CN116041403A - Preparation method of Vanuepivir - Google Patents
Preparation method of Vanuepivir Download PDFInfo
- Publication number
- CN116041403A CN116041403A CN202210736138.2A CN202210736138A CN116041403A CN 116041403 A CN116041403 A CN 116041403A CN 202210736138 A CN202210736138 A CN 202210736138A CN 116041403 A CN116041403 A CN 116041403A
- Authority
- CN
- China
- Prior art keywords
- reaction
- nupi
- compound
- preparing
- reagent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title abstract description 16
- 238000005886 esterification reaction Methods 0.000 claims abstract description 33
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 22
- 239000002994 raw material Substances 0.000 claims abstract description 22
- 125000006239 protecting group Chemical group 0.000 claims abstract description 21
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 claims abstract description 16
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 claims abstract description 16
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 claims abstract description 16
- 238000000746 purification Methods 0.000 claims abstract description 10
- 238000007259 addition reaction Methods 0.000 claims abstract description 6
- 238000005805 hydroxylation reaction Methods 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 39
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 27
- 239000002904 solvent Substances 0.000 claims description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- 239000003153 chemical reaction reagent Substances 0.000 claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 15
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical group CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 14
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 13
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 claims description 13
- 230000032050 esterification Effects 0.000 claims description 13
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical group [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 8
- 229940126062 Compound A Drugs 0.000 claims description 6
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 239000012298 atmosphere Substances 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- BYLOHCRAPOSXLY-UHFFFAOYSA-N dichloro(diethyl)silane Chemical compound CC[Si](Cl)(Cl)CC BYLOHCRAPOSXLY-UHFFFAOYSA-N 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 239000011261 inert gas Substances 0.000 claims description 6
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 claims description 6
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical group CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 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 6
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 6
- 229920002554 vinyl polymer Chemical group 0.000 claims description 6
- DGMOBVGABMBZSB-UHFFFAOYSA-N 2-methylpropanoyl chloride Chemical compound CC(C)C(Cl)=O DGMOBVGABMBZSB-UHFFFAOYSA-N 0.000 claims description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- 235000019253 formic acid Nutrition 0.000 claims description 5
- LSACYLWPPQLVSM-UHFFFAOYSA-N isobutyric acid anhydride Chemical compound CC(C)C(=O)OC(=O)C(C)C LSACYLWPPQLVSM-UHFFFAOYSA-N 0.000 claims description 5
- LIKFHECYJZWXFJ-UHFFFAOYSA-N dimethyldichlorosilane Chemical group C[Si](C)(Cl)Cl LIKFHECYJZWXFJ-UHFFFAOYSA-N 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- ICNCZFQYZKPYMS-UHFFFAOYSA-N 2-methylpropanoyl bromide Chemical compound CC(C)C(Br)=O ICNCZFQYZKPYMS-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- MAYIDWCWWMOISO-UHFFFAOYSA-N dichloro-bis(ethenyl)silane Chemical compound C=C[Si](Cl)(Cl)C=C MAYIDWCWWMOISO-UHFFFAOYSA-N 0.000 claims description 3
- OPTDDWCXQQYKGU-UHFFFAOYSA-N diphenyldichloromethane Chemical compound C=1C=CC=CC=1C(Cl)(Cl)C1=CC=CC=C1 OPTDDWCXQQYKGU-UHFFFAOYSA-N 0.000 claims description 3
- 229940047889 isobutyramide Drugs 0.000 claims description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 3
- 238000007171 acid catalysis Methods 0.000 claims description 2
- 238000005815 base catalysis Methods 0.000 claims description 2
- 229950009297 pivoxil Drugs 0.000 claims 1
- 239000002351 wastewater Substances 0.000 abstract description 12
- 239000002699 waste material Substances 0.000 abstract description 8
- 239000000047 product Substances 0.000 description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
- 230000008569 process Effects 0.000 description 11
- 102000004190 Enzymes Human genes 0.000 description 10
- 108090000790 Enzymes Proteins 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- 238000006555 catalytic reaction Methods 0.000 description 6
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000012300 argon atmosphere Substances 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 4
