CN107759577B - GS5816 intermediate, preparation method and application - Google Patents
GS5816 intermediate, preparation method and application Download PDFInfo
- Publication number
- CN107759577B CN107759577B CN201710919030.6A CN201710919030A CN107759577B CN 107759577 B CN107759577 B CN 107759577B CN 201710919030 A CN201710919030 A CN 201710919030A CN 107759577 B CN107759577 B CN 107759577B
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- gas
- reaction
- solvent
- 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 170
- 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 title abstract description 16
- 229960000863 velpatasvir Drugs 0.000 title abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 81
- 150000001875 compounds Chemical class 0.000 claims abstract description 79
- 238000006243 chemical reaction Methods 0.000 claims abstract description 76
- 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 claims abstract description 52
- 229940125797 compound 12 Drugs 0.000 claims abstract description 52
- 238000006482 condensation reaction Methods 0.000 claims abstract description 42
- 239000003960 organic solvent Substances 0.000 claims abstract description 40
- 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 claims abstract description 38
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims description 105
- 239000007789 gas Substances 0.000 claims description 58
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 54
- 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 claims description 29
- 229940126543 compound 14 Drugs 0.000 claims description 29
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 19
- 125000006239 protecting group Chemical group 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 17
- 238000004519 manufacturing process Methods 0.000 claims description 17
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 230000001681 protective effect Effects 0.000 claims description 16
- 150000001408 amides Chemical group 0.000 claims description 13
- NJTZSWLQBQJUHK-UHFFFAOYSA-N CCCP(=O)=O Chemical group CCCP(=O)=O NJTZSWLQBQJUHK-UHFFFAOYSA-N 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 239000003513 alkali Substances 0.000 claims description 10
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 9
- 229940125846 compound 25 Drugs 0.000 claims description 9
- 229910052786 argon Inorganic materials 0.000 claims description 8
- 230000009615 deamination Effects 0.000 claims description 8
- 238000006481 deamination reaction Methods 0.000 claims description 8
- 150000007529 inorganic bases Chemical class 0.000 claims description 8
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 7
- 229940011051 isopropyl acetate Drugs 0.000 claims description 7
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical group CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 7
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 6
- 150000007522 mineralic acids Chemical class 0.000 claims description 6
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 claims description 5
- 229940125961 compound 24 Drugs 0.000 claims description 5
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical group CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 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
- 238000009776 industrial production Methods 0.000 abstract description 5
- 239000008186 active pharmaceutical agent Substances 0.000 abstract description 3
- 239000012535 impurity Substances 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- 238000004440 column chromatography Methods 0.000 abstract description 2
- 230000003287 optical effect Effects 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- 238000000926 separation method Methods 0.000 abstract description 2
- 229940088679 drug related substance Drugs 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- 238000005406 washing Methods 0.000 description 39
- 229940125898 compound 5 Drugs 0.000 description 33
- 238000001914 filtration Methods 0.000 description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
- 238000004128 high performance liquid chromatography Methods 0.000 description 29
- 238000003756 stirring Methods 0.000 description 28
- 239000000243 solution Substances 0.000 description 27
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 21
- 229940126142 compound 16 Drugs 0.000 description 21
- 229940126214 compound 3 Drugs 0.000 description 21
- -1 1-ethyl- (3-dimethylaminopropyl) carbonyl Chemical group 0.000 description 20
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 19
- 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 19
- 229940126657 Compound 17 Drugs 0.000 description 19
- 229940125758 compound 15 Drugs 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 238000001035 drying Methods 0.000 description 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- 239000003153 chemical reaction reagent Substances 0.000 description 14
- 238000007796 conventional method Methods 0.000 description 14
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical group CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 13
- USXXIRQDHZXYHX-UHFFFAOYSA-N 2,3,4-tribromopyridine Chemical compound BrC1=CC=NC(Br)=C1Br USXXIRQDHZXYHX-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 150000003863 ammonium salts Chemical class 0.000 description 12
- 150000008280 chlorinated hydrocarbons Chemical group 0.000 description 12
- 150000008282 halocarbons Chemical group 0.000 description 12
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical group O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 238000006467 substitution reaction Methods 0.000 description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 11
- 238000001816 cooling Methods 0.000 description 11
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical group CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
- 239000003814 drug Substances 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
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 235000011114 ammonium hydroxide Nutrition 0.000 description 8
- 238000001514 detection method Methods 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 230000002140 halogenating effect Effects 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 7
- 238000012544 monitoring process Methods 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 6
- 239000005695 Ammonium acetate Substances 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229940043376 ammonium acetate Drugs 0.000 description 6
- 235000019257 ammonium acetate Nutrition 0.000 description 6
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 238000002386 leaching Methods 0.000 description 6
- 150000007530 organic bases Chemical class 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 238000004821 distillation Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical group CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- 208000005176 Hepatitis C Diseases 0.000 description 4
- 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
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 150000002825 nitriles Chemical class 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 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 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000001099 ammonium carbonate Substances 0.000 description 3
- 235000012501 ammonium carbonate Nutrition 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 3
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 3
- 235000011130 ammonium sulphate Nutrition 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000008034 disappearance Effects 0.000 description 3
- 150000008040 ionic compounds Chemical group 0.000 description 3
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000007864 suspending Methods 0.000 description 3
- 125000003944 tolyl group Chemical group 0.000 description 3
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 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
- VMHZXXPDUOVTHD-UHFFFAOYSA-N 2,3,4-trichloropyridine Chemical compound ClC1=CC=NC(Cl)=C1Cl VMHZXXPDUOVTHD-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
- 239000007821 HATU Substances 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 239000012359 Methanesulfonyl chloride 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
- 150000001335 aliphatic alkanes Chemical class 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
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 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
- 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
- 150000002500 ions Chemical class 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 239000003495 polar organic solvent Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 2
- GRGCWBWNLSTIEN-UHFFFAOYSA-N trifluoromethanesulfonyl chloride Chemical compound FC(F)(F)S(Cl)(=O)=O GRGCWBWNLSTIEN-UHFFFAOYSA-N 0.000 description 2
- 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
- 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
- 229910001870 ammonium persulfate Inorganic materials 0.000 description 1
- 229940124404 anti-hepatitis c virus drug Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid 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
- 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
- 208000015181 infectious disease Diseases 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
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 150000005837 radical ions Chemical class 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
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 238000001291 vacuum drying Methods 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
- 238000010626 work up procedure 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a GS5816 intermediate, a preparation method and application. The present invention provides a process for the preparation of compound 12 comprising the steps of: compound 12 is obtained by condensation reaction of compound 13 with compound 9 in the presence of a condensing agent in an organic solvent. The preparation method disclosed by the invention is mild in reaction conditions, simple and safe in operation, free of special purification equipment, free of column chromatography separation operation in a post-treatment process, and easy in control of chiral isomers, the yield of the preparation of the vipatavir by taking the compound 12 disclosed by the invention as an intermediate is high, the chemical and optical purity of the prepared vipatavir is more than 99.50%, all impurities are less than 0.10%, the drug substance standard can be achieved, the cost is low, and the preparation method is suitable for industrial production.
Description
Technical Field
The invention relates to a GS5816 intermediate, a preparation method and application thereof.
Background
Another anti-hepatitis C virus drug Epclusa (Sofosbuvir 400mg + Velpatasvir 100mg) was approved by Gilidd scientific at 2016 (6 months) and the first anti-hepatitis C drug was used to treat the major genotype 1-6. Is known as the third generation anti-hepatitis C heavy explosive after searching for non-Buwei and Harvoni.
The 2016 10-month Jilide science company announced 4 global clinical research results in that the three-in-one tablet of sofosbuvir, vipatavir (Velpatasvir) and Voxilaprevir has obvious curative effect on the patients with gene 1-6 type HCV infection. The novel compound drug for resisting hepatitis C, which takes Velpatasvir as a compound drug, is approved by FDA to be on the market in 7 months in 2017, has drug names Vosevi and Vosevi, can quickly become a star drug in the field of resisting hepatitis C, and has wide market prospect.
