CN105294713A - Velpatasvir intermediate and preparation method thereof - Google Patents
Velpatasvir intermediate and preparation method thereof Download PDFInfo
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- CN105294713A CN105294713A CN201510647298.XA CN201510647298A CN105294713A CN 105294713 A CN105294713 A CN 105294713A CN 201510647298 A CN201510647298 A CN 201510647298A CN 105294713 A CN105294713 A CN 105294713A
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- iodine
- bromine
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- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- NEADWTKOYDYIHL-UHFFFAOYSA-N 3-(2-bromoacetyl)-5,9,10,11-tetrahydronaphtho[7,6-c]isochromen-8-one Chemical compound O=C1CCCC2=C1C=C1OCC3=CC(C(=O)CBr)=CC=C3C1=C2 NEADWTKOYDYIHL-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 52
- 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 claims abstract description 8
- 239000003054 catalyst Substances 0.000 claims abstract description 6
- 229910052751 metal Inorganic materials 0.000 claims abstract description 5
- 239000002184 metal Substances 0.000 claims abstract description 5
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 29
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 12
- 229910052740 iodine Inorganic materials 0.000 claims description 12
- 239000011630 iodine Substances 0.000 claims description 12
- -1 Boc- Chemical class 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 229940126214 compound 3 Drugs 0.000 claims description 4
- 238000005984 hydrogenation reaction Methods 0.000 claims description 4
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 3
- 239000005695 Ammonium acetate Substances 0.000 claims description 3
- 229940043376 ammonium acetate Drugs 0.000 claims description 3
- 235000019257 ammonium acetate Nutrition 0.000 claims description 3
- 229940125904 compound 1 Drugs 0.000 claims description 3
- 230000002140 halogenating effect Effects 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 238000007336 electrophilic substitution reaction Methods 0.000 claims description 2
- 230000002829 reductive effect Effects 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 6
- 229910052794 bromium Inorganic materials 0.000 claims 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 5
- 229910052801 chlorine Inorganic materials 0.000 claims 5
- 239000000460 chlorine Substances 0.000 claims 5
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims 3
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims 2
- 239000003638 chemical reducing agent Substances 0.000 claims 1
- 238000006264 debenzylation reaction Methods 0.000 claims 1
- 238000006356 dehydrogenation reaction Methods 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 239000003446 ligand Substances 0.000 claims 1
- 210000004185 liver Anatomy 0.000 claims 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims 1
- 208000005176 Hepatitis C Diseases 0.000 abstract 1
- 238000005859 coupling reaction Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 43
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 239000012141 concentrate Substances 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 239000008213 purified water Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 238000005070 sampling Methods 0.000 description 6
- 239000012074 organic phase Substances 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
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 230000000630 rising effect Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- 0 CCC*CC(CC)(*N)*(*)C[C@@](C)C1C(C*C)*1 Chemical compound CCC*CC(CC)(*N)*(*)C[C@@](C)C1C(C*C)*1 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 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 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 1
- BMQDAIUNAGXSKR-UHFFFAOYSA-N (3-hydroxy-2,3-dimethylbutan-2-yl)oxyboronic acid Chemical compound CC(C)(O)C(C)(C)OB(O)O BMQDAIUNAGXSKR-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- XRXMNWGCKISMOH-UHFFFAOYSA-N 2-bromobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Br XRXMNWGCKISMOH-UHFFFAOYSA-N 0.000 description 1
- MHHDMDLNVVCTAJ-UHFFFAOYSA-N 2-iodo-1h-imidazole Chemical compound IC1=NC=CN1 MHHDMDLNVVCTAJ-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- FBBULQBHAYOSGZ-UHFFFAOYSA-N IN1C(CCC1=O)=O.[N] Chemical compound IN1C(CCC1=O)=O.[N] FBBULQBHAYOSGZ-UHFFFAOYSA-N 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 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
