CN111233869B - 用于制备瑞德西韦关键中间体的新化合物及其制备方法 - Google Patents
用于制备瑞德西韦关键中间体的新化合物及其制备方法 Download PDFInfo
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- CN111233869B CN111233869B CN202010168364.6A CN202010168364A CN111233869B CN 111233869 B CN111233869 B CN 111233869B CN 202010168364 A CN202010168364 A CN 202010168364A CN 111233869 B CN111233869 B CN 111233869B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 150000001875 compounds Chemical class 0.000 title abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 49
- 238000000034 method Methods 0.000 claims abstract description 16
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 9
- 230000008569 process Effects 0.000 claims abstract description 9
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 8
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 6
- 239000007848 Bronsted acid Substances 0.000 claims abstract description 5
- 239000002841 Lewis acid Substances 0.000 claims abstract description 5
- 150000004791 alkyl magnesium halides Chemical class 0.000 claims abstract description 5
- 150000002338 glycosides Chemical class 0.000 claims abstract description 5
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims abstract description 5
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims abstract description 3
- 230000009471 action Effects 0.000 claims abstract description 3
- 229930182478 glucoside Natural products 0.000 claims abstract description 3
- 150000008131 glucosides Chemical class 0.000 claims abstract description 3
- 229930182470 glycoside Natural products 0.000 claims abstract description 3
- 239000011777 magnesium Substances 0.000 claims abstract description 3
- 229910052749 magnesium Inorganic materials 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- FYADHXFMURLYQI-UHFFFAOYSA-N 1,2,4-triazine Chemical compound C1=CN=NC=N1 FYADHXFMURLYQI-UHFFFAOYSA-N 0.000 claims description 14
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 10
- 239000011630 iodine Substances 0.000 claims description 10
- 229910052740 iodine Inorganic materials 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 9
- 229910052794 bromium Chemical group 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical group C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 claims description 5
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 claims description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 230000002140 halogenating effect Effects 0.000 claims description 3
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical class O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 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
- JONIMGVUGJVFQD-UHFFFAOYSA-N (4-methylphenyl)sulfonylformonitrile Chemical compound CC1=CC=C(S(=O)(=O)C#N)C=C1 JONIMGVUGJVFQD-UHFFFAOYSA-N 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 2