US20150361073 of gillidd science discloses a preparation method of vipatavir (Velpatasvir or GS5816), which has weak fluorescence of raw materials, and is difficult to control chirality in a synthesis process, so that an intermediate with high chiral purity is difficult to obtain, and further, API preparation cost is high and difficulty is high.
Therefore, the problem to be solved at present is to find a preparation method of Velpatasvir (Velpatasvir or GS5816) which is convenient for controlling chiral isomers in the reaction process, high in chiral purity and chemical purity of the prepared product, high in total yield, simple and convenient to operate, low in production cost and suitable for industrial production, and meets the standards of raw material medicines.
Disclosure of Invention
The invention aims to overcome the defects that in the prior art, in the preparation method of Velpatasvir (Velpatasvir or GS5816), chiral isomers are difficult to control in the reaction process, the obtained product has poor chiral purity, low total yield and high production cost, cannot meet the raw material medicine standard, and is not suitable for industrial production, and the like, and provides a GS5816 intermediate, a preparation method and application. The preparation method disclosed by the invention is mild in reaction conditions, short in steps, high in yield, high in purity of the prepared product, low in production cost and suitable for industrial production, and can reach the standard of raw material medicines (API).
The present invention provides a process for the preparation of compound 12, comprising the steps of: in an organic solvent, in the presence of a condensing agent, carrying out condensation reaction on a compound 13 and a compound 9 to obtain a compound 12;
the preparation method of the compound 12 can be a conventional method of the condensation reaction in the field, and the following reaction method and conditions are particularly preferred in the invention:
in the preparation method of the compound 12, the organic solvent is preferably an amide solvent; the amide solvent is preferably N, N-Dimethylformamide (DMF).
In the method for preparing the compound 12, the condensing agent is preferably 1-ethyl- (3-dimethylaminopropyl) carbonyl diimine hydrochloride (EDCI), 2- (7-azobenzotriazol) -N, N, N ', N ' -tetramethyluronium Hexafluorophosphate (HATU), benzotriazol-N, N, N ', N ' -tetramethyluronium Hexafluorophosphate (HBTU), O-benzotriazol-N, N, N ', N ' -tetramethyluronium tetrafluoroborate (TBTU), benzotriazol-1-tris (trimethylamino) -trifluorophosphate (BOP), chlorotriazolylphosphonium hexafluorophosphate (PyClOP), benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate (PyBOP), N, N ' -Dicyclohexylcarbodiimide (DCC), (2-oximino-cyanoethyl acetate) -N, N-dimethyl-morpholinylurea hexafluorophosphate (COMU), ethyl 2-oximinocyanoacetate (Oxyma) and propylphosphoric anhydride (T)3P) is selected. Said propyl phosphoric anhydride (T)3P) may be conventional commercially available propyl phosphoric anhydride (T)3P) reagent, e.g. propylphosphoric anhydride (T) at 50% by mass3P) N, N-Dimethylformamide (DMF) solution, wherein the mass concentration refers to the mass percentage of the propyl phosphoric anhydride to the total mass of the propyl phosphoric anhydride N, N-dimethylformamide solution.
In the method for preparing the compound 12, the molar ratio of the condensing agent to the compound 13 is preferably 1 to 3, more preferably 1 to 1.5, for example, 1.1.
In the preparation method of the compound 12, the molar ratio of the compound 9 to the compound 13 is preferably 1 to 3, more preferably 1 to 1.5, for example 1.1.
In the method for producing compound 12, the condensation reaction temperature is preferably 0 to 40 ℃, more preferably 10 to 30 ℃, for example, 20 to 25 ℃.
In the method for preparing the compound 12, the progress of the condensation reaction can be monitored by a detection method (for example, HPLC, TLC or NMR) which is conventional in the art, and generally the time when the compound 13 disappears is used as the end point of the reaction, and the time of the condensation reaction is preferably 1 hour to 10 hours, more preferably 2 hours to 8 hours, for example 5 hours to 6 hours.
The preparation method of the compound 12 preferably adopts the following steps: and (3) dripping a mixture of the compound 13 and an organic solvent into a mixture of the compound 9, a condensing agent and the organic solvent at 0-10 ℃ to perform condensation reaction to obtain the compound 12.
The preparation method of the compound 12 preferably adopts the following post-treatment steps: after the reaction is finished, cooling, dripping water, stirring, filtering and washing to obtain the compound 12. The temperature reduction is preferably carried out to 5-10 ℃. The stirring time is preferably 2 to 3 hours.
The preparation method of the compound 12 preferably further comprises a preparation method of a compound 13, which comprises the following steps: in an organic solvent, carrying out a deamination protecting group reaction on the compound 14 and acid to prepare the compound 13;
wherein, the P is an amino protecting group, preferably tert-butyloxycarbonyl, benzyloxycarbonyl or P-toluenesulfonyl.
The preparation method of the compound 13 can be a conventional method of the reaction for removing the amino protecting group in the field, and the following reaction method and conditions are particularly preferred in the invention:
in the preparation method of the compound 13, the organic solvent is preferably an ester solvent; the ester solvent is preferably isopropyl acetate.
In the preparation method of the compound 13, the acid is preferably an inorganic acid; the inorganic acid is preferably hydrogen chloride. The hydrogen chloride may be used in gaseous form or as a solution thereof, preferably as a solution of hydrogen chloride in isopropyl acetate.
In the preparation method of the compound 13, the molar ratio of the acid to the compound 14 is preferably 1 to 10, more preferably 4 to 6, for example 5.
In the method for producing compound 13, the reaction temperature for removing the amino protecting group is preferably 40 to 100 ℃, more preferably 50 to 70 ℃, for example, 60 to 65 ℃.
In the preparation method of compound 13, the progress of the amino protecting group removing reaction can be monitored by a conventional detection method in the art (e.g., HPLC, TLC or NMR), and generally, the end point of the reaction is the time when compound 14 disappears, and the time of the amino protecting group removing reaction is preferably 1 hour to 10 hours, more preferably 2 hours to 8 hours, for example 2 hours to 6 hours.
The method of preparing compound 12 preferably further comprises a method of preparing compound 14, comprising the steps of: under the protection of protective gas, in an organic solvent and in the presence of alkali, carrying out condensation reaction on a compound 25 and a compound 24 to obtain the compound 14;
p is as defined above.
The preparation method of the compound 14 can be a conventional method of the condensation reaction in the field, and the following reaction method and conditions are particularly preferred in the invention:
in the preparation method of the compound 14, the protective gas is preferably nitrogen and/or argon.
In the preparation method of the compound 14, the organic solvent is preferably an amide solvent; the amide solvent is preferably N, N-Dimethylformamide (DMF).
In the preparation method of the compound 14, the base is preferably an inorganic base; the inorganic base is preferably potassium carbonate.
In the preparation method of the compound 14, the molar ratio of the base to the compound 25 is preferably 1 to 3, more preferably 1.00 to 1.50, for example, 1.05.
In the preparation method of the compound 14, the molar ratio of the compound 24 to the compound 25 is preferably 1 to 3, more preferably 1.00 to 1.50, for example, 1.05.
In the method for producing compound 14, the condensation reaction temperature is preferably 10 to 50 ℃, and more preferably 20 to 40 ℃.
In the preparation method of the compound 14, the progress of the condensation reaction can be monitored by a detection method (for example, HPLC, TLC or NMR) which is conventional in the art, and is generally the end point of the reaction when the compound 25 disappears, and the time of the condensation reaction is preferably 1 hour to 5 hours, more preferably 2 hours to 4 hours, for example 3 hours.
The present invention also provides a process for the preparation of compound 8, comprising the steps of: after the compound 12 is prepared according to the preparation method, the compound 12 and a halogenating reagent are subjected to substitution reaction in an organic solvent to obtain the compound 8;
wherein L represents a leaving group, e.g., p-toluenesulfonyl (Tos), methanesulfonyl (-OMs), trifluoromethanesulfonyl (-OSO)2CF3) Br, Cl or I; the halogenating reagent is p-toluenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, tribromopyridine, trichloropyridine or triiodopyridine.
