CN110981879B - Method for preparing NS5A inhibitor-wipatasvir - Google Patents
Method for preparing NS5A inhibitor-wipatasvir Download PDFInfo
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- CN110981879B CN110981879B CN201911249397.7A CN201911249397A CN110981879B CN 110981879 B CN110981879 B CN 110981879B CN 201911249397 A CN201911249397 A CN 201911249397A CN 110981879 B CN110981879 B CN 110981879B
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- 238000000034 method Methods 0.000 title claims abstract description 21
- 101800001014 Non-structural protein 5A Proteins 0.000 title claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 64
- 238000002360 preparation method Methods 0.000 claims abstract description 28
- -1 amine compound Chemical class 0.000 claims abstract description 17
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 16
- 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 10
- 229960000863 velpatasvir Drugs 0.000 claims abstract description 10
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 8
- 230000009471 action Effects 0.000 claims abstract description 7
- 239000003513 alkali Substances 0.000 claims abstract description 7
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 7
- 239000007800 oxidant agent Substances 0.000 claims abstract description 7
- 230000001590 oxidative effect Effects 0.000 claims abstract description 6
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 4
- 125000006239 protecting group Chemical group 0.000 claims abstract description 4
- 239000002994 raw material Substances 0.000 claims abstract description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 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 claims description 9
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 5
- 239000003112 inhibitor Substances 0.000 claims description 5
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical group Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 4
- NVSLOKHCHIFJDR-UHFFFAOYSA-N 9-bromo-3-(2-bromoacetyl)-5,9,10,11-tetrahydronaphtho[7,6-c]isochromen-8-one Chemical compound O=C1C(Br)CCC2=C1C=C1OCC3=CC(C(=O)CBr)=CC=C3C1=C2 NVSLOKHCHIFJDR-UHFFFAOYSA-N 0.000 claims description 4
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 4
- 239000005695 Ammonium acetate Substances 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 229940043376 ammonium acetate Drugs 0.000 claims description 4
- 235000019257 ammonium acetate Nutrition 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- DKJIYBHPQAHWAE-JQWIXIFHSA-N (2S,4S)-1-benzoyl-4-(methoxymethyl)pyrrolidine-2-carboxylic acid Chemical compound C(C1=CC=CC=C1)(=O)N1[C@@H](C[C@@H](C1)COC)C(=O)O DKJIYBHPQAHWAE-JQWIXIFHSA-N 0.000 claims description 3
- ZDDHZGNIEZLPTM-STQMWFEESA-N (2S,4S)-4-(methoxymethyl)-1-phenylmethoxycarbonylpyrrolidine-2-carboxylic acid Chemical compound C(C1=CC=CC=C1)OC(=O)N1[C@@H](C[C@@H](C1)COC)C(=O)O ZDDHZGNIEZLPTM-STQMWFEESA-N 0.000 claims description 3
- OHPUCEUCBHBIAW-IUCAKERBSA-N (2s,4s)-4-(methoxymethyl)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound COC[C@H]1C[C@@H](C(O)=O)N(C(=O)OC(C)(C)C)C1 OHPUCEUCBHBIAW-IUCAKERBSA-N 0.000 claims description 3
- WOWLKCKDFFLLPJ-UHFFFAOYSA-N 9,10a-dihydrobenzo[g]chromen-8-one Chemical compound O1C2C(=CC=C1)C=C1C=CC(CC1=C2)=O WOWLKCKDFFLLPJ-UHFFFAOYSA-N 0.000 claims description 3
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 claims description 3
- GOJLQSAREKTKPT-MRVPVSSYSA-N (2r)-2-(methoxycarbonylamino)-2-phenylacetic acid Chemical compound COC(=O)N[C@@H](C(O)=O)C1=CC=CC=C1 GOJLQSAREKTKPT-MRVPVSSYSA-N 0.000 claims description 2
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 2
- 239000001099 ammonium carbonate Substances 0.000 claims description 2
- 235000012501 ammonium carbonate Nutrition 0.000 claims description 2
- XJMWHXZUIGHOBA-UHFFFAOYSA-N azane;propanoic acid Chemical compound N.CCC(O)=O XJMWHXZUIGHOBA-UHFFFAOYSA-N 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Chemical group O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000000758 substrate Substances 0.000 claims description 2
- 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
- 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 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims 1
- 238000006555 catalytic reaction Methods 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 239000012074 organic phase Substances 0.000 description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 239000000706 filtrate Substances 0.000 description 16
- 239000012265 solid product Substances 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- 238000000967 suction filtration Methods 0.000 description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 238000001035 drying Methods 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- 239000012043 crude product Substances 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- 229960000583 acetic acid Drugs 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000004537 pulping Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 208000005176 Hepatitis C Diseases 0.000 description 3
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 208000019425 cirrhosis of liver Diseases 0.000 description 3
- 229940039283 epclusa Drugs 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 238000011031 large-scale manufacturing process Methods 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 229960000329 ribavirin Drugs 0.000 description 3
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- 241000711549 Hepacivirus C Species 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- BCUYCAJGSMCQMH-UHFFFAOYSA-N O1CCCC1.ClC1=C(C(C(=C(C1=O)Cl)Cl)=O)Cl Chemical compound O1CCCC1.ClC1=C(C(C(=C(C1=O)Cl)Cl)=O)Cl BCUYCAJGSMCQMH-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 101800001554 RNA-directed RNA polymerase Proteins 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000003205 genotyping method Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 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
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000007086 side reaction Methods 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
- 239000002904 solvent Substances 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 125000003554 tetrahydropyrrolyl group Chemical group 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for preparing NS5A inhibitor-wiepatasvir, which mainly comprises five steps, 1) carrying out butt reaction on reaction starting raw materials VPM1, VPM2 and VPM3 under the action of alkali catalysis to prepare an intermediate VP 1; 2) removing amino protecting groups from the intermediate VP1 by a deprotection reagent to obtain an intermediate VP 2; 3) intermediate VP2 and amine compound are cyclized to prepare intermediate VP 3; 4) reacting the intermediate VP3 with VPM4 under the action of a condensing agent to prepare an amide compound intermediate VP 4; 5) and carrying out oxidation reaction on the intermediate VP4 under the action of an oxidant to prepare Velpatasvir. The preparation process of the vipetavir has the characteristics of simplified route, simple reaction conditions, operable enhancement and higher product yield, and is more suitable for large-scale industrial production.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to a method for preparing NS5A inhibitor-wipatasvir.
Background
HCV viruses have 6 genotypes in total. The standard treatment regimen is combination of polyethylene glycol interferon (Peg-IFN) and Ribavirin (RBV), the total cure rate is less than 50%, and sufficient dose needs to be adhered to for continuous treatment for more than one year. Peg-IFN which needs to be injected for 1 time in 1 week has the defects of more adverse reactions, poor drug interaction, poor patient compliance and the like, and has limitation on clinical use. Thus, direct antiviral Drugs (DAAs) for treating hepatitis C, which can improve the cure rate, shorten the treatment time, and be used in a full oral form instead of Peg-IFN, are continuously emerging.
Epclusa is a novel pan-genotypic hepatitis C drug developed by Gilidard scientific, and is a compound tablet consisting of NS5B inhibitor sofosbuvir and NS5A inhibitor vepatavir (velpatasvir, VEL), which is orally taken once a day. Epclusa is approved by the FDA and the European Union respectively for treating adult patients infected with gene 1-6 type hepatitis C virus in 2016, can be used for patients without liver cirrhosis or compensated liver cirrhosis alone, and can also be used for treating patients with uncompensated liver cirrhosis by combining with ribavirin. Epclusa obtains better curative effect in each genotype patient, is expected to avoid genotyping test and improves the cure rate of hepatitis C patients.
However, the synthesis process of the vipitavir in the prior art has the defects of complex route, poor operability, low yield and the like, and is not suitable for large-scale production and preparation, which limits the application of the medicine to a certain extent. Therefore, it is necessary to design and develop a new preparation process of wipatavir, which can simplify the preparation process, has higher yield and is suitable for large-scale production.
Disclosure of Invention
Aiming at the problems in the prior art, the invention discloses a method for preparing NS5A inhibitor-wipatasvir, which has the advantages of short route, simple preparation conditions, enhanced operability and suitability for large-scale production.
The technical scheme of the invention is as follows: a method for preparing NS5A inhibitor-wipatasvir comprises the following specific synthetic route:
wherein X ═ Cl or Br;
r is tert-butyloxycarbonyl, benzyloxycarbonyl or benzoyl.
The specific synthesis steps are as follows:
1) preparation of intermediate VP 1: carrying out butt reaction on reaction starting raw materials VPM1, VPM2 and VPM3 under the catalysis of alkali to prepare an intermediate VP 1;
2) preparation of intermediate VP 2: removing amino protecting groups from the intermediate VP1 by a deprotection reagent to obtain an intermediate VP 2;
3) preparation of intermediate VP 3: intermediate VP2 and amine compound are cyclized to prepare intermediate VP 3;
4) preparation of intermediate VP 4: reacting the intermediate VP3 with (R) -2- (methoxycarbonylamino) -2-phenyl acetic acid (VPM4) under the action of a condensing agent to prepare an amide compound intermediate VP 4;
5) and carrying out oxidation reaction on the intermediate VP4 under the action of an oxidant to prepare Velpatasvir.
In step 1, VPM1 is selected from the group consisting of 9-bromo-3- (2-bromoacetyl) -10, 11-dihydro-5H-benzo [ D ] naphtho [2,3-B ] pyran-8 (9H) -one, 9-bromo-3- (2-chloroacetyl) -10, 11-dihydro-5H-benzo [ D ] naphtho [2,3-B ] pyran-8 (9H) -one; the selection range of VPM2 includes (2S,4S) -1- (tert-butoxycarbonyl) -4- (methoxymethyl) -pyrrolidine-2-carboxylic acid, (2S,4S) -1- (benzyloxycarbonyl) -4- (methoxymethyl) -pyrrolidine-2-carboxylic acid and (2S,4S) -1- (benzoyl) -4- (methoxymethyl) -pyrrolidine-2-carboxylic acid.
In step 1, the charging molar ratio of VPM1, VPM2 and VPM3 is as follows: 1:1.02: 1.02-1: 1.05: 1.05.
In the step 1, the selection range of the alkali reagent comprises sodium carbonate, cesium carbonate, potassium carbonate and sodium hydroxide; preferably, the alkali reagent is selected from potassium carbonate or cesium carbonate; the feeding molar ratio of the alkali reagent to the VPM1 is as follows: 2:1 to 3: 1.
In the step 2, the selection range of the deprotection reagent comprises hydrochloric acid, sulfuric acid, acetic acid, sodium methoxide, sodium ethoxide, ammonia methanol and palladium carbon/hydrogen; preferably, the amine compound is hydrochloric acid, sodium methoxide, ammonia methanol, or palladium on carbon/hydrogen.
Further, when the deprotecting reagent is other than palladium on carbon, the molar ratio of the deprotecting reagent to VP1 fed is: 1.05: 1-10.0: 1; when the deprotection reagent is palladium carbon, the mass of the palladium carbon is 10% of the mass of the substrate.
In step 3, the amine compound is selected from ammonium carbonate, ammonium formate, ammonium acetate and ammonium propionate; preferably, the amine compound is ammonium formate or ammonium acetate; the feeding molar ratio of the amine compound to the VP2 is as follows: 3.0:1 to 5.0: 1.
In step 4, the condensing agent is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), N '-Carbonyldiimidazole (CDI) or a combination of N, N' -Dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBt); the charging molar ratio of VP3, VPM4 and the condensing agent is as follows: 1.0:1.1: 1.5-1.0: 1.5: 1.8.
In step 5, the selection range of the oxidant comprises dichloro dicyano benzoquinone (DDQ) and tetrachlorobenzoquinone; the feeding molar ratio of the intermediate VP4 to the oxidant is as follows: 1.0: 1.5-1.0: 2.5.
The invention has the beneficial effects that:
1. the invention discloses a method for preparing NS5A inhibitor-wipatasvir, which comprises the steps of carrying out butt coupling on three main fragments by a one-pot method to construct a wipatasvir nuclear structure, and then carrying out deprotection, cyclization, substitution and oxidation reactions to prepare the wipatasvir and derivatives thereof, wherein the whole preparation route is greatly simplified, the reaction condition is simple, the operation is enhanced, the product yield is high, the method is more suitable for large-scale industrial production, and the enlarged application of the medicament is facilitated;
2. in the preparation route disclosed by the invention, nitrogen atoms on a tetrahydropyrrole ring are protected by amino protecting groups, so that the generation of side reactions and the production of impurities are effectively reduced, and an intermediate product is easy to treat and purify.
Detailed Description
The following examples further illustrate the present invention but are not to be construed as limiting the invention. Modifications and substitutions to methods, procedures, or conditions of the invention may be made without departing from the spirit of the invention.
Example 1:
the synthetic route is as follows:
step one, preparation of VP 1:
9-bromo-3- (2-bromoacetyl) -10, 11-dihydro-5H-benzo [ D ] naphtho [2,3-B ] pyran-8 (9H) -one (VPM1) (20g, 45mmol, 1.0eq), (2S,4S) -1- (tert-butoxycarbonyl) -4- (methoxymethyl) -pyrrolidine-2-carboxylic acid (VPM2) (11.6g, 46mmol, 1.02eq), cesium carbonate (29.3g, 90mmol, 2.0eq), and 300mL tetrahydrofuran were added to a 1000mL reaction flask at room temperature, stirred, warmed to 50-55 ℃ for reaction, and monitored by TLC for reaction. TLC showed that the starting material VPM2 remained below 2%, cooled to 30-35 deg.C, and then 100mL of VPM3 in tetrahydrofuran (13.2g, 46mmol, 1.02eq) was added dropwise. After the dripping is finished, the temperature is raised to 50-55 ℃ for reaction, and the reaction is monitored by TLC. After the reaction, the mixture was cooled to room temperature, 500mL of water and 500mL of ethyl acetate were added, the mixture was stirred, and the mixture was allowed to stand for liquid separation, the aqueous layer was extracted with ethyl acetate (200 mL. times.3), the organic phases were combined, washed with saturated brine (200 mL. times.1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, 400mL of n-heptane was added to the residue, and the mixture was slurried, filtered, and dried to obtain 31.9g of VP1 as a solid product with a yield of 86%.
Step two, preparation of VP 2:
the intermediate VP1(31.9g, 38mmol, 1.0eq) and 200mL of ethanol were added to a 500mL reaction flask, stirred to dissolve, cooled to 0-5 deg.C, and then the prepared 8mL of 5N hydrochloric acid solution (38mmol, 1.05eq) was slowly added dropwise. After the dripping is finished, the temperature is raised to 75-80 ℃ for reaction, and the reaction is monitored by TLC. After the reaction is finished, 500mL of water is added, stirring is carried out, 20% sodium hydroxide solution is dropwise added until the solution is nearly neutral, isopropyl ether (200mL multiplied by 3) is used for extraction, organic phases are combined, saturated saline solution (150mL multiplied by 1) is used for washing, anhydrous sodium sulfate is used for drying, suction filtration is carried out, filtrate is decompressed and concentrated to be dry, 300mL of ether is added into residual liquid for pulping, suction filtration is carried out, and 25.8g of solid product VP2 is obtained after drying, and the yield is 92%.
Step three, preparation of VP 3:
a500 mL reaction flask was charged with intermediate VP2(25.8g, 35mmol, 1.0eq), ammonium formate (6.7g, 105mmol, 3.0eq) and 200mL ethylene glycol methyl ether, stirred, warmed to 100 ℃ and 105 ℃ for reaction, and monitored by TLC. After the reaction is finished, cooling to 30-35 ℃, adding 150mL of water for quenching, stirring, separating an organic phase, extracting a water layer by using toluene (100mL multiplied by 3), combining the organic phases, washing by using saturated saline (150mL multiplied by 1), drying by using anhydrous sodium sulfate, performing suction filtration, concentrating a filtrate under reduced pressure until the filtrate is dry, adding 200mL of n-hexane into a residual solution for pulping, performing suction filtration, and drying to obtain 21.2g of a solid product VP3 with the yield of 87%.
Step four, preparation of VP 4:
a500 mL reaction flask was charged with intermediate VP3(21.2g, 31mmol, 1.0eq), intermediate VPM4(7.1g, 34mmol, 1.1eq) and 200mL dichloromethane, stirred to dissolve, EDCI (8.9g, 47mmol, 1.5eq) and HOBt (6.3g, 47mmol, 1.5eq) were added, the temperature was raised to 30-35 ℃ for reaction, and the reaction was monitored by TLC. After the reaction, 100mL of 10% acetic acid aqueous solution and 200mL of dichloromethane are added, stirring is carried out for 30min, layers are separated, an organic phase is taken out, the organic phase is respectively washed by saturated sodium bicarbonate aqueous solution (100mL multiplied by 1) and saturated sodium chloride aqueous solution (100mL multiplied by 1), anhydrous sodium sulfate is dried, suction filtration is carried out, and the filtrate is decompressed and concentrated to obtain a solid crude product. The crude product was recrystallized from 200mL of ethyl acetate and n-hexane (2:1) to give 23.3g of VP4 as a solid product. Yield: 86 percent.
Step five, preparing Velpatasvir:
under the protection of nitrogen, intermediate VP4(23.3g, 26mmol, 1.0eq) and 200mL of tetrahydrofuran were added to a 500mL reaction flask, stirred to dissolve, cooled to 0-5 ℃, glacial acetic acid was added, and 50mL of DDQ solution in tetrahydrofuran (8.9g, 39mmol, 1.5eq) was added dropwise. After the addition, the reaction was carried out at 0-5 ℃ and monitored by TLC. After the reaction is finished, dropwise adding 10% sodium hydroxide solution to adjust the pH to be nearly neutral, adding 150mL of water and 300mL of dichloromethane, stirring, standing and layering; the aqueous layer was extracted with dichloromethane (200 mL. times.3), the organic phases were combined, washed with saturated aqueous sodium chloride (200 mL. times.1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude solid. The crude product was recrystallized from 200mL of isopropanol and water (2:1) to give 20.7g of Velpatasvir as a solid product. Yield: 89 percent.
Example 2:
the synthetic route is as follows:
step one, preparation of VP 1:
9-bromo-3- (2-chloroacetyl) -10, 11-dihydro-5H-benzo [ D ] naphtho [2,3-B ] pyran-8 (9H) -one (VPM1) (30g, 74mmol, 1.0eq), (2S,4S) -1- (benzyloxycarbonyl) -4- (methoxymethyl) -pyrrolidine-2-carboxylic acid (VPM2) (22.9g, 78mmol, 1.05eq), potassium carbonate (30.6g, 222mmol, 3.0eq), and 400mL acetonitrile were added to a 1000mL reaction flask at room temperature, stirred, warmed to 50-55 deg.C for reaction, and monitored by TLC for reaction. TLC showed that the starting material VPM2 remained below 2%, cooled to 30-35 deg.C, and then 100mL of VPM3 in acetonitrile (22.3g, 78mmol, 1.05eq) was added dropwise. After the dripping is finished, the temperature is raised to 50-55 ℃ for reaction, and the reaction is monitored by TLC. After the reaction, the mixture is cooled to room temperature, 500mL of water and 600mL of ethyl acetate are added, stirring and standing are carried out for liquid separation, the water layer is extracted by ethyl acetate (300mL multiplied by 3), organic phases are combined, the mixture is washed by saturated saline (300mL multiplied by 1), anhydrous sodium sulfate is dried and filtered, the filtrate is concentrated to be dry under reduced pressure, 500mL of n-hexane is added into the residual liquid for pulping, filtering and drying are carried out, 51.1g of a solid product VP1 is obtained, and the yield is 88%.
Step two, preparation of VP 2:
a500 mL reaction flask was charged with intermediate VP1(51.1g, 59mmol, 1.0eq)5.1g palladium on charcoal and 300mL methanol, stirred, replaced with nitrogen, then reacted with hydrogen, warmed to 35-40 deg.C, and monitored by TLC. After the reaction is finished, cooling to room temperature, carrying out suction filtration, recovering a filter cake, sealing with water, storing, concentrating the filtrate under reduced pressure until the filtrate is dried, and drying to obtain 41g of a solid product VP2 with the yield of 95%.
Step three, preparation of VP 3:
a1000 mL reaction flask was charged with intermediate VP2(41g, 56mmol, 1.0eq), ammonium acetate (21.5g, 280mmol, 5.0eq) and 400mL ethylene glycol ethyl ether, stirred, warmed to 100 ℃ and 105 ℃ for reaction, and monitored by TLC. After the reaction is finished, cooling to 30-35 ℃, adding 300mL of water for quenching, stirring, separating an organic phase, extracting a water layer by using toluene (200mL multiplied by 3), combining the organic phases, washing by using saturated saline (200mL multiplied by 1), drying by using anhydrous sodium sulfate, performing suction filtration, concentrating a filtrate under reduced pressure to dryness, adding 500mL of n-hexane into a residual solution, pulping, performing suction filtration, and drying to obtain 33.3g of a solid product VP3 with the yield of 86%.
Step four, preparation of VP 4:
a1000 mL reaction flask was charged with intermediate VP3(33.3g, 48mmol, 1.0eq), intermediate VPM4(13g, 63mmol, 1.3eq) and 300mL dichloromethane, stirred to dissolve, and then added with CDI (13.9g, 86mmol, 1.8eq) and HOBt (11.6g, 86mmol, 1.8eq), heated to 30-35 deg.C for reaction, and monitored by TLC for reaction. After the reaction, 200mL of 10% acetic acid aqueous solution and 300mL of dichloromethane are added, stirring is carried out for 30min, layers are separated, an organic phase is taken out, the organic phase is respectively washed by saturated sodium bicarbonate aqueous solution (200mL multiplied by 1) and saturated sodium chloride aqueous solution (200mL multiplied by 1), anhydrous sodium sulfate is dried, suction filtration is carried out, and the filtrate is decompressed and concentrated to obtain a solid crude product. The crude product was recrystallized from 300mL of ethyl acetate and n-hexane (2:1) to yield 36.2g of VP4 as a solid product. Yield: 85 percent.
Step five, preparing Velpatasvir:
under the protection of nitrogen, intermediate VP4(36.2g, 40mmol, 1.0eq) and 300mL of tetrahydrofuran were added to a 1000mL reaction flask, stirred to dissolve, cooled to 0-5 ℃, glacial acetic acid was added, and 150mL of tetrachlorobenzoquinone tetrahydrofuran solution (24.6g, 100mmol, 2.5eq) was added dropwise. After the addition, the reaction was carried out at 0-5 ℃ and monitored by TLC. After the reaction is finished, dropwise adding 10% sodium hydroxide solution to adjust the pH to be nearly neutral, adding 200mL of water and 400mL of dichloromethane, stirring, standing and layering; the aqueous layer was extracted with dichloromethane (200 mL. times.3), the organic phases were combined, washed with saturated aqueous sodium chloride (300 mL. times.1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude solid. The crude product was recrystallized from 300mL of isopropanol and water (2:1) to yield 32.5g of Velpatasvir as a solid product. Yield: 90 percent.
Example 3:
the synthetic route is as follows:
step one, preparation of VP 1:
9-bromo-3- (2-bromoacetyl) -10, 11-dihydro-5H-benzo [ D ] naphtho [2,3-B ] pyran-8 (9H) -one (VPM1) (15g, 33mmol, 1.0eq), (2S,4S) -1- (benzoyl) -4- (methoxymethyl) -pyrrolidine-2-carboxylic acid (VPM2) (9.2g, 35mmol, 1.05eq), cesium carbonate (23.3g, 66mmol, 2.0eq), and 200mL tetrahydrofuran were stirred at room temperature, warmed to 50-55 deg.C for reaction, and monitored by TLC. TLC showed that the starting material VPM2 remained below 2%, cooled to 30-35 deg.C, and then 80mL of VPM3 in tetrahydrofuran (10g, 35mmol, 1.05eq) was added dropwise. After the dripping is finished, the temperature is raised to 50-55 ℃ for reaction, and the reaction is monitored by TLC. After the reaction, the mixture was cooled to room temperature, 300mL of water and 400mL of ethyl acetate were added, the mixture was stirred, and the mixture was allowed to stand for liquid separation, the aqueous layer was extracted with ethyl acetate (150 mL. times.3), the organic phases were combined, washed with saturated brine (200 mL. times.1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, 300mL of n-heptane was added to the residue, and the mixture was slurried, filtered, and dried to obtain 24.2g of VP1 as a solid product with a yield of 86%.
Step two, preparation of VP 2:
intermediate VP1(24.2g, 29mmol, 1.0eq) and 200mL of methanol were added to a 500mL reaction flask, dissolved with stirring, cooled to 0-5 deg.C, and 145mL of a 2N hydrochloric acid solution (290mmol, 10.0eq) was added slowly. After the addition, the temperature is raised to 20-25 ℃ for reaction, and the reaction is monitored by TLC. After the reaction is finished, the solvent is evaporated under reduced pressure, 200mL of methyl tert-ether is added into the residue for pulping, suction filtration and drying to obtain 19.1g of a solid product VP2 with the yield of 90%.
Step three, preparation of VP 3:
a500 mL reaction flask was charged with intermediate VP2(19.1g, 26mmol, 1.0eq), ammonium formate (6.6g, 104mmol, 4.0eq) and 200mL ethylene glycol methyl ether, stirred, warmed to 100 ℃ and 105 ℃ for reaction, and monitored by TLC. After the reaction is finished, cooling to 30-35 ℃, adding 150mL of water for quenching, stirring, separating an organic phase, extracting a water layer by using toluene (100mL multiplied by 3), combining the organic phases, washing by using saturated saline (150mL multiplied by 1), drying by using anhydrous sodium sulfate, performing suction filtration, concentrating a filtrate to be dry under reduced pressure, adding 150mL of n-heptane into a residual solution for pulping, performing suction filtration, and drying to obtain 15.3g of a solid product VP3 with the yield of 85%.
Step four, preparation of VP 4:
a500 mL reaction flask was charged with intermediate VP3(15.3g, 22mmol, 1.0eq), intermediate VPM4(6.9g, 33mmol, 1.5eq) and 200mL dichloromethane, stirred to dissolve, DCC (8.2g, 40mmol, 1.8eq) and HOBt (5.4g, 40mmol, 1.8eq) were added, the temperature was raised to 30-35 ℃ for reaction, and the reaction was monitored by TLC. After the reaction, 80mL of 10% acetic acid aqueous solution and 200mL of dichloromethane are added, stirring is carried out for 30min, layers are separated, an organic phase is taken out, the organic phase is respectively washed by saturated sodium bicarbonate aqueous solution (100mL multiplied by 1) and saturated sodium chloride aqueous solution (100mL multiplied by 1), anhydrous sodium sulfate is dried, suction filtration is carried out, and the filtrate is decompressed and concentrated to obtain a solid crude product. The crude product was recrystallized from 150mL of ethyl acetate and n-hexane (2:1) to yield 17.2g of VP4 as a solid product. Yield: 88 percent.
Step five, preparing Velpatasvir:
under the protection of nitrogen, intermediate VP4(17.2g, 19mmol, 1.0eq) and 200mL of tetrahydrofuran were added to a 500mL reaction flask, stirred to dissolve, cooled to 0-5 deg.C, glacial acetic acid was added, and 50mL of DDQ solution in tetrahydrofuran (8.6g, 38mmol, 2.0eq) was added dropwise. After the addition, the reaction was carried out at 0-5 ℃ and monitored by TLC. After the reaction is finished, dropwise adding 10% sodium hydroxide solution to adjust the pH to be nearly neutral, adding 100mL of water and 300mL of dichloromethane, stirring, standing and layering; the aqueous layer was extracted with dichloromethane (150 mL. times.3), the organic phases were combined, washed with saturated aqueous sodium chloride (150 mL. times.1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude solid. The crude product was recrystallized from 150mL of isopropanol and water (2:1) to give 15.1g of Velpatasvir as a solid product. Yield: 88 percent.
The foregoing illustrates and describes the principles, general features, and advantages of the present invention. However, the above description is only an example of the present invention, the technical features of the present invention are not limited thereto, and any other embodiments that can be obtained by those skilled in the art without departing from the technical solution of the present invention should be covered by the claims of the present invention.
Claims (9)
1. The method for preparing NS5A inhibitor-wipatasvir is characterized in that the specific synthetic route is as follows:
wherein X ═ Cl or Br;
r is tert-butyloxycarbonyl, benzyloxycarbonyl or benzoyl;
the specific synthesis steps are as follows:
1) preparation of intermediate VP 1: carrying out butt-joint reaction on reaction starting raw materials VPM1, VPM2 and VPM3 under the catalytic action of an alkali reagent to prepare an intermediate VP 1;
2) preparation of intermediate VP 2: removing amino protecting groups from the intermediate VP1 by a deprotection reagent to obtain an intermediate VP 2;
3) preparation of intermediate VP 3: intermediate VP2 and amine compound are cyclized to prepare intermediate VP 3;
4) preparation of intermediate VP 4: the intermediate VP3 reacts with (R) -2- (methoxycarbonylamino) -2-phenylacetic acid under the action of a condensing agent to prepare an amide compound intermediate VP 4;
5) and carrying out oxidation reaction on the intermediate VP4 under the action of an oxidant to prepare Velpatasvir.
2. The process of claim 1 for the preparation of NS5A inhibitor vipatavir, wherein in step 1, VPM1 is selected from the group consisting of 9-bromo-3- (2-bromoacetyl) -10, 11-dihydro-5H-benzo [ D ] naphtho [2,3-B ] pyran-8 (9H) -one, 9-bromo-3- (2-chloroacetyl) -10, 11-dihydro-5H-benzo [ D ] naphtho [2,3-B ] pyran-8 (9H) -one; VPM2 was selected from (2S,4S) -1- (tert-butoxycarbonyl) -4- (methoxymethyl) -pyrrolidine-2-carboxylic acid, (2S,4S) -1- (benzyloxycarbonyl) -4- (methoxymethyl) -pyrrolidine-2-carboxylic acid and (2S,4S) -1- (benzoyl) -4- (methoxymethyl) -pyrrolidine-2-carboxylic acid.
3. The method for preparing NS5A inhibitor wipatasvir as claimed in claim 1, wherein VPM1, VPM2 and VPM3 are fed in a molar ratio of: 1:1.02: 1.02-1: 1.05: 1.05.
4. The process of claim 1 wherein in step 1, the alkaline agent is selected from the group consisting of sodium carbonate, cesium carbonate, potassium carbonate, sodium hydroxide; the feeding molar ratio of the alkali reagent to the VPM1 is as follows: 2:1 to 3: 1.
5. The method of claim 1, wherein in step 2, the deprotecting reagent is selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid, sodium methoxide, sodium ethoxide, ammonia methanol, and palladium on charcoal/hydrogen.
6. The method for preparing NS5A inhibitor wipatasvir according to claim 5, wherein when the deprotecting reagent is other than palladium on carbon/hydrogen, the molar ratio of deprotecting reagent to VP1 is: 1.05: 1-10.0: 1; when the deprotection reagent is palladium carbon/hydrogen, the mass of the palladium carbon is 10 percent of that of the substrate.
7. The method of claim 1, wherein in step 3, the amine compound is selected from the group consisting of ammonium carbonate, ammonium formate, ammonium acetate, ammonium propionate; the feeding molar ratio of the amine compound to the VP2 is as follows: 3.0:1 to 5.0: 1.
8. The process of claim 1, wherein in step 4, the condensing agent is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N '-carbonyldiimidazole or a combination of N, N' -dicyclohexylcarbodiimide and 1-hydroxybenzotriazole; the charging molar ratio of VP3, VPM4 and the condensing agent is as follows: 1.0:1.1: 1.5-1.0: 1.5: 1.8.
9. The process of claim 1 wherein in step 5, the oxidizing agent is selected from the group consisting of dichlorodicyanoquinone, tetrachlorobenzoquinone; the feeding molar ratio of the intermediate VP4 to the oxidant is as follows: 1.0: 1.5-1.0: 2.5.
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