- 150000002443 hydroxylamines Chemical class 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000002912 waste gas Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 241000711573 Coronaviridae Species 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 229940104302 cytosine Drugs 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000012265 solid product Substances 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 238000003828 vacuum filtration Methods 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000010815 organic waste Substances 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- ZNBNBTIDJSKEAM-UHFFFAOYSA-N 4-[7-hydroxy-2-[5-[5-[6-hydroxy-6-(hydroxymethyl)-3,5-dimethyloxan-2-yl]-3-methyloxolan-2-yl]-5-methyloxolan-2-yl]-2,8-dimethyl-1,10-dioxaspiro[4.5]decan-9-yl]-2-methyl-3-propanoyloxypentanoic acid Chemical compound C1C(O)C(C)C(C(C)C(OC(=O)CC)C(C)C(O)=O)OC11OC(C)(C2OC(C)(CC2)C2C(CC(O2)C2C(CC(C)C(O)(CO)O2)C)C)CC1 ZNBNBTIDJSKEAM-UHFFFAOYSA-N 0.000 description 1
- OSHIQPFXKULOPB-UHFFFAOYSA-N 6-(hydroxyamino)-1h-pyrimidin-2-one Chemical compound ONC1=CC=NC(=O)N1 OSHIQPFXKULOPB-UHFFFAOYSA-N 0.000 description 1
- 241001678559 COVID-19 virus Species 0.000 description 1
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical class C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- XCUAIINAJCDIPM-XVFCMESISA-N N(4)-hydroxycytidine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=NO)C=C1 XCUAIINAJCDIPM-XVFCMESISA-N 0.000 description 1
- 108010084311 Novozyme 435 Proteins 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 229910000378 hydroxylammonium sulfate Inorganic materials 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- -1 propylidene ketone Chemical class 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
- 238000004065 wastewater treatment Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
-
- 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)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
Abstract
In order to reduce waste generation and raw material cost, the embodiment of the invention provides a preparation method of the Vanuepivir, which comprises the following steps: cytidine is taken as a raw material, and Mo Nupi is obtained after hydroxylation reaction, protective group addition reaction, esterification reaction, deprotection reaction and purification in sequence; according to the embodiment of the invention, the cytidine is used as a raw material, and Mo Nupi is obtained after the steps of hydroxylation reaction, protective group addition reaction, esterification reaction, deprotection reaction and purification in sequence, and the cytidine with lower cost is used as the raw material, so that the preparation method is higher in yield, higher in raw material utilization rate, less in generation of follow-up waste and wastewater, lower in cost compared with the existing route and more environment-friendly.
Description
Technical Field
The invention relates to a preparation method of a Vanuepivir.
Background
Mo Nupi the virus is a ribonucleoside analogue which inhibits replication of the novel coronavirus infectious pathogen SARS-CoV-2. The data show that Mo Nupi can effectively reduce the risk of hospitalization and death of early-stage novel coronavirus infected patients by 30%, and is an effective means for early treatment of novel coronavirus light infected patients.
The synthesis method of Mo Nupi is mainly characterized in that uridine is used as a raw material, reactions such as protection, esterification, substitution, hydroxylamine, deprotection and the like are adopted for preparation and production, the ortho-hydroxyl protection is adopted for the propylidene ketone, the esterification reaction is adopted for the isobutyric anhydride or the enzyme catalysis reaction, and the problems of single raw material use, complex operation, serious pollution and high cost exist.
Disclosure of Invention
The embodiment of the invention provides a preparation method of a Vanuepivir, which is used for reducing waste generation and raw material cost.
The embodiment of the invention is realized by the following technical scheme:
the embodiment of the invention provides a preparation method of a Vanuepivir, which comprises the following steps:
cytidine is used as a raw material, and Mo Nupi is obtained after hydroxylation reaction, protective group addition reaction, esterification reaction, deprotection reaction and purification in sequence.
Further, cytidine is used as a raw material, and Mo Nupi is obtained after hydroxylamine reaction, protecting group reaction, esterification reaction, deprotection reaction and purification in sequence; comprising the following steps:
carrying out hydroxylamine reaction on the compound B and hydroxylamine in an alcohol aqueous solution to obtain a compound C;
the compound C and the protecting group reagent are subjected to acid or base catalysis in a first solvent and are subjected to protecting group reaction to protect the o-hydroxyl of the compound C in an inert gas atmosphere to generate a compound D;
the compound D and the esterification reagent are subjected to esterification reaction under the alkali condition in a second solvent, a catalyst and an inert gas atmosphere to generate a compound E;
and (3) carrying out deprotection reaction on the compound E and a deprotection reagent in a third solvent, and purifying to obtain Mo Nupi, namely the compound A.