- WLLIXJBWWFGEHT-UHFFFAOYSA-N [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical compound CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F WLLIXJBWWFGEHT-UHFFFAOYSA-N 0.000 claims description 2
- 235000011114 ammonium hydroxide Nutrition 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
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims description 2
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 claims description 2
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 claims description 2
- KRRBFUJMQBDDPR-UHFFFAOYSA-N tetrabutylazanium;cyanide Chemical compound N#[C-].CCCC[N+](CCCC)(CCCC)CCCC KRRBFUJMQBDDPR-UHFFFAOYSA-N 0.000 claims description 2
- PCZOZSATUTWXIC-UHFFFAOYSA-N tetraethylazanium;cyanide Chemical compound N#[C-].CC[N+](CC)(CC)CC PCZOZSATUTWXIC-UHFFFAOYSA-N 0.000 claims description 2
- OSXXGBUMRXAAFP-UHFFFAOYSA-N tetramethylazanium;cyanide Chemical compound N#[C-].C[N+](C)(C)C OSXXGBUMRXAAFP-UHFFFAOYSA-N 0.000 claims description 2
- STMPXDBGVJZCEX-UHFFFAOYSA-N triethylsilyl trifluoromethanesulfonate Chemical compound CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F STMPXDBGVJZCEX-UHFFFAOYSA-N 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims 2
- 239000012336 iodinating agent Substances 0.000 claims 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Inorganic materials [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims 1
- 238000001308 synthesis method Methods 0.000 claims 1
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- -1 (phenoxy) phosphoryl Chemical group 0.000 description 28
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 239000012074 organic phase Substances 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000003208 petroleum Substances 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000003480 eluent Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 229950000077 iodol Drugs 0.000 description 4
- DBTNVRCCIDISMV-UHFFFAOYSA-L lithium;magnesium;propane;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-].C[CH-]C DBTNVRCCIDISMV-UHFFFAOYSA-L 0.000 description 4
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- WAUGGYPDCQZJKK-UHFFFAOYSA-N 1h-pyrrol-3-amine Chemical compound NC=1C=CNC=1 WAUGGYPDCQZJKK-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 201000011001 Ebola Hemorrhagic Fever Diseases 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 230000026045 iodination Effects 0.000 description 3
- 238000006192 iodination reaction Methods 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- RWWYLEGWBNMMLJ-MEUHYHILSA-N remdesivir Drugs C([C@@H]1[C@H]([C@@H](O)[C@@](C#N)(O1)C=1N2N=CN=C(N)C2=CC=1)O)OP(=O)(N[C@@H](C)C(=O)OCC(CC)CC)OC1=CC=CC=C1 RWWYLEGWBNMMLJ-MEUHYHILSA-N 0.000 description 3
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 3
- DYIWIWUIZMJRQQ-HQRSTYDCSA-N (3R,4R,5R)-2-(4-chloropyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-bis(phenylmethoxy)-5-(phenylmethoxymethyl)oxolan-2-ol Chemical compound C1=CC=C(C=C1)COC[C@@H]2[C@H]([C@H](C(O2)(C3=CC=C4N3N=CN=C4Cl)O)OCC5=CC=CC=C5)OCC6=CC=CC=C6 DYIWIWUIZMJRQQ-HQRSTYDCSA-N 0.000 description 2