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- GCUVBACNBHGZRS-UHFFFAOYSA-N cyclopenta-1,3-diene cyclopenta-2,4-dien-1-yl(diphenyl)phosphane iron(2+) Chemical compound [Fe++].c1cc[cH-]c1.c1cc[c-](c1)P(c1ccccc1)c1ccccc1 GCUVBACNBHGZRS-UHFFFAOYSA-N 0.000 description 1
- 238000005695 dehalogenation reaction Methods 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- ADOJHDXDOIEMNB-UHFFFAOYSA-N methyl 2-bromo-5-iodobenzoate Chemical class COC(=O)C1=CC(I)=CC=C1Br ADOJHDXDOIEMNB-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 1
- 229940093916 potassium phosphate Drugs 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- JQRYUMGHOUYJFW-UHFFFAOYSA-N pyridine;trihydrobromide Chemical compound [Br-].[Br-].[Br-].C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1 JQRYUMGHOUYJFW-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 229960004249 sodium acetate Drugs 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005406 washing Methods 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of a Velpatasvir (GS-5816) intermediate compound which serves as a hepatitis C resisting compound and is as shown in a formula 1, as well as preparation methods of a compound as shown in a formula 3 and a compound as shown in a formula 9. The compound as shown in the formula 3 and the compound as shown in the formula 9 are used for preparing a compound as shown in a formula 2 by nucleophilic substitution under the alkaline conditions; the compound as shown in the formula 2 is used for preparing the compound as shown in the formula 1 by a coupling reaction in the presence of a metal catalyst.
Description
Technical field
The present invention relates to Velpatasvir(GS-5816) intermediate and preparation method thereof.
Background technology
Velpatasvir (GS-5816) is the antiviral of new generation of lucky De Famo Saite limited liability company exploitation, and its structural formula is as follows.
Compound 2 is synthesis Velpatasvir (GS-5816) important intermediate, and current CN201280004097 reports its synthetic method (as route 1):
Route 1.Velpatasvir (GS-5816) synthetic route
There is following point in the method: the first, starting material is expensive, and the longer whole piece route cost that causes of route is higher.The second, in reaction, relate to the linked reaction of two step palladium chtalyst, dehalogenation impurity is more, take two, disposable pass imidazole ring, temperature is higher, and the side reaction of reaction is more simultaneously, purifying and difficulty thereof, at present by means of only crossing the means of purification purifying such as post, industrialization difficulty is larger.
Summary of the invention
In order to solve the expensive raw material price that existing issue exists, reaction scheme is long, cannot technology prepare Velpatasvir(GS-5816) problem, inventor is realized by technical scheme below: (as shown in Scheme 2) is prepared into compound 12 with compound 13 by halo, the linked reaction that metal catalytic occurs for compound 12 and compound 14 is prepared into compound 11, chemical combination 11 prepares compound 10 by reductive agent reduction, compound 10 is prepared into compound 9 at the hydroxy activated reagent react such as methylsulfonyl chloride or Tosyl chloride further, compound 8 and halogenating agent generation electrophilic substitution are prepared into compound 7, there is esterification in the basic conditions and prepare compound 6 in compound 7 and compound 15, ShiShimonoseki ring is there is and prepares compound 5 in compound 6 at ammonium acetate, compound 5 in the presence of an oxidizer oxydehydrogenation is prepared into compound 4, compound 4 hydrogenation under metal catalyst exists takes off benzyl and prepares compound 3, there is nucleophilic substitution reaction and prepare compound 2 in compound 3 and compound 9, linked reaction is there is and prepares compound 1 in compound 2 under palladium catalyst exists.
Route 2. compound 1 synthetic route
For a better understanding of the present invention, be explained in detail by concrete example below, should be noted that, following examples not limit the scope of the present invention, obviously, those of ordinary skill in the art according to illustrating, can make various correction and change to the present invention herein within the scope of the present invention, and these are revised and change and also include scope of the present invention in.
example 1
2-bromo-benzoic acid 402g is added in 3L reaction flask, nitrogen N-iodosuccinimide 500g, tetrahydrofuran (THF) 1L, vitriol oil 450g, room temperature reaction is after 5 hours, TLC (hexane: ethyl acetate 1:2) puts in plate to be controlled, iodine develops the color, raw material point disappears, after concentrated tetrahydrofuran (THF), add methyl alcohol 1L, sulfuric acid 250g back flow reaction, control in TLC (hexane: ethyl acetate 1:2), after intermediate reaction is complete, be cooled to 0-5 DEG C, drip 40% sodium hydroxide and be neutralized to neutrality, after concentrated solvent methyl alcohol, add extraction into ethyl acetate product, anhydrous magnesium sulfate drying, concentrate to obtain 12a product 610g, 89.5%.
example 2
In 5L reaction flask, under argon shield, 2-bromo-5-iodo-benzoic acid methyl esters 610g (12a), add toluene 3L, Potassium ethanoate 380g, connection pinacol borate 490g, 2-dicyclohexyl phosphorus-2'-methyl diphenyl 35g, palladium 20g, temperature rising reflux reacts 1 hour, TLC (hexane: ethyl acetate 1:2) puts in plate to be controlled, iodine develops the color, raw material point disappears, be cooled to room temperature, add potassiumphosphate 1200g and 715g iodoimidazole thing 14a, under argon shield, be warming up to back flow reaction to control in 2 hours, TLC (hexane: ethyl acetate 1:2) puts in plate to be controlled, iodine develops the color, raw material point disappears, be cooled to room temperature, separatory, after organic phase adds 1L diluted ethyl acetate, 2 times are washed with saturated nacl aqueous solution 2L, organic phase pad diatomite filtration, add N-acetyl-L-cysteine 100g, stirring at room temperature 12 hours, add 5% sodium hydroxide 2L to wash twice, dry, concentrated have solid to separate out, stop concentrated, drip 2L normal hexane stirring at room temperature crystallization 5 hours, filter to obtain 11a product 700g, yield 77%.
example 3
In 5L reaction flask; under nitrogen protection, add 11a700g, anhydrous tetrahydro furan 3.5L; be cooled to 0 to 5 DEG C; slowly add lithium aluminum hydride 70g in batches, finish, be naturally warming up to room temperature reaction 6 hours; sampling adds sal glauberi cancellation; TLC (hexane: ethyl acetate 1:4) puts in plate to be controlled, and iodine develops the color, and raw material point disappears; add 1200g sal glauberi cancellation reaction; attentional manipulation temperature, filter, filter cake 1L tetrahydrofuran (THF) washs; filtrate merges concentrated; obtain 10a product 600g, yield 93%, is directly used in the next step.
example 4
In 5L reaction flask, add 10a compound 550g under nitrogen protection, methylene dichloride 2.6L; diisopropylethylamine 460g is cooled to 0 to 5 DEG C, starts slowly to drip methylsulfonyl chloride 150g, finishes; maintain this thermotonus 1 hour, sampling TLC (hexane: ethyl acetate 1:4) is put in plate and is controlled, and starting material 10a disappears; slowly drip purified water and be neutralized to neutrality; separatory, organic phase anhydrous magnesium sulfate drying, concentrates to obtain 9a product 530g; yield 82.54%, is directly used in the next step.
example 5
Add 8 compound 700g in 5L reaction flask, add methylene dichloride 3.5L, methyl alcohol 250mL, add pyridinium tribromide 880g under room temperature in batches, finish reaction 30 minutes, TLC (hexane: ethyl acetate 1:4) puts in plate to be controlled, iodine develops the color, and raw material 8 disappearance, adds 6% sodium sulfite solution 1L and wash, 1L1N salt acid elution, purified water washing, to neutral, commonly used and is concentrated into about 2L, be cooled to room temperature, filter, obtain 7a product 800g, yield 87%.
example 6
7a compound 700g is added, compound 500g, cesium carbonate 560g in 5L reaction flask, 2-methyltetrahydrofuran 3.5L, be warming up to 50 DEG C of reactions 20 hours, TLC (hexane: ethyl acetate 1:4) puts in plate to be controlled, and starting material 7a point disappears, be cooled to room temperature, add 3.5L purified water to wash twice, anhydrous magnesium sulfate drying, concentrate to obtain 6a product 800g, yield 79.2%, is directly used in the next step.
example 7
6a compound 800g is added, ammonium acetate 1000g, ethylene glycol monomethyl ether 350mL in 5L reaction flask, toluene 3.5L temperature rising reflux reacts 2 hours, TLC (hexane: ethyl acetate 1:4) puts in plate to be controlled, and starting material 6a point disappears, and is cooled to room temperature, after adding ethyl acetate 3.5L dilution, add saturated sodium bicarbonate solution 3.5L to wash, saturated nacl aqueous solution 3.5L washs, anhydrous magnesium sulfate drying, concentrate to obtain 5a product 650g, yield 84.8%.
example 8
620g compound 5a is added in 5L reaction flask, Manganse Dioxide 1000g, methylene dichloride 4L, room temperature reaction 2 hours, sampling TLC (hexane: ethyl acetate 1:4) is put in plate and is controlled, and starting material point disappears, filter, filter cake adds 2L washed with dichloromethane, concentrates to obtain 4a product 600g, yield 97%.
example 9
4a compound 650g is added, dehydrated alcohol, Raney Ni 6.5g in 5L hydrogenation reaction cauldron, nitrogen replacement 3 times, hydrogen exchange three times, hydrogenation 5 hours between maintenance pressure 0.1 to 0.2MPa, sampling TLC (hexane: ethyl acetate 1:4) is put in plate and is controlled, and starting material 4a point disappears, and filters, after filtrate concentrates most of solvent, add toluene 1300mL, rising temperature for dissolving, slow cooling crystallization, obtain 3a product 500g, yield 95%.
example 10
3a compound 300g is added in 5L reaction flask, the 9a compound 450g of activation, DMF 600g, cesium carbonate 550g stirring at room temperature 12 hours sampling TLC (hexane: ethyl acetate 1:1) is put in plate and is controlled, starting material point disappears, after adding 3L diluted ethyl acetate, add 2L purified water and wash 2 times, anhydrous magnesium sulfate drying, concentrate to obtain 2a product 530g, yield 79.3%.
example 11
In 5L reaction flask, 2a compound 530g is added under argon shield, add [1, two (diphenylphosphino) ferrocene of 1'-] palladium chloride 25g, sodium-acetate 270g, N, dinethylformamide 2.6L, be warming up to 100 DEG C of reactions 6 hours, sampling TLC (hexane: ethyl acetate 1:1) is put in plate and is controlled, starting material 2a point disappears, be cooled to room temperature, proceed to 10L reaction flask, after adding 3L ethyl acetate and the dilution of 2L purified water, separatory, organic phase filters palladium removing after adding diatomite, organic phase saturated nacl aqueous solution washs, anhydrous magnesium sulfate drying, be concentrated into 2L, be cooled to 0 to 5 DEG C of filtration, filter cake vacuum-drying obtains 400g yellow solid 1a, yield 83.8%.
example 12
Under nitrogen protection, add 102g1a, add 500mL methylene dichloride to dissolve, add 1 of 4mol/LHCl, 4-dioxane solution 500mL, stirring at room temperature 1 hour, TLC (hexane: ethyl acetate 1:1) puts in plate to be controlled, starting material point disappears, stopped reaction, after concentrated solvent, add (R)-2-(methyloxycarbonylamino)-2-toluylic acid 29g, COMU60g, DMF500mL, diisopropylethylamine 223Ml, 25 DEG C are reacted 1 hour, after adding ethyl acetate 1L dilution, add 1L purified water and wash 2 times, anhydrous magnesium sulfate drying, after concentrated, add 500mL methyl alcohol to heat up 60 DEG C and dissolve, slow dropping 250mL purified water, separate out solid, finish, be cooled to 50 DEG C of insulations 1 hour, be cooled to room temperature to filter, concentrate to obtain Velpatasvir (GS-5816) product 90.5g, yield 78.2%.H-NMR(400MHz，CD
3OD)δ7.94-7.67(m,4H),7.59(d,J=9.1Hz,1H),7.52(s,1H),7.48-7.33(m,4H),7.11(d,J=18.7Hz,1H),5.68(d,J=6.3Hz,1H),5.48-5.33(m,1H),5.23(dd,J=24.1,15.7Hz,1H),5.17-5.03(m,3H),4.22(dd,J=17.0,9.6Hz,1H),4.16-4.01(m,1H),3.91(d,J=24.1Hz,1H),3.83-3.68(m,1H),3.68-3.59(m,3H),3.59-3.49(m,3H),3.38(ddd,J=15.9,9.6,5.7Hz,2H),3.28-3.14(m,5H),3.10(dd,J=14.0,8.2Hz,1H),3.00(dd,J=17.8,9.6Hz,1H),2.92(dd,J=14.5,6.7Hz,1H),2.73-2.41(m,2H),2.40-2.11(m,2H),2.11-1.83(m,2H),1.54(t,J=9.7Hz,2H),1.24(d,J=6.2Hz,1H),1.06(t,J=8.0Hz,1H),0.99(d,J=6.8Hz,1H),0.94(d,J=6.6Hz,2H),0.85(d,J=6.7Hz,2H)。
Claims (5)
1. anti-third liver medicine Velpatasvir(GS-5816) preparation method of midbody compound 1, it is characterized in that:
With formula 3 compound
with formula 9 compound
formula 2 compound is prepared in the basic conditions by nucleophilic substitution reaction,
Wherein: X
1for chlorine, bromine, iodine; R
2for Boc-, Cbz-; R
3for p-toluenesulfonyl, methylsulfonyl;
Formula 2 compound prepares formula 1 compound by linked reaction under metal catalyst exists,
。
2. compound 3 described in claim 1,
。
3. right wants compound 9 described in 1,
Wherein: X
1for chlorine, bromine, iodine; R
2for Boc-, Cbz-; R
3for p-toluenesulfonyl, methylsulfonyl.
4. the preparation method of compound 3 shown in claim 1, is characterized in that: formula 8 compound
the formula for preparing 7 compound is reacted with halogenating agent,
Wherein: X
4for bromine, atomic iodine;
Formula 7 compound and formula 15 compound
there is nucleophilic substitution reaction in the basic conditions and prepare formula 6 compound,
；
Formula 6 compound and ammonium acetate react the formula for preparing 5 compound,
；
Formula 5 dehydrogenation under oxygenant Manganse Dioxide exists prepares formula 4 compound,
；
Formula 4 compound is under metal catalyst exists, and hydrogenation debenzylation is prepared into formula 3 compound,
。
5. the preparation method of compound 9 described in claim 1, is characterized in that:
Halogenating agent and formula 13 compound generation electrophilic substitution are prepared into formula 12 compound,
Wherein: X
1, X
2independently selected from chlorine, bromine, iodine;
Formula 12 compound and formula 14 compound
formula 11 compound is prepared at Phosphine ligands and palladium acetate catalyst existent condition,
Wherein: X
1for chlorine, bromine, iodine; X
3for bromine, iodine; R
2for Boc-, Cbz-;
Formula 11 is reduced in the presence of a reducing agent and is prepared into formula 10 compound,
Wherein: X
1for being chlorine, bromine, iodine;
Formula 10 compound and hydroxy activated reagent react are prepared into formula 9 compound,
Wherein: X
1, R
2as defined above; R
3for p-toluenesulfonyl, methylsulfonyl.
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| CN106220639A (en) * | 2016-07-22 | 2016-12-14 | 上海众强药业有限公司 | A kind of Wei Patawei intermediate novel crystal forms |
| WO2017060820A1 (en) * | 2015-10-08 | 2017-04-13 | Mylan Laboratories Limited | Process for the preparation of velpatasvir |
| CN107573355A (en) * | 2016-11-30 | 2018-01-12 | 上海博志研新药物技术有限公司 | Wei Patawei, wherein mesosome and preparation method |
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| WO2017060820A1 (en) * | 2015-10-08 | 2017-04-13 | Mylan Laboratories Limited | Process for the preparation of velpatasvir |
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| CN107674062B (en) * | 2016-11-30 | 2020-03-27 | 上海博志研新药物技术有限公司 | Anti-hepatitis C drug intermediate, preparation method and application |
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