Further, the alcohol in the aqueous solution of the alcohol is one or more of ethanol, propanol, isopropanol and glycerol.
Further, the first solvent, the second solvent and the third solvent are one or more of dichloromethane, acetone, toluene, acetonitrile, hexane, ethyl acetate and tetrahydrofuran.
Further, the structural formula of the protecting group reagent is as follows:
wherein R is C or Si; r1 is methyl, phenyl, ethyl or vinyl; r2 is methyl, phenyl, ethyl or vinyl.
Further, the protecting group reagent is dichlorodimethylsilane, dichlorodiphenylmethane, 2-dimethoxypropane, acetone, dichlorodiethylsilane or divinyl dichlorosilane.
Further, the deprotection reagent is tetrabutylammonium fluoride, formic acid, hydrochloric acid or p-toluenesulfonic acid.
Further, the catalyst is 4-dimethylaminopyridine or pyridine.
Further, the structural formula of the esterification reagent is as follows:
wherein X is Cl, OH, br or NH 2 。
Further, the esterifying reagent is isobutyric acid, isobutyryl chloride, isobutyric anhydride, isobutyryl bromide or isobutyramide.
Compared with the prior art, the embodiment of the invention has the following advantages and beneficial effects:
according to the preparation method of the Vanupiprevir, the cytidine is used as the raw material, and the Mo Nupi pyrr is obtained after the hydroxylamine reaction, the protecting group adding reaction, the esterification reaction, the deprotection reaction and the purification in sequence, and the cytidine with lower cost is used as the raw material, so that the preparation method is higher in yield, higher in raw material utilization rate, less in generation of follow-up waste and wastewater, lower in cost compared with the existing route, and more environment-friendly.
Drawings
In order to more clearly illustrate the technical solutions of the exemplary embodiments of the present invention, the drawings that are needed in the examples will be briefly described below, it being understood that the following drawings only illustrate some examples of the present invention and therefore should not be considered as limiting the scope, and that other related drawings may be obtained from these drawings without inventive effort for a person skilled in the art.
Fig. 1 is a schematic flow chart of a preparation method of Mo Nupi.
Fig. 2 shows nmr hydrogen spectrum data of Mo Nupi of the example 1.
Fig. 3 shows nmr spectrum data of Mo Nupi of the example 1.
Detailed Description
For the purpose of making apparent the objects, technical solutions and advantages of the present invention, the present invention will be further described in detail with reference to the following examples and the accompanying drawings, wherein the exemplary embodiments of the present invention and the descriptions thereof are for illustrating the present invention only and are not to be construed as limiting the present invention.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. However, it will be apparent to one of ordinary skill in the art that: no such specific details are necessary to practice the invention. In other instances, well-known structures, circuits, materials, or methods have not been described in detail in order not to obscure the invention.
Throughout the specification, references to "one embodiment," "an embodiment," "one example," or "an example" mean: a particular feature, structure, or characteristic described in connection with the embodiment or example is included within at least one embodiment of the invention. Thus, the appearances of the phrases "in one embodiment," "in an example," or "in an example" in various places throughout this specification are not necessarily all referring to the same embodiment or example. Furthermore, the particular features, structures, or characteristics may be combined in any suitable combination and/or sub-combination in one or more embodiments or examples. Moreover, those of ordinary skill in the art will appreciate that the illustrations provided herein are for illustrative purposes and that the illustrations are not necessarily drawn to scale. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.
In the description of the present invention, the terms "front", "rear", "left", "right", "upper", "lower", "vertical", "horizontal", "high", "low", "inner", "outer", etc. indicate orientations or positional relationships based on the orientations or positional relationships shown in the drawings, merely to facilitate description of the present invention and simplify description, and do not indicate or imply that the devices or elements referred to must have a specific orientation, be configured and operated in a specific orientation, and therefore should not be construed as limiting the scope of the present invention.
Examples
In order to reduce waste generation and raw material cost, the embodiment of the invention provides a preparation method of the Vanuepivir, which comprises the following steps:
cytidine is used as a raw material, and Mo Nupi is obtained after hydroxylation reaction, protective group addition reaction, esterification reaction, deprotection reaction and purification in sequence.
Methods for synthesizing Mo Nupi by cytosine are also known in the art. Some processes are needed for cytosine to produce N4-hydroxycytosine, which is also an intermediate for synthesizing the target product compound A (Mo Nupi). The route of the embodiment of the invention mainly aims at realizing optimization of a synthesis route of the Vanupiprevir, and is a method adopting cytidine as a starting material, and does not relate to a subsequent process of synthesizing N4-hydroxycytidine by cytosine.
