CN115385932A - Intermediate of pyridone derivative and preparation method thereof - Google Patents
Intermediate of pyridone derivative and preparation method thereof Download PDFInfo
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- CN115385932A CN115385932A CN202210563489.8A CN202210563489A CN115385932A CN 115385932 A CN115385932 A CN 115385932A CN 202210563489 A CN202210563489 A CN 202210563489A CN 115385932 A CN115385932 A CN 115385932A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 175
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 626
- 238000006243 chemical reaction Methods 0.000 claims abstract description 155
- 238000004519 manufacturing process Methods 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims description 159
- 238000000034 method Methods 0.000 claims description 132
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 99
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 81
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 81
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 69
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 62
- 125000002837 carbocyclic group Chemical group 0.000 claims description 62
- 239000003960 organic solvent Substances 0.000 claims description 55
- 238000006482 condensation reaction Methods 0.000 claims description 51
- 239000003795 chemical substances by application Substances 0.000 claims description 50
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 40
- 229910052799 carbon Inorganic materials 0.000 claims description 37
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 claims description 36
- 150000004703 alkoxides Chemical class 0.000 claims description 35
- 150000001721 carbon Chemical group 0.000 claims description 35
- 238000006467 substitution reaction Methods 0.000 claims description 31
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 31
- 239000003054 catalyst Substances 0.000 claims description 28
- 150000002191 fatty alcohols Chemical class 0.000 claims description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 26
- -1 sodium alkoxide Chemical class 0.000 claims description 25
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical group COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 23
- 229910052736 halogen Inorganic materials 0.000 claims description 23
- 150000002367 halogens Chemical group 0.000 claims description 23
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 claims description 22
- 238000007363 ring formation reaction Methods 0.000 claims description 22
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 20
- 238000005917 acylation reaction Methods 0.000 claims description 20
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 20
- 239000004593 Epoxy Substances 0.000 claims description 19
- 230000035484 reaction time Effects 0.000 claims description 19
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 18
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 18
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 18
- 239000002585 base Substances 0.000 claims description 18
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 18
- 229910052794 bromium Inorganic materials 0.000 claims description 18
- 229910052801 chlorine Inorganic materials 0.000 claims description 18
- 239000000460 chlorine Substances 0.000 claims description 18
- 125000006239 protecting group Chemical group 0.000 claims description 17
- 238000003756 stirring Methods 0.000 claims description 17
- 238000006266 etherification reaction Methods 0.000 claims description 16
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 15
- 238000001953 recrystallisation Methods 0.000 claims description 15
- 159000000003 magnesium salts Chemical class 0.000 claims description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 13
- 238000007112 amidation reaction Methods 0.000 claims description 13
- 238000005906 dihydroxylation reaction Methods 0.000 claims description 13
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 12
- 150000007530 organic bases Chemical class 0.000 claims description 12
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical group ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 12
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical group C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 claims description 12
- 238000002425 crystallisation Methods 0.000 claims description 11
- 230000008025 crystallization Effects 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 11
- UJJLJRQIPMGXEZ-BYPYZUCNSA-N (2s)-oxolane-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCO1 UJJLJRQIPMGXEZ-BYPYZUCNSA-N 0.000 claims description 10
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 10
- 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 10
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 235000019253 formic acid Nutrition 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 229910003002 lithium salt Inorganic materials 0.000 claims description 10
- 159000000002 lithium salts Chemical class 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 9
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 9
- 239000000463 material Substances 0.000 claims description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 8
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 239000011737 fluorine Substances 0.000 claims description 8
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical group [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- 150000001350 alkyl halides Chemical class 0.000 claims description 7
- 239000003759 ester based solvent Substances 0.000 claims description 7
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 229940126062 Compound A Drugs 0.000 claims description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 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
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 239000003849 aromatic solvent Substances 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 150000002576 ketones Chemical class 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 229940002612 prodrug Drugs 0.000 claims description 6
- 239000000651 prodrug Substances 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- 230000010933 acylation Effects 0.000 claims description 5
- 150000001408 amides Chemical class 0.000 claims description 5
- MFSHZGFPADYOTO-UHFFFAOYSA-N chloromethyl methyl carbonate Chemical compound COC(=O)OCCl MFSHZGFPADYOTO-UHFFFAOYSA-N 0.000 claims description 5
- 238000009833 condensation Methods 0.000 claims description 5
- 230000005494 condensation Effects 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- CGRKYEALWSRNJS-UHFFFAOYSA-N sodium;2-methylbutan-2-olate Chemical compound [Na+].CCC(C)(C)[O-] CGRKYEALWSRNJS-UHFFFAOYSA-N 0.000 claims description 5
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 claims description 4
- BTOJSYRZQZOMOK-UHFFFAOYSA-N 4-chloro-7-(4-methylphenyl)sulfonylpyrrolo[2,3-d]pyrimidine Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C2=NC=NC(Cl)=C2C=C1 BTOJSYRZQZOMOK-UHFFFAOYSA-N 0.000 claims description 4
- 229940123734 Endonuclease inhibitor Drugs 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 4
- 230000001476 alcoholic effect Effects 0.000 claims description 4
- 150000001348 alkyl chlorides Chemical class 0.000 claims description 4
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 4
- 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 4
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 4
- 230000001419 dependent effect Effects 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 150000002240 furans Chemical class 0.000 claims description 4
- 229910052744 lithium Inorganic materials 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- ZRLVQFQTCMUIRM-UHFFFAOYSA-N potassium;2-methylbutan-2-olate Chemical compound [K+].CCC(C)(C)[O-] ZRLVQFQTCMUIRM-UHFFFAOYSA-N 0.000 claims description 4
- 229910000077 silane Inorganic materials 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical group O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 claims description 4
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims description 3
- 239000004210 ether based solvent Substances 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- 230000000171 quenching effect Effects 0.000 claims description 3
- DVCFNCQPOANJGU-BYPYZUCNSA-N (2s)-oxolane-2-carbonyl chloride Chemical compound ClC(=O)[C@@H]1CCCO1 DVCFNCQPOANJGU-BYPYZUCNSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- SYBYTAAJFKOIEJ-UHFFFAOYSA-N 3-Methylbutan-2-one Chemical compound CC(C)C(C)=O SYBYTAAJFKOIEJ-UHFFFAOYSA-N 0.000 claims description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 2
- ZXJNLESZLXITNL-BYPYZUCNSA-N O=C([C@H]1OCCC1)Br Chemical compound O=C([C@H]1OCCC1)Br ZXJNLESZLXITNL-BYPYZUCNSA-N 0.000 claims description 2
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical group [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 2
- 239000005456 alcohol based solvent Substances 0.000 claims description 2
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 1
- 239000003513 alkali Substances 0.000 claims 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims 1
- 239000011630 iodine Substances 0.000 claims 1
- 229910052740 iodine Inorganic materials 0.000 claims 1
- 239000004973 liquid crystal related substance Substances 0.000 claims 1
- 238000012805 post-processing Methods 0.000 claims 1
- 239000011541 reaction mixture Substances 0.000 claims 1
- 238000010626 work up procedure Methods 0.000 claims 1
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 18
- 238000001035 drying Methods 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 239000012022 methylating agents Substances 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000006264 debenzylation reaction Methods 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical group COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000004537 pulping Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- DKACXUFSLUYRFU-UHFFFAOYSA-N tert-butyl n-aminocarbamate Chemical compound CC(C)(C)OC(=O)NN DKACXUFSLUYRFU-UHFFFAOYSA-N 0.000 description 2
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- NJTZSWLQBQJUHK-UHFFFAOYSA-N CCCP(=O)=O Chemical compound CCCP(=O)=O NJTZSWLQBQJUHK-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- MOIPGXQKZSZOQX-UHFFFAOYSA-N carbonyl bromide Chemical compound BrC(Br)=O MOIPGXQKZSZOQX-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000005453 ketone based solvent Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- NIQQIJXGUZVEBB-UHFFFAOYSA-N methanol;propan-2-one Chemical compound OC.CC(C)=O NIQQIJXGUZVEBB-UHFFFAOYSA-N 0.000 description 1
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
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- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
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- C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
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Abstract
The invention discloses an intermediate of pyridone derivative and a preparation method thereof; the new intermediate compound of the invention, namely the compound formula I, the compound formula E or the compound formula C, can be used for efficiently preparing the pyridone derivative; the preparation method has the advantages of short reaction period, low cost, high yield, high product purity, suitability for industrial mass production, simple and convenient operation, environmental protection, high safety and the like.
Description
Technical Field
The invention belongs to the technical field of chemical drug synthesis, and relates to an intermediate of a pyridone derivative of a cap-dependent endonuclease inhibitor and a preparation method thereof.
Background
The cap-dependent endonuclease inhibitor pyridone derivative is a medicament which is researched and developed by companies independently and is used for resisting influenza viruses, and CN110637016A discloses the pyridone derivative and a synthetic method thereof, wherein the synthetic route is shown as follows:
the method has the disadvantages of long reaction period; the reagent is expensive and the cost is high; the yield is low; 10g and 2a at T 3 The ethyl acetate solution of P has a closed reaction at 100 ℃, potential safety hazards exist, the purity of the obtained product is low, and the product is separated by using a chiral column and is not suitable for industrial large-scale production; in the preparation process of 10f, stannic chloride reacts to generate hydrogen chloride gas, and equipment is easy to corrode after water absorption; the pollution to the environment is great; when the hydroxyl protective group is removed, namely debenzylation (from 10h to II-6 steps), various problems such as low yield of reversible reaction and the like are easy to occur.
Disclosure of Invention
Aiming at the problems, the invention provides a new intermediate of the pyridone derivative and a preparation method thereof, the new intermediate can be used for efficiently preparing the pyridone derivative, and the method has the advantages of short reaction period, low cost, high yield, high product purity, suitability for industrial mass production, simple and convenient operation, environmental protection and high safety.
The present invention also provides a process for the preparation of compound formula F, comprising the steps of:
reacting the compound of formula E with an aliphatic alcohol in the presence of an alkoxide to produce a compound of formula F:
wherein R is 2 、R 3 Together with the carbon atom to which they are both attached form C 3-8 A carbocyclic ring;
n is an integer of 1 to 9.
In one embodiment of the invention, in the preparation of the compound of formula F, n may be 4, 5 or 6, for example 5.
In one embodiment of the present invention, the compound of formula F is prepared by a process wherein C is 3-8 The carbocyclic ring may be C 3-4 Carbocycle, such as a three membered carbocycle.
In one embodiment of the present invention, the alkoxide in the preparation method of the compound of formula F may be an alkoxide which is conventional in the art. The alkoxide may be a sodium alkoxide and/or a potassium alkoxide, such as sodium tert-amylate, sodium tert-butoxide, potassium tert-amylate.
In one embodiment of the present invention, in the preparation process of the compound of formula F, the alkoxide is preferably added in solid form.
In one embodiment of the present invention, in the preparation method of the compound of formula F, the molar ratio of the compound of formula E to the alkoxide may be 1:0.1 to 10; preferably 1:3-6, more preferably 1:4-5.
In one embodiment of the present invention, in the preparation method of the compound of formula F, the fatty alcohol may be a fatty alcohol conventional in the art. The fatty alcohol can be C2-10 fatty alcohol, and can also be ethanol, n-propanol, n-butanol, n-pentanol, n-hexanol, preferably n-hexanol.
In one embodiment of the present invention, the compound of formula F may be prepared by a method wherein the molar ratio of the compound of formula E to the fatty alcohol (e.g., n-hexanol) is 1:1-15, preferably 1:7-11, more preferably 1:8-10.
In one embodiment of the present invention, the compound of formula F is prepared by a method wherein the substitution reaction is carried out in an organic solvent. The organic solvent can be one or more of epoxy solvents, halogenated alkane solvents, aromatic solvents and ester solvents. The epoxy-based solvent may be THF. The haloalkane solvent may be a chloroalkane solvent, such as dichloromethane. The aromatic hydrocarbon solvent may be toluene. The ester solvent may be ethyl acetate. The organic solvent can also be one or a combination of THF, dichloromethane, toluene and ethyl acetate. The organic solvent is more preferably an epoxy-based solvent, such as THF.
In one embodiment of the present invention, in the preparation method of the compound of formula F, the reaction temperature of the substitution reaction may be less than 50 ℃, for example, -10 to 10 ℃ or less than 0 ℃.
In one embodiment of the present invention, the reaction time of the reaction in the preparation method of the compound of formula F is equal to or greater than 97% of the conversion rate of the compound of formula e. The conversion of the compound of formula e can be detected using conventional detection, e.g. HPLC.
In one embodiment of the present invention, the reaction mass in the process for the preparation of the compound of formula F consists of: the compound of formula E, the fatty alcohol, and the alkoxide, or, the organic solvent, the compound of formula E, the fatty alcohol, and the alkoxide.
