%) in the whole process route, and in the actual operation process, we further find that the reaction process has more byproducts and cannot be further optimized simply by adjusting the reaction conditions. Through experimental verification and analysis of byproducts, the impurities of the lactone are mainly derived from an intermediate state of ketone generated after the lactone ring is opened, and the intermediate state has high reactivity and can continuously react with excessive metal reagents to obtain other byproducts. Furthermore, we improved the synthetic route to compound 03, as detailed in the following formula:
we propose a transformation in two steps to convert the sugar lactone compound to the key intermediate III (Weinreb amide), which is a non-ketonic compound during the reaction with the metalorganic base and which only after quenching of the reaction produces an intermediate of the ketonic structure. Therefore, the yield of the third step is greatly improved. The yield of 40 percent of the original route is improved to about 70 to 85 percent, and the production cost of the Reidesvir is greatly reduced.
Disclosure of Invention
The invention aims to develop a method for preparing a key intermediate (VII) of the RudeSewei, which can improve the yield and reduce the production cost, so that the RudeSewei is suitable for industrial mass production.
The invention provides a method for preparing a key intermediate (VII) of Rudesevir. The method comprises the following steps:
1) obtaining an intermediate shown as a formula (II) by ring opening of the full benzyl protection lactone shown as the formula (I):
2) reacting the intermediate obtained in the step 1) as shown in the formula (II) with a proper hydroxyl protecting group to obtain an intermediate as shown in the formula (III):
3) reacting the intermediate obtained in the step 2) and the compound (IV), removing protecting groups, and closing rings in molecules to obtain the compound shown in the formula (V):
4) carrying out substitution reaction on the intermediate obtained in the step 3) and shown in the formula (V) to obtain a compound shown in the formula (VI):
5) removing a protecting group from the intermediate obtained in the step 4) shown in the formula (VI) to obtain a compound shown in the formula (VI):
in the step 1), the compound (I) reacts with N, O-dimethylhydroxylamine hydrochloride with the assistance of Lewis acid or Grignard reagent to directly obtain Weinreb amide (II).
Furthermore, the dosage of the N, O-dimethylhydroxylamine hydrochloride is 1-5 times of the equivalent of the compound (I). Preferably 1.5 to 3 times equivalent.
The Lewis acid used in the step 1) is aluminum trichloride, zinc chloride or alkylaluminum, such as dimethylaluminum chloride, trimethylaluminum, triethylaluminum, tributylaluminum or triisobutylaluminum.
Further, the Lewis acid is preferably an alkylaluminum such as dimethylaluminum chloride or trimethylaluminum.
Furthermore, the dosage of the Lewis acid is 1-5 times of the dosage of the N, O-dimethylhydroxylamine hydrochloride. Preferably 1 to 2 times equivalent.
When a combination of lewis and N, O-dimethylhydroxylamine hydrochloride is used in the step 1), the solvent is selected from dichloromethane, chloroform, dichloroethane, benzene, toluene, N-hexane, cyclohexane, or the like.
The Grignard reagent used in the step 1) is methyl magnesium chloride, methyl magnesium bromide, ethyl magnesium chloride, ethyl magnesium bromide, propyl magnesium chloride, propyl magnesium bromide, isopropyl magnesium chloride, isopropyl magnesium bromide, n-butyl magnesium chloride, n-butyl magnesium bromide, isobutyl magnesium chloride, isobutyl magnesium bromide, n-pentyl magnesium chloride or n-pentyl magnesium bromide, etc.
Further, the Grignard reagent is preferably isopropyl magnesium chloride or isopropyl magnesium bromide.
Furthermore, the dosage of the Grignard reagent is 0.8-2 times of the dosage of the N, O-dimethylhydroxylamine hydrochloride.
In the step 1), when the grignard reagent and the N, O-dimethylhydroxylamine hydrochloride are combined, the solvent is selected from diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, N-hexane, toluene, or the like.
In the step 2), R is 2-tetrahydropyranyl, p-methoxybenzyl, methoxymethyl, trimethylsilyl, dimethyl tert-butyl silyl or tert-butyl diphenyl silyl and the like.