According to the embodiment of the invention, the cytidine is used as a raw material, and Mo Nupi is obtained after the steps of hydroxylation reaction, protective group addition reaction, esterification reaction, deprotection reaction and purification in sequence, and the cytidine with lower cost is used as the raw material, so that the preparation method is higher in yield, higher in raw material utilization rate, less in subsequent waste and wastewater production, lower in cost and more environment-friendly than the existing route.
Further, cytidine is used as a raw material, and Mo Nupi is obtained after hydroxylamine reaction, protecting group reaction, esterification reaction, deprotection reaction and purification in sequence; referring to fig. 1, the method includes:
s1, carrying out hydroxylamine reaction on a compound B and hydroxylamine in an alcohol aqueous solution to obtain a compound C;
s2, protecting the o-hydroxyl of the compound C by the reaction of the protecting group in the presence of acid or alkali catalysis and inert gas atmosphere in a first solvent to generate a compound D;
s3, carrying out esterification reaction on the compound D and an esterification reagent in a second solvent under the alkali condition, a catalyst and an inert gas atmosphere to generate a compound E;
s4, performing deprotection reaction on the compound E and a deprotection reagent in a third solvent, and purifying to obtain Mo Nupi-wei compound A.
Compared with other routes, the preparation method provided by the embodiment of the invention has less waste generation. In other routes of the prior art that require enzyme-catalyzed esterification, the enzyme-catalyzed reaction process often requires the addition of large amounts of buffering agents.
In patent CN112608357a, enzymes such as esterifying enzyme Novozyme 435 and protease BLP are used to catalyze the esterification reaction. The purpose of adding a buffer is mainly that the pH change of a reaction solution affects the activity of an enzyme in the enzyme catalytic reaction process, the price of a selected catalytic esterifying enzyme is often too high, and in order to improve the efficiency of the enzyme catalytic reaction and the utilization rate of the enzyme, the buffer (phosphoric acid, hydrochloric acid, sodium hydroxide, potassium hydroxide, monopotassium phosphate, dipotassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, tris-HCl and the like) is needed to be added, and the means is also necessary for all Mo Nupi-V synthesis routes adopting the enzyme catalytic reaction, and the use amount of the enzyme is increased if the buffer is not added. The addition of buffer during subsequent processing can result in the generation of large amounts of wastewater, which can lead to increased costs during industrial production.
The waste generated in the Mo Nupi process of the embodiment of the invention is mainly organic waste water and waste gas, and the long-term contact of the organic waste water and the waste gas in the production treatment process can cause harm to human bodies, and the improper treatment of the waste water and the waste gas or the direct discharge of the waste water and the waste gas can cause pollution to the environment. The preparation route provided by the embodiment of the invention has fewer steps, is simple to operate, generates fewer organic wastewater compared with the traditional route, and causes less pollution to the environment in wastewater treatment and exhaust emission.
Further, the alcohol in the aqueous solution of the alcohol is one or more of ethanol, propanol, isopropanol and glycerol.
Further, the first solvent, the second solvent and the third solvent are one or more of dichloromethane, acetone, toluene, acetonitrile, hexane, ethyl acetate and tetrahydrofuran.
Further, the structural formula of the protecting group reagent is as follows:
wherein R is C or Si; r1 is methyl, phenyl, ethyl or vinyl; r2 is methyl, phenyl, ethyl or vinyl.
Further, the protecting group reagent is dichlorodimethylsilane, dichlorodiphenylmethane, 2-dimethoxypropane, acetone, dichlorodiethylsilane or divinyl dichlorosilane.
Further, the deprotection reagent is tetrabutylammonium fluoride, formic acid, hydrochloric acid or p-toluenesulfonic acid.
Further, the catalyst is 4-dimethylaminopyridine or pyridine.
In the route adopted by the embodiment of the invention, the esterification reaction catalyzed by the esterifying enzyme is not used, and the esterification process adopts 4-dimethylaminopyridine or pyridine and the like to catalyze the reaction under the action of alkali, so that no buffer is needed to be additionally added, and the liquid reduces the generation of wastewater.