"reaction material" in the present invention means a material for synthesizing the compound, excluding materials in the post-treatment step, and the reaction material is all materials added to the reaction.
In one embodiment of the present invention, in the preparation of the compound of formula F, the compound of formula F can be
In one embodiment of the present invention, in the preparation of the compound of formula F, the compound of formula E can be
In one embodiment of the present invention, the compound of formula F is prepared by a process comprising the steps of: dissolving the compound of formula E and the fatty alcohol (e.g. n-hexanol) in the organic solvent, adding the alkoxide, stirring to react at a temperature below 50 ℃ (e.g. -10 ℃, preferably-10-0 ℃ or below 0 ℃), optionally including a post-treatment step.
The present invention also provides a process for the preparation of compound formula E, comprising the steps of: in a solvent in the presence of a base, (S) -tetrahydrofuran formyl halide
With a compound of formula D to give an amide of the formulaThe reaction produces a compound of formula E:
wherein R is 2 、R 3 Together with the carbon atom to which they are jointly attached form C 3-8 A carbocyclic ring; y is halogen.
In one embodiment of the present invention, the compound of formula E is prepared by a process wherein C is 3-8 The carbocyclic ring may be C 3-4 Carbocycle, such as a three membered carbocycle.
In one embodiment of the present invention, in the preparation of the compound of formula E, the halogen may be fluorine, chlorine, bromine or iodine, for example chlorine or bromine.
In one embodiment of the invention, the compound of formula E is prepared by a process which comprises
((S) -tetrahydrofuran carbonyl halide) may be (S) -tetrahydrofuran carbonyl chloride or (S) -tetrahydrofuran carbonyl bromide.
In one embodiment of the present invention, in the preparation method of the compound of formula E, the base may be an organic base; it is also possible to use nitrogen-containing organic bases, such as DIEA (N, N-diisopropylethylamine) and/or triethylamine.
In one embodiment of the present invention, the compound of formula E is prepared by a process wherein the molar ratio of the compound of formula D to the base is 1:1-5, e.g., 1:2.
In one embodiment of the present invention, in the preparation method of the compound of formula E, the solvent may be a solvent conventional in the art. The solvent is preferably an organic solvent; the solvent can be one or more selected from epoxy solvents, halogenated alkane solvents, aromatic solvents and ester solvents. The epoxy solvent may be THF or 1,4-dioxane. The haloalkane solvent can be a chloroalkane solvent, such as dichloromethane or 1,2-dichloroethane. The aromatic hydrocarbon solvent may be toluene. The ester solvent may be ethyl acetate. The solvent can also be DCM (dichloromethane), toluene, THF, ethyl acetate, 1,2-dichloroethane, or 1,4-dioxane.
In one embodiment of the present invention, in the preparation method of the compound of formula E, the reaction temperature of the reaction is-20 to 50 ℃, preferably-10 to 10 ℃ or below 0 ℃.
In one embodiment of the present invention, in the preparation method of the compound of formula E, the reaction time of the reaction is generally based on the completion of the reaction of the compound of formula D. The reaction time of the reaction may be from 0.1 to 6 hours, for example from 0.3 to 5 hours, preferably from 0.5 to 3 hours.
In one embodiment of the present invention, the compound of formula E is prepared by a process wherein the molar ratio of the compound of formula D to the (S) -tetrahydrofuran carbonyl halide is 1:1.0-3.0, preferably 1.2-2.0.
In one embodiment of the present invention, the compound of formula E is prepared by a process comprising the steps of: dissolving the compound of formula D in a solvent, adding the base, adding the (S) -tetrahydrofuran carbonyl halide
The reaction produces the compound of formula E.
In one embodiment of the present invention, the reaction mass of the preparation process of the compound of formula E consists of: the base, the solvent, the (S) -tetrahydrofuran carbonyl halide
And said compound of formula D.
In one embodiment of the present invention, in the preparation of the compound of formula E, the compound of formula E may be
In one embodiment of the present invention, in the preparation of the compound of formula E, the compound of formula D may be
In one embodiment of the present invention, the (S) -tetrahydrofuran carbonyl halide
Added to the reaction by dropwise addition.
In one embodiment of the present invention, the (S) -tetrahydrofuran carbonyl halide
Before the reaction solution is added, it is dissolved in the solvent.
In one embodiment of the present invention, the process for preparing the compound of formula E further comprises a post-treatment step.
In one embodiment of the present invention, in the preparation method of the compound of formula E, the post-treatment step may comprise the steps of: quenching, extracting, concentrating and recrystallizing.
In a certain embodiment of the present invention, in the preparation method of the compound of formula E, the solvent for recrystallization is selected from one or more of an ester solvent, an alcohol solvent and an ether solvent. The alcoholic solvent is preferably EtOH. The ether solvent is preferably MTBE (tert-butyl methyl ether). The solvent for recrystallization may be an alcohol solvent and an ether solvent, such as EtOH and MTBE. The volume ratio of the alcohol solvent to the ether solvent may be 0.1 to 10, more preferably 1 to 5:10.
in one embodiment of the present invention, the compound of formula E is prepared by a process wherein the (S) -tetrahydrofuranic acid
Can be prepared by the following steps: and (S) -tetrahydrofuran formic acid and an acylating reagent are subjected to acylation reaction.
In one embodiment of the present invention, the acylating reagent may be an acylating reagent conventional in the art, such as oxalyl chloride, oxalyl bromide or thionyl chloride.
In one embodiment of the present invention, the molar ratio of the acylating agent to the (S) -tetrahydrofuran carboxylic acid in the acylation reaction may be (0.9-6): 1, for example (1-3): 1.
In one embodiment of the invention, the acylation reaction is carried out in a solvent which is conventional in such reactions in the art, for example an aromatic hydrocarbon solvent such as toluene.
In one embodiment of the present invention, the acylation reaction further comprises adding a catalyst. The catalyst may be DMF. The mass to volume ratio of the (S) -tetrahydrofuranic acid to the catalyst may be 5-100g/mL, for example 10-30g/mL.
In one embodiment of the present invention, the reaction mass of the acylation reaction consists of: (S) -tetrahydrofuran formic acid, the solvent, the acylating agent and a catalyst.
In one embodiment of the present invention, the reaction temperature of the acylation reaction may be-20 to 30 deg.C, for example, 0 to 10 deg.C.
In one embodiment of the present invention, the acylation reaction time may be 0.1 to 6 hours, for example 1 to 3 hours.
The present invention also provides a process for the preparation of compound formula F, comprising the steps of:
(1) Acylating resolving agent (S) -tetrahydrofuran formic acid, and reacting with compound D to generate compound E:
(2) Reacting the compound of formula E with an aliphatic alcohol in the presence of an alkoxide to form a compound of formula F:
wherein R is 2 、R 3 N is as described above; y represents halogen, preferably chlorine or bromine.
In the preferred embodiment thereof, among others, the preferred embodiments,
R 2 、R 3 together with the carbon atom to which they are both attached form a ternary carbocycle, n is 5, i.e.:
(1) Acylating resolving agent (S) -tetrahydrofuran formic acid, and reacting with compound d to generate compound e;
(2) The compound formula e and n-hexanol are subjected to substitution reaction in the presence of alkoxide to generate a compound formula f
And/or, in the step (1), the reagent adopted for acylation is preferably oxalyl chloride, oxalyl bromide or thionyl chloride;
and/or, in step (1), the reaction time of the reaction is generally based on the completion of the reaction of the compound of formula D. The reaction time of the reaction may be from 0.1 to 6 hours, for example from 0.3 to 5 hours, preferably from 0.5 to 3 hours;
and/or, in step (1), the
((S) -tetrahydrofuranoyl halide) is preferably (S) -tetrahydrofuranoyl chloride or (S) -tetrahydrofuranoyl bromide;
and/or, in step (1), the reaction is carried out in an organic solvent in the presence of an organic base; the organic base is preferably DIEA (N, N-diisopropylethylamine) or triethylamine; and/or, the organic solvent is preferably DCM (dichloromethane), toluene, THF, ethyl acetate, 1,2-dichloroethane, 1,4-dioxane; preferably, the molar ratio of compound of formula D to organic base is 1:1-5, more preferably 1:2;
and/or, in the step (1), the reaction temperature is-20-50 ℃, preferably-10 ℃ or below 0 ℃;
and/or, in step (1), the molar ratio of compound of formula D to (S) -tetrahydrofuranic acid is 1:1.0-3.0, preferably 1.2-2.0;
and/or, in the step (1), a recrystallization step is further included, and the recrystallization solvent is at least one of an ester solvent, an alcohol solvent and an ether solvent, preferably EtOH and MTBE, and the volume ratio of the two is preferably 0.1-10, more preferably 1-5:10.
and/or in the step (1), the steps are as follows: dissolving the compound shown in the formula D and an organic base in an organic solvent, and cooling; adding (S) -tetrahydrofuran formyl halide dissolved in an organic solvent, and stirring for reaction at a temperature of between 20 ℃ below zero and 50 ℃ (preferably between 10 ℃ below zero and 10 ℃ below zero or below 0 ℃);
and/or, in the step (2), the alkoxide is preferably sodium alkoxide and potassium alkoxide, and is more preferably sodium tert-amylate, sodium tert-butylate, potassium tert-butylate and potassium tert-amylate.
And/or, in step (2), preferably the alkoxide is added in solid form;
and/or, in the step (2), the fatty alcohol is C 2-10 The fatty alcohol of (1) can be ethanol, n-propanol, n-butanol, n-pentanol, n-hexanol, preferably n-hexanol;
and/or, in step (2), the compound of formula E and a fatty alcohol (e.g. n-hexanol) are present in a molar ratio of 1:1-15, preferably 1:8-10;
and/or, in step (2), the compound of formula E and alkoxide are present in a molar ratio of 1:0.1 to 10; preferably 1:3-6 or 1:4-5;
and/or, in the step (2), reacting in an organic solvent, wherein the organic solvent is preferably THF, dichloromethane, toluene, ethyl acetate;
and/or, in the step (2), the preparation method comprises the following steps: dissolving compound of formula E and fatty alcohol (such as n-hexanol) in organic solvent, adding alkoxide, stirring at a temperature below 50 deg.C (such as-10 deg.C or below 0 deg.C), and optionally including post-treatment.
The present invention also provides a process for the preparation of compound formula H, comprising the steps of: in a solvent, in the presence of methanesulfonic anhydride and a condensing agent, carrying out a condensation reaction on a compound shown in a formula F and a compound shown in a formula G to generate a compound shown in a formula H;
wherein R is 2 、R 3 Together with the carbon atom to which they are jointly attached form C 3-8 A carbocyclic ring;
n is an integer of 1 to 9.
In one embodiment of the invention, in the process for the preparation of the compound of formula H, n may be 4, 5 or 6, for example 5.
In one embodiment of the present invention, the compound of formula H, C 3-8 The carbocyclic ring may be C 3-4 Carbocycle, such as a three membered carbocycle.
In one embodiment of the present invention, in the preparation process of the compound of formula H, the condensing agent may be a condensing agent conventional in the art, such as phosphoric anhydride, and also such as T 3 P (propylphosphoric anhydride). The T is 3 P may be pure T 3 P or T 3 An organic solution of P. The T is 3 The organic solution of P is preferably T 3 Ethyl acetate solution of P or T 3 DMF solution of P, wherein T 3 The mass concentration of P is preferably 50%.
In one embodiment of the present invention, in the method for preparing the compound of formula H, the molar ratio of the compound of formula F to the condensing agent can be 1:1-3.
In one embodiment of the present invention, the reaction time of the condensation reaction in the preparation method of the compound of formula H is usually 2 to 24 hours, preferably 2 to 12 hours, and more preferably 4 to 10 hours, based on the completion of the reaction of the compound of formula F.
In one embodiment of the present invention, in the preparation method of the compound of formula H, the reaction temperature of the condensation may be a reaction temperature conventional in the art. The condensation may also be carried out at a reaction temperature of from 40 to 90 deg.C, for example from 50 to 80 deg.C.
In one embodiment of the present invention, in the method for preparing the compound of formula H, the molar ratio of the compound of formula F to the compound of formula G can be 1:1-3; such as 1.
In one embodiment of the present invention, the compound of formula H can be prepared in a process wherein the molar ratio of the compound of formula F to the methanesulfonic anhydride is 1:1-5, e.g., 1:1-3.
In one embodiment of the present invention, in the preparation method of the compound of formula H, the solvent may be a solvent that is conventional in the art. The solvent may be an organic solvent. The organic solvent can be one or more selected from epoxy solvents, amide solvents, aromatic solvents and ester solvents. The epoxy-based solvent may be a furan-based solvent, such as THF. The aromatic hydrocarbon solvent may be toluene. The ester solvent may be ethyl acetate. The amide solvent may be DMA or DMF. The solvent may also be selected from one or more of esters, furans, toluene, DMA and DMF, e.g. ethyl acetate.
In one embodiment of the present invention, the reaction mass in the preparation process of the compound of formula H consists of: the solvent, methanesulfonic anhydride, the condensing agent, the compound of formula F, and the compound of formula G.
In one embodiment of the present invention, in the preparation of the compound of formula H, the compound of formula F can be
In one embodiment of the present invention, in the preparation of the compound of formula H, the compound of formula H may be
In one embodiment of the present invention, the preparation method of the compound of formula H further comprises a post-treatment step, for example, recrystallization (e.g., recrystallization using a mixed solvent of a ketone solvent and an alcohol solvent) is performed. The ketone solvent can be acetone, butanone, methyl ethyl ketone, methyl butanone, methyl isobutyl ketone, cyclohexanone, etc.; the alcohol solvent can be methanol, ethanol, isopropanol, n-butanol, octanol, cyclohexanol, sec-butanol, etc.
In one embodiment of the present invention, the process for preparing the compound of formula H comprises the steps of: dissolving the compound of formula F, the compound of formula G and the condensing agent (e.g., T3P) in the organic solvent, heating to 40-90 ℃, adding methanesulfonic anhydride, reacting at 50-80 ℃, optionally including a post-treatment step.
The process for preparing the compound of formula H further comprises: the compound of formula E and the fatty alcohol are subjected to a substitution reaction in the presence of an alkoxide to form a compound of formula F:
wherein R is 2 、R 3 Together with the carbon atom to which they are jointly attached form C 3-8 A carbocyclic ring;
n is an integer of 1 to 9; preferably, the reaction conditions and steps of the substitution reaction are as described previously.
The present invention also provides a process for the preparation of compound formula H, comprising the steps of:
the compound of formula F is condensed with a compound of formula G to form a compound of formula H, preferably in the presence of T 3 P and methanesulfonic anhydride are subjected to condensation reaction:
wherein the content of the first and second substances,
R 2 、R 3 together with the carbon atom to which they are jointly attached form C 3-8 Carbocyclic ring, preferably C 3-4 Carbocyclic, more preferably, ternary carbocyclic rings; n is an integer from 1 to 9, preferably 4, 5 or 6, more preferably 5.
In the preferred embodiment thereof, the first and second,
R 2 、R 3 together with the carbon atom to which they are attached form a ternary carbocyclic ring, n is 5, i.e. the compound of formula f and the compound of formula G undergo a condensation reaction to form the compound of formula h, preferably in the presence of T 3 P and methanesulfonic anhydride are subjected to condensation reaction:
and/or the reaction time is 2 to 24 hours, preferably 2 to 12 hours, more preferably 4 to 10 hours;
and/or the reaction temperature is 40-90 ℃, preferably 50-80 ℃;
and/or, the molar ratio of compound of formula F to compound of formula G is 1:1-3, preferably 1.1-2;
and/or the molar ratio of compound of formula F to methanesulfonic anhydride is 1:1-5, preferably 1:1-3;
and/or during the addition of T 3 P, methanesulfonic anhydride in an organic solvent, wherein the organic solvent is preferably one or more of esters (such as ethyl acetate), furans, toluene, DMA and DMF;
and/or, the compounds of the formulae F and T 3 The molar ratio of P can be 1:1-3, e.g., 1:1-2;
and/or, said T 3 P can be pure T3P or an organic solution of T3P, the organic solution of T3P is preferably an ethyl acetate solution of T3P or a DMF solution of T3P, wherein the mass concentration of T3P is preferably 50%.
And/or, further comprising a post-treatment step comprising performing recrystallization (e.g., using ketone and alcohol solvents);
and/or the steps are as follows: mixing the compound of formula F, the compound of formula G and T 3 Dissolving P in organic solvent, heating to 40-90 deg.c, adding methanesulfonic anhydride and reacting at 50-80 deg.c, and optional post-treatment;
and/or, the compound of formula F or formula F is prepared by the above method.
The present invention also provides a process for the preparation of a compound of formula III, comprising the steps of: the compound formula E is subjected to (d) substitution reaction, (E) condensation reaction, (f) hydroxyl protecting group removing reaction and (g) etherification reaction shown as the following formula to prepare a compound formula III;
(d) And (3) substitution reaction:
(e) Condensation reaction:
(f) And (3) hydroxyl protecting group removal reaction:
(g) And (3) etherification reaction:
wherein R is 2 、R 3 Together with the carbon atom to which they are jointly attached form C 3-8 A carbocyclic ring; y is halogen;
n is an integer of 1 to 9; r 5 Are groups that form prodrugs.
In one embodiment of the present invention, the halogen in the preparation process of the compound of formula III is fluorine, chlorine, bromine or iodine, for example chlorine or bromine.
In one embodiment of the present invention, in the preparation method of the compound of formula III, C 3-8 The carbocyclic ring may be C 3-4 Carbocycle, such as a three membered carbocycle.
In one embodiment of the present invention, in the preparation of the compound of formula III, n may be 4, 5 or 6, for example 5.
In one embodiment of the present invention, the compound of formula III, R is prepared by a process 5 Is preferably-CH 2 -O-C(＝O)-O-R 6 ，R 6 Is C 1-4 An alkyl group; r 5 More preferably-CH 2 -O-C(＝O)-O-CH 3 。
In one embodiment of the present invention, the reaction conditions and steps of the (d) substitution reaction are preferably as described above.
In one embodiment of the present invention, preferably, the reaction conditions and steps of the (e) condensation reaction are as described above.
In one embodiment of the present invention, preferably, the (f) dehydroxylating protecting group reaction comprises the following steps: reacting a compound of formula H with a dehydroxylation protecting group in the presence of a lithium or magnesium salt to obtain a compound of formula II:
in the step (f) of the hydroxyl protecting group removing reaction, the compound shown in the formula H and lithium salt or magnesium salt are heated in an organic solvent (preferably DMA) for reaction to obtain a compound shown in the formula II, and a post-treatment step can be optionally included;
in the (f) dehydroxylation protecting group reaction, the lithium salt is preferably LiCl; the magnesium salt is preferably MgCl 2 ；
In the step (f) of the hydroxyl-protecting group removing reaction, the reaction temperature of the step (f) of the hydroxyl-protecting group removing reaction is 95-120 ℃.
The (g) etherification reaction comprises the steps of: heating the compound shown in the formula II, chloromethyl methyl carbonate, potassium carbonate and potassium iodide in an organic solvent (preferably DMA) to react to generate a compound shown in the formula III; optionally including a post-treatment step; wherein the heating is preferably 40 to 60 ℃, and more preferably 45 to 55 ℃; and/or the reaction time is preferably 4 to 12 hours, more preferably 4 to 10 hours.
The present invention also provides a process for the preparation of compound formula C, comprising the steps of:
in a solvent, carrying out a condensation reaction between a compound shown in a formula A and a compound shown in a formula B in the presence of a condensing agent to generate a compound shown in a formula C; the condensing agent is sulfonic silane ester;
wherein R is 2 、R 3 Together with the carbon atom to which they are jointly attached form C 3-8 A carbocyclic ring.
In one embodiment of the present invention, the compound of formula C is prepared by a process wherein the condensing agent is TMSOTf.
In one embodiment of the present invention, the compound has formula C 3-8 The carbocyclic ring may be C 3-4 Carbocycle, such as a three membered carbocycle.
In one embodiment of the present invention, in the preparation method of the compound of formula C, the solvent may be a solvent conventional in the art, and the solvent may be an epoxy solvent, such as THF.
In one embodiment of the present invention, the compound of formula C is prepared in a process wherein the molar ratio of the compound of formula A to the compound of formula B is 1:1-5, e.g., 1:1-1.5 or 1.3-3.
In one embodiment of the present invention, in the preparation method of the compound of formula C, the reaction temperature of the condensation reaction may be a reaction temperature conventional in the art, for example, controlled below-15 ℃, preferably below-25 ℃.
In one embodiment of the present invention, the compound of formula C is prepared by a process comprising the steps of: said compound A and said compound B are dissolved in THF, said condensing agent (preferably TMSOTf) is added while controlling the temperature below-15 deg.C, the reaction is stirred, optionally including a post-treatment step.
In one embodiment of the present invention, in the preparation of the compound of formula C, the compound of formula C may be
In one embodiment of the present invention, in the preparation of the compound of formula C, the compound of formula B may be
In one embodiment of the present invention, in the preparation method of the compound of formula C, the reaction materials in the preparation method of the compound of formula C are composed of: the solvent, the condensing agent, the compound of formula B, and the compound of formula A.
The present invention also provides a process for the preparation of compound formula D, comprising the steps of: in a solvent, in the presence of a base and a catalyst, a ring closure reaction of a compound of formula C occurs to form a compound of formula D:
wherein R is 2 、R 3 Together with the carbon atom to which they are jointly attached form C 3-8 A carbocyclic ring.
In one embodiment of the present invention, in the preparation of the compound of formula D, C 3-8 The carbocyclic ring may be C 3-4 Carbocycle, such as a three membered carbocycle.
In one embodiment of the present invention, in the preparation method of the compound of formula D, the solvent may be a solvent that is conventional in the art. The solvent may be an organic solvent. The solvent can be one or more of halogenated alkane solvent, aromatic hydrocarbon solvent, epoxy solvent and ether solvent. The ether solvent may be methyl tert-butyl ether or isopropyl ether. The epoxy-based solvent may be THF. The haloalkane solvent may be dichloromethane. The aromatic hydrocarbon solvent may be toluene. The solvent may also be selected from one or more of THF, halogenated alkanes (e.g. DCM), ethers (e.g. methyl tert-butyl ether) and toluene.
In one embodiment of the present invention, in the preparation method of the compound of formula D, the base may be an organic base, and may also be a nitrogen-containing organic base, such as morpholine.
In one embodiment of the present invention, the compound of formula D is prepared by a process wherein the molar ratio of the compound of formula C to the base is 1:1-20, e.g., 1:5-10, further e.g., 1.
In one embodiment of the present invention, in the preparation method of the compound of formula D, the catalyst can be a palladium catalyst, preferably a palladium carbon catalyst, such as Pd (PPh) 3 ) 4 。
In one embodiment of the invention, the compound of formula D may be prepared in a process wherein the molar ratio of the compound of formula C to the catalyst is from 1, 0.001 to 0.5, such as from 1, 0.001 to 0.03, further such as from 1, 0.001 to 0.005.
In one embodiment of the present invention, the reaction mass of the process for the preparation of the compound of formula D consists of: the solvent, the base, the catalyst, and the compound of formula C.
In one embodiment of the present invention, in the preparation method of the compound of formula D, the compound of formula D may be
In one embodiment of the present invention, in the preparation of the compound of formula D, the compound of formula C may be
In one embodiment of the present invention, the preparation method of the compound of formula D further comprises a post-treatment step, for example, including crystallization using an ether solvent.
In one embodiment of the present invention, the ether solvent may be MTBE, isopropyl ether, diethyl ether, THF, 2-methyltetrahydrofuran, 1,4-dioxane, etc.
In one embodiment of the present invention, the process for preparing the compound of formula D further comprises: in a solvent, carrying out a condensation reaction between a compound shown in a formula A and a compound shown in a formula B in the presence of a condensing agent to generate a compound shown in a formula C; the condensing agent is a silane condensing agent;
wherein R is 2 、R 3 Together with the carbon atom to which they are jointly attached form C 3-8 A carbocyclic ring.
Preferably, the reaction conditions and steps of the condensation reaction are as previously described.
The present invention also provides a process for the preparation of compound formula D, comprising the steps of:
(1) The compound of formula a is condensed with a compound of formula B in the presence of a condensing agent to form a compound of formula C, preferably TMSOTf:
(2) The compound shown in the formula C undergoes a ring closing reaction to generate a compound shown in the formula D, and optionally, ether solvents are used for crystallization:
wherein R is 2 、R 3 As described above.
In the preferred embodiment thereof, among others, the preferred embodiments,
R 2 、R 3 and itThe carbon atoms to which they are attached together form a three membered carbocyclic ring, that is:
(1) The compound of formula a is condensed with a compound of formula b in the presence of a condensing agent to form a compound of formula c, preferably TMSOTf:
(2) And (3) carrying out a ring closing reaction on the compound shown in the formula c to generate a compound shown in the formula d, and optionally, using an ether solvent for crystallization:
and/or, in step (1), the reaction solvent is preferably THF;
and/or, in the step (1), the reaction temperature is controlled below-15 ℃; preferably below-25 ℃;
and/or, in step (1), the molar ratio of compound of formula a to compound of formula B is 1:1-5, preferably 1:1-1.5 or 1.3-3;
and/or, in the step (1), the preparation method comprises the following steps:
compound A and compound B are dissolved in THF, and a condensing agent (preferably TMSOTf) is added while controlling the temperature below-15 deg.C, and the reaction is stirred, optionally including a post-treatment step.
And/or, in the step (2), the ether solvent is MTBE or isopropyl ether;
and/or, in step (2), the ring-closing reaction occurs in the presence of morpholine, a catalyst and an organic solvent; the catalyst is preferably a palladium on carbon catalyst, such as Pd (PPh) 3 ) 4 (ii) a And/or, the molar ratio of compound a to morpholine may be 1:1-40, preferably 1:1-20, more preferably 1; and/or, the molar ratio of compound a to palladium on carbon catalyst is preferably 1.001 to 0.5, e.g., 1;
and/or, in the step (2), the organic solvent is preferably one or more of THF, halogenated alkane (such as DCM), ether (such as methyl tert-butyl ether), and toluene;
and/or, in the step (2), the method further comprises a post-treatment step, wherein the post-treatment step comprises crystallization by using an ether solvent;
and/or, in the step (2), the compound of the formula C is dissolved in an organic solvent, and morpholine and Pd (PPh) are added 3 ) 4 Stirring for reaction; optionally including a post-treatment step including crystallization using an ethereal solvent.
The present invention also provides a process for the preparation of compound formula a, comprising the steps of:
esterifying compound formula 1a with methylating agent to obtain compound formula 1b, reacting with Boc hydrazine, and removing
Protection produces the compound of formula a:
among the preferred embodiments, in the esterification reaction:
the methylating agent is dimethyl sulfate, dimethyl carbonate and methyl iodide;
and/or the reaction temperature is 10-30 ℃;
and/or the reaction time is 3-7h;
and/or the reaction solvent is DMA;
and/or, the molar ratio of compound 1a to methylating agent is 1:1-5, preferably 1.3;
the present invention also provides a process for the preparation of a compound of formula II or formula III, wherein the preparation of formula II comprises step (1) and the preparation of formula III comprises steps (1), (2):
(1) Reacting a compound of formula H with a dehydroxylating protecting group in the presence of a lithium or magnesium salt to give a compound of formula II:
(2) Etherification of the compound of formula II produces the compound of formula III:
wherein R is 2 、R 3 N is as defined above, R 5 Are groups that form prodrugs.
In the preferred embodiment thereof, among others, the preferred embodiments,
in step (1), the compound of formula H and lithium salt or magnesium salt are heated and reacted in an organic solvent (preferably DMA) to prepare formula II, and a post-treatment step is optionally included;
and/or, in step (1), the lithium salt is preferably LiCl; the magnesium salt is preferably MgCl 2 ；
And/or in the step (1), the reaction temperature is 95-120 ℃;
and/or, in step (2), R 5 Is preferably-CH 2 -O-C(＝O)-O-R 6 ，R 6 Is C 1-4 An alkyl group; r is 5 More preferably-CH 2 -O-C(＝O)-O-CH 3 ；
And/or, in the step (2), the compound shown in the formula II, chloromethyl methyl carbonate, potassium carbonate and potassium iodide are heated and reacted in an organic solvent (preferably DMA) to generate a compound shown in the formula III; optionally including a post-treatment step; wherein, the heating is preferably to 40 to 60 ℃, and more preferably to 45 to 55 ℃; and/or, reacting for 4 to 12 hours (preferably 4 to 10 hours);
and/or, the process for the preparation of the compound of formula II or formula III further comprises: any one or any combination of the processes for the preparation of the compound of formula F/F (formula F or formula F) as described above, the processes for the preparation of the compound of formula H/H (formula H or formula H) as described above, the processes for the preparation of the compound of formula D/D (formula D or formula D) as described above, or the processes for the preparation of the compound of formula a as described above;
and/or, a process for the preparation of a compound of formula II or a compound of formula III, wherein the process for the preparation of the compound of formula II comprises the steps (1) to (4) and the process for the preparation of the compound of formula III comprises the steps (1) to (5):
(1) Preparation of compound formula D:
carrying out condensation reaction on the compound shown in the formula A and the compound shown in the formula B in the presence of a condensing agent to generate a compound shown in the formula C, wherein the condensing agent is TMSOTf;
carrying out a ring closing reaction on the compound formula C to generate a compound formula D, and optionally, crystallizing by using an ether solvent;
(2) Preparation of compound formula F:
acylating resolving agent (S) -tetrahydrofuran formic acid, and reacting with compound D to generate compound E;
carrying out substitution reaction on the compound shown in the formula E and fatty alcohol in the presence of alkoxide to generate a compound shown in the formula F;
(3) Preparation of compound formula H:
the compound of formula F is condensed with a compound of formula G to form a compound of formula H, preferably in the presence of T 3 P and methanesulfonic anhydride;
(4) Preparation of compound formula II:
carrying out dehydroxylation protecting group reaction on a compound formula H in the presence of lithium salt or magnesium salt to obtain a compound formula II;
(5) Preparation of compound formula III:
after etherification reaction of the compound shown in the formula II, a compound shown in the formula III is generated;
wherein R is 2 、R 3 N is as defined above, R 5 As described above; the process for the preparation of compound formula a is as described in any one of the above, the process for the preparation of compound formula D is as described in any one of the above, the process for the preparation of compound formula F is as described in any one of the above, and the process for the preparation of compound formula H is as described in any one of the above;
wherein, optionally, the compound of formula a is prepared as described in any one of the above methods;
wherein, preferably, in the preparation method, R 2 、R 3 Together with the carbon atom to which they are attached form a three-membered carbocyclic ring, n is 5, the compound of formula IIThe compound of formula 2, the compound of formula III is the following formula 3
The preparation method of the compound of formula 2 comprises the steps (1) to (4) (i.e., formula a-formula 2), and the preparation method of the compound of formula 3 comprises the steps (1) to (5) (i.e., formula a-formula 3):
alternatively, the compound of formula a is prepared according to any one of the methods described above.
The present invention also provides a process for the preparation of a compound of formula III, comprising the steps of: the compound shown in the formula A is subjected to condensation reaction (a), cyclization reaction (b), amidation reaction (c), substitution reaction (d), condensation reaction (e), dehydroxylation protecting group reaction (f) and etherification reaction (g) shown in the formula to prepare a compound shown in the formula III;
(a) Condensation reaction:
(b) Cyclization reaction:
(c) Amidation reaction:
(d) Substitution reaction:
(e) Condensation reaction:
(f) And (3) hydroxyl protecting group removal reaction:
(g) And (3) etherification reaction:
wherein R is 2 、R 3 Together with the carbon atom to which they are jointly attached form C 3-8 A carbocyclic ring; y is halogen;
n is an integer of 1 to 9; r 5 Are groups that form prodrugs.
In one embodiment of the present invention, the halogen in the preparation process of the compound of formula III is fluorine, chlorine, bromine or iodine, for example chlorine or bromine.
In one embodiment of the present invention, in the preparation method of the compound of formula III, C 3-8 The carbocyclic ring may be C 3-4 Carbocycle, such as a three membered carbocycle.
In one embodiment of the present invention, in the preparation of the compound of formula III, n may be 4, 5 or 6, for example 5.
In one embodiment of the present invention, the compound of formula III, R is prepared by a process 5 Is preferably-CH 2 -O-C(＝O)-O-R 6 ，R 6 Is C 1-4 An alkyl group; r is 5 More preferably-CH 2 -O-C(＝O)-O-CH 3 。
In one embodiment of the present invention, preferably, the reaction conditions and steps of the condensation reaction (a) are as described above.
In one embodiment of the present invention, preferably, the reaction conditions and steps of the (b) cyclization reaction are as described above.
In one embodiment of the present invention, preferably, the reaction conditions and steps of the reaction conditions of the (c) amidation reaction are as described above.
In one embodiment of the present invention, preferably, the reaction conditions and steps of the (d) substitution reaction are as described above.
In one embodiment of the present invention, preferably, the reaction conditions and steps of the condensation reaction (e) are as described above.
In one embodiment of the present invention, preferably, the reaction conditions and steps of the (f) dehydroxylation protecting group reaction are as described above.
In one embodiment of the present invention, preferably, the reaction conditions and steps of the (g) etherification reaction are as described above.
The present invention also provides a process for the preparation of compound formula H, comprising the steps of: the compound A is subjected to condensation reaction (a), cyclization reaction (b), amidation reaction (c), substitution reaction (d) and condensation reaction (e) shown as the following formula to prepare a compound H;
(a) Condensation reaction:
(b) Cyclization reaction:
(c) Amidation reaction:
(d) And (3) substitution reaction:
(e) Condensation reaction:
wherein R is 2 、R 3 Together with the carbon atom to which they are jointly attached form C 3-8 A carbocyclic ring; y is halogen;
n is an integer of 1 to 9; r 5 Is a group that forms a prodrug.
In one embodiment of the invention, the halogen in the preparation of the compound of formula H is fluorine, chlorine, bromine or iodine, for example chlorine or bromine.
In one embodiment of the present invention, the compound of formula H, C 3-8 The carbocyclic ring may be C 3-4 Carbocycle, such as a three membered carbocycle.
In one embodiment of the invention, in the preparation of the compound of formula H, n may be 4, 5 or 6, for example 5.
In one embodiment of the invention, the compound of formula H is prepared by a process wherein R 5 Is preferably-CH 2 -O-C(＝O)-O-R 6 ，R 6 Is C 1-4 An alkyl group; r is 5 More preferably-CH 2 -O-C(＝O)-O-CH 3 。
In one embodiment of the present invention, the reaction conditions and steps of the condensation reaction of (a) are preferably as described above.
In one embodiment of the present invention, the reaction conditions and steps of the reaction conditions of the (b) cyclization reaction are preferably as described above.
In one embodiment of the present invention, preferably, the reaction conditions and steps of the reaction conditions of the (c) amidation reaction are as described above.
In one embodiment of the present invention, preferably, the reaction conditions and steps of the (d) substitution reaction are as described above.
In one embodiment of the present invention, the reaction conditions and steps of the condensation reaction (e) are preferably as described above.
The present invention provides a compound of formula I,
wherein the content of the first and second substances,
R 1 selected from H,
R 2 、R 3 Together with the carbon atom to which they are both attached form C 3-8 Carbocyclic ring, preferably C 3-4 Carbocyclic, more preferably, a three membered carbocyclic ring;
R 4 is halogen, preferably F;
m is an integer from 1 to 4, preferably 2 or 3; n is an integer from 1 to 9, preferably 4, 5 or 6, more preferably 5;
x is S or O, preferably S.
Among the preferred embodiments, the compound of formula I can be
Wherein R is 4 And n is as described above;
among the preferred embodiments, compounds of formula I are selected from:
wherein R is 2 、R 3 N is as described above;
the compound of formula F is preferably
The compound of formula H is preferably
The present invention also provides compounds of formula E:
wherein R is 2 、R 3 As described above;
in a preferred embodiment, the compounds of formula e are
The present invention also provides compounds of formula C:
wherein R is 2 、R 3 As described above;
among the preferred embodiments, compounds of formula c are
The invention also provides the use of compound formula C, compound formula E, compound formula F, compound formula H-a, compound formula H-b, compound formula C, compound formula E, compound formula F or compound formula H for the preparation of a cap-dependent endonuclease inhibitor pyridone derivative (preferably compound formula II, compound formula III, compound formula 2 or compound formula 3) or an analogue thereof.
The present invention also provides a method for preparing a pyridone derivative (preferably the compound formula II, the compound formula III, the compound formula 2 or the compound formula 3) or an analog thereof, via the compound formula C, the compound formula E, the compound formula F, the compound formula C, the compound formula E, the compound formula F or the compound formula H.
The present invention also provides a process for the preparation of a pyridone derivative, preferably a compound of formula II, formula III, formula 2 or formula 3, or an analogue thereof, comprising any one or any combination of the processes for the preparation of a compound of formula F/F (formula F or formula F) as described in any one of the above, a process for the preparation of a compound of formula H/H (formula H or formula H) as described in any one of the above or a process for the preparation of a compound of formula D/D (formula D or formula D) as described in any one of the above.
The present invention also provides a pharmaceutical composition comprising a compound of formula II/2 (formula II or formula 2) and/or formula III/3 (formula III or formula 3) and a pharmaceutically acceptable carrier/adjuvant, wherein the compound of formula II/2 (formula II or formula 2) or formula III/3 (formula III or formula 3) is prepared as described previously, or via compound formula C, compound formula E, compound formula F, compound formula H, compound formula C, compound formula E, compound formula F or compound formula H, or a process for its preparation comprising any one or any combination of the processes for the preparation of compound formula F/F (formula F or formula F) described in any one of the above, compound formula H/H (formula H or formula H) described in any one of the above, or the processes for the preparation of compound formula D/D (formula D or formula D) described in any one of the above.