The preparation method of the compound 8 can be a conventional method of the substitution reaction in the field, and the following reaction conditions are particularly preferred in the invention:
in the preparation method of the compound 8, the organic solvent is preferably a halogenated hydrocarbon solvent; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane.
In the preparation method of the compound 8, the molar ratio of the halogenating agent to the compound 12 is preferably 1 to 3, more preferably 1.1 to 1.5, for example 1.1.
In the preparation method of the compound 8, when tribromopyridine is used as a halogenating reagent, the tribromopyridine can be a commercially available tribromopyridine reagent conventional in the art, such as a methanol solution of tribromopyridine.
In the method 2 for producing the compound 8, the temperature of the substitution reaction is preferably 0 to 40 ℃, and more preferably 10 to 15 ℃.
In the preparation method of the compound 8, the progress of the substitution reaction can be monitored by a detection method (such as HPLC, TLC or NMR) which is conventional in the art, and generally the disappearance of the compound 12 is taken as a reaction end point, and the time of the substitution reaction is preferably 1 hour to 10 hours, more preferably 2 hours to 5 hours, for example 3 hours.
The preparation method of the compound 8 preferably adopts the following steps: and (3) dropwise adding a halogenated reagent into a mixed solution formed by the compound 12 and an organic solvent at 0-5 ℃ to perform substitution reaction to obtain the compound 8.
The preparation method of the compound 8 preferably adopts the following post-treatment steps: after the reaction is finished, filtering, washing and drying to obtain the compound 8. The filtration, washing and drying can be carried out by methods conventional in the art for such procedures. The washing is preferably performed by using an alcohol solvent, and the alcohol solvent is preferably methanol.
The invention also provides a preparation method of the compound 6, which comprises the following steps: after the compound 8 is prepared according to the preparation method, the compound 8 and the compound 7 are subjected to nucleophilic substitution reaction in an organic solvent in the presence of alkali under the protection of protective gas to obtain the compound 6;
wherein, the definition of P is the same as that of the previous description; l represents a leaving group, e.g., p-toluenesulfonyl (Tos), methanesulfonyl (-OM)s), trifluoromethanesulfonyl (-OSO)2CF3) Br, Cl or I.
The preparation method of the compound 6 can be a conventional method of nucleophilic substitution reaction in the field, and the following reaction method and conditions are particularly preferred in the invention:
in the preparation method of the compound 6, the protective gas is preferably nitrogen and/or argon.
In the preparation method of the compound 6, the organic solvent is preferably one or more of an amide solvent, a nitrile solvent, an ether solvent and a halogenated hydrocarbon solvent. The amide solvent is preferably N, N-Dimethylformamide (DMF). The nitrile solvent is preferably acetonitrile. The ether solvent is preferably tetrahydrofuran. The halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane.
In the preparation method of the compound 6, the base can be an inorganic base or an organic base; the inorganic base is preferably potassium carbonate and/or sodium carbonate. The organic base is preferably triethylamine and/or N, N-diisopropylethylamine.
In the method for preparing the compound 6, the molar ratio of the base to the compound 8 is preferably 1 to 3, more preferably 1.00 to 1.20, for example, 1.05.
In the preparation method of the compound 6, the molar ratio of the compound 7 to the compound 8 is preferably 1 to 3, more preferably 1.00 to 1.20, for example, 1.05.
In the method for producing the compound 6, the temperature of the nucleophilic substitution reaction is preferably 10 to 50 ℃, more preferably 15 to 45 ℃, for example, 20 to 40 ℃.
In the preparation method of the compound 6, the progress of the nucleophilic substitution reaction can be monitored by a conventional monitoring method in the art (e.g., TLC, HPLC, or NMR), and generally the end point of the reaction is the time when the compound 8 disappears, and the time of the nucleophilic substitution reaction is preferably 5 hours to 24 hours, more preferably 10 hours to 20 hours, for example 16 hours.
The preparation method of the compound 6 can adopt the following post-treatment steps: and after the reaction is finished, cooling, adding water, stirring, filtering, washing and drying to obtain the purified compound 6. The temperature is preferably reduced to 5-10 ℃. The stirring time may be 2 to 3 hours. The washing and drying may be carried out by methods conventional in the art for such procedures. The washing may be with water. The drying may be vacuum drying.
The present invention also provides a process for the preparation of compound 17, comprising the steps of: after the compound 12 is prepared according to the preparation method, the compound 12 and ammonium salt are subjected to condensation reaction in an organic solvent under the protection of protective gas to prepare the compound 17;
the preparation method of the compound 17 can be a conventional method of the condensation reaction in the field, and the following reaction method and conditions are particularly preferred in the invention:
in the preparation method of the compound 17, the protective gas is preferably nitrogen and/or argon.
In the preparation method of the compound 17, the organic solvent is preferably an aromatic hydrocarbon solvent; the aromatic hydrocarbon solvent is preferably toluene.
In the preparation method of the compound 17, the ammonium salt is an ionic compound formed by an ammonium ion and an acid radical ion generated by the reaction of ammonia and acid. The ammonium salt is preferably one or more of ammonium acetate, ammonium chloride, ammonium nitrate, ammonium carbonate and ammonium sulfate.
In the preparation method of the compound 17, the molar ratio of the ammonium salt to the compound 12 is preferably 1 to 40, more preferably 15 to 25, for example 20.
In the method for producing the compound 17, the condensation reaction is preferably carried out at a temperature of 50 to 120 ℃ such as 80 to 100 ℃.
In the preparation method of compound 17, the progress of the condensation reaction can be monitored by a conventional detection method in the art (e.g., TLC, HPLC, or NMR), and is generally the end point of the reaction when compound 12 and the intermediate state disappear, and the time of the condensation reaction is preferably 5 hours to 24 hours, more preferably 15 hours to 22 hours, e.g., 20 hours.
The preparation method of the compound 17 can adopt the following post-treatment steps: after the reaction is finished, adding an alcohol solvent, washing and removing the solvent to obtain the purified compound 17. The alcohol solvent is preferably n-butanol. The washing and removal of the solvent may be carried out by methods conventional in the art for such procedures. The washing is preferably carried out with water and/or a saturated aqueous sodium chloride solution. The solvent removal is preferably carried out by distillation under reduced pressure.
The present invention also provides a process for the preparation of compound 16, comprising the steps of: after the compound 17 is prepared according to the preparation method, the compound 17 and a halogenating reagent are subjected to substitution reaction in an organic solvent to prepare the compound 16;
wherein L is as defined above; the halogenating reagent is p-toluenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, tribromopyridine, trichloropyridine or triiodopyridine.
The preparation method of the compound 16 can be a conventional method of the substitution reaction in the field, and the following reaction conditions are particularly preferred in the invention:
in the preparation method of the compound 16, the organic solvent is preferably a halogenated hydrocarbon solvent; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane.
In the method for preparing the compound 16, the molar ratio of the halogenating agent to the compound 17 is preferably 1 to 3, more preferably 1.1 to 1.5, for example 1.1.
In the preparation method of the compound 16, when tribromopyridine is used as a halogenating reagent, the tribromopyridine can be a commercially available tribromopyridine reagent conventional in the art, such as a methanol solution of tribromopyridine.
In the method for producing compound 16, the temperature of the substitution reaction is preferably 0 to 40 ℃, and more preferably 10 to 15 ℃.
In the preparation method of compound 16, the progress of the substitution reaction can be monitored by a detection method (such as HPLC, TLC or NMR) which is conventional in the art, and generally the disappearance of compound 17 is taken as a reaction end point, and the time of the substitution reaction is preferably 1 hour to 10 hours, more preferably 2 hours to 5 hours, for example 3 hours.