Further, the structural formula of the esterification reagent is as follows:
wherein X is Cl, OH, br or NH 2 。
Further, the esterifying reagent is isobutyric acid, isobutyryl chloride, isobutyric anhydride, isobutyryl bromide or isobutyramide.
Example 1
A method for preparing a bernoulli formulation comprising:
(1) Hydroxylamines: cytidine (compound B) 50.00g (205.6 mmol), hydroxylamine sulfate 50.612g (308.4 mmol) and 400mL of isopropyl alcohol, 100mL of distilled water were added to a 1L three-necked round bottom flask equipped with a stirrer and a thermometer. The mixture was stirred and heated to 70 ℃ and the solid suspension was dissolved and after 10 minutes the reaction mixture became homogeneous. The reaction mixture was stirred at 70 ℃ for 5 hours. The reaction was monitored by HPLC until cytidine was 3% or less. The heating was turned off and the suspension was allowed to cool slowly to room temperature (25 ℃) over about 3 hours, then cooled to-5 ℃ in an ice-salt bath and stirred for an additional 3 hours. The solid was isolated by desolventizing filtration, washed with ice water (100 mL. Times.3), and dried overnight in a vacuum oven (50 ℃ C.) to give 47.71g of a white crystalline solid (compound C) in 89.5% yield.
(2) And (3) protection: into a 100mL three-necked round bottom flask equipped with a stirrer, a thermometer and a condenser was charged 50mL of methylene chloride, 5.18g (20 mmol) of a hydroxylamines product (compound C), 3.03g (30 mmol) of triethylamine, and the mixture was dissolved by stirring at room temperature (25 ℃ C.) under an argon atmosphere. 2.61g (20.2 mmol) of dimethyldichlorosilane were added dropwise. Controlling the dropping speed to ensure that the temperature in the dropping process is not more than 35 ℃, heating to 60 ℃ after dropping, preserving heat for 3 hours, and stopping the reaction after the HPLC detects that the C of the reaction compound is less than or equal to 3 percent. The reaction solution was extracted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and crystallized from n-heptane, and dried overnight in a vacuum oven (50 ℃) to give 5.96g of a white crystallized product (compound D) in 94.5% yield.
(3) Esterification reaction: a1000 mL three-necked round bottom flask equipped with a stirrer, a thermometer, and a condenser reflux tube was charged with 20.00g (63.42 mmol) of the above-mentioned protected product (compound D), 32.09g (317.10 mmol) of triethylamine, 3.87g (31.71 mmol) of 4-dimethylaminopyridine and 400mL of tetrahydrofuran under an argon atmosphere. The reaction flask was cooled to 0±5 ℃ in an ice bath. Isobutyryl chloride 14.87g (139.56 mmol) was slowly added dropwise over 2 hours, and the reaction was stopped when compound D was detected to be 2% or less by HPLC after 6 hours at 0 ℃. The solvent was concentrated under reduced pressure and crystallized from n-heptane and dried in a vacuum oven (50 ℃) overnight to give 20.62g of the product as white crystals (compound E) in a yield of 84.3%.
(4) Deprotection: into a 1L three-necked round bottom flask equipped with a stirrer and a thermometer were charged 20g (51.89 mmol) of compound E obtained by the esterification reaction, 400ml of tetrahydrofuran, 7.79g (129.72 mmol) of acetic acid and 33.92g (129.72 mmol) of tetrabutylammonium fluoride. The reaction was then stirred at room temperature (25 ℃) for 5-6 h until all compound E was completely reacted. The reaction solution was extracted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate, dried and filtered, and concentrated under reduced pressure. The residue was taken up in 50mL of ethanol, 100mL of MTBE and heated until the residue was completely dissolved, then cooled to room temperature and stirred for 1h until the solid had completely precipitated, the solid product was obtained by vacuum filtration, the filter cake was washed with 100mL of MTBE and dried overnight in a vacuum oven (50 ℃) to give 13.38g of the white crystalline product (compound a) in 78.3% yield.
The structural confirmation of compound a is shown with reference to fig. 2 and 3. As can be seen from a combination of fig. 2 and 3, the white crystal product prepared by the preparation method is Mo Nupi.