- IQSWGVASEKJVFI-CZCXDNFNSA-N (3R,4R,5R)-3,4-bis[[tert-butyl(dimethyl)silyl]oxy]-5-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-(4-chloropyrrolo[2,1-f][1,2,4]triazin-7-yl)oxolan-2-ol Chemical compound CC(C)(C)[Si](C)(C)OC[C@@H]1[C@H]([C@H](C(O1)(C2=CC=C3N2N=CN=C3Cl)O)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C IQSWGVASEKJVFI-CZCXDNFNSA-N 0.000 description 2
- HRADVHZVMOMEPU-UHFFFAOYSA-N 3-iodopyrrolidine-2,5-dione Chemical compound IC1CC(=O)NC1=O HRADVHZVMOMEPU-UHFFFAOYSA-N 0.000 description 2
- ONTLBVKRDUFQFP-UHFFFAOYSA-N 4-chloropyrrolo[2,1-f][1,2,4]triazine Chemical compound ClC1=NC=NN2C=CC=C12 ONTLBVKRDUFQFP-UHFFFAOYSA-N 0.000 description 2
- GIGJBWHZOFAQNS-BIVLTTKXSA-N C(C1=CC=CC=C1)O[C@H]1C(O[C@@H]([C@H]1OCC1=CC=CC=C1)COCC1=CC=CC=C1)(O)C1=CC=C2C(=NC=NN21)SC Chemical compound C(C1=CC=CC=C1)O[C@H]1C(O[C@@H]([C@H]1OCC1=CC=CC=C1)COCC1=CC=CC=C1)(O)C1=CC=C2C(=NC=NN21)SC GIGJBWHZOFAQNS-BIVLTTKXSA-N 0.000 description 2
- VRIAKQCGLJNRLZ-OJYYSWAESA-N C1=CC=C(C=C1)COC([C@@H]2[C@]([C@](C(=O)O2)(O)OCC3=CC=CC=C3)(O)OCC4=CC=CC=C4)O Chemical compound C1=CC=C(C=C1)COC([C@@H]2[C@]([C@](C(=O)O2)(O)OCC3=CC=CC=C3)(O)OCC4=CC=CC=C4)O VRIAKQCGLJNRLZ-OJYYSWAESA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 241000526636 Nipah henipavirus Species 0.000 description 2
- 241000725643 Respiratory syncytial virus Species 0.000 description 2
- 241000315672 SARS coronavirus Species 0.000 description 2
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 229910003002 lithium salt Inorganic materials 0.000 description 2
- 159000000002 lithium salts Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- QMNWYGTWTXOQTP-UHFFFAOYSA-N 1h-triazin-6-one Chemical compound O=C1C=CN=NN1 QMNWYGTWTXOQTP-UHFFFAOYSA-N 0.000 description 1
- YQVMCGYJLCKMEN-UHFFFAOYSA-N 4-bromopyrrolo[2,1-f][1,2,4]triazine Chemical compound BrC1=NC=NN2C=CC=C12 YQVMCGYJLCKMEN-UHFFFAOYSA-N 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- MENYRYNFSIBDQN-UHFFFAOYSA-N 5,5-dibromoimidazolidine-2,4-dione Chemical compound BrC1(Br)NC(=O)NC1=O MENYRYNFSIBDQN-UHFFFAOYSA-N 0.000 description 1
- RVKWZPPPAXQOGC-UYVBYVPASA-N CC(C)(C)[Si](C)(C)OC([C@@H]1[C@H]([C@H](C(=O)O1)O)O)O Chemical compound CC(C)(C)[Si](C)(C)OC([C@@H]1[C@H]([C@H](C(=O)O1)O)O)O RVKWZPPPAXQOGC-UYVBYVPASA-N 0.000 description 1
- 241000711573 Coronaviridae Species 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 208000030820 Ebola disease Diseases 0.000 description 1
- 241001115402 Ebolavirus Species 0.000 description 1
- 241000711950 Filoviridae Species 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 241000127282 Middle East respiratory syndrome-related coronavirus Species 0.000 description 1