Further, R is preferably 2-tetrahydropyranyl or trimethylsilyl.
The solvent used in the step 2) is dichloromethane, chloroform, dichloroethane, tetrahydrofuran, diethyl ether, dioxane, N-dimethylformamide, N-methylpyrrolidone, toluene or dimethyl sulfoxide and the like.
Optionally, a protecting group may be added or not added in step 3).
Further, it is preferable to add a protecting group such as trimethylchlorosilane and the like.
In the step 3), X can be halogen, such as bromine or iodine.
Said step 3) is carried out by coupling the intermediate (III) with the compound (IV) in the presence of an organic base such as n-butyllithium, sec-butyllithium, tert-butyllithium, phenylmagnesium chloride, phenylmagnesium bromide, methylmagnesium chloride, methylmagnesium bromide, ethylmagnesium chloride, ethylmagnesium bromide, propylmagnesium chloride, propylmagnesium bromide, isopropylmagnesium chloride, isopropylmagnesium bromide, n-butylmagnesium chloride, n-butylmagnesium bromide, isobutylmagnesium chloride, isobutylmagnesium bromide, n-pentylmagnesium chloride, or n-pentylmagnesium bromide.
Further, when X is bromine, the organic base is preferably selected from n-butyllithium, sec-butyllithium or tert-butyllithium.
Further, when X is iodine, the organic base may be selected from one or a combination of two different organic bases as described above, such as phenylmagnesium chloride and isopropylmagnesium chloride.
Further, the organic base used is, for example, an organic magnesium compound, and a complex containing a lithium salt may be used, or a lithium salt may be added separately.
The dosage of the compound (IV) in the step 3) is 1-3 times of the dosage of the intermediate (III).
The dosage of the organic base in the step 3) is 1-5 times of the dosage of the compound (IV).
The deprotection and intramolecular cyclization in the step 3) are carried out under an acidic condition, and the acid used can be selected from p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, glacial acetic acid, trifluoroacetic acid, sulfamic acid, camphorsulfonic acid, hydrochloric acid or sulfuric acid.
The solvent used in the step 3) is dichloromethane, chloroform, dichloroethane, tetrahydrofuran, diethyl ether, dioxane, N-dimethylformamide, N-methylpyrrolidone, toluene, xylene or dimethyl sulfoxide and the like.
The invention provides a method for preparing a key intermediate (VII) of Rudexiwei. The method takes a compound available in the market as a starting material, prepares the high-purity intermediate (VII) through three-step reaction in high yield, has simple and convenient preparation and lower cost, and is suitable for industrial production.
Obviously, many modifications, substitutions, and alterations are possible in light of the above teachings of the invention, without departing from the basic technical ideas of the invention, as defined by the following general technical knowledge and conventional practices of the art.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The starting materials and equipment used in the embodiment of the present invention are known products and are obtained by purchasing commercially available products.
Example 1: synthesis of intermediate (2R, 3R, 4R) -2, 3, 5-tris (phenyloxy) -4-hydroxy-N-methoxy-N-methylpentanamide.
Adding N, O-dimethylhydroxylamine hydrochloride and a tetrahydrofuran solution of a compound 01 into a reaction bottle, cooling the system to 15 ℃, then dropwise adding the tetrahydrofuran solution of an isopropyl Grignard reagent into the reaction system, and stirring for 2 hours at the temperature of 20 ℃. After the system TLC monitored reaction was completed, saturated aqueous ammonium chloride solution was added to quench, the mixture was extracted with ethyl acetate, and the organic phase was concentrated to give crude product of product 02 as a pale yellow oil which was used directly in the next reaction.
Example 2: synthesis of intermediate (2R, 3S, 4R) -2, 3, 5-tris (phenyloxy) -N-methoxy-N-methyl-4- ((trimethylstyryl) oxy) pentanamide.
Dissolving the crude product of the compound 02 in dichloromethane, adding imidazole as alkali, then dropwise adding a dichloro solution of trimethylchlorosilane, and reacting the system for 48 hours at room temperature. System TLC after the reaction was complete, quench the reaction with water, separate the layers, extract the aqueous phase 2 times with dichloromethane, combine the organic phases, concentrate the organic phases, and separate the crude product using column chromatography to afford compound 03 as a pale yellow oil (80% yield over two steps).