The method adopted in the embodiment 1 of the invention has the advantages of less solvent consumption, less wastewater generation and great cost saving. For example, in example 3 of patent CN112608357a, the process produces about 6.69L of wastewater per 1mol of esterification product produced (including about 0.49L of reaction solvent THF, about 2.45L of buffer solution, about 2.45L of water added during extraction, about 1.3L of crystallization solvent and hydration, minus about 80% recovery solvent) calculated for the yield and material usage given. Whereas the esterification process of example 1 of the present invention produced about 1.70L of wastewater per 1mol of esterification product (including 1.5L of reaction solvent and 0.2L of crystallization solvent). In contrast, the esterification process, per 1 ton produced, can produce about 13.4 tons less wastewater than patent CN112608357a (considering solvent recovery as 80%).
Example 2
A method for preparing a bernoulli formulation comprising:
(1) Hydroxylamines: the same as in example 1.
(2) And (3) protection: in a 100mL three-necked round bottom flask equipped with a stirrer, a thermometer and a condenser reflux tube, 50mL of acetone, 5.18g (20 mmol) of a hydroxylamine product (Compound C), 0.38g (2 mmol) of p-toluenesulfonic acid monohydrate, 2.40g (23 mmol) of 2, 2-dimethoxypropane were charged, and the reaction was stirred at room temperature under argon atmosphere for 18 hours until the reaction compound C was detected to be 3% or less by HPLC, and the reaction was stopped. The acetone was removed by concentration under reduced pressure, the residue was dissolved in ethyl acetate, followed by desolventizing and filtration, and crystallized from n-heptane, and dried overnight in a vacuum oven (50 ℃) to give 5.91g of a white crystallized product (compound D) in 98.7% yield.
(3) Esterification reaction: a1000 mL three-necked round bottom flask equipped with a stirrer, a thermometer, and a condenser reflux tube was charged with 20.00g (63.42 mmol) of the above-mentioned protected product (compound D), 32.09g (317.10 mmol) of triethylamine, 3.87g (31.71 mmol) of 4-dimethylaminopyridine and 400mL of tetrahydrofuran under an argon atmosphere. The reaction flask was cooled to 0±5 ℃ in an ice bath. Isobutyryl chloride 14.87g (139.56 mmol) was slowly added dropwise over 2 hours, and the reaction was stopped when compound D was detected to be 2% or less by HPLC after 6 hours at 0 ℃. The solvent was concentrated under reduced pressure and crystallized from n-heptane and dried in a vacuum oven (50 ℃) overnight to give 19.56g of the product as white crystals (compound E) in 83.5% yield.
(4) Deprotection: to a 200ml round-bottomed flask were added 6.51g (17.6 mmol) of the product compound E from the previous step and 100ml of formic acid, the reaction mixture was stirred at room temperature for 3h and the reaction was controlled to completion by HPLC. Concentrated in vacuo to give the product as a clear pale powder as an oil. 30 mL of ethanol are added, then the solvent is removed under reduced pressure, 50mL of MTBE is added and dissolved with heating. And then cooling and crystallizing at room temperature. The solid product was collected by vacuum filtration and the filter cake was washed with MTBE and dried overnight in a vacuum oven (50 ℃) to give 4.34g of the white crystalline product (Compound A) in 74.9% yield.
Example 3
A method for preparing a bernoulli formulation comprising:
(1) Hydroxylamines: the same as in example 1.
(2) And (3) protection: 200mL of acetone and 5.18g (20 mmol) of hydroxylamine product (Compound C) were charged into a 500mL three-necked round bottom flask equipped with a stirrer, a thermometer and a condenser reflux tube, 2.5mL of sulfuric acid was slowly added dropwise while stirring at room temperature, and after completion of the reaction of Compound C was detected by TLC, the reaction solution was neutralized with triethylamine, followed by stopping the reaction. The acetone was removed by concentration under reduced pressure, and the residue was dissolved in ethyl acetate, then desolventized and filtered, and crystallized in hexane, and dried overnight in a vacuum oven (50 ℃) to give 5.89g of a white crystallized product (compound D) in 98.5% yield.
(3) Esterification reaction: 9.88g (33 mmol) of the above-mentioned protected product (compound D), 0.25g (2 mmol) of 4-dimethylaminopyridine and 110mL of ethyl acetate were charged under argon atmosphere into a 250mL three-necked round bottom flask equipped with a stirrer, a thermometer and a condenser reflux tube, and the solution was stirred. Then, 8.40g (83 mmol) of triethylamine and 6.33g (40 mmol) of isobutyric anhydride were added dropwise, and the dropping speed was not controlled too fast. The reaction was stirred at room temperature for 8 hours, and the reaction was stopped when compound D was detected by hplc to be 2% or less. The reaction was extracted with dichloromethane and the organic phase was washed with saturated aqueous sodium bicarbonate. The solvent was concentrated under reduced pressure and crystallized in hexane, and the product obtained by filtration was dried in a vacuum oven (50 ℃) overnight to give 10.87g of a white crystallized product (compound E) in 89.1% yield.