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 108020000999 Viral RNA Proteins 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- WEVYAHXRMPXWCK-FIBGUPNXSA-N acetonitrile-d3 Chemical compound [2H]C([2H])([2H])C#N WEVYAHXRMPXWCK-FIBGUPNXSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- IWCVDCOJSPWGRW-UHFFFAOYSA-M magnesium;benzene;chloride Chemical compound [Mg+2].[Cl-].C1=CC=[C-]C=C1 IWCVDCOJSPWGRW-UHFFFAOYSA-M 0.000 description 1
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical group [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000001668 nucleic acid synthesis Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229940000673 orphan drug Drugs 0.000 description 1
- 239000002859 orphan drug Substances 0.000 description 1
- 238000009520 phase I clinical trial Methods 0.000 description 1
- 238000009521 phase II clinical trial Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 230000007847 structural defect Effects 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- YXFFZXXBNIUFLK-UHFFFAOYSA-N trifluoromethylsulfonyl benzenesulfonate Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C1=CC=CC=C1 YXFFZXXBNIUFLK-UHFFFAOYSA-N 0.000 description 1
- 230000003612 virological effect Effects 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
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Abstract
本发明涉及一种用于合成瑞德西韦关键中间体的新的化合物II,及其制备方法。该化合物II的制备方法包括以下步骤:(a)式(V)所示的4‑X‑吡咯[2,1‑f][1,2,4]三嗪经过卤化得到式(IV)所示的4‑X‑7‑卤代‑吡咯[2,1‑f][1,2,4]三嗪;(b)通过添加镁或烷基卤化镁与式(VI)所示的核糖内酯衍生物反应生成如式(III)所示的糖苷化物;(c)在合适的溶剂中糖苷化物(III)在氰化剂、路易斯酸、布朗斯台德酸的作用下将羟基转化为氰基得到化合物II。本发明制得的化合物可以通过氨化反应生成瑞德西韦所需的关键中间体I。本发明提供了一种新的化合物II以及与现有技术不同的,反应选择性高、可批量制备瑞德西韦关键中间体的工艺路线。
Description
技术领域
本发明涉及药物合成技术领域,具体涉及一类制备瑞德西韦关键中间体的新的化合物,以及这类化合物的制备方法。本发明还涉及用该类化合物制备瑞德西韦中间体的生产工艺。
背景技术
瑞德西韦(remdesivir),化学名为((S)-(((2R,3S,4R,5R)-5-(4-氨基吡咯[2,1-f][1,2,4]三嗪-7-基)-5-氰基-3,4-二羟基四氢呋喃-2-基)甲氧基)(苯氧基)磷酰基)-L-丙氨酸-2-乙基丁酯,其化学结构式为:
瑞德西韦(Remdesivir),由吉利德科学公司Gilead Science开发,是一种病毒RNA依赖的RNA聚合酶(rdrp)抑制剂,可以通过抑制病毒核酸合成而发挥抗病毒作用。瑞德西韦目前在全球并未上市,I期和II期临床试验的适应证为抗埃博拉病毒(丝状病毒),该适应症并未开展III期试验。针对埃博拉病毒的研究表明,瑞德西韦具有很强的抗丝状病毒效果。相关细胞和动物实验还发现,瑞德西韦对于呼吸道合胞病毒(respiratory syncytialvirus,RSV)、冠状病毒、尼帕病毒(Nipah virus)均有抑制效果。
瑞德西韦分别于2015年9月在美国和2016年1月在欧洲获得治疗埃博拉病毒感染的孤儿药资格。2018年11月,刚果当局批准对埃博拉病毒感染的临床研究中,一项名为PALM的三期试验,用于评价ZMapp、瑞德西韦、REGN-EB3和MAb-114四种药物中治疗的最佳选择。中期结果表明瑞德西韦组患者存活率最低,随即该治疗组的试验被停止,这也意味着该药在埃博拉疾病的研究上暂时受阻。经体外细胞实验和动物模型实验证实瑞德西韦对非典型性肺炎冠状病毒(SARS-CoV) 和中东呼吸综合症冠状病毒(MERS-CoV)均具有抗病毒作用。
吉利德科学公司开发了两条合成瑞德西韦的工艺路线,并申请了专利(CN107074902 A)。
由于路线一以4-氨基-7-溴-吡咯[2,1-f][1,2,4]三嗪为起始原料合成瑞德西韦。该化合物中包含胺基基团,对随后的锂-卤交换、氰化反应均有不利影响。在路线一中通过硅烷保护氨基,再进行锂-卤交换形成相应的锂盐。将锂盐添加到内酯当中获得相应的羟基化合物。由于氨基保护难以彻底、低温反应难以控制、丁基锂添加的速度等因素导致反应效率不高,产量多变。
为了解决上述工艺中存在的问题,吉利德科学公司开发了第二条路线。该工艺中仍然采用氨基取代的吡咯[2,1-f][1,2,4]三嗪为起始原料,但是卤素由溴改为碘,为了获得更好的金属交换效果。该工艺并未能从根本上解决路线一中存在的问题,仍然需要采用硅烷保护基对氨基进行保护,随后在低温下进行反应。这种改进生产更稳定,但是其反应收率仅40%。三嗪环上氨基的碱性和亲核性对下一步的羟基活化和氰基取代反应也存在不利影响。
由于先天结构缺陷导致目前已知的工艺路线无法实现高效的反应和稳定的收率,对批量生产瑞德西韦构成巨大的障碍。
本发明人提供了一种新的化合物,以及与现有技术不同的,反应选择性高、可批量制备瑞德西韦关键中间体的工艺路线。该中间体采用活性相对较弱的卤素或甲硫基替换影响偶联反应和取代反应的胺基,有效避免了副反应的发生和额外试剂的添加,从而大大提升了反应效率。
发明内容
针对以上情况,本发明提供了一种合成瑞德西韦关键中间体的新化合物,制备方法及其用途。
本发明提供了一种式(II)所示的化合物:
X为氟、氯、溴、碘或甲硫基;
Y为溴或碘;
各PG独立地为羟基保护基,或者,相邻碳原子上的两个PG基团一起形成-C(R1)2-基团;
R1为H、C1-C6烷基、苯基或取代的苯基。
上述化合物可以下述任一结构式表示:
上述化合物的制备方法如下:
(a)式(V)所示的4-X-吡咯[2,1-f][1,2,4]三嗪与卤化试剂混合反应得到式(IV)所示的4-X-7-卤代-吡咯[2,1-f][1,2,4]三嗪;
(b)通过添加镁或烷基卤化镁与式(VI)所示的核糖内酯衍生物反应生成如式(III)所示的糖苷化物;
(c)在合适的溶剂中糖苷化物(III)在氰化剂、路易斯酸、布朗斯台德酸的作用下将羟基转化为氰基得到化合物II;
其中,
X为氟、氯、溴、碘或甲硫基;
Y为溴或碘;
各PG独立地为羟基保护基,或者,相邻碳原子上的两个PG基团一起形成-C(R1)2-基团;
R1为H、C1-C6烷基、苯基或取代的苯基。
反应步骤(a)中,卤化选用碘代试剂或溴代试剂在合适的溶剂中反应;所述碘代试剂为碘或碘代丁二酰亚胺;所述溴代试剂为溴素、溴代琥珀酰亚胺或二溴海因。
反应步骤(b)中,所述烷基卤化镁为iPrMgCl、iPrMgCl-LiCl或PhMgCl。
反应步骤(c)中,所述氰化剂为TMSCN、TBSCN、TESCN、HCN、KCN、NaCN、4-甲苯磺酰氰、CuCN、四丁基氰化铵、四甲基氰化铵或四乙基氰化铵;所述路易斯酸为TMSOTf、TBSOTf、TESOTf、BF3、BF3-OEt2、4-甲苯磺酰基氯化物、苯磺酰基氯、4-甲苯磺酰基三氟甲磺酸酯、苯磺酰基三氟甲磺酸酯、甲基磺酰氯或甲基磺酸酐;所述布朗斯台德酸为三氟甲基磺酸、苯磺酸或三氟乙酸;所述溶剂为二氯甲烷。
本发明的另一目的是提供上述化合物II合成瑞德西韦关键中间体的用途。
本发明的另一目的是提供一种将上述化合物II通过氨化,合成瑞德西韦关键中间体的方法。
其中,
X为氟、氯、溴、碘或甲硫基;
各PG独立地为羟基保护基,或者,相邻碳原子上的两个PG基团一起形成-C(R1)2-基团;
R1为H、C1-C6烷基、苯基或取代的苯基。
化合物II合成化合物I过程中氨化所采用的氨化试剂包括:氨气、氨水。
本发明的有益效果是:
本发明的新化合物II,用于合成瑞德西韦关键中间体I有如下益处:可以克服现有技术中反应条件苛刻,副反应多,不适用于大生产的缺点;本发明的瑞德西韦关键中间体合成工艺反应效率更高,易于商业化生产。
具体实施方式
下面结合实施例来详细说明本发明的技术内容,这些实例只是进一步详细说明本发明的特征,而不是本发明范围或本发明权利要求范围的限制。
实施例1
(2R,3R,4R,5R)-2-(4-氯吡咯[2,1-f][1,2,4]三嗪-7-基)-3,4-二苄氧基-5-((苄氧)甲基)四氢呋喃-2-氰基
将吡咯[1,2-f][1,2,4]三嗪-4(3H)-酮 (50 g, 0.37 mol)加到300 g三氯氧磷中,加热到60℃。反应完毕后,冷却至室温。将反应混合物缓慢导入冰水浴中。用饱和碳酸钠溶液中和反应液,乙酸乙酯萃取两次。合并有机相减压浓缩得到 4-氯吡咯[1,2-f][1,2,4]三嗪,直接用于下一步。
将4-氯吡咯[1,2-f][1,2,4]三嗪加入100mlTHF和100ml二氯甲烷中。将反应液冷却到0℃以下,分批加入碘代丁二酰亚胺(NIS)(90 g, 0.41mol)。低温反应完毕,向反应液中加入200ml乙酸乙酯稀释。向混合物加入300ml水搅拌10min,过滤收集滤饼。滤液静置分层,收集有机相减压浓缩。合并滤饼和浓缩物,硅胶柱层析(乙酸乙酯/石油醚=0~100%)获得80.3 g 4-氯-7-碘吡咯[1,2-f][1,2,4]三嗪,收率78%. 分子量:278.9,LCMS m/z:279.9(M+H)+. 1H NMR (400MHz, DMSO-d6) δ 8.00 (s, 1H), 6.90 (d, d, J=7.5 Hz,1H),6.51 (d, J=7.5 Hz, 1H).
氮气保护下,向反应瓶中加入4-氯-7-碘吡咯[1,2-f][1,2,4]三嗪(27.9 g,100mmol)和500ml四氢呋喃,冷却到-10℃。缓慢加入iPrMgCl-LiCl (1 M 四氢呋喃溶液,100 ml, 100 mmol) 控制内温不超过0 ℃。搅拌30min后,反应液冷却到–20℃。将2,3,5-三苄氧基-D-核糖酸-1,4-内酯 (41.8 g, 100 mmol) 的四氢呋喃溶液缓慢滴入反应液中,控制内温不超过-20℃。搅拌1h后,反应液升至0℃。用15ml甲醇淬灭反应,加入500ml 1M稀盐酸。加入500ml乙酸乙酯萃取两次,合并有机相,1M碳酸氢钠水溶液洗涤。减压浓缩有机相,快速通过短硅胶层析柱(洗脱剂:乙酸乙酯:石油醚)获得 43.5 g (3R,4R,5R)-2-(4-氯吡咯[2,1-f][1,2,4]三嗪-7-基)-3,4-二苄氧基-5-((苄氧)甲基)四氢呋喃-2-醇,收率76%。1H NMR (400 MHz, DMSO-d6 ) δ 7.91 (s, 1H), 7.40 – 7.27 (m, 15H), 6.24 (d, J =5.9 Hz, 1H), 5.89 (d, J = 5.0 Hz, 1H), 5.05 – 4.84 (m, 4H), 4.62 (s, 2H),4.45 (s, 2H), 3.91 – 3.80 (m, 1H), 3.72 – 3.40 (m, 3H).
氮气保护下,向反应瓶中加入(3R,4R,5R)-2-(4-氯吡咯[2,1-f][1,2,4]三嗪-7-基)-3,4-二苄氧基-5-((苄氧)甲基)四氢呋喃-2-醇(5.72 g,10.0 mmol)和40ml二氯甲烷。搅拌下冷却至-20℃,缓慢加入TMSOTf(2.66 g,12.0mmol),搅拌30min。缓慢滴入TMSCN(1.2g,12.0 mmol),搅拌2小时。加入2 ml三乙胺,反应液升至0℃。随后加入碳酸氢钠和水,搅拌10min。静置分层,水相用二氯甲烷萃取。合并有机相减压浓缩,浓缩物快速通过短硅胶层析柱(洗脱剂:乙酸乙酯:石油醚)获得5.1g(2R,3R,4R,5R)-2-(4-氯吡咯[2,1-f][1,2,4]三嗪-7-基)-3,4-二苄氧基-5-((苄氧)甲基)四氢呋喃-2-氰基,收率88%。1H NMR(400MHz ,DMSO-d6)δ7.87-7.95(m ,1H) ,7.25-7.45(m ,13H) ,7.02-7.22(m ,1H),6.81-6.89(m,1H),6.72-6.78(m,1H),5.06-5.21(m,1H),4.32-4.95(m,7H),4.03-4.23(m,2H),3.64-3.92(m,2H).