Example 3: synthesis of intermediate (3R, 4R, 5R) -2- (4-aminopyrrolo [2, 1-f ] [1, 2, 4] triazin-7-yl) -3, 4-bis (phenyloxy) -5- ((phenyloxy) methyl) tetrahydrofu ran-2-ol.
Suspending the compound 04 in a tetrahydrofuran solution, adding trimethylchlorosilane, stirring the system for 30 minutes at room temperature, cooling to 0 ℃, adding phenylmagnesium chloride into the reaction system, and continuously stirring the system for 30 minutes. Further cooling the reaction system to 0 ℃, then dropwise adding isopropyl magnesium chloride into the reaction system, maintaining the temperature of the reaction system to be not higher than 5 ℃, continuously stirring the system for 15 minutes, then further cooling the system to-20 ℃, slowly dropwise adding a tetrahydrofuran solution of the compound 03 into the reaction system, and maintaining the reaction temperature to be not higher than-20 ℃ in the dropwise adding process. Slowly heating the system to 0 ℃, then quenching the reaction by using a methanol/acetic acid/water mixed solution, heating the reaction system to room temperature, stirring for 30 minutes, concentrating under reduced pressure to remove an organic phase, adding ethyl acetate and 1N hydrochloric acid into a residual water phase, separating liquid, sequentially washing the organic phase by using 10% sodium bicarbonate and a saturated sodium chloride aqueous solution, drying by using anhydrous sodium sulfate, filtering and concentrating the organic phase to obtain a crude product of the compound 05, and further purifying the crude product by using column chromatography to obtain the compound 05 (off-white solid, yield 80%).
Example 4: synthesis of intermediate (3R, 4R, 5R) -2- (4-aminopyrorrolo [2, 1-f ] [1, 2, 4] triazin-7-yl) -3, 4-bis (phenyloxy) -5- ((phenyloxy) methyl) tetrahydrofu ran-2-ol
Suspending the compound 04 in tetrahydrofuran, adding trimethylchlorosilane, stirring the system at room temperature for 20 minutes, cooling to-78 ℃, slowly dropwise adding a butyl lithium n-hexane solution into the reaction system, and maintaining the temperature of the system to be not higher than-75 ℃ in the dropwise adding process. After the completion of the addition, the system was stirred for 10 minutes while maintaining the temperature, and then a tetrahydrofuran solution of compound 03 was added dropwise to the reaction system. After TLC monitoring the reaction was completed, the reaction was quenched with acetic acid, then the system was concentrated under reduced pressure to remove the organic phase, the residue was separated by adding water and dichloromethane, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound 05, which was further purified using column chromatography to give compound 05 (off-white solid, yield 75%).
Example 5: synthesis of intermediate (2R, 3R, 4R, 5R) -2- (4-aminopyraprolo [2, 1-f ] [1, 2, 4] triazin-7-yl) -3, 4-bis (phenyloxy) -5- ((phenyloxy) methyl) tetrahydrofu ran-2-carbonitrile
Compound 05 was dissolved in dichloromethane and then cooled to-78 ℃ and trifluoromethanesulfonic acid was added slowly. The temperature was maintained for 10 minutes with stirring, and then a solution of TMSOTf in tetrahydrofuran was added dropwise, during which the system was maintained at a temperature not higher than-78 ℃. After the dropwise addition, the TMSCN was slowly added dropwise to the reaction system, and after the dropwise addition was completed, the temperature was maintained and stirring was continued for 2 hours. After TLC monitoring reaction, triethylamine is added into the reaction system, then the system is warmed to room temperature, and then sodium bicarbonate water solution is slowly added. Separating, extracting the water phase with dichloromethane for 2 times, combining the organic phases, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the filtrate to obtain crude product. The crude product was purified using column chromatography to afford compound 06 (off-white solid, yield 80%).