(4) Deprotection: to a 200ml round bottom flask was added 5.92g (16.0 mmol) of the product compound E from the previous step and 100ml of formic acid. The reaction mixture was stirred at room temperature for 3h. The reaction was quenched by HPLC. The reaction mixture was concentrated in vacuo to give the product as a clear pale powder oil. 30 mL of ethanol are added, then the solvent is removed under reduced pressure, 50mL of MTBE is added and dissolved with heating. And then cooling and crystallizing at room temperature. The solid product was collected by vacuum filtration and the filter cake was washed with MTBE and dried overnight in a vacuum oven (50 ℃) to give 3.88g of the white crystalline product (Compound A) in 73.7% yield.
The foregoing description of the embodiments has been provided for the purpose of illustrating the general principles of the invention, and is not meant to limit the scope of the invention, but to limit the invention to the particular embodiments, and any modifications, equivalents, improvements, etc. that fall within the spirit and principles of the invention are intended to be included within the scope of the invention.
Claims (10)
1. A method for preparing a knoop-pivoxil, comprising:
cytidine is used as a raw material, and Mo Nupi is obtained after hydroxylation reaction, protective group addition reaction, esterification reaction, deprotection reaction and purification in sequence.
2. The method for preparing Mo Nupi of claim 1, wherein cytidine is used as a raw material, and Mo Nupi of the raw material is obtained by hydroxylamine reaction, protecting group reaction, esterification reaction, deprotection reaction and purification in sequence; comprising the following steps:
carrying out hydroxylamine reaction on the compound B and hydroxylamine in an alcohol aqueous solution to obtain a compound C;
the compound C and the protecting group reagent are subjected to acid or base catalysis in a first solvent and are subjected to protecting group reaction to protect the o-hydroxyl of the compound C in an inert gas atmosphere to generate a compound D;
the compound D and the esterification reagent are subjected to esterification reaction under the alkali condition in a second solvent, a catalyst and an inert gas atmosphere to generate a compound E;
and (3) carrying out deprotection reaction on the compound E and a deprotection reagent in a third solvent, and purifying to obtain Mo Nupi, namely the compound A.
3. The method for preparing Mo Nupi as claimed in claim 2, wherein the alcohol in the aqueous solution of alcohol is one or more of ethanol, propanol, isopropanol and glycerol.
4. The method of preparing Mo Nupi of claim 2, wherein the first, second and third solvents are one or more of dichloromethane, acetone, toluene, acetonitrile, hexane, ethyl acetate and tetrahydrofuran.
5. The method of preparing Mo Nupi of claim 2, wherein the protecting group reagent has the formula:
wherein R is C or Si; r1 is methyl, phenyl, ethyl or vinyl; r2 is methyl, phenyl, ethyl or vinyl.
6. The method for preparing Mo Nupi of claim 2, wherein the protecting group reagent is dichlorodimethylsilane, dichlorodiphenylmethane, 2-dimethoxypropane, acetone, dichlorodiethylsilane or divinyl dichlorosilane.
7. The method for preparing Mo Nupi of claim 2, wherein the deprotecting reagent is tetrabutylammonium fluoride, formic acid, hydrochloric acid or p-toluenesulfonic acid.