实施例2
(2R,3R,4R,5R)-2-(4-溴吡咯[2,1-f][1,2,4]三嗪-7-基)-3,4-二苄氧基-5-((苄氧)甲基)四氢呋喃-2-氰基
以与实施例1中所述类似的反应,使用4-溴吡咯[1,2-f][1,2,4]三嗪得到标题化合物(5.2g)。1HNMR(400MHz,DMSO-d6)δ8.03(s,1H),7.30-7.43(m,13H),7.10-7.19(m,1H),6.80-6.88(m,1H),6.70-6.76(m,1H),6.40(bs,2H),5.13-4.94(m, 1H),4.30-4.83(m,7H),4.10-4.19(m,2H),3.60-3.91(m,2H).
实施例3
(2R,3R,4R,5R)-2-(4-甲硫基吡咯[2,1-f][1,2,4]三嗪-7-基)-3,4-二苄氧基-5-((苄氧)甲基)四氢呋喃-2-氰基
将4-甲硫基吡咯[1,2-f][1,2,4]三嗪加入100mlTHF和100ml二氯甲烷中。将反应液冷却到0℃以下,分批加入碘代丁二酰亚胺(NIS)(67.7g, 0.41mol)。低温反应完毕,向反应液中加入200ml乙酸乙酯稀释。向混合物加入300ml水搅拌10min,过滤收集滤饼。滤液静置分层,收集有机相减压浓缩。合并滤饼和浓缩物,硅胶柱层析(乙酸乙酯/石油醚=0~100%)获得82.3g 4-甲硫基-7-碘吡咯[1,2-f][1,2,4]三嗪,收率69%. 分子量:290.9,质谱:291.9 (M+H)+. 1H NMR (400MHz, DMSO-d6) δ 8.42 (s, 1H), 6.72 (d, d, J=7.5 Hz,1H), 6.42 (d, J=7.5 Hz, 1H), 2.62(s, 1H).
氮气保护下,向反应瓶中加入4-甲硫基-7-碘吡咯[1,2-f][1,2,4]三嗪(29.1 g,100mmol)和500ml四氢呋喃,冷却到-30℃。缓慢加入iPrMgCl-LiCl (1 M 四氢呋喃溶液,100 ml, 100 mmol) 控制内温不超过-15 ℃。搅拌30min后,反应液冷却到–30℃。将2,3,5-三苄氧基-D-核糖酸-1,4-内酯 (41.8 g, 100 mmol, 1.0 equiv) 的四氢呋喃溶液缓慢滴入反应液中,控制内温不超过-20℃。搅拌1h后,反应液升至0℃。用15ml甲醇淬灭反应,加入500ml 1M稀盐酸。加入500ml乙酸乙酯萃取两次,合并有机相,1M碳酸氢钠水溶液洗涤。减压浓缩有机相,快速通过短硅胶层析柱(洗脱剂:乙酸乙酯:石油醚)获得油状物 40.8g(3R,4R,5R)-2-(4-甲硫基吡咯[2,1-f][1,2,4]三嗪-7-基)-3,4-二苄氧基-5-((苄氧)甲基)四氢呋喃-2-醇,收率70%,分子量:583.2,LCMS:584.2。
氮气保护下,向反应瓶中加入(3R,4R,5R)-2-(4-甲硫基吡咯[2,1-f][1,2,4]三嗪-7-基)-3,4-二苄氧基-5-((苄氧)甲基)四氢呋喃-2-醇(2.9 g,4.9mmol)和20ml二氯甲烷。搅拌下冷却至-20℃,缓慢加入TMSOTf(1.33g,6.0mmol),搅拌30min。缓慢滴入TMSCN(0.6 g,6.0mmol),搅拌2小时。加入1ml三乙胺,反应液升至0℃。随后加入碳酸氢钠和水,搅拌10min。静置分层,水相用二氯甲烷萃取。合并有机相减压浓缩,浓缩物快速通过短硅胶层析柱(洗脱剂:乙酸乙酯:石油醚)获得2.3g(2R,3R,4R,5R)-2-(4-甲硫基吡咯[2,1-f][1,2,4]三嗪-7-基)-3,4-二苄氧基-5-((苄氧)甲基)四氢呋喃-2-氰基,收率80%。1H NMR(400MHz,CDCl3)δ8.18 (s, 1H), 7.43-7.21 (m, 15H), 6.80 (d, J = 4.7 Hz, 1H), 6.68 (d,J = 4.7 Hz, 1H), 4.71 (s, 2H), 4.65-4.37 (m, 5H), 4.35 -4.13 (m, 2H), 3.88(dd, J = 10.5, 2.9 Hz, 1H), 3.74 (dd, J = 10.5, 3.5 Hz, 1H), 2.65 (s, 3H)
实施例4
(2R,3R,4R,5R)-2-(4-氯吡咯[2,1-f][1,2,4]三嗪-7-基)-3,4-二(叔丁基二甲基硅氧基)-5-((叔丁基二甲基硅氧基)甲基)四氢呋喃-2-氰基
氮气保护下,向反应瓶中加入4-氯-7-碘吡咯[1,2-f][1,2,4]三嗪(2.79 g,10mmol)和50ml四氢呋喃,冷却到-10℃。缓慢加入三氟甲磺酸、iPrMgCl-LiCl (1 M 四氢呋喃溶液, 10 ml, 10 mmol) 控制内温不超过0 ℃。搅拌30min后,反应液冷却到–20℃。将2,3,5-叔丁基二甲基硅氧基-D-核糖酸-1,4-内酯 (4.90 g, 10 mmol) 的四氢呋喃溶液缓慢滴入反应液中,控制内温不超过-20℃。搅拌1h后,反应液升至0℃。用2ml甲醇淬灭反应,加入50ml 1M稀盐酸。加入50ml乙酸乙酯萃取两次,合并有机相,1M碳酸氢钠水溶液洗涤。减压浓缩有机相,快速通过短硅胶层析柱(洗脱剂:乙酸乙酯:石油醚)获得 4.4g(3R,4R,5R)-2-(4-氯吡咯[2,1-f][1,2,4]三嗪-7-基)-3,4-二(叔丁基二甲基硅氧基)-5-((叔丁基二甲基硅氧基)甲基)四氢呋喃-2-醇,收率68%,质谱:643.3,LCMS:644.3
氮气保护下,向反应瓶中加入(3R,4R,5R)-2-(4-氯吡咯[2,1-f][1,2,4]三嗪-7-基)3,4-二(叔丁基二甲基硅氧基)-5-((叔丁基二甲基硅氧基)甲基)四氢呋喃-2-醇(3.2g,5.0 mmol)和20ml二氯甲烷。搅拌下冷却至-20℃,缓慢加入TMSOTf(1.33g,6.0mmol),搅拌30min。缓慢滴入TMSCN(0.6 g,6.0mmol),搅拌2小时。加入1ml三乙胺,反应液升至0℃。随后加入碳酸氢钠和水,搅拌10min。静置分层,水相用二氯甲烷萃取。合并有机相减压浓缩,浓缩物快速通过短硅胶层析柱(洗脱剂:乙酸乙酯:石油醚)获得2.3 g(2R,3R,4R,5R)-2-(4-氯吡咯[2,1-f][1,2,4]三嗪-7-基)-3,4-二(叔丁基二甲基硅氧基)-5-((叔丁基二甲基硅氧基)甲基)四氢呋喃-2-氰基,收率71%。1H NMR (400 MHz, CDCl3 ) δ 8.02 (s, 1H),6.02 (d, J = 5.0 Hz, 1H), 5.81 (d, J = 5.0 Hz, 1H), 4.45-4.39 (m, 2H), 4.03(1H), 3.88 – 3.74 (m, 2H), 1.02-0.87(m, 27H), 0.12-0.25(m, 18H).
实施例5
(2R,3R,4R,5R)-2-(4-溴吡咯[2,1-f][1,2,4]三嗪-7-基)-3,4-二(叔丁基二甲基硅氧基)-5-((叔丁基二甲基硅氧基)甲基)四氢呋喃-2-氰基
以与实施例4中所述类似的反应,使用4-溴-7-碘吡咯[1,2-f][1,2,4]三嗪得到标题化合物(2.5g)。1H NMR (400 MHz, CDCl3 ) δ 8.04 (s, 1H), 6.02 (d, J = 5.0 Hz,1H), 5.81 (d, J = 5.2 Hz, 1H), 4.45-4.39 (m, 2H), 4.03(1H), 3.88 – 3.74 (m,2H), 1.02-0.87(m, 27H), 0.12-0.25(m, 18H).
实施例6
(2R,3R,4R,5R)-2-(4-甲硫基吡咯[2,1-f][1,2,4]三嗪-7-基)-3,4-二(叔丁基二甲基硅氧基)-5-((叔丁基二甲基硅氧基)甲基)四氢呋喃-2-氰基
以与实施例4中所述类似的反应,使用4-甲硫基-7-碘吡咯[1,2-f][1,2,4]三嗪得到标题化合物(1.8g)。1H NMR (400 MHz, CDCl3 ) δ 7.92 (s, 1H), 6.02 (d, J = 5.0Hz, 1H), 5.81 (d, J = 5.0 Hz, 1H), 4.45-4.39 (m, 2H), 4.03(1H), 3.88 – 3.74(m, 2H),2.68 (s, 3H)1.02-0.87(m, 27H), 0.12-0.25(m, 18H).
实施例7
瑞德西韦关键中间体I的制备
由化合物II合成瑞德西韦关键中间体I采用如下方法制备。
制备瑞德西韦关键中间体(2R,3R,4R,5R)-2-(4-氨基吡咯[2,1-f][1,2,4]三嗪-7-基)-3,4-二苄氧基-5-((苄氧)甲基)四氢呋喃-2-氰基
向反应瓶中加入(2R,3R,4R,5R)-2-(4-氯吡咯[2,1-f][1,2,4]三嗪-7-基)-3,4-二苄氧基-5-((苄氧)甲基)四氢呋喃-2-氰基(2.4 g,4.2mmol)和10 ml四氢呋喃,搅拌。室温下,加入6 ml氨甲醇溶液(7M)搅拌1小时。密闭反应容器,升温至50℃,搅拌至反应结束。减压浓缩有机溶剂,加入50ml水稀释。加入50ml乙酸乙酯萃取两次,合并有机相。减压浓缩有机相,快速通过短硅胶层析柱(洗脱剂:乙酸乙酯:石油醚)获得2.0 g (2R,3R,4R,5R)-2-(4-氨基吡咯[2,1-f][1,2,4]三嗪-7-基)-3,4-二苄氧基-5-((苄氧)甲基)四氢呋喃-2-氰基,收率85%,分子量:561.2,质谱m/z 562[M+H]。1HNMR(400MHz,CD3CN)δ7.95(s,0.5H),7.89(s,0.5H),7.30-7.43(m,13H),7.10-7.19(m,1H),6.80-6.88(m,1H),6.70-6.76(m,1H),6.40(bs,2H),5.10(d,J=3.9Hz,0.5H),4.96(d,J=1Hz,0.5H),4.30-4.83(m,7H),4.10-4.19(m ,2H),3.60-3.91(m ,2H).
Claims (6)
1.一种化合物II的制备方法,其特征在于包括以下步骤:
(a)式(V)所示的4-X-吡咯[2,1-f][1,2,4]三嗪与卤化试剂混合反应得到式(IV)所示的4-X-7-卤代-吡咯[2,1-f][1,2,4]三嗪;
(b)通过添加镁或烷基卤化镁与式(VI)所示的核糖内酯衍生物反应生成如式(III)所示的糖苷化物;
(c)在合适的溶剂中糖苷化物(III)在氰化剂、路易斯酸、布朗斯台德酸的作用下将羟基转化为氰基得到化合物II;
其中,
X为氯或溴;
Y为碘;
各PG独立地为羟基保护基,或者,相邻碳原子上的两个PG基团一起形成-C(R1)2-基团;R1为H、C1-C6烷基、苯基或取代的苯基。
2.根据权利要求1所述的制备方法,其特征在于,反应步骤(a)中,所述卤化试剂为碘代试剂,所述碘代试剂为碘或碘代丁二酰亚胺。
3.根据权利要求1所述的制备方法,其特征在于,反应步骤(b)中,所述烷基卤化镁为iPrMgCl或iPrMgCl-LiCl。
4.根据权利要求1所述的制备方法,其特征在于,反应步骤(c)中,所述氰化剂为TMSCN、TBSCN、TESCN、HCN、KCN、NaCN、4-甲苯磺酰氰、CuCN、四丁基氰化铵、四甲基氰化铵或四乙基氰化铵;所述路易斯酸为TMSOTf、TBSOTf、TESOTf、BF3、BF3-OEt2;所述布朗斯台德酸为三氟甲基磺酸、苯磺酸或三氟乙酸;所述溶剂为二氯甲烷。
6.根据权利要求5所述的合成方法,其特征在于,采用的氨化试剂为氨气或氨水。
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