Example 6: synthesis of intermediate (2R, 3R, 4S, 5R) -2- (4-aminopyridrolo [2, 1-f ] [1, 2, 4] triazin-7-yl) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofunan-2-carbonitrile
Dissolving the compound 06 in anhydrous dichloromethane, cooling the system to-78 ℃, and protecting the system with argon. And then, slowly dropwise adding boron trichloride into the reaction system, and after dropwise adding, slowly heating the system to-40 ℃ and reacting for 2 hours. And after TLC monitoring reaction, cooling the system to-78 ℃ again, adding methanol and triethylamine into the system to quench the reaction, and after quenching, heating the reaction to room temperature. And (3) concentrating the reaction system under reduced pressure, pulping the residue with n-hexane, and collecting the solid. Subsequently, methanol and water were added to the residue and heated to 45 ℃, the system was further concentrated under reduced pressure until methanol was removed, and white solids were precipitated by cooling, followed by collecting the solids by filtration to obtain compound 07 (white solid, yield 85%).
Claims (10)
1. A method for preparing a Rudesevir key intermediate compound shown as a formula (VII) is characterized by comprising the following steps:
1) the ring opening of the full benzyl protection lactone shown in the formula (I) is used for obtaining an intermediate shown in the formula (II):
2) reacting the intermediate obtained in the step 1) as shown in the formula (II) with a proper hydroxyl protecting group to obtain an intermediate as shown in the formula (III):
3) reacting the intermediate obtained in the step 2) and the compound (IV), removing protecting groups, and closing rings in molecules to obtain the compound shown in the formula (V):
4) carrying out substitution reaction on the intermediate obtained in the step 3) and shown in the formula (V) to obtain a compound shown in the formula (VI):
5) removing a protecting group from the intermediate obtained in the step 4) shown in the formula (VI) to obtain a compound shown in the formula (VII):
in the step 3), X is bromine or iodine.
2. The method for preparing the intermediate shown in the formula (VII) according to claim 1, characterized in that in the step 1), the compound (I) is reacted with N, O-dimethylhydroxylamine hydrochloride with the aid of Lewis acid or Grignard reagent to directly obtain the compound (II).
3. The method of claim 2, wherein the lewis acid used in step 1) is one of aluminum trichloride, zinc chloride, dimethylaluminum chloride, trimethylaluminum, triethylaluminum, tributylaluminum, or triisobutylaluminum.
4. The method as claimed in claim 2, wherein the Grignard reagent used in the step 1) is methyl magnesium chloride, methyl magnesium bromide, ethyl magnesium chloride, ethyl magnesium bromide, propyl magnesium chloride, propyl magnesium bromide, n-butyl magnesium chloride, n-butyl magnesium bromide, isobutyl magnesium chloride, isobutyl magnesium bromide, n-pentyl magnesium chloride or n-pentyl magnesium bromide.
5. The method according to claim 4, wherein the propyl magnesium chloride is isopropyl magnesium chloride and the propyl magnesium bromide is isopropyl magnesium bromide.
6. The method according to claim 1, wherein R in step 2) is 2-tetrahydropyranyl, p-methoxybenzyl, methoxymethyl, trimethylsilyl, dimethyl-t-butylsilyl, or t-butyldiphenylsilyl.
7. The method of claim 1, wherein trimethyl silicon chloride is added in step 3).
8. The process according to claim 1, wherein an organic base is added in step 3), said organic base being n-butyllithium, isobutyllithium, tert-butyllithium, phenylmagnesium chloride, phenylmagnesium bromide, methylmagnesium chloride, methylmagnesium bromide, ethylmagnesium chloride, ethylmagnesium bromide, propylmagnesium chloride, propylmagnesium bromide, n-butylmagnesium chloride, n-butylmagnesium bromide, isobutylmagnesium chloride, isobutylmagnesium bromide, n-pentylmagnesium chloride or n-pentylmagnesium bromide.
9. The method of claim 8, wherein the propyl magnesium chloride is isopropyl magnesium chloride and the propyl magnesium bromide is isopropyl magnesium bromide.
10. The method of claim 1, wherein the deprotection and intramolecular cyclization in step 3) occurs under acidic conditions using an acid selected from the group consisting of p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, glacial acetic acid, trifluoroacetic acid, sulfamic acid, camphorsulfonic acid, hydrochloric acid and sulfuric acid.
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