8. The method for preparing Mo Nupi of claim 2, wherein the catalyst is 4-dimethylaminopyridine or pyridine.
9. The method of preparing Mo Nupi of claim 2, wherein the esterification reagent has the structural formula:
wherein X is Cl, OH, br or NH 2 。
10. The method of preparing Mo Nupi of claim 2, wherein the esterifying reagent is isobutyric acid, isobutyryl chloride, isobutyric anhydride, isobutyryl bromide or isobutyramide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210736138.2A CN116041403A (en) | 2022-09-29 | 2022-09-29 | Preparation method of Vanuepivir |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210736138.2A CN116041403A (en) | 2022-09-29 | 2022-09-29 | Preparation method of Vanuepivir |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116041403A true CN116041403A (en) | 2023-05-02 |
Family
ID=86120573
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210736138.2A Pending CN116041403A (en) | 2022-09-29 | 2022-09-29 | Preparation method of Vanuepivir |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116041403A (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112552288A (en) * | 2021-02-19 | 2021-03-26 | 南京桦冠生物技术有限公司 | Preparation method of 4-oxime-5' - (2-methylpropionyl) uridine |
| CN113278040A (en) * | 2021-06-16 | 2021-08-20 | 苏州立新制药有限公司 | Preparation method of 5' -isobutyryl-N4-hydroxycytidine |
| CN113880903A (en) * | 2021-09-23 | 2022-01-04 | 厦门蔚嘉制药有限公司 | Preparation method of monabivir |
| CN114315933A (en) * | 2021-09-30 | 2022-04-12 | 海化生命(厦门)科技有限公司 | Preparation method of potential anti-new coronavirus medicine monatipivir |
| WO2022200847A1 (en) * | 2021-03-20 | 2022-09-29 | Optimus Drugs Private Limited | Improved process for molnupiravir |
-
2022
- 2022-09-29 CN CN202210736138.2A patent/CN116041403A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112552288A (en) * | 2021-02-19 | 2021-03-26 | 南京桦冠生物技术有限公司 | Preparation method of 4-oxime-5' - (2-methylpropionyl) uridine |
| WO2022200847A1 (en) * | 2021-03-20 | 2022-09-29 | Optimus Drugs Private Limited | Improved process for molnupiravir |
| CN113278040A (en) * | 2021-06-16 | 2021-08-20 | 苏州立新制药有限公司 | Preparation method of 5' -isobutyryl-N4-hydroxycytidine |
| CN113880903A (en) * | 2021-09-23 | 2022-01-04 | 厦门蔚嘉制药有限公司 | Preparation method of monabivir |
| CN114315933A (en) * | 2021-09-30 | 2022-04-12 | 海化生命(厦门)科技有限公司 | Preparation method of potential anti-new coronavirus medicine monatipivir |
Non-Patent Citations (1)
| Title |
|---|
| VIJAYAGOPAL GOPALSAMUTHIRAM ET AL., 《ORG. PROCESS RES. DEV.》, vol. 25, no. 12, 9 December 2021 (2021-12-09), pages 2679 - 2685 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6949668B2 (en) | Process for producing 5-(3-cyanophenyl)-3-formylbenzoic acid compound | |
| KR20150018524A (en) | Process for the preparation of 2-deoxy-2-fluoro-2-methyl-d-ribofuranosyl nucleoside compounds | |
| US20100249415A1 (en) | Process for preparation of temsirolimus | |
| WO2011010967A1 (en) | Process for producing flurocytidine derivatives | |
| WO2008069440A1 (en) | The preparation method of 2-de0xy-l-rib0se | |
| CN116041403A (en) | Preparation method of Vanuepivir | |
| CN107827938B (en) | Preparation method of 1,2, 3-tri-O-acetyl-5-deoxy- β -D-ribose | |
| CN111269263A (en) | Rudexilvir side chain intermediate and preparation method thereof | |
| CN109836404B (en) | Epirubicin hydrochloride intermediate compound | |
| EP4249462A1 (en) | Method for producing ketone derivative | |
| CN114717280A (en) | Synthesis method of monopilavir | |
| CN112961198B (en) | Preparation method of purine nucleotide intermediate | |
| WO2008116387A1 (en) | A preparation process for taxol and derivatives thereof | |
| CN114014864A (en) | Preparation process of traasiril compound | |
| AU2006209556A1 (en) | Process for production of 5-chloro-2,4-dihydroxypyridine | |
| CN114315575A (en) | Preparation method and application of photoinitiator intermediate | |
| WO2016030911A2 (en) | Improved process for the preparation of lacosamide and its novel intermediate | |
| CN111362989A (en) | Preparation method of Sofosbuvir key intermediate | |
| CN108484690B (en) | Preparation method of 1,2, 3-tri-O-acetyl-5-deoxy-beta-D-ribose | |
| CN109206465B (en) | Method for synthesizing adenosine cyclophosphate | |
| CN101128449A (en) | Process of preparing docetaxel | |
| CN112409420B (en) | Purification method of 2 '-fluoro-2' -deoxyuridine | |
| KR101241321B1 (en) | Improved preparation method of Decitabine | |
| CN113336780B (en) | Preparation method of 2-formyl-4- (4-cyanophenoxy) phenylboronic acid pinacol ester | |
| CN111018825B (en) | Synthetic method of 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |