CN107674062B - 抗丙肝药物中间体、制备方法及应用 - Google Patents
抗丙肝药物中间体、制备方法及应用 Download PDFInfo
- Publication number
- CN107674062B CN107674062B CN201710918856.0A CN201710918856A CN107674062B CN 107674062 B CN107674062 B CN 107674062B CN 201710918856 A CN201710918856 A CN 201710918856A CN 107674062 B CN107674062 B CN 107674062B
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- solvent
- gas
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 106
- 239000003814 drug Substances 0.000 title abstract description 14
- 229940079593 drug Drugs 0.000 title abstract description 13
- 208000005176 Hepatitis C Diseases 0.000 title abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 53
- 229940125773 compound 10 Drugs 0.000 claims abstract description 47
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims abstract description 47
- 238000000034 method Methods 0.000 claims abstract description 46
- 125000006239 protecting group Chemical group 0.000 claims abstract description 20
- 239000002253 acid Substances 0.000 claims abstract description 14
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims description 108
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 32
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 28
- 230000009615 deamination Effects 0.000 claims description 17
- 238000006481 deamination reaction Methods 0.000 claims description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 150000008280 chlorinated hydrocarbons Chemical group 0.000 claims description 14
- 150000008282 halocarbons Chemical class 0.000 claims description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- 150000007522 mineralic acids Chemical class 0.000 claims description 6
- 150000007524 organic acids Chemical class 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 4
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 3
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 7
- 238000009776 industrial production Methods 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 4
- 239000012535 impurity Substances 0.000 abstract description 3
- 230000003287 optical effect Effects 0.000 abstract description 3
- 238000004440 column chromatography Methods 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- 238000000926 separation method Methods 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 description 73
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 35
- 238000005406 washing Methods 0.000 description 26
- 238000003756 stirring Methods 0.000 description 24
- 238000001914 filtration Methods 0.000 description 22
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 21
- 229940126214 compound 3 Drugs 0.000 description 21
- 229940125898 compound 5 Drugs 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- -1 benzyloxycarbonyl (CBz) Chemical class 0.000 description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 238000006482 condensation reaction Methods 0.000 description 17
- 238000004128 high performance liquid chromatography Methods 0.000 description 17
- 239000003960 organic solvent Substances 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical group O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 11
- 238000004519 manufacturing process Methods 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- NJTZSWLQBQJUHK-UHFFFAOYSA-N CCCP(=O)=O Chemical compound CCCP(=O)=O NJTZSWLQBQJUHK-UHFFFAOYSA-N 0.000 description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical group CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- FHCUMDQMBHQXKK-CDIODLITSA-N velpatasvir Chemical compound C1([C@@H](NC(=O)OC)C(=O)N2[C@@H](C[C@@H](C2)COC)C=2NC(=CN=2)C=2C=C3C(C4=CC5=CC=C6NC(=NC6=C5C=C4OC3)[C@H]3N([C@@H](C)CC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)=CC=CC=C1 FHCUMDQMBHQXKK-CDIODLITSA-N 0.000 description 9
- 229960000863 velpatasvir Drugs 0.000 description 9
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 8
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 8
- 235000011114 ammonium hydroxide Nutrition 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 238000007796 conventional method Methods 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 7
- 238000012544 monitoring process Methods 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000003513 alkali Substances 0.000 description 6
- 150000001408 amides Chemical class 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 150000002825 nitriles Chemical class 0.000 description 6
- 150000007530 organic bases Chemical class 0.000 description 6
- 230000001681 protective effect Effects 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- 150000003863 ammonium salts Chemical class 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000007864 suspending Methods 0.000 description 3
- 229960004295 valine Drugs 0.000 description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical group C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- 239000007821 HATU Substances 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000012317 TBTU Substances 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- KPFBUSLHFFWMAI-HYRPPVSQSA-N [(8r,9s,10r,13s,14s,17r)-17-acetyl-6-formyl-3-methoxy-10,13-dimethyl-1,2,7,8,9,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-17-yl] acetate Chemical compound C1C[C@@H]2[C@](CCC(OC)=C3)(C)C3=C(C=O)C[C@H]2[C@@H]2CC[C@](OC(C)=O)(C(C)=O)[C@]21C KPFBUSLHFFWMAI-HYRPPVSQSA-N 0.000 description 2
- GPDHNZNLPKYHCN-DZOOLQPHSA-N [[(z)-(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-morpholin-4-ylmethylidene]-dimethylazanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.CCOC(=O)C(\C#N)=N/OC(=[N+](C)C)N1CCOCC1 GPDHNZNLPKYHCN-DZOOLQPHSA-N 0.000 description 2
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical compound N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 description 2
- 229910000071 diazene Inorganic materials 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- LCFXLZAXGXOXAP-UHFFFAOYSA-N ethyl 2-cyano-2-hydroxyiminoacetate Chemical compound CCOC(=O)C(=NO)C#N LCFXLZAXGXOXAP-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 239000003495 polar organic solvent Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 2
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- PAWQVTBBRAZDMG-UHFFFAOYSA-N 2-(3-bromo-2-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC(Br)=C1F PAWQVTBBRAZDMG-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- MTJRPZFKWMLWLW-UHFFFAOYSA-N CCC[P] Chemical compound CCC[P] MTJRPZFKWMLWLW-UHFFFAOYSA-N 0.000 description 1
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 1
- MZBLZLWXUBZHSL-FZNJKFJKSA-N O=C([C@H]1N2C[C@H](OC3=NC4=CC(OC)=CC=C4N=C3C(F)(F)CCCC[C@@H]3C[C@H]3OC(=O)N[C@H](C2=O)C(C)(C)C)[C@H]1CC)N[C@]1(C(=O)NS(=O)(=O)C2(C)CC2)C[C@H]1C(F)F Chemical compound O=C([C@H]1N2C[C@H](OC3=NC4=CC(OC)=CC=C4N=C3C(F)(F)CCCC[C@@H]3C[C@H]3OC(=O)N[C@H](C2=O)C(C)(C)C)[C@H]1CC)N[C@]1(C(=O)NS(=O)(=O)C2(C)CC2)C[C@H]1C(F)F MZBLZLWXUBZHSL-FZNJKFJKSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- GOPYZMJAIPBUGX-UHFFFAOYSA-N [O-2].[O-2].[Mn+4] Chemical class [O-2].[O-2].[Mn+4] GOPYZMJAIPBUGX-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 235000012501 ammonium carbonate Nutrition 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 229910001870 ammonium persulfate Inorganic materials 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 229940124404 anti-hepatitis c virus drug Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910052593 corundum Inorganic materials 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940039283 epclusa Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 229940029169 harvoni Drugs 0.000 description 1
- 150000008040 ionic compounds Chemical group 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940099596 manganese sulfate Drugs 0.000 description 1
- 239000011702 manganese sulphate Substances 0.000 description 1
- 235000007079 manganese sulphate Nutrition 0.000 description 1
- SQQMAOCOWKFBNP-UHFFFAOYSA-L manganese(II) sulfate Chemical compound [Mn+2].[O-]S([O-])(=O)=O SQQMAOCOWKFBNP-UHFFFAOYSA-L 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229960002063 sofosbuvir Drugs 0.000 description 1
- TTZHDVOVKQGIBA-IQWMDFIBSA-N sofosbuvir Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@]2(F)C)O)CO[P@@](=O)(N[C@@H](C)C(=O)OC(C)C)OC=2C=CC=CC=2)C=CC(=O)NC1=O TTZHDVOVKQGIBA-IQWMDFIBSA-N 0.000 description 1
- 229940076569 sofosbuvir 400 mg Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 229940039243 velpatasvir 100 mg Drugs 0.000 description 1
- 229950004638 voxilaprevir Drugs 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 229910001845 yogo sapphire Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
Description
Claims (9)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201611083256 | 2016-11-30 | ||
CN2016110832569 | 2016-11-30 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN107674062A CN107674062A (zh) | 2018-02-09 |
CN107674062B true CN107674062B (zh) | 2020-03-27 |
Family
ID=61039839
Family Applications (8)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201710917345.7A Active CN107805256B (zh) | 2016-11-30 | 2017-09-30 | 维帕他韦中间体及制备方法和应用 |
CN201710917630.9A Active CN107573380B (zh) | 2016-11-30 | 2017-09-30 | 维帕他韦中间体、制备方法及应用 |
CN201710938737.1A Active CN107674064B (zh) | 2016-11-30 | 2017-09-30 | 维帕他韦中间体、制备方法及维帕他韦的制备方法 |
CN201710919393.XA Active CN107674063B (zh) | 2016-11-30 | 2017-09-30 | Gs5816中间体及制备方法和应用 |
CN201710918856.0A Active CN107674062B (zh) | 2016-11-30 | 2017-09-30 | 抗丙肝药物中间体、制备方法及应用 |
CN201911009963.7A Active CN110698489B (zh) | 2016-11-30 | 2017-09-30 | 维帕他韦中间体、制备方法及应用 |
CN201710919030.6A Active CN107759577B (zh) | 2016-11-30 | 2017-09-30 | Gs5816中间体、制备方法及应用 |
CN201710919762.5A Active CN107573355B (zh) | 2016-11-30 | 2017-09-30 | 维帕他韦、其中间体及制备方法 |
Family Applications Before (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201710917345.7A Active CN107805256B (zh) | 2016-11-30 | 2017-09-30 | 维帕他韦中间体及制备方法和应用 |
CN201710917630.9A Active CN107573380B (zh) | 2016-11-30 | 2017-09-30 | 维帕他韦中间体、制备方法及应用 |
CN201710938737.1A Active CN107674064B (zh) | 2016-11-30 | 2017-09-30 | 维帕他韦中间体、制备方法及维帕他韦的制备方法 |
CN201710919393.XA Active CN107674063B (zh) | 2016-11-30 | 2017-09-30 | Gs5816中间体及制备方法和应用 |
Family Applications After (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201911009963.7A Active CN110698489B (zh) | 2016-11-30 | 2017-09-30 | 维帕他韦中间体、制备方法及应用 |
CN201710919030.6A Active CN107759577B (zh) | 2016-11-30 | 2017-09-30 | Gs5816中间体、制备方法及应用 |
CN201710919762.5A Active CN107573355B (zh) | 2016-11-30 | 2017-09-30 | 维帕他韦、其中间体及制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (8) | CN107805256B (zh) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106831737B (zh) * | 2017-02-27 | 2020-03-17 | 上海众强药业有限公司 | 维帕他韦及其衍生物的制备 |
CN111018870B (zh) * | 2019-11-29 | 2021-07-23 | 南京正济医药研究有限公司 | 一种维帕他韦中间体的制备方法 |
CN113072615B (zh) * | 2021-03-24 | 2023-01-10 | 上海法默生物科技有限公司 | 一种维帕他韦中间体的制备方法 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104487442A (zh) * | 2012-05-16 | 2015-04-01 | 吉利德法莫赛特有限责任公司 | Hcv ns5b的抗病毒化合物抑制剂 |
CN105294713A (zh) * | 2015-10-09 | 2016-02-03 | 重庆康施恩化工有限公司 | Velpatasvir中间体及其制备方法 |
CN105732765A (zh) * | 2016-02-01 | 2016-07-06 | 杭州科巢生物科技有限公司 | 丙肝药物维帕他韦的新合成方法 |
CN105837584A (zh) * | 2011-11-16 | 2016-08-10 | 吉利德制药有限责任公司 | 作为抗病毒化合物的缩合的咪唑基咪唑 |
CN106831737A (zh) * | 2017-02-27 | 2017-06-13 | 上海众强药业有限公司 | 维帕他韦及其衍生物的制备 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA3095528C (en) * | 2010-11-17 | 2023-07-18 | Gilead Pharmasset Llc | Antiviral compounds |
TW202014413A (zh) * | 2014-06-11 | 2020-04-16 | 美商基利法瑪席特有限責任公司 | 製備抗病毒化合物之方法 |
CN107501280A (zh) * | 2017-09-05 | 2017-12-22 | 安徽华昌高科药业有限公司 | 一种维帕他韦的合成方法 |
-
2017
- 2017-09-30 CN CN201710917345.7A patent/CN107805256B/zh active Active
- 2017-09-30 CN CN201710917630.9A patent/CN107573380B/zh active Active
- 2017-09-30 CN CN201710938737.1A patent/CN107674064B/zh active Active
- 2017-09-30 CN CN201710919393.XA patent/CN107674063B/zh active Active
- 2017-09-30 CN CN201710918856.0A patent/CN107674062B/zh active Active
- 2017-09-30 CN CN201911009963.7A patent/CN110698489B/zh active Active
- 2017-09-30 CN CN201710919030.6A patent/CN107759577B/zh active Active
- 2017-09-30 CN CN201710919762.5A patent/CN107573355B/zh active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105837584A (zh) * | 2011-11-16 | 2016-08-10 | 吉利德制药有限责任公司 | 作为抗病毒化合物的缩合的咪唑基咪唑 |
CN104487442A (zh) * | 2012-05-16 | 2015-04-01 | 吉利德法莫赛特有限责任公司 | Hcv ns5b的抗病毒化合物抑制剂 |
CN105294713A (zh) * | 2015-10-09 | 2016-02-03 | 重庆康施恩化工有限公司 | Velpatasvir中间体及其制备方法 |
CN105732765A (zh) * | 2016-02-01 | 2016-07-06 | 杭州科巢生物科技有限公司 | 丙肝药物维帕他韦的新合成方法 |
CN106831737A (zh) * | 2017-02-27 | 2017-06-13 | 上海众强药业有限公司 | 维帕他韦及其衍生物的制备 |
Also Published As
Publication number | Publication date |
---|---|
CN107674063B (zh) | 2020-03-27 |
CN107674063A (zh) | 2018-02-09 |
CN107573380A (zh) | 2018-01-12 |
CN107805256A (zh) | 2018-03-16 |
CN107573380B (zh) | 2020-06-02 |
CN107674064A (zh) | 2018-02-09 |
CN107759577B (zh) | 2020-03-27 |
CN107674064B (zh) | 2020-03-27 |
CN107573355A (zh) | 2018-01-12 |
CN107674062A (zh) | 2018-02-09 |
CN107573355B (zh) | 2020-03-17 |
CN107805256B (zh) | 2020-03-31 |
CN107759577A (zh) | 2018-03-06 |
CN110698489A (zh) | 2020-01-17 |
CN110698489B (zh) | 2022-02-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN107674062B (zh) | 抗丙肝药物中间体、制备方法及应用 | |
CN102985416A (zh) | 制备凝血酶特异性抑制剂的方法 | |
CN114031543A (zh) | 一种帕罗韦德中间体的制备方法 | |
CN108424389A (zh) | 一种伊伐布雷定杂质的制备方法 | |
CN111072660B (zh) | 一种瑞来巴坦的简便制备方法 | |
WO2019049824A1 (ja) | 保護l-カルノシン誘導体、l-カルノシン、および結晶性l-カルノシン亜鉛錯体の製造方法 | |
WO2020248341A1 (zh) | 一种缬沙坦的制备方法 | |
EP2643308B1 (en) | Process for the preparation of taurolidine and its intermediates thereof | |
CN105418477B (zh) | 降低雷迪帕韦中间体中非对映异构体杂质含量的方法 | |
CN105985316A (zh) | 一种曲格列汀及其盐的制备方法 | |
CN112375055A (zh) | 依替巴肽关键原料l-高级精氨酸的制备方法 | |
CN109574860B (zh) | 一种制备维兰特罗的方法 | |
CN107573345B (zh) | 一种艾代拉利司及其中间体的制备方法 | |
CN114539285A (zh) | 一种玛巴洛沙韦的制备方法 | |
CN113583021B (zh) | 一种螺哌啶利福霉素的合成方法 | |
CN107602454A (zh) | 新型磺酰胺类化合物及其制备方法和用途 | |
CN113024637B (zh) | 一种以水溶性炔酰胺作为缩合剂制备卡非佐米的方法 | |
CN111269157B (zh) | 一种氨磺必利杂质及其制备方法 | |
CN111943894A (zh) | 一种4,7-二氮杂螺[2.5]辛烷类化合物的合成方法 | |
CN113651808A (zh) | 一种硝呋太尔相关物质及其制备方法和用途 | |
CN117263879A (zh) | 二甲基吗啉衍生物的制备方法 | |
CN114805220A (zh) | 一种喹唑啉酮类化合物的制备方法 | |
CN117486878A (zh) | 一种恩那司他的制备方法 | |
CN113072466A (zh) | 达泊西汀杂质的合成方法 | |
CN116606233A (zh) | 一种s-三苯甲基-l-半胱氨酰胺的制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Anti hepatitis C drug intermediate, preparation method and Application Effective date of registration: 20211227 Granted publication date: 20200327 Pledgee: Bank of Shanghai Limited by Share Ltd. Pudong branch Pledgor: SHANGHAI BOCIMED PHARMACEUTICAL Co.,Ltd. Registration number: Y2021310000159 |
|
CP03 | Change of name, title or address | ||
CP03 | Change of name, title or address |
Address after: 201203 Building 1, Lane 647, Songtao Road, Zhangjiang High Tech Park, Pudong New Area, Shanghai Patentee after: Shanghai Yunshengyan neoplasm Technology Co.,Ltd. Address before: Room A679-04, Building No. 2, 351 GuoShoujing Road, China (Shanghai) Free Trade Pilot Area, Pudong New Area, Shanghai, 201203 Patentee before: SHANGHAI BOCIMED PHARMACEUTICAL Co.,Ltd. |