The present invention also provides a composition comprising a compound of formula III as described above, and further comprising one or more compounds of formula II as described above and/or of formula H as described above; preferably, the compound formula II is a compound formula 2, and/or the compound formula III is a compound formula 3, and/or the compound formula H is a compound formula H; more preferably, the compound of formula II is present in an amount of no more than 0.50% and/or the compound of formula H is present in an amount of no more than 0.10%, and/or the compound of formula III is prepared as described in any of the above methods, and/or the compound of formula II is prepared as described in any of the above methods, and/or the compound of formula H is prepared as described in any of the above methods.
The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula III as described above and a pharmaceutically acceptable carrier, and further comprising a compound of formula II as described above and/or a compound of formula H as described above; preferably, the compound formula II is a compound formula 2, and/or the compound formula III is a compound formula 3, and/or the compound formula H is a compound formula H; more preferably, the compound of formula II is present in an amount of no more than 1.50% (e.g. no more than 1.0%, 0.5%) and/or the compound of formula H is present in an amount of no more than 0.10% and/or the compound of formula III is prepared according to any of the methods described above, and/or the compound of formula II is prepared according to any of the methods described above, and/or the compound of formula H is prepared according to any of the methods described above.
The compound of formula III
The compound of formula II
The compound of formula H is
The compound of formula F is
A compound of formula D
A compound of the formula E
The compound of formula 3 is
The compound of formula 2 is
A compound of the formula h
The compound of formula f is
A compound of the formula d
A compound of the formula e
The beneficial technical effects are as follows:
1. preparation of Compounds of formulae D to II/III:
1) In the process from the formula D to the formula II/III, the required configuration is obtained by adopting a chemical resolution method without adopting a chiral column resolution method reported in CN110637016A in the prior art. The method is simple and convenient to operate and easy for industrial production; in addition, the quantity of formula G that significantly reduces and the quantity of other materials, effectively reduced manufacturing cost:
2) In the process from a compound formula D to a compound formula II/III, a benzyl protecting group is replaced by n-hexyl at the resolution stage of a formula D/D (formula D or formula D), so that the selectivity of the reaction of the formula G is obviously improved;
3) In the process from the formula D to the formula II/III, the yield is obviously improved;
4) In the step of D/D (formula D or formula D) -E/E (formula E or formula E), a specific resolving agent (S) -tetrahydrofuran-formic acid with a specific S configuration is adopted, so that the resolving yield is obviously improved compared with that of an R configuration or other resolving agents;
5) In the step of D/D (formula D or formula D) -E/E (formula E or formula E), the acylation reagent such as oxalyl chloride is used for acylating the (S) -tetrahydrofuran-formic acid, so that the method is low in cost, environment-friendly, high in yield and short in reaction time;
6) In the step of a compound D/D (a formula E or a formula E) -E/E (the formula E or the formula E), a resolving agent is activated by acyl halide, and then ((S) -tetrahydrofuran formyl halide) reacts with the compound D to generate a stable resolving salt;
7) In the steps from E/E (formula E or formula E) to F/F (formula F or formula F), the preparation is carried out by a one-pot method, separation is not needed, the operation is simplified, the yield is high, the reaction time is short, the variety of required reaction materials is few, and the preparation method is safe and environment-friendly; the new intermediate compound, formula E, is reacted in the presence of relatively inexpensive and safe alkoxides to prepare the compound, formula F, in high yield; due to the high reactivity of the new intermediate compound, namely the formula E, few byproducts are generated in the reaction process, and the post-treatment is simple;
8) In the steps from E/E (formula E or formula E) to F/F (formula F or formula F), the compound F/F can be effectively prepared only by using alkoxide and n-hexanol, and the method has the advantages of low cost, high yield and high purity; in addition, the alkoxide is in a solid form, can be directly added, only needs conventional conditions for storage, is convenient to operate and has no potential safety hazard;
9) In the steps from F/F (formula F or formula F) to H/H (formula H or formula H), methanesulfonic anhydride is used for condensation reaction, compared with methanesulfonic acid, the reaction selectivity is remarkably improved, the yield and the purity are remarkably improved, the reaction conditions are mild, the safety is high, and the reaction time is short;
10 In the steps from H/H (formula H or formula H) to formula II, in the prior art, the debenzylation difficulty is high after condensation of CN110637016A, a large process byproduct is easy to generate, the yield is low, and the method adopts the formula H/H (formula H or formula H) to remove hexyl to obtain II, so that the yield and the quality are obviously improved.
11 The final product prepared by the preparation method has obviously low impurity content and high purity.
2. Preparation of Compounds of formulae A/1a to D:
1) In the preparation process of the formula D, the inventor surprisingly discovers that the methyl ester compound is easier to react, the reaction period can be greatly shortened, and the cost can be reduced compared with the ethyl ester compound used in the prior art.
2) In the preparation process of the formula D, the inventor surprisingly discovers that the methyl ester compound is more beneficial to the reaction, the yield of the formula D/D (formula D or formula D) is obviously improved, and the purity is more than 95 percent;
3) In the preparation process of the formula D, a high-purity product can be obtained without column chromatography separation, and the preparation method is more suitable for industrial production;
4) In the preparation process of the formula D, stannic chloride is used in the prior art, hydrogen chloride gas is generated in the reaction process, equipment is easily corroded after water absorption, and the operation safety is poor.
3. The invention provides a brand-new intermediate compound formula I (preferably a compound formula F and a compound formula H), a compound formula E (preferably a compound formula E), a compound formula C (preferably a compound formula C) and a preparation method thereof, and has the advantages of short reaction period, low cost, high yield, high product purity, suitability for industrial mass production, simplicity and convenience in operation, environmental friendliness, high safety and the like.
The invention provides a brand new route for preparing the compound shown in the formula III, and in the new route, the total yield of the compound shown in the formula III is greatly improved, the post-treatment steps in the route are simplified, the reaction time is shortened, and the production cost is reduced by using a new intermediate compound shown in the formula C, an intermediate compound shown in the formula E, an intermediate compound shown in the formula F and an intermediate compound shown in the formula H.
Detailed Description
The invention is further illustrated below with reference to specific embodiments. The operating parameters in the examples are for illustration only and are not intended to be a full limitation of the scope of the invention; the reagents and starting materials used in the present invention are commercially available unless otherwise specified.
Example 1
At room temperature (about 20 ℃ C.) the compound of formula 1a 892g was dissolved in 3L N, N-dimethylacetamide, replaced with nitrogen three times, and 608g NaHCO was added 3 Adding 594g of dimethyl sulfate/DMA (1L) solution, keeping the temperature basically unchanged, adding for about 20min, and keeping the room temperature for stirring and reacting for 5h after the addition is finished; 5L of water was added dropwise at room temperature, the temperature was raised from 22 ℃ to 30 ℃, EA was added for extraction, and concentration was carried out to dryness to obtain the compound of formula 1b 940g, with a yield of 99.7%.
Example 2
940g of the compound of formula 1b obtained in example 1 was dissolved in 3.76L of N, N-dimethylacetamide, 2270g of pyridine-p-toluenesulfonic acid was added, and the temperature was raised to 60 ℃; under the protection of nitrogen, 620g of Boc hydrazine DMA solution is slowly added at 60 ℃, after the addition is finished, the reaction is carried out for 5h at 60 ℃, the reaction liquid is cooled to 25 ℃, ethanol/water is dropwise added for crystallization, the mixture is filtered and dried to obtain a white solid compound of formula 1c'940g, and the yield is 69.5%.
Example 3
The compound of formula 1c'940g obtained in example 2 was dissolved in 9L of dichloromethane and cooled to 0 ℃; under the protection of nitrogen, 5140g of trifluoroacetic acid is slowly added; after the addition, the temperature is raised to the room temperature, and the reaction is carried out for 2 hours at the room temperature; concentrate, extract with DCM, adjust pH to 8-9, concentrate, add dichloromethane: pulping with petroleum ether (1:5) to obtain solid; drying to obtain the compound A612.0 g with the yield of 88.9%.
Example 4
Dissolving 600g of the compound shown in the formula A and 646.2g of the compound shown in the formula b, which are obtained in the example 3, in 6L THF, dropwise adding TMSOTf 631.8g under the temperature controlled below-15 ℃, and continuously stirring and reacting for 3 hours under the temperature controlled below-15 ℃; quenched with saturated NaHCO3 solution, extracted with EA, and concentrated to give the compound of formula c1.26 kg.
LC-MS(470.2)； 1 H NMR(400MHz，CDCl3)δ：0.51-0.71(3H),0.92-0.98(1H),3.18-3.39(1H),3.73-3.88(6H),4.23-4.53(2H),5.14-5.27(5H),5.65-5.73(1H),6.19-6.50(2H),7.22-7.44(6H)。
EXAMPLE 5 Synthesis of Compound of formula d
The compound obtained in example 4, of formula c1.26kg, was dissolved in 10.2L THF, 1.91kg morpholine was added and stirred; 12.66gPd (PPh) was added 3 ) 4 Stirring and reacting for 2 hours; adding 20.4L of MTBE, and stirring at room temperature for 1h; filtering and drying to obtain 628.8g of compound formula d with the purity of 97.01% and the yield of the two steps of 81.3%.
EXAMPLE 6 Synthesis of Compound of formula e
1) 294.9g (S) -tetrahydrofuran formic acid is dissolved by 1.1L toluene, 12.5mL DMF is dripped in, 599.6g oxalyl chloride is dripped in at 15 ℃, after dripping is finished, the temperature is preserved at 5 ℃ for reaction for 3h, and the reaction liquid is dried in a spinning way to obtain acyl chloride;
2) Taking another reaction bottle, adding 500g of the compound obtained in the example 5, shown as the formula d, and adding 4L of DCM and stirring; adding 364.5g DIEA; cooling to-10 deg.C; dissolving acyl chloride obtained in the step 1) by using 1L of DCM, and dropwise adding the solution into the reaction solution to react for 3 hours at minus 10 ℃ with stirring; the reaction was quenched with saturated ammonium chloride solution, extracted, concentrated, recrystallized from EtOH: MTBE =1.5 (V/V), filtered, and dried to give 286.2g of compound formula e, purity 97.5%, yield 44.8%.
LC-MS(452.2)； 1 H NMR(400MHz，DMSO)δ：0.37-0.86
(4H),1.82-2.18(4H),3.66-4.04(6H),5.01-5.16(3H),5.94-5.98(1H),6.29-6.32(1H),7.28-7.71(16H)。
EXAMPLE 7 Synthesis of Compound of formula f
The compound obtained in example 6 of formula e 185g and n-hexanol 418.9g were added to THF 1.85L, cooled to-10 ℃; adding 225.7g of sodium tert-amylate, stirring and reacting; stopping the reaction when the compound of the formula e is less than or equal to 3 percent by HPLC monitoring; adding water for quenching, extracting, combining organic layers, washing, drying, filtering, concentrating to obtain crude product, further recrystallizing with n-heptane, filtering, air drying to obtain compound f 125g with purity of 97.5% and yield of 87.8%,
LC-MS(348.2)， 1 H NMR(400MHz，CDCl3)δ：0.68-1.83(15H),3.53-4.16(6H),4.88-4.4.91(1H),6.99-7.02(1H),7.82-7.84(1H),8.06-8.10(1H)。
EXAMPLE 8 Synthesis of Compound of formula h
54.1G of the compound obtained in example 7, 45.3G of the compound of formula G, T 3 P Ethyl acetate solution 118.5g(T 3 The mass concentration of P is 50 percent) is added into 270mL of EA, the temperature is raised to 65 ℃, 27.1g of methanesulfonic anhydride is added, and the mixture is continuously heated to 75-80 ℃ to react for 6h; concentrating, DCM extracting, washing with saturated sodium bicarbonate solution and saturated brine, drying, EA pulping to obtain compound h with purity of 93.2%, further recrystallizing with mixed solvent of acetone methanol =1:1 (V/V), filtering, drying to obtain compound h 51.7g, with target configuration (R-S) purity of 98.5% and yield of 56.0%.
LC-MS(594.3)，1H NMR(400MHz，DMSO)δ：0.72-0.90(7H),1.28-1.70(8H),3.38-3.52(2H),3.90-4.17(5H),4.54-4.58(1H),5.42-5.78(3H),6.82-7.41(5H),7.40-7.43(2H)。
Examples 9-10 Synthesis of Compounds of formula 2
Example 9
The compound obtained in example 8 of formula h 12.80g is added to 130mL of DMA and 10.28g of MgCl 2 Heating to 110 ℃, preserving the temperature for reaction, and monitoring by HPLC (high performance liquid chromatography) until the reaction is finished; cooling to 0 ℃; adding dilute hydrochloric acid and water, and crystallizing; filtering and drying to obtain 10.50g of the compound of formula 2 with the purity of 98.4 percent and the yield of 95.5 percent.
Example 10
14.99g of the compound obtained in example 8, shown as formula h, is added with 150mL of DMA and 9.83g of LiCl, the mixture is heated to 105 ℃ and is kept for reaction, and HPLC (high performance liquid chromatography) is used for monitoring until the reaction is finished; cooling to 10 ℃; adding dilute hydrochloric acid and water, and crystallizing; filtering and drying to obtain 11.57g of the compound of formula 2 with the purity of 98.3 percent and the yield of 90.0 percent.
EXAMPLE 11 Synthesis of Compound of formula 3
Adding 2 10g of the compound formula obtained in example 10, 3.6g of chloromethyl methyl carbonate, DMA1L, 5.4g of potassium carbonate and 3.2g of potassium iodide into a reaction bottle, heating to 55 ℃, and preserving the temperature for 6 hours; filtering, and cooling to 10 ℃; dripping hydrochloric acid and water, and crystallizing; filtration and drying gave 9.8g of compound of formula 3, purity 99.4%, yield 83.6%. Wherein the content of the formula 2 is less than 0.50 percent, and the content of the formula h is less than 0.10 percent.
Claims (29)
1. A process for the preparation of a compound of formula F, characterized in that it comprises the following steps:
the compound of formula E and the fatty alcohol are subjected to a substitution reaction in the presence of an alkoxide to form a compound of formula F:
wherein R is 2 、R 3 Together with the carbon atom to which they are jointly attached form C 3-8 A carbocyclic ring;
n is an integer of 1 to 9.
2. A process for the preparation of a compound of formula F according to claim 1, wherein n is 4, 5 or 6, such as 5;
and/or, said C 3-8 The carbocyclic ring being C 3-4 Carbocycle, such as a three membered carbocycle;
and/or the alkoxide is a sodium alkoxide and/or a potassium alkoxide, such as sodium tert-amylate, sodium tert-butylate, potassium tert-amylate;
and/or, the alkoxide is preferably added in solid form;
and/or, the compound of formula E and the alkoxide are in a molar ratio of 1:0.1 to 10; preferably 1:3-6, more preferably 1:4-5;
and/or the fatty alcohol is C 2-10 The fatty alcohol of (1) can be ethanol, n-propanol, n-butanol, n-pentanol, n-hexanol, preferably n-hexanol;
and/or, the compound of formula E and the fatty alcohol (e.g., n-hexanol) are present in a molar ratio of 1:1-15, preferably 1:7-11, more preferably 1:8-10;
and/or, the substitution reaction is carried out in an organic solvent;
and/or the reaction temperature of the substitution reaction is lower than 50 ℃, such as-10 ℃ or below 0 ℃;
and/or, the reaction mass in the preparation process of the compound of formula F consists of: the compound of formula E, the fatty alcohol, and the alkoxide, or, an organic solvent, the compound of formula E, the fatty alcohol, and the alkoxide;
and/or the compound of formula F is
And/or the compound of formula E is
3. The process for preparing the compound of formula F according to claim 2, wherein the organic solvent is selected from one or more of epoxy solvents, haloalkane solvents, aromatic solvents and ester solvents; the epoxy solvent may be THF; the haloalkane solvent can be a chloroalkane solvent, such as dichloromethane; the aromatic hydrocarbon solvent may be toluene; the ester solvent may be ethyl acetate; the organic solvent is preferably one or a combination of more of THF, dichloromethane, toluene and ethyl acetate;
and/or, in a process for the preparation of the compound of formula F, the process comprising the steps of: dissolving the compound of formula E and the fatty alcohol (e.g. n-hexanol) in the organic solvent, adding the alkoxide, and reacting under stirring at a temperature of less than 50 ℃ (e.g. -10 ℃ or below 0 ℃), optionally including a post-treatment step.
4. A process for the preparation of the compound of formula F according to claim 3, comprising a process for the preparation of the compound of formula E, comprising the steps of: in a solvent in the presence of a base, (S) -tetrahydrofuran formyl halide
Reacting with compound formula D to form compound formula E:
wherein R is 2 、R 3 Together with the carbon atom to which they are jointly attached form C 3-8 A carbocyclic ring; y is halogen;
preferably, C is 3-8 The carbocyclic ring being C 3-4 Carbocycle, such as a three membered carbocycle;
and/or the halogen is fluorine, chlorine, bromine or iodine, for example chlorine or bromine;
and/or the base is an organic base; can be a nitrogen-containing organic base such as DIEA (N, N-diisopropylethylamine) and/or triethylamine;
and/or the molar ratio of the compound of formula D to the base is 1:1-5, e.g., 1:2;
and/or the solvent is an organic solvent; the solvent can be one or more of epoxy solvents, halogenated alkane solvents, aromatic solvents and ester solvents; the epoxy solvent can be THF or 1,4-dioxane; the haloalkane solvent can be a chloroalkane solvent, such as dichloromethane or 1,2-dichloroethane; the aromatic hydrocarbon solvent may be toluene; the ester solvent may be ethyl acetate; the solvent can also be DCM (dichloromethane), toluene, THF, ethyl acetate, 1,2-dichloroethane, or 1,4-dioxane;
and/or the reaction temperature of the reaction is-20-50 ℃, preferably-10 ℃ or below 0 ℃;
and/or the reaction time of the reaction is 0.1 to 6h, for example 0.3 to 5h, preferably 0.5 to 3h;
and/or the compound of formula D is present in a molar ratio to (S) -tetrahydrofuran carbonyl halide of 1:1.0-3.0, preferably 1.2-2.0;
and/or, the compound of formula E is prepared by a process comprising the steps of: dissolving the compound shown in the formula D in a solvent, adding the alkali, and adding the (S) -tetrahydrofuran formyl halide to react to generate a compound shown in the formula E;
and/or, the reaction mass in the preparation process of the compound of formula E consists of: said solvent, said base, said (S) -tetrahydrofuran carbonyl halide, and said compound of formula D;
and/or the compound of formula E is
And/or the compound of formula D is
And/or adding the (S) -tetrahydrofuran formyl halide into the reaction in a dropwise manner;
and/or dissolving the (S) -tetrahydrofuran formyl halide in the solvent before adding the (S) -tetrahydrofuran formyl halide into the reaction liquid;
and/or the process for the preparation of the compound of formula E further comprises a work-up step; preferably, the post-processing step may include the steps of: quenching, extracting, concentrating and recrystallizing;
and/or the (S) -tetrahydrofuran carbonyl halide is prepared by the following steps: the (S) -tetrahydrofuran formic acid and the halogen acylation reagent are subjected to acylation reaction.
5. The process for preparing the compound of formula F according to claim 4, wherein the solvent for recrystallization in the post-treatment step in the process for preparing the compound of formula E is selected from one or more of ester solvents, alcohol solvents and ether solvents; the alcoholic solvent is preferably EtOH; the ether solvent is preferably MTBE; the solvent for recrystallization may be an alcoholic solvent and an etheric solvent such as EtOH and MTBE; preferably, the volume ratio of the alcoholic solvent to the ethereal solvent may be from 0.1 to 10, more preferably from 1 to 5:10;
and/or, in the acylation reaction, the molar ratio of the haloacylating agent to the (S) -tetrahydrofuran carboxylic acid is (0.9-6): 1, e.g., (1-3): 1;
and/or, in the acylation reaction, the halogen acylation reagent is oxalyl chloride, oxalyl bromide or thionyl chloride;
and/or, the acylation reaction is carried out in a solvent, preferably an aromatic hydrocarbon solvent, such as toluene;
and/or, the acylation reaction further comprises adding a catalyst; the catalyst may be DMF; preferably, the mass to volume ratio of the (S) -tetrahydrofuranic acid to the catalyst may be 5-100g/mL, such as 10-30g/mL;
and/or, the reaction temperature of the acylation reaction can be-20 ℃ to 30 ℃, e.g., 0 ℃ to 10 ℃;
and/or the acylation reaction time may be from 0.1 to 6 hours, for example from 1 to 3 hours;
and/or, the reaction mass of the acylation reaction consists of: (S) -tetrahydrofuran carboxylic acid, the solvent, the acylating agent and a catalyst.
6. A process for the preparation of a compound of formula E, characterized in that it comprises the steps of: in a solvent in the presence of a base, (S) -tetrahydrofuran formyl halide
(ii) amidation reaction with compound formula D to produce compound formula E:
wherein R is 2 、R 3 Together with the carbon atom to which they are jointly attached form C 3-8 A carbocyclic ring; y is halogen;
the reaction conditions and steps in the process for the preparation of the compound of formula E are as described in any one of claims 4 to 5.
7. A process for the preparation of a compound of formula F, characterized in that it comprises the following steps:
(1) Acylating resolving agent (S) -tetrahydrofuran formic acid, and reacting with compound D to generate compound E:
(2) Reacting the compound of formula E with an aliphatic alcohol in the presence of an alkoxide to form a compound of formula F:
wherein the content of the first and second substances,
R 2 、R 3 together with the carbon atom to which they are jointly attached form C 3-8 Carbocyclic ring, preferably C 3-4 Carbocyclic, more preferably, ternary carbocyclic rings; n is an integer from 1 to 9, preferably 4, 5 or 6, more preferably 5;
y represents halogen, preferably chlorine or bromine.
8. The production method according to claim 7, wherein:
R 2 、R 3 together with the carbon atom to which they are both attached form a ternary carbocycle, n is 5, i.e.:
(1) Acylating resolving agent (S) -tetrahydrofuran formic acid, and reacting with compound d to generate compound e;
(2) The compound formula e and n-hexanol are subjected to substitution reaction in the presence of alkoxide to generate a compound formula f
And/or, in the step (1), the reagent adopted for acylation is preferably oxalyl chloride or oxalyl bromide or thionyl chloride;
and/or, in step (1), the
(S) -tetrahydrofuranoyl halide is preferably (S) -tetrahydrofuranoyl chloride or (S) -tetrahydrofuranoyl bromide;
and/or, in step (1), the reaction is carried out in an organic solvent in the presence of an organic base; the organic base is preferably DIEA (N, N-diisopropylethylamine) or triethylamine; and/or, the organic solvent is preferably DCM (dichloromethane), toluene, THF, ethyl acetate, 1,2-dichloroethane, 1,4-dioxane; preferably, the molar ratio of compound of formula D to organic base is 1:1-5, more preferably 1:2;
and/or, in the step (1), the reaction temperature is-20 to 50 ℃, preferably-10 to 10 ℃ or below 0 ℃;
and/or, in step (1), the molar ratio of the compound of formula D to (S) -tetrahydrofuranic acid is 1:1.0 to 1:3.0, preferably 1.2 to 1;
and/or, in the step (1), a recrystallization step is further included, the recrystallization solvent is at least one of an ester solvent, an alcohol solvent and an ether solvent, preferably EtOH and MTBE, and the volume ratio of the two solvents is preferably 0.1-10, more preferably 1:5-10;
and/or in the step (1), the steps are as follows: dissolving the compound shown in the formula D and an organic base in an organic solvent, and cooling; adding (S) -tetrahydrofuran formyl halide dissolved in an organic solvent, and stirring for reaction at a temperature of between 20 ℃ below zero and 50 ℃ (preferably between 10 ℃ below zero and 10 ℃ below zero or below 0 ℃);
and/or, in the step (2), the alkoxide is preferably sodium alkoxide salt and potassium alkoxide salt, and is more preferably sodium tert-amylate, sodium tert-butoxide, potassium tert-butoxide and potassium tert-amylate;
and/or, in step (2), preferably the alkoxide is added in solid form;
and/or, in step (2), the fatty alcohol is C 2-10 The fatty alcohol of (1) can be ethanol, n-propanol, n-butanol, n-pentanol, n-hexanol, preferably n-hexanol;
and/or, in step (2), the molar ratio of compound formula E to fatty alcohol is 1:1-15, preferably 1:8-10;
and/or, in step (2), the compound of formula E and alkoxide are present in a molar ratio of 1:0.1 to 10; preferably 1:3-6 or 1:4-5;
and/or, in the step (2), reacting in an organic solvent, wherein the organic solvent is preferably THF, dichloromethane, toluene, ethyl acetate;
and/or, in the step (2), the preparation method comprises the following steps: dissolving the compound of formula E and a fatty alcohol in an organic solvent, adding an alkoxide, stirring and reacting at a temperature of less than 50 ℃ (such as-10 ℃ or below 0 ℃), and optionally including a post-treatment step.
9. A process for the preparation of a compound of formula H, characterized in that it comprises the following steps: in a solvent, in the presence of methanesulfonic anhydride and a condensing agent, carrying out a condensation reaction on a compound shown in a formula F and a compound shown in a formula G to generate a compound shown in a formula H;
wherein R is 2 、R 3 Together with the carbon atom to which they are jointly attached form C 3-8 A carbocyclic ring;
n is an integer of 1 to 9.
10. A process for the preparation of a compound of formula H according to claim 9, wherein n is 4, 5 or 6, such as 5;
and/or, said C 3-8 The carbocyclic ring being C 3-4 Carbocycle, such as a three membered carbocycle;
and/or the condensing agent is a phosphoric anhydride, e.g. T 3 P; said T is 3 P may be pure T 3 P or T 3 An organic solution of P; the T is 3 The organic solution of P is preferably T 3 Ethyl acetate solution of P or T 3 DMF solution of P, wherein T 3 The mass concentration of P is preferably 50%;
and/or the molar ratio of the compound of formula F to the condensing agent is 1:1-3;
and/or the reaction time of the condensation reaction is 2 to 24 hours, preferably 2 to 12 hours, and more preferably 4 to 10 hours;
and/or the reaction temperature of the condensation is 40 to 90 ℃, for example 50 to 80 ℃;
and/or, the molar ratio of said compound of formula F to said compound of formula G is 1:1-3; e.g., 1.1-2;
and/or the compound of formula F is present in a molar ratio to the methanesulfonic anhydride of 1:1-5, e.g., 1:1-3;
and/or the solvent is an organic solvent; the organic solvent can be one or more of epoxy solvents, amide solvents, aromatic solvents and ester solvents; the epoxy-based solvent may be a furan-based solvent, such as THF; the aromatic hydrocarbon solvent may be toluene; the ester solvent may be ethyl acetate; the amide solvent can be DMA or DMF; the solvent may also be selected from one or more of esters, furans, toluene, DMA and DMF, e.g. ethyl acetate;
and/or the reaction mass in the preparation process of the compound of formula H consists of: the solvent, methanesulfonic anhydride, the condensing agent, the compound of formula F, and the compound of formula G;
and/or the compound of formula F is
And/or the compound of formula H is
And/or, the preparation method of the compound of the formula H further comprises a post-treatment step, such as recrystallization, for example, recrystallization by using a mixed solvent of a ketone solvent and an alcohol solvent; the ketone solvent can be acetone, butanone, methyl ethyl ketone, methyl butanone, methyl isobutyl ketone, cyclohexanone, etc.; the alcohol solvent can be methanol, ethanol, isopropanol, n-butanol, octanol, cyclohexanol, sec-butanol, etc.;
and/or, the steps of the preparation process of the compound of formula H are: reacting said compound of formula F, said compound of formula G and said condensing agent (e.g. T) 3 P) is dissolved in the organic solvent, the temperature is raised to 40 to 90 ℃, methanesulfonic anhydride is added, and the reaction is carried out at 50 to 80 DEG COptionally including a post-treatment step;
and/or, the compound of formula H is prepared by a process further comprising: the compound of formula E and the fatty alcohol are subjected to a substitution reaction in the presence of an alkoxide to form a compound of formula F:
wherein R is 2 、R 3 Together with the carbon atom to which they are jointly attached form C 3-8 A carbocyclic ring;
n is an integer of 1 to 9; preferably, the reaction conditions and steps of the substitution reaction are as described in any one of claims 1 to 5 or 7 to 8.
11. A process for the preparation of compound formula H comprising the steps of:
the compound of formula F is condensed with a compound of formula G to form a compound of formula H, preferably in the presence of T 3 P and methanesulfonic anhydride are subjected to condensation reaction:
wherein the content of the first and second substances,
R 2 、R 3 together with the carbon atom to which they are jointly attached form C 3-8 Carbocyclic ring, preferably C 3-4 Carbocyclic, more preferably, a three membered carbocyclic ring; n is an integer from 1 to 9, preferably 4, 5 or 6, more preferably 5.
12. The production method according to claim 11, wherein:
R 2 、R 3 together with the carbon atom to which it is attached form a three-membered carbocyclic ring, n is 5, i.e. the condensation of compound formula f with compound formula G to give compound formula h, preferably in the presence of T 3 P and methanesulfonic anhydride are subjected to condensation reaction:
and/or the reaction time is 2-24 h; preferably 2 to 12 hours, more preferably 4 to 10 hours;
and/or the reaction temperature is 40-90 ℃, preferably 50-80 ℃;
and/or, the molar ratio of compound of formula F to compound of formula G is 1:1-3, preferably 1.1-2;
and/or the molar ratio of compound of formula F to methanesulfonic anhydride is 1:1-5, preferably 1:1-3;
and/or, during the addition of T 3 Carrying out condensation reaction on the P and methanesulfonic anhydride in an organic solvent, wherein the organic solvent is preferably one or more of esters, furans, toluene, DMA and DMF;
and/or, the compounds of the formulae F and T 3 The molar ratio of P is 1:1-3, e.g., 1:1-2;
and/or, said T 3 P may be pure T 3 P or T 3 An organic solution of P, said T 3 The organic solution of P is preferably T 3 Ethyl acetate solution of P or T 3 DMF solution of P, wherein T 3 The mass concentration of P is preferably 50%;
and/or, further comprises a post-treatment step, including recrystallization (such as recrystallization by using a mixed solvent of a ketone solvent and an alcohol solvent);
and/or the steps are as follows: mixing the compound of formula F, the compound of formula G and T 3 Dissolving P in an organic solvent, heating to 40-90 ℃, adding methanesulfonic anhydride, reacting at 50-80 ℃, and optionally performing a post-treatment step;
and/or, the compound of formula F or formula F is prepared according to the process of any one of claims 1 to 5 or 7 to 8.
13. A process for the preparation of a compound of formula III, characterized in that it comprises the steps of: the compound formula E is subjected to (d) substitution reaction, (E) condensation reaction, (f) hydroxyl protecting group removing reaction and (g) etherification reaction shown as the following formula to prepare a compound formula III;
(d) And (3) substitution reaction:
(e) Condensation reaction:
(f) And (3) hydroxyl protecting group removal reaction:
(g) And (3) etherification reaction:
wherein R is 2 、R 3 Together with the carbon atom to which they are jointly attached form C 3-8 A carbocyclic ring; y is halogen;
n is an integer of 1 to 9; r 5 Is a prodrug-forming group;
preferably, the halogen is fluorine, chlorine, bromine or iodine; such as chlorine or bromine;
preferably, C is 3-8 The carbocyclic ring being C 3-4 Carbocycle, such as a three membered carbocycle;
preferably, n is 4, 5 or 6, such as 5;
preferably, R 5 is-CH 2 -O-C(＝O)-O-R 6 ，R 6 Is C 1-4 An alkyl group; r is 5 More preferably-CH 2 -O-C(＝O)-O-CH 3 ；
Preferably, the reaction conditions and steps of the (d) substitution reaction are as described in any one of claims 1 to 5 or 7 to 8;
preferably, the reaction conditions and steps of the (e) condensation reaction are as described in any one of claims 9 to 12;
preferably, the (f) dehydroxylation protecting group reaction comprises the following steps: reacting a compound of formula H with a dehydroxylation protecting group in the presence of a lithium or magnesium salt to obtain a compound of formula II: more preferably, the reaction conditions and steps of the (f) dehydroxylation protecting group reaction satisfy one or more of the following conditions:
(1) In the step (f), in the dehydroxylation protecting group reaction, the compound shown as the formula H and lithium salt or magnesium salt are heated and reacted in an organic solvent (preferably DMA) to prepare a compound shown as the formula II, and a post-treatment step is optionally included;
(2) In the (f) dehydroxylation protecting group reaction, liCl is preferably selected as lithium salt; the magnesium salt is preferably MgCl 2 ；
And (3) in the step (f) of the hydroxyl protecting group removing reaction, the reaction temperature of the step (f) of the hydroxyl protecting group removing reaction is 90-120 ℃;
preferably, the (g) etherification reaction comprises the steps of: heating the compound shown in the formula II, chloromethyl methyl carbonate, potassium carbonate and potassium iodide in an organic solvent (preferably DMA) to react to generate a compound shown in the formula III; optionally including a post-treatment step; wherein the heating is preferably 40 to 60 ℃, and more preferably 45 to 55 ℃; and/or the reaction time is preferably 4 to 12 hours, more preferably 4 to 10 hours.
14. A process for the preparation of a compound of formula C, characterized in that it comprises the following steps: in a solvent, carrying out a condensation reaction between a compound shown in a formula A and a compound shown in a formula B in the presence of a condensing agent to generate a compound shown in a formula C; the condensing agent is sulfonic silane ester;
wherein R is 2 、R 3 Together with the carbon atom to which they are jointly attached form C 3-8 A carbocyclic ring.
15. A process for the preparation of the compound of formula C according to claim 14,
and/or, the condensing agent is TMSOTf;
and/or, said C 3-8 The carbocyclic ring being C 3-4 Carbocycle, such as a three membered carbocycle;
and/or the solvent is an epoxy based solvent, such as THF;
and/or the molar ratio of said compound of formula a to said compound of formula B is 1:1-5, e.g., 1:1-1.5 or 1.3-3;
and/or the reaction temperature of the condensation reaction is controlled below-15 ℃, preferably below-25 ℃;
and/or the compound of formula C is
And/or the compound of formula B is
And/or, in the preparation method of the compound of formula C, the reaction materials in the preparation method of the compound of formula C consist of: the solvent, the condensing agent, the compound of formula B, and the compound of formula a;
preferably, the preparation method of the compound of formula C comprises the following steps: dissolving said compound A and said compound B in THF, adding said condensing agent while controlling the temperature below-15 deg.C, stirring to react, optionally including a post-treatment step.
16. A process for the preparation of a compound of formula D, characterized in that it comprises the following steps:
in a solvent, in the presence of a base and a catalyst, a ring closure reaction of a compound of formula C occurs to form a compound of formula D:
wherein R is 2 、R 3 Together with the carbon atom to which they are jointly attached form C 3-8 A carbocyclic ring.
17. A process for the preparation of compound of formula D according to claim 16, wherein C is 3-8 The carbocyclic ring being C 3-4 Carbocycle, such as a three membered carbocycle;
and/or the solvent is an organic solvent; the solvent can be one or more of halogenated alkane solvent, aromatic hydrocarbon solvent, epoxy solvent and ether solvent; the ether solvent can be methyl tert-butyl ether or isopropyl ether; the epoxy solvent may be THF; the haloalkane solvent can be dichloromethane; the aromatic hydrocarbon solvent may be toluene; the solvent can also be selected from one or more of THF, halogenated alkane, ether and toluene;
and/or the base is an organic base, which may be a nitrogen-containing organic base, such as morpholine;
and/or the molar ratio of the compound of formula C to the base is 1:1-20, e.g., 1:5-10;
and/or the catalyst is a palladium catalyst, preferably a palladium on carbon catalyst, such as Pd (PPh) 3 ) 4 ；
And/or, the molar ratio of the compound of formula C to the catalyst is from 1.001 to 0.5, such as from 1.001 to 0.03, further such as from 1.001 to 0.005;
and/or the reaction mass in the preparation process of the compound of formula D consists of: the solvent, the base, the catalyst, and the compound of formula C;
and/or the compound of formula D is
And/or the compound of formula C is
And/or, the preparation method of the compound of formula D further comprises a post-treatment step, such as crystallization by using an ether solvent; the ether solvent can be MTBE, isopropyl ether, diethyl ether, THF, 2-methyltetrahydrofuran or 1,4-dioxane;
and/or, the compound of formula D is prepared by a process further comprising: in a solvent, carrying out a condensation reaction between a compound shown in a formula A and a compound shown in a formula B in the presence of a condensing agent to generate a compound shown in a formula C; the condensing agent is a silane condensing agent;
wherein R is 2 、R 3 Together with the carbon atom to which they are jointly attached form C 3-8 A carbocyclic ring;
preferably, the reaction conditions and steps of the condensation reaction to prepare the compound of formula C are as described in claims 14 or 15.
18. A process for the preparation of a compound of formula D comprising the steps of:
(1) The compound of formula a is condensed with a compound of formula B in the presence of a condensing agent to form a compound of formula C, preferably TMSOTf:
(2) The compound shown in the formula C undergoes a ring closing reaction to generate a compound shown in the formula D, and optionally, ether solvents are used for crystallization:
wherein R is 2 、R 3 Together with the carbon atom to which they are both attached form C 3-8 Carbocyclic ring, preferably C 3-4 Carbocyclic, more preferably a three membered carbocyclic ring.
19. The method of claim 18, wherein:
R 2 、R 3 together with the carbon atom to which they are commonly attached form a ternary carbocycle, i.e.:
(1) The compound of formula a is condensed with a compound of formula b in the presence of a condensing agent to form a compound of formula c, preferably TMSOTf:
(2) Carrying out ring closure reaction on the compound shown in the formula c to generate a compound shown in the formula d, and optionally, using an ether solvent for crystallization:
and/or, in step (1), the reaction solvent is preferably THF;
and/or, in the step (1), the reaction temperature is controlled below-15 ℃, preferably below-25 ℃;
and/or, in step (1), the molar ratio of compound of formula a to compound of formula B is 1:1-5, preferably 1:1-1.5 or 1.3-3;
and/or, in the step (1), the preparation method comprises the following steps:
dissolving compound A and compound B in THF, adding condensing agent, preferably TMSOTf, at a temperature controlled below-15 deg.C, stirring for reaction, optionally including post-treatment step;
and/or, in the step (2), the ether solvent is MTBE or isopropyl ether;
and/or, in step (2), the ring-closing reaction occurs in the presence of morpholine, a catalyst and an organic solvent; the catalyst is preferably a palladium on carbon catalyst, such as Pd (PPh) 3 ) 4 (ii) a And/or the molar ratio of compound a to morpholine is 1:1-40, preferably 1:1-20, more preferably 1; and/or, the molar ratio of compound a to palladium on carbon catalyst is preferably 1.001 to 0.5, e.g., 1;
and/or, in the step (2), the organic solvent is preferably one or more of THF, halogenated alkane (such as DCM), ether (such as methyl tert-butyl ether), and toluene;
and/or, in the step (2), the method further comprises a post-treatment step, wherein the post-treatment step comprises crystallization by using an ether solvent;
and/or, in the step (2), the compound of the formula C is dissolved in an organic solvent, and morpholine and Pd (PPh) are added 3 ) 4 Stirring for reaction; can optionally compriseAnd a post-treatment step, which comprises using an ether solvent for crystallization.
20. A process for the preparation of a compound of formula III, characterized in that it comprises the steps of: the compound A is subjected to condensation reaction (a), cyclization reaction (b), amidation reaction (c), substitution reaction (d), condensation reaction (e), dehydroxylation protecting group reaction (f) and etherification reaction (g) shown as the following formula to prepare a compound III;
(a) Condensation reaction:
(b) Cyclization reaction:
(c) Amidation reaction:
(d) And (3) substitution reaction:
(e) Condensation reaction:
(f) And (3) hydroxyl protecting group removal reaction:
(g) And (3) etherification reaction:
wherein R is 2 、R 3 Together with the carbon atom to which they are jointly attached form C 3-8 A carbocyclic ring; y is halogen;
n is an integer of 1 to 9; r 5 Is a prodrug-forming group;
preferably, C is 3-8 The carbocyclic ring may be C 3-4 Carbocycle, such as a three membered carbocycle;
preferably, n is 4, 5 or 6, such as 5;
preferably, the halogen is fluorine, chlorine, bromine or iodine, for example chlorine or bromine;
preferably, in the preparation method of the compound shown in the formula III, R 5 Is preferably-CH 2 -O-C(＝O)-O-R 6 ，R 6 Is C 1-4 An alkyl group; r 5 More preferably-CH 2 -O-C(＝O)-O-CH 3 ；
Preferably, the reaction conditions and steps of the (a) condensation reaction are as described in claim 14 or 15;
preferably, the reaction conditions and steps of said (b) cyclization reaction are as described in any one of claims 16-19;
preferably, the reaction conditions and steps of the (c) amidation reaction are as set forth in claim 6;
preferably, the reaction conditions and steps of the (d) substitution reaction are as described in any one of claims 1-5 and 7-8;
preferably, the reaction conditions and steps of the (e) condensation reaction are as described in any one of claims 9-12;
preferably, the reaction conditions and steps of said (f) dehydroxylating protecting group reaction are as set forth in claim 13;
preferably, the reaction conditions and steps of the (g) etherification reaction are as set forth in claim 13.
21. A process for the preparation of a compound of formula H, characterized in that it comprises the steps of: the compound shown in the formula A is subjected to condensation reaction (a), cyclization reaction (b), amidation reaction (c), substitution reaction (d) and condensation reaction (e) shown in the formula to prepare a compound shown in the formula H;
(a) Condensation reaction:
(b) Cyclization reaction:
(c) Amidation reaction:
(d) And (3) substitution reaction:
(e) Condensation reaction:
wherein R is 2 、R 3 Together with the carbon atom to which they are jointly attached form C 3-8 A carbocyclic ring; y is halogen;
n is an integer of 1 to 9;
preferably, the halogen is fluorine, chlorine, bromine or iodine, for example chlorine or bromine;
preferably, C is 3-8 The carbocyclic ring may be C 3-4 Carbocycle, such as a three membered carbocycle;
preferably, n is 4, 5 or 6, such as 5;
preferably, the reaction conditions and steps of the (a) condensation reaction are as defined in claim 14 or 15;
preferably, the reaction conditions and steps of said (b) cyclization reaction are as described in any one of claims 16-19;
preferably, the reaction conditions and steps of the (c) amidation reaction are as set forth in claim 6;
preferably, the reaction conditions and steps of the (d) substitution reaction are as described in any one of claims 1 to 5, 7 to 8;
preferably, the reaction conditions and steps of the (e) condensation reaction are as described in any one of claims 9 to 12.
22. A process for the preparation of a compound of formula II or formula III, wherein the preparation of formula II comprises step (1) and the preparation of formula III comprises steps (1), (2):
(1) Reacting a compound of formula H with a dehydroxylation protecting group in the presence of a lithium or magnesium salt to obtain a compound of formula II:
(2) Etherification of the compound of formula II to produce the compound of formula III:
wherein R is 2 、R 3 Together with the carbon atom to which they are jointly attached form C 3-8 Carbocyclic ring, preferably C 3-4 Carbocyclic, more preferably, ternary carbocyclic rings; n is an integer of 1 to 9, preferably 4, 5 or 6, more preferably 5,R 5 Are groups that form prodrugs.
23. The method according to claim 22, wherein the reaction mixture is a mixture of two or more of the above-mentioned components,
in the step (1), the compound of formula H and lithium salt or magnesium salt are heated and reacted in an organic solvent (preferably DMA) to prepare formula II, and a post-treatment step is optionally included;
and/or, in step (1), the lithium salt is preferably LiCl; the magnesium salt is preferably MgCl 2 ；
And/or in the step (1), the reaction temperature is 95-120 ℃;
and/or, in step (2), R 5 Is preferably-CH 2 -O-C(＝O)-O-R 6 ，R 6 Is C 1-4 An alkyl group; r 5 More preferably-CH 2 -O-C(＝O)-O-CH 3 ；
And/or, in the step (2), the compound shown in the formula II, chloromethyl methyl carbonate, potassium carbonate and potassium iodide are heated and reacted in an organic solvent (preferably DMA) to generate a compound shown in the formula III; optionally including a post-treatment step; wherein, the heating is preferably to 40 to 60 ℃, and more preferably to 45 to 55 ℃; and/or, reacting for 4 to 12 hours, more preferably for 4 to 10 hours;
and/or, the process for the preparation of the compound of formula II or formula III further comprises: any one or any combination of the process for the preparation of a compound of formula F/F (formula F or formula F) as defined in any one of claims 7 to 8, the process for the preparation of a compound of formula H/H (formula H or formula H) as defined in any one of claims 11 to 12, and the process for the preparation of a compound of formula D/D (formula D or formula D) as defined in any one of claims 18 to 19;
and/or, a process for the preparation of a compound of formula II or a compound of formula III, wherein the process for the preparation of the compound of formula II comprises the steps (1) to (4) and the process for the preparation of the compound of formula III comprises the steps (1) to (5):
(1) Preparation of compound formula D:
carrying out condensation reaction on the compound shown in the formula A and the compound shown in the formula B in the presence of a condensing agent to generate a compound shown in the formula C, wherein the condensing agent is TMSOTf;
carrying out a ring closing reaction on the compound formula C to generate a compound formula D, and optionally, crystallizing by using an ether solvent;
(2) Preparation of compound formula F:
acylating resolving agent (S) -tetrahydrofuran formic acid, and reacting with compound D to generate compound E;
carrying out substitution reaction on the compound shown in the formula E and fatty alcohol in the presence of alkoxide to generate a compound shown in the formula F;
(3) Preparation of compound formula H:
the compound of formula F is condensed with a compound of formula G to form a compound of formula H, preferably in the presence of T 3 P and methanesulfonic anhydride;
(4) Preparation of compound formula II:
carrying out dehydroxylation protecting group reaction on a compound formula H in the presence of lithium salt or magnesium salt to obtain a compound formula II;
(5) Preparation of compound formula III:
after etherification reaction of the compound shown in the formula II, a compound shown in the formula III is generated;
wherein R is 2 、R 3 N is as defined in claim 1, R 5 The group for forming a prodrug is preferably-CH 2 -O-C(＝O)-O-R 6 ，R 6 Is C 1-4 An alkyl group; r 5 More preferably-CH 2 -O-C(＝O)-O-CH 3 ；
The process for the preparation of the compound of formula D is as described in any one of claims 18 to 19, the process for the preparation of the compound of formula F is as described in any one of claims 7 to 8, the process for the preparation of the compound of formula H is as described in any one of claims 11 to 12;
wherein, preferably, in the preparation method, R 2 、R 3 Together with the carbon atom to which they are attached form a ternary carbocycle, n is 5, the compound of formula II is of the following formula 2, the compound of formula III is of the following formula 3
The preparation method of the compound of formula 2 comprises the steps of (1) to (4) (i.e., formula a-formula 2), and the preparation method of the compound of formula 3 comprises the steps of (1) to (5) (i.e., formula a-formula 3):
24. a compound of formula I, formula E or formula C:
wherein the content of the first and second substances,
R 1 selected from H,
R 2 、R 3 Together with the carbon atom to which they are jointly attached form C 3-8 Carbocyclic ring, preferably C 3-4 Carbocyclic, more preferably, ternary carbocyclic rings;
R 4 is halogen, preferably F;
m is an integer from 1 to 4, preferably 2 or 3; n is an integer from 1 to 9, preferably 4, 5 or 6, more preferably 5;
x is S or O, preferably S.
25. A compound of formula I according to claim 24, formula E or formula C: it is characterized in that; the compound of formula I is selected from:
the compound of formula F is preferably
The compound of formula H is preferably
Preferably, the first and second liquid crystal display panels are,a compound of the formula E
Preferably, the compound of formula C is
26. Use of a compound of formula C according to claim 24 or 25, a compound of formula E according to claim 24 or 25, a compound of formula F according to claim 25, a compound of formula H-a according to claim 25, a compound of formula H-b according to claim 25, a compound of formula C according to claim 25, a compound of formula E according to claim 25, a compound of formula F according to claim 25 or a compound of formula H according to claim 25 for the preparation of a cap-dependent endonuclease inhibitor pyridone derivative or an analogue thereof, or a process for the preparation of a pyridone derivative or an analogue thereof, prepared via compound of formula C, compound of formula E, compound of formula F, compound of formula H, compound of formula C, compound of formula E, compound of formula F or formula H, or compound of formula H, or a process for the preparation of a compound of formula F/F (formula F or formula F) according to any one of claims 1 to 5 and 7 to 8, a compound of formula H (formula H) or a process for the preparation of formula H (formula D) or any of formula D) according to any of claims 1 to 5 and 7 to 8.
27. A pharmaceutical composition comprising a compound of formula II/2 (formula II or formula 2) or formula III/3 (formula III or formula 3) and a pharmaceutically acceptable carrier/adjuvant, wherein the compound of formula II/2 (formula II or formula 2) or formula III/3 (formula III or formula 3) is prepared according to the process of any one of 13, 20, 22 or 23 or via the process of preparation of compound formula C, compound formula E, compound formula F, compound formula H, compound formula C, compound formula E, compound formula F or compound formula H or comprises the compound of formula F/F (formula F or formula F) of any one of claims 1-5 and 7-8, the process of preparation of compound formula H/H (formula H or formula H) of any one of claims 9-12 and 21 or the process of preparation of compound formula D/D (formula D or formula D) of any one of claims 16-19 or any combination thereof.
28. A composition comprising a compound of formula III, and further comprising a compound of formula II and/or a compound of formula H; preferably, the compound formula II is a compound formula 2, and/or the compound formula III is a compound formula 3, and/or the compound formula H is a compound formula H; more preferably, the compound of formula II is present in an amount of not more than 0.50% and/or the compound of formula H is present in an amount of not more than 0.10%, and/or the compound of formula III is prepared according to the process of claim 13, 20, 22 or 23, and/or the compound of formula II is prepared according to the process of claim 22 or 23, and/or the compound of formula H is prepared according to the process of any one of claims 9-12 and 21.
29. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula III and a pharmaceutically acceptable carrier/adjuvant, and further comprising a compound of formula II and/or a compound of formula H; preferably, the compound formula II is a compound formula 2, and/or the compound formula III is a compound formula 3, and/or the compound formula H is a compound formula H; more preferably, the compound of formula II is present in an amount of not more than 1.50% (e.g. not more than 1.0%, not more than 0.5%) and/or the compound of formula H is present in an amount of not more than 0.10%, and/or the compound of formula III is prepared according to the process of claim 13, 20, 22 or 23, and/or the compound of formula II is prepared according to the process of claim 22 or 23, and/or the compound of formula H is prepared according to the process of any one of claims 9-12 and 21.
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