The preparation method of the compound 16 preferably adopts the following steps: and (3) dropwise adding a halogenated reagent into a mixed solution formed by the compound 17 and an organic solvent at 0-5 ℃ to perform substitution reaction to obtain the compound 16.
In the preparation method of the compound 16, the following post-treatment steps are preferably adopted: after the reaction is finished, the compound 16 is obtained by filtering, washing and drying. The filtration, washing and drying can be carried out by methods conventional in the art for such procedures. The washing is preferably performed by using an alcohol solvent, and the alcohol solvent is preferably methanol.
The present invention also provides a process for the preparation of compound 15, comprising the steps of: after the compound 16 is prepared according to the preparation method, the compound 16 and the compound 7 are subjected to nucleophilic substitution reaction in an organic solvent in the presence of alkali under the protection of protective gas to prepare the compound 15;
wherein, the definition of P is the same as that of the previous description; l represents a leaving group, e.g., p-toluenesulfonyl (Tos), methanesulfonyl (-OMs), trifluoromethanesulfonyl (-OSO)2CF3) Br, Cl or I.
The preparation method of the compound 15 can be a conventional method of nucleophilic substitution reaction in the field, and the following reaction conditions are particularly preferred in the invention:
in the preparation method of the compound 15, the protective gas is preferably nitrogen and/or argon.
In the preparation method of the compound 15, the organic solvent is preferably an amide solvent, and the amide solvent is preferably N, N-Dimethylformamide (DMF).
In the preparation method of the compound 15, the base is preferably an inorganic base, and the inorganic base is preferably potassium carbonate.
In the method for preparing the compound 15, the molar ratio of the base to the compound 16 is preferably 1.00 to 3.00, more preferably 1.00 to 1.50, for example, 1.05.
In the preparation method of the compound 15, the molar ratio of the compound 7 to the compound 16 is preferably 1.00 to 3.00, more preferably 1.00 to 1.50, for example, 1.05.
In the method for producing the compound 15, the temperature of the nucleophilic substitution reaction is preferably 10 to 60 ℃, and more preferably 20 to 40 ℃.
In the preparation method of the compound 15, the progress of the nucleophilic substitution reaction can be monitored by a conventional monitoring method in the art (such as HPLC, TLC or NMR), and generally the disappearance of the compound 16 is taken as a reaction end point, and the time of the nucleophilic substitution reaction is preferably 10 hours to 30 hours, more preferably 12 hours to 20 hours, such as 16 hours.
In the process for the preparation of compound 15, the following work-up steps are preferably employed: after the reaction is finished, cooling, adding water, stirring, filtering and drying to obtain the compound 15. The temperature reduction is preferably to a temperature of-5 ℃ to 10 ℃, for example 5 ℃ to 10 ℃. The water is preferably added dropwise, and the dropwise adding speed is based on the system temperature not exceeding 10 ℃. The stirring, filtration and drying can be carried out by methods conventional in the art for such procedures.
The invention also provides a process for the preparation of compound 5, which is process a or process B;
method a which comprises the steps of: after the compound 6 is prepared according to the preparation method, the compound 6 and ammonium salt are subjected to condensation reaction in an organic solvent under the protection of protective gas to obtain a compound 5;
p is as defined above;
the method B comprises the following steps: after the compound 15 is prepared according to the preparation method, the compound 15 and ammonium salt are subjected to condensation reaction in an organic solvent under the protection of protective gas to obtain the compound 5;
p is as defined above.
The preparation method A of the compound 5 can be a conventional method of the condensation reaction in the field, and the following reaction method and conditions are particularly preferred in the invention:
in the preparation method A of the compound 5, the protective gas is preferably nitrogen and/or argon.
In the preparation method A of the compound 5, the organic solvent is preferably an aromatic hydrocarbon solvent; the aromatic hydrocarbon solvent is preferably toluene.
In the method a for producing the compound 5, the ammonium salt is an ionic compound formed of an ammonium ion and an acid ion generated by reacting ammonia with an acid. The ammonium salt is preferably one or more of ammonium acetate, ammonium chloride, ammonium nitrate, ammonium carbonate and ammonium sulfate.
In the method a for preparing the compound 5, the molar ratio of the ammonium salt to the compound 6 is preferably 1 to 40, more preferably 15 to 25, for example 20.
In the method a for producing the compound 5, the condensation reaction temperature is preferably 50 to 120 ℃, more preferably 60 to 110 ℃, for example 80 to 100 ℃.
In the method a for producing the compound 5, the progress of the condensation reaction can be monitored by a monitoring method (e.g., TLC, HPLC, or NMR) which is conventional in the art, and the progress of the condensation reaction is generally at the end of the reaction when the compound 6 and the intermediate state disappear, and the time of the condensation reaction is preferably 5 hours to 24 hours, more preferably 15 hours to 22 hours, e.g., 20 hours.
The preparation method A of the compound 5 preferably adopts the following post-treatment steps: and after the reaction is finished, adding an alcohol solvent, washing and removing the solvent to obtain the purified compound 5. The alcohol solvent can be n-butanol. The washing and removal of the solvent may be carried out by methods conventional in the art for such procedures. The washing is preferably carried out with water and/or a saturated aqueous sodium chloride solution. The solvent removal is preferably carried out by distillation under reduced pressure.
The preparation method B of the compound 5 can be a conventional method of the condensation reaction in the field, and the following reaction method and conditions are particularly preferred in the invention:
in the preparation method B of the compound 5, the protective gas is preferably nitrogen and/or argon.
In the preparation method B of the compound 5, the organic solvent is preferably an aromatic hydrocarbon solvent; the aromatic hydrocarbon solvent is preferably toluene.
In the method B for producing the compound 5, the ammonium salt is an ionic compound formed of an ammonium ion and an acid ion generated by reacting ammonia with an acid. The ammonium salt is preferably one or more of ammonium acetate, ammonium chloride, ammonium nitrate, ammonium carbonate and ammonium sulfate.
In the preparation method B of the compound 5, the molar ratio of the ammonium salt to the compound 15 is preferably 1 to 40, more preferably 15 to 25, for example 20.
In the method B for producing the compound 5, the condensation reaction temperature is preferably 50 to 120 ℃, more preferably 60 to 110 ℃, for example 80 to 100 ℃.
In the method B for producing the compound 5, the progress of the condensation reaction can be monitored by a conventional monitoring method in the art (for example, TLC, HPLC, or NMR), and is generally the end point of the reaction when the compound 15 and the intermediate state disappear, and the time of the condensation reaction is preferably 5 hours to 24 hours, more preferably 15 hours to 22 hours, for example 20 hours.
The preparation method B of the compound 5 can adopt the following post-treatment steps: and after the reaction is finished, adding an alcohol solvent, washing and removing the solvent to obtain the purified compound 5. The alcohol solvent is preferably n-butanol. The washing and removal of the solvent may be carried out by methods conventional in the art for such procedures. The washing is preferably carried out with water and/or a saturated aqueous sodium chloride solution. The solvent removal is preferably carried out by distillation under reduced pressure.
The invention also provides a preparation method of the compound 4, which comprises the following steps: after the compound 5 is prepared according to the preparation method, the compound 5 and an oxidant are subjected to oxidation reaction in an organic solvent under the protection of protective gas to obtain a compound 4;
p is as defined above.
The preparation method of the compound 4 can be a conventional method of the oxidation reaction in the field, and the following reaction method and conditions are particularly preferred in the invention:
in the preparation method of the compound 4, the protective gas is preferably nitrogen and/or argon.
In the preparation method of the compound 4, the organic solvent is preferably a halogenated hydrocarbon solvent; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane.
In the method for preparing the compound 4, the oxidizing agent is preferably manganese dioxide, dichlorodicyanoquinone (DDQ), chloranil, N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS) andPd/Al2O3/O2one or more of (a). The manganese dioxide is preferably active manganese dioxide which is currently used. The preparation method of the manganese dioxide can adopt a conventional preparation method in the field.
In the preparation method of the compound 4, the molar ratio of the oxidant to the compound 5 is preferably 1 to 20, more preferably 5 to 15, for example 10.
In the method for producing the compound 4, the temperature of the oxidation reaction is preferably 0 to 40 ℃, more preferably 1 to 20 ℃, for example, 5 to 10 ℃.
In the preparation method of the compound 4, the progress of the oxidation reaction can be monitored by a detection method (such as TLC, HPLC or NMR) which is conventional in the art, and generally the time when the compound 5 disappears is taken as the end point of the reaction, and the time of the oxidation reaction is preferably 5 hours to 24 hours, such as 10 hours to 15 hours.
The preparation method of the compound 4 preferably adopts the following post-treatment steps: after the reaction is finished, adding diatomite into the reaction solution, stirring, filtering, removing the solvent, then adding the ether solvent and the inorganic alkaline water solution, refluxing, filtering, removing part of the solvent, adding seed crystals, and crystallizing to obtain the compound 4. The stirring, filtration and removal of the solvent can be carried out by methods conventional in the art for such procedures. The ether solvent may be methyl t-butyl ether. The inorganic base is preferably sodium hydroxide or potassium hydroxide. The mass concentration of the aqueous inorganic alkali solution is preferably 5% to 40%, more preferably 5% to 15%, for example 10%, and the mass concentration is a percentage of the mass of the inorganic alkali to the total mass of the aqueous inorganic alkali solution. The term "removing part of the solvent" means that the ratio of the volume of the removed solvent to the total volume of the solvent in the filtrate is 0.2-0.7. The temperature of the crystallization is preferably 0-20 ℃. Preferably, after partial solvent is removed, adding an adverse solvent for crystallization; the poor solvent is preferably an alkane solvent, and the alkane solvent is preferably n-heptane.
The invention also provides a preparation method of the compound 3, which comprises the following steps: after the compound 4 is prepared according to the preparation method, the compound 4 and acid are subjected to deamination protecting group reaction to obtain the compound 3;
wherein P is an amino protecting group such as t-butyloxycarbonyl (Boc), benzyloxycarbonyl (CBz) or P-toluenesulfonyl (Tosyl).
The preparation method of the compound 3 can be a conventional method for the deamination protecting group reaction in the field, and the following reaction method and conditions are particularly preferred in the invention:
the preparation method of the compound 3 can be carried out in a solvent or under the condition of no solvent; when carried out in a solvent, the solvent is preferably one or more of an alcohol solvent, a halogenated hydrocarbon solvent and an ether solvent. The alcohol solvent is preferably methanol. The halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane. The ether solvent is preferably tetrahydrofuran.
In the preparation method of the compound 3, the acid can be an organic acid or an inorganic acid. The organic acid is preferably one or more of trifluoromethanesulfonic acid, benzenesulfonic acid and methanesulfonic acid. The inorganic acid is preferably hydrochloric acid and/or sulfuric acid. The hydrochloric acid can be a conventional commercially available hydrochloric acid reagent, the mass concentration of the hydrochloric acid can be 20-37%, and the mass concentration refers to the mass percentage of the hydrogen chloride in the total mass of the hydrochloric acid solution.
In the preparation method of the compound 3, the molar ratio of the acid to the compound 4 is preferably 1 to 20, more preferably 5 to 15, for example 10.
In the method for producing the compound 3, the reaction temperature of the deamination protecting group is preferably 40 to 70 ℃, for example, 60 to 65 ℃.
In the preparation method of the compound 3, the progress of the reaction of the deamination protecting group can be monitored by a conventional detection method in the field (such as TLC, HPLC or NMR), and generally the end point of the reaction is the time when the compound 4 disappears, and the reaction time of the deamination protecting group is preferably 1 to 10 hours, such as 2 to 6 hours.
The preparation method of the compound 3 preferably adopts the following post-treatment steps: and after the reaction is finished, adding a solvent, stirring, filtering, suspending the solid in an organic solvent, adjusting the pH to 11-12, washing, and removing the solvent to obtain the purified compound 3. The solvent is preferably an ether solvent, and the ether solvent is preferably methyl tert-butyl ether. The organic solvent is preferably a halogenated hydrocarbon solvent; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane. The pH is preferably adjusted by using an organic base; the organic base is preferably ammonia. The ammonia water can be a conventional commercial ammonia water reagent in the field, the mass concentration of the ammonia water can be 5% -25%, and the mass concentration refers to the mass percentage of ammonia gas in the total mass of the ammonia water solution. The washing and removal of the solvent may be carried out by methods conventional in the art for such procedures. The washing is preferably carried out with water and/or a saturated aqueous sodium chloride solution. The solvent removal is preferably carried out by distillation under reduced pressure.
The invention also provides a preparation method of the vipatavir 1(GS5816), which comprises the following steps: after the compound 3 is prepared according to the preparation method, the compound 3 and MOC-L-valine are subjected to condensation reaction in an organic solvent in the presence of alkali, a catalyst and a condensing agent to obtain the wipatavir 1;
the preparation method of the vipatavir 1 can be a conventional method in the field of condensation reaction, and the following reaction methods and conditions are particularly preferred in the invention:
in the preparation method of the wipatavir 1, the organic solvent is preferably a polar organic solvent; the polar organic solvent is preferably one or more of a nitrile solvent, an amide solvent and an ether solvent. The nitrile solvent is preferably acetonitrile. The amide solvent is preferably N, N-Dimethylformamide (DMF). The ethereal solvent is preferably Tetrahydrofuran (THF).
In the preparation method of the vipetavir 1, the catalyst is preferably 1-hydroxybenzotriazole (HOBt).
In the preparation method of the vipetavir 1, the molar ratio of the catalyst to the compound 3 is preferably 1 to 5, more preferably 2 to 4, for example 2.6.
In the preparation method of wipatavir 1, the condensing agent is preferably 1-ethyl- (3-dimethylaminopropyl) carbonyl diimine hydrochloride (EDCI), 2- (7-azobenzotriazol) -N, N, N ', N ' -tetramethyluronium Hexafluorophosphate (HATU), benzotriazol-N, N, N ', N ' -tetramethyluronium Hexafluorophosphate (HBTU), O-benzotriazol-N, N, N ', N ' -tetramethyluronium tetrafluoroborate (TBTU), benzotriazol-1-tris (trimethyl amino) -trifluorophosphate (BOP), chlorotriazolylphosphonium hexafluorophosphate (PyClOP), benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate (PyBOP), N, N ' -Dicyclohexylcarbodiimide (DCC), (2-oximino-cyanoethyl acetate) -N, N-dimethyl-morpholinylurea hexafluorophosphate (COMU), ethyl 2-oximinocyanoacetate (Oxyma) and propylphosphoric anhydride (T)3P) is selected.
In the preparation method of the vipetavir 1, the molar ratio of the condensing agent to the compound 3 is preferably 1 to 5, more preferably 2 to 4, for example 2.5.
In the preparation method of the vipetavir 1, the base is preferably an organic base; the organic base is preferably N, N-Diisopropylethylamine (DIPEA) and/or triethylamine.
In the preparation method of wipatavir 1, the molar ratio of the base to the compound 3 is preferably 1 to 5, more preferably 2 to 4, such as 3.5.
In the preparation method of wipatavir 1, the condensation reaction temperature is preferably-5 ℃ to 30 ℃, more preferably 0 ℃ to 20 ℃, for example 0 ℃ to 15 ℃.
In the preparation method of vipetavir 1, the progress of the condensation reaction may be monitored by a monitoring method (e.g., TLC, HPLC, or NMR) which is conventional in the art, and is generally the end point of the reaction when compound 3 disappears, and the time of the condensation reaction is preferably 5 hours to 24 hours, more preferably 10 hours to 20 hours, e.g., 12 hours to 16 hours.
The preparation method of the vipetavir 1 preferably adopts the following reaction steps: and (3) sequentially adding the compound 3 and alkali into a mixture formed by MOC-L-valine, a catalyst, a condensing agent and an organic solvent, and carrying out condensation reaction to obtain the wipatavir 1.
The preparation method of the vipetavir 1 can adopt the following post-treatment steps: and after the reaction is finished, extracting, filtering, washing and removing the solvent to obtain the purified wipatavir 1. The extraction, filtration, washing and removal of the solvent can be carried out by methods conventional in the art for such procedures. The solvent used for extraction can be isopropyl acetate and water. The washing may be performed by using an aqueous sodium hydroxide solution, a saturated aqueous sodium chloride solution and water in this order. The molar concentration of the sodium hydroxide aqueous solution can be 0.5mol/L (namely 0.5N); the molar concentration refers to the ratio of the molar weight of the sodium hydroxide to the total volume of the sodium hydroxide aqueous solution. The solvent removal can be carried out by distillation under reduced pressure.
The preparation method of the vipotavir 1 can adopt the following route
Route 1:
route 2:
the invention also provides intermediate compounds 3, 4, 5, 6, 8, 12, 13, 14, 15, 16 and 17 for preparing the wipatavir 1, wherein the structural formula is shown as follows:
the invention also provides a preparation method of the intermediate compounds 3, 4, 5, 6, 8, 12, 13, 14, 15, 16 and 17 for preparing the wipatavir, and the reaction steps are the same as those described above.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
In the invention, the room temperature refers to the ambient temperature and is 10-35 ℃.
The positive progress effects of the invention are as follows: the preparation method disclosed by the invention is mild in reaction conditions, simple and safe in operation, free of special purification equipment, high in yield (up to 67%) and low in cost, avoids column chromatography separation operation in a post-treatment process, and is suitable for industrial production, and the prepared vipatavir is high in purity (the chemical and optical purity is more than 99.50%, and all impurities are less than 0.10%, and can reach the standards of raw medicines).
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
EXAMPLE 1 preparation of Compound 14 (P is Boc)
Compound 25(1.96kg, 5.29mol,1.0eq) and compound 24(1.37kg, 1.05eq) were dissolved in N, N-Dimethylformamide (DMF), potassium carbonate (730.8g,1.05eq) was added, nitrogen was replaced three times in vacuo, and the mixture was heated to 20-40 ℃ and stirred for 3 hours. TLC showed complete reaction of compound 25. Cooling to 5-10 deg.C, dropping water, 5-10 deg.C, stirring for 2-3 hr, filtering, washing filter cake with water, and drying to obtain 2.85kg of compound 14 with yield 98.0% and HPLC purity 98.56%.
EXAMPLE 2 preparation of Compound 13 (P is Boc, i.e.t-butyloxycarbonyl)
Dissolving compound 14(2.85kg, 5.18mol, 1eq) in isopropyl acetate, adding isopropyl acetate/hydrogen chloride (1.33L,5eq), heating under reflux (60-65 ℃), reacting for 2-6 hours, TLC shows complete reaction, cooling to room temperature, slowly dropping methyl tert-butyl ether, stirring at 0-10 ℃ for 2-5 hours after dropping, filtering, suspending the solid in dichloromethane, adding saturated sodium bicarbonate, stirring for 1 hour, filtering, washing the organic phase with water and saturated sodium chloride, concentrating and drying to obtain 2.21kg of compound 13, yield 95.0%, and HPLC purity 98.86%.
EXAMPLE 3 preparation of Compound 8 (method 2, L is Br)
Compound 12(3.02kg, 4.72mol, 1.0eq) was dissolved in dichloromethane, and a solution of tribromopyridine (1.66kg, 1.1eq) in methanol was added under ice-cooling (0 ℃ C. -5 ℃ C.), stirred at 10 ℃ C. -15 ℃ C. for 3 hours, and TLC showed completion of the reaction. Filtering, leaching a filter cake with Dichloromethane (DCM), leaching with methanol, and drying at 50 ℃ to obtain 3.26kg of bright yellow solid compound 8, wherein the yield is 96.0 percent, and the HPLC purity is 98.64 percent.
EXAMPLE 4 preparation of Compound 12
Compound 13(2.21kg,4.92mol,1.0eq) was dissolved in N, N-Dimethylformamide (DMF) for use.
Compound 9(1.3kg, 1.1eq) was added at a mass concentration of 50% propyl phosphoric anhydride (T)3P) N, N-Dimethylformamide (DMF) solution (5.02kg,1.1eq) (the mass concentration is the mass percentage of the propylphosphoric anhydride to the total mass of the propylphosphoric anhydride N, N-dimethylformamide solution)Dissolving in DMF, cooling to 0-10 deg.c, dropping the solution, stirring at 20-25 deg.c for 5-6 hr, TLC to show complete reaction of compound 13, dropping water at 5-10 deg.c, stirring at 5-10 deg.c for 2-3 hr, filtering, washing the filter cake with water, and drying to obtain 3.06kg of compound 12 in 97.0% yield and HPLC purity of 98.71%.
EXAMPLE 5 preparation of Compound 17
Compound 12(3.06kg, 4.77mol,1.0eq) was dissolved in toluene, ammonium acetate (7.40kg, 20eq) was added, nitrogen was vacuum-replaced three times, and the mixture was heated to 80-100 deg.C (external temperature) and stirred for 20 hours. TLC showed complete reaction, and was cooled to room temperature (20 ℃ -25 ℃). Adding n-butanol, washing with water and saturated brine, and concentrating to obtain 2.93kg of compound 17 with yield of 99.0% and HPLC purity of 98.95%.
EXAMPLE 6 preparation of Compound 6 (P is Boc; L is Br)
Compound 8(1.96kg, 2.73mol,1.0eq) and compound 7(659g, 1.05eq) were dissolved in N, N-Dimethylformamide (DMF), potassium carbonate (376.3g,1.05eq) was added, nitrogen was replaced three times in vacuo, and the mixture was heated to 20-40 ℃ and stirred for 16 hours. TLC showed complete reaction of compound 8. Cooling to 5-10 deg.C, dropping water, 5-10 deg.C, stirring for 2-3 hr, filtering, washing filter cake with water, and drying to obtain 2.25kg of compound 6 with yield 95.0% and HPLC purity 98.46%.
EXAMPLE 7 preparation of Compound 16 (L is Br)
Compound 17(2.93kg, 4.72mol, 1.0eq) was dissolved in dichloromethane, and a solution of tribromopyridine (1.66kg, 1.1eq) in methanol was added under ice-cooling (0 ℃ C. -5 ℃ C.), stirred at 10 ℃ C. -15 ℃ C. for 3 hours, and TLC showed completion of the reaction. Filtering, leaching a filter cake with Dichloromethane (DCM), leaching with methanol, and drying at 50 ℃ to obtain 3.19kg of bright yellow solid compound 16 with the yield of 96.7 percent and the HPLC purity of 98.92 percent.
EXAMPLE 8 preparation of Compound 15 (P is Boc; L is Br)
Compound 16(3.19kg, 4.71mol,1.0eq) and compound 7(1.13kg, 1.05eq) were dissolved in N, N-Dimethylformamide (DMF), potassium carbonate (682.3g,1.05eq) was added, nitrogen was replaced three times in vacuo, and the mixture was heated to 20-40 ℃ and stirred for 16 hours. TLC showed compound 16 was completely reacted. Cooling to 5-10 deg.C, dropping water, 5-10 deg.C, stirring for 2-3 hr, filtering, washing filter cake with water, and drying to obtain 3.79kg of compound 15 with yield 95.0% and HPLC purity 98.57%.
EXAMPLE 9 preparation of Compound 5 (P is Boc)
Compound 6(2.25kg, 2.59mol,1.0eq) was dissolved in toluene, ammonium acetate (4.01kg, 20eq) was added, nitrogen was vacuum-replaced three times, and the mixture was heated to 80-100 deg.C (external temperature) and stirred for 20 hours. TLC shows complete reaction, the temperature is reduced to 20-25 ℃, n-butyl alcohol and organic phase are added, water and saturated saline are used for washing, and 2.13kg of compound 5 is obtained by concentration, the yield is 99.0%, and the HPLC purity is 98.87%.
EXAMPLE 10 preparation of Compound 5 (P is Boc)
Compound 15(3.79kg, 4.47mol,1.0eq) was dissolved in toluene, ammonium acetate (6.40kg, 20eq) was added, nitrogen was replaced three times in vacuo, and the mixture was heated to 80-100 deg.C (external temperature) and stirred for 20 hours. TLC showed complete reaction, and was cooled to room temperature (20 ℃ -25 ℃). Adding n-butanol, washing with water and saturated brine, and concentrating to obtain 3.63kg of compound 5 with yield 98.0% and HPLC purity 99.04%.
EXAMPLE 11 preparation of Compound 4 (P is Boc)
Adding a raw material compound 5(2.13kg,2.55mol,1.0eq) into dichloromethane, adding at 10-20 ℃, adding active manganese dioxide (2.22kg,10eq) under the protection of nitrogen, stirring at 15-20 ℃ for 10-15 hours, monitoring the complete reaction of the compound 5 by HPLC, adding diatomite into a reaction solution, stirring, filtering, leaching by dichloromethane, concentrating to dryness, adding methyl tert-butyl ether and 10% potassium hydroxide aqueous solution (the mass concentration refers to the mass percentage of potassium hydroxide in the total mass of the potassium hydroxide aqueous solution), refluxing at 60 ℃ overnight, filtering, concentrating the filtrate to a small volume (the ratio of the volume of the removed solvent to the total volume of the filtrate is 0.7), adding seed crystals, stirring for 2-3 hours, then dropwise adding n-heptane, stirring at 0-20 ℃ for 1-2 hours, filtering to obtain 2.05kg of a compound 4 with the yield of 99.29%, HPLC purity 99.15%.
EXAMPLE 12 preparation of Compound 4 (P is Boc)
Adding a raw material compound 5(3.63kg,4.38mol,1.0eq) into dichloromethane, adding at 10-20 ℃, adding activated manganese dioxide (3.81kg,10eq) under the protection of nitrogen, stirring at 5-10 ℃ for 10-15 hours, monitoring the complete reaction of the compound 5 by HPLC, adding diatomite into a reaction solution, stirring, filtering, leaching by dichloromethane, concentrating to dryness, adding methyl tert-butyl ether and 10% potassium hydroxide aqueous solution (the mass concentration refers to the mass percentage of potassium hydroxide in the total mass of the potassium hydroxide aqueous solution), refluxing at 60 ℃ overnight, filtering, concentrating the filtrate to a small volume (the ratio of the volume of the removed solvent to the total volume of the filtrate is 0.7), adding seed crystals, stirring for 2-3 hours, then dropwise adding n-heptane, stirring at 0-20 ℃ for 1-2 hours, filtering to obtain 3.62kg of a compound 4 with the yield of 90.0%, HPLC purity 99.30%.
Preparation of active manganese dioxide: weighing 20g of manganese sulfate, dissolving in 500mL of distilled water, adding 10mL of concentrated ammonia water, shaking up, adding 90mL of ammonium persulfate solution, stirring while adding, boiling for 10min, adding 1-2 drops of ammonia water, and standing until the solution is clear. And (3) carrying out suction filtration by using a Buchner funnel, washing for 10 times by using ammonia water, washing for 2-3 times by using hot water, washing for 12 times by using sulfuric acid, and finally washing by using hot water until no sulfuric acid reaction exists. Drying at 110 +/-5 ℃ for 3-4 h, and storing in a dryer for later use.
EXAMPLE 13 preparation of Compound 3 (P is Boc)
Dissolving compound 4(2.05kg, 2.45mol, 1.0eq) in methanol, adding trifluoromethanesulfonic acid (3.67kg, 10eq), heating under reflux (60 ℃ -65 ℃) for 2-6 hours, TLC shows that compound 4 is completely reacted, cooling to room temperature, slowly dropping methyl tert-butyl ether, stirring at 0-10 ℃ for 2-5 hours after dropping, filtering, suspending the solid in dichloromethane, adding ammonia water, adjusting pH to 11-12, stirring for 1 hour, filtering, washing the organic phase with water and saturated sodium chloride, and concentrating to obtain 1.66kg of compound 3, yield 93.5%, and HPLC purity 99.30%.
EXAMPLE 14 preparation of Wipatavir 1
MOC-L-valine (1.01kg 2.5eq), 1-hydroxybenzotriazole (HOBt) (0.84kg,2.6eq), 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (EDCI) (1.1kg,2.5eq) and acetonitrile were added to the reaction vessel and stirred at 10-15 ℃ for 1 hour. Cooled to 0-10 ℃ and compound 3(1.66kg,2.29mol, 1eq) was added followed by dropwise addition of N, N-Diisopropylethylamine (DIPEA) (1.18kg, 3.5 eq). Stirring for 12-16 hours at 0-15 ℃. TLC checked complete reaction of compound 3. Slowly adding isopropyl acetate and water, filtering, separating liquid, washing organic phase with 0.5N sodium hydroxide, saturated sodium chloride aqueous solution and water, concentrating dry solvent to obtain 1.98kg of the vitaspiravir 1, wherein the yield is 98.0%, the HPLC purity is 99.80%, and the maximum single impurity content is 0.05%.
Claims (10)
1. A process for the preparation of compound 12, characterized by the steps of: dripping a mixture formed by the compound 13 and an organic solvent into a mixture formed by the compound 9, a condensing agent and the organic solvent at 0-10 ℃ for condensation reaction to obtain the compound 12; the condensing agent is propyl phosphoric anhydride; the molar ratio of the condensing agent to the compound 13 is 1-3;
2. a process for the preparation of compound 12 according to claim 1, wherein:
in the preparation method of the compound 12, the organic solvent is an amide solvent;
and/or the presence of a gas in the gas,
in the preparation method of the compound 12, the molar ratio of the compound 9 to the compound 13 is 1-3;
and/or the presence of a gas in the gas,
in the preparation method of the compound 12, the condensation reaction temperature is 0-40 ℃;
and/or the presence of a gas in the gas,
in the method for producing the compound 12, the condensation reaction is carried out for 1 to 10 hours.
3. A process for the preparation of compound 12 according to claim 2, wherein:
in the preparation method of the compound 12, the amide solvent is N, N-dimethylformamide;
and/or the presence of a gas in the gas,
in the preparation method of the compound 12, the molar ratio of the condensing agent to the compound 13 is 1-1.5;
and/or the presence of a gas in the gas,
in the preparation method of the compound 12, the molar ratio of the compound 9 to the compound 13 is 1-1.5;
and/or the presence of a gas in the gas,
in the preparation method of the compound 12, the condensation reaction temperature is 10-30 ℃;
and/or the presence of a gas in the gas,
in the method for producing the compound 12, the condensation reaction is carried out for 2 to 8 hours.
4. A process for the preparation of compound 12 according to claim 1, wherein:
the method for preparing compound 12 further comprises a method for preparing compound 13, which comprises the following steps: in an organic solvent, carrying out a deamination protecting group reaction on the compound 14 and acid to prepare the compound 13;
wherein P is tert-butyloxycarbonyl, benzyloxycarbonyl or P-toluenesulfonyl.
5. A process for the preparation of compound 12 according to claim 4, wherein:
in the preparation method of the compound 13, the organic solvent is an ester solvent;
and/or the presence of a gas in the gas,
in the preparation method of the compound 13, the acid is an inorganic acid;
and/or the presence of a gas in the gas,
in the preparation method of the compound 13, the molar ratio of the acid to the compound 14 is 1-10;
and/or the presence of a gas in the gas,
in the preparation method of the compound 13, the reaction temperature for removing the amino protecting group is 40-100 ℃;
and/or the presence of a gas in the gas,
in the method for producing the compound 13, the reaction time for removing the amino protecting group is 1 to 10 hours.
6. A process for the preparation of compound 12 according to claim 5, wherein:
in the preparation method of the compound 13, the ester solvent is isopropyl acetate;
and/or the presence of a gas in the gas,
in the preparation method of the compound 13, the inorganic acid is hydrogen chloride;
and/or the presence of a gas in the gas,
in the preparation method of the compound 13, the molar ratio of the acid to the compound 14 is 4-6;
and/or the presence of a gas in the gas,
in the preparation method of the compound 13, the reaction temperature for removing the amino protecting group is 50-70 ℃;
and/or the presence of a gas in the gas,
in the method for producing the compound 13, the reaction time for removing the amino protecting group is 2 to 8 hours.
7. A process for the preparation of compound 12 according to claim 4, wherein:
the method of preparing compound 12 further includes a method of preparing compound 14, comprising the steps of: under the protection of protective gas, in an organic solvent and in the presence of alkali, carrying out condensation reaction on a compound 25 and a compound 24 to obtain the compound 14;
wherein P is defined as in claim 4.
8. A process for the preparation of compound 12 according to claim 7, wherein:
in the preparation method of the compound 14, the protective gas is nitrogen and/or argon;
and/or the presence of a gas in the gas,
in the preparation method of the compound 14, the organic solvent is an amide solvent;
and/or the presence of a gas in the gas,
in the preparation method of the compound 14, the base is an inorganic base;
and/or the presence of a gas in the gas,
in the preparation method of the compound 14, the molar ratio of the alkali to the compound 25 is 1-3;
and/or the presence of a gas in the gas,
in the preparation method of the compound 14, the molar ratio of the compound 24 to the compound 25 is 1-3;
and/or the presence of a gas in the gas,
in the preparation method of the compound 14, the condensation reaction temperature is 10-50 ℃;
and/or the presence of a gas in the gas,
in the method for producing the compound 14, the condensation reaction is carried out for 1 to 5 hours.
9. Compound 12 and compound 13, the structures of which are shown below:
10. a process for the preparation of compound 13, characterized in that it comprises the following steps: in an organic solvent, carrying out a deamination protecting group reaction on the compound 14 and acid to prepare the compound 13;
wherein P is defined as in claim 4; the reaction conditions are as defined in any one of claims 3 to 8.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2016110832569 | 2016-11-30 | ||
| CN201611083256 | 2016-11-30 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107759577A CN107759577A (en) | 2018-03-06 |
| CN107759577B true CN107759577B (en) | 2020-03-27 |
Family
ID=61039839
Family Applications (8)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710917630.9A Active CN107573380B (en) | 2016-11-30 | 2017-09-30 | Wipatasvir intermediate, preparation method and application |
| CN201710917345.7A Active CN107805256B (en) | 2016-11-30 | 2017-09-30 | Wipatasvir intermediate, preparation method and application |
| CN201710938737.1A Active CN107674064B (en) | 2016-11-30 | 2017-09-30 | Wipatasvir intermediate, preparation method and preparation method of Wipatasvir |
| CN201710919393.XA Active CN107674063B (en) | 2016-11-30 | 2017-09-30 | GS5816 intermediate, preparation method and application |
| CN201710919762.5A Active CN107573355B (en) | 2016-11-30 | 2017-09-30 | Vipatasvir, intermediate and preparation method thereof |
| CN201710918856.0A Active CN107674062B (en) | 2016-11-30 | 2017-09-30 | Anti-hepatitis C drug intermediate, preparation method and application |
| CN201911009963.7A Active CN110698489B (en) | 2016-11-30 | 2017-09-30 | Wipatasvir intermediate, preparation method and application |
| CN201710919030.6A Active CN107759577B (en) | 2016-11-30 | 2017-09-30 | GS5816 intermediate, preparation method and application |
Family Applications Before (7)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710917630.9A Active CN107573380B (en) | 2016-11-30 | 2017-09-30 | Wipatasvir intermediate, preparation method and application |
| CN201710917345.7A Active CN107805256B (en) | 2016-11-30 | 2017-09-30 | Wipatasvir intermediate, preparation method and application |
| CN201710938737.1A Active CN107674064B (en) | 2016-11-30 | 2017-09-30 | Wipatasvir intermediate, preparation method and preparation method of Wipatasvir |
| CN201710919393.XA Active CN107674063B (en) | 2016-11-30 | 2017-09-30 | GS5816 intermediate, preparation method and application |
| CN201710919762.5A Active CN107573355B (en) | 2016-11-30 | 2017-09-30 | Vipatasvir, intermediate and preparation method thereof |
| CN201710918856.0A Active CN107674062B (en) | 2016-11-30 | 2017-09-30 | Anti-hepatitis C drug intermediate, preparation method and application |
| CN201911009963.7A Active CN110698489B (en) | 2016-11-30 | 2017-09-30 | Wipatasvir intermediate, preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (8) | CN107573380B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106831737B (en) * | 2017-02-27 | 2020-03-17 | 上海众强药业有限公司 | Preparation of vipatavir and derivatives thereof |
| CN111018870B (en) * | 2019-11-29 | 2021-07-23 | 南京正济医药研究有限公司 | Preparation method of vipatavir intermediate |
| CN113072615B (en) * | 2021-03-24 | 2023-01-10 | 上海法默生物科技有限公司 | Preparation method of vipatavir intermediate |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104487442A (en) * | 2012-05-16 | 2015-04-01 | 吉利德法莫赛特有限责任公司 | Antiviral compounds inhibitors of HCV NS5B |
| CN105294713A (en) * | 2015-10-09 | 2016-02-03 | 重庆康施恩化工有限公司 | Velpatasvir intermediate and preparation method thereof |
| CN105732765A (en) * | 2016-02-01 | 2016-07-06 | 杭州科巢生物科技有限公司 | Novel synthesis method of hepatitis drug velpatasvir |
| CN105837584A (en) * | 2011-11-16 | 2016-08-10 | 吉利德制药有限责任公司 | Condensed imidazolylimidazoles as antiviral compounds |
| CN106831737A (en) * | 2017-02-27 | 2017-06-13 | 上海众强药业有限公司 | The preparation of Wei Patawei and its derivative |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ726475A (en) * | 2010-11-17 | 2018-07-27 | Gilead Pharmasset Llc | Antiviral compounds |
| TW202014413A (en) * | 2014-06-11 | 2020-04-16 | 美商基利法瑪席特有限責任公司 | Processes for preparing antiviral compounds |
| CN107501280A (en) * | 2017-09-05 | 2017-12-22 | 安徽华昌高科药业有限公司 | A kind of Wei Patawei synthetic method |
-
2017
- 2017-09-30 CN CN201710917630.9A patent/CN107573380B/en active Active
- 2017-09-30 CN CN201710917345.7A patent/CN107805256B/en active Active
- 2017-09-30 CN CN201710938737.1A patent/CN107674064B/en active Active
- 2017-09-30 CN CN201710919393.XA patent/CN107674063B/en active Active
- 2017-09-30 CN CN201710919762.5A patent/CN107573355B/en active Active
- 2017-09-30 CN CN201710918856.0A patent/CN107674062B/en active Active
- 2017-09-30 CN CN201911009963.7A patent/CN110698489B/en active Active
- 2017-09-30 CN CN201710919030.6A patent/CN107759577B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105837584A (en) * | 2011-11-16 | 2016-08-10 | 吉利德制药有限责任公司 | Condensed imidazolylimidazoles as antiviral compounds |
| CN104487442A (en) * | 2012-05-16 | 2015-04-01 | 吉利德法莫赛特有限责任公司 | Antiviral compounds inhibitors of HCV NS5B |
| CN105294713A (en) * | 2015-10-09 | 2016-02-03 | 重庆康施恩化工有限公司 | Velpatasvir intermediate and preparation method thereof |
| CN105732765A (en) * | 2016-02-01 | 2016-07-06 | 杭州科巢生物科技有限公司 | Novel synthesis method of hepatitis drug velpatasvir |
| CN106831737A (en) * | 2017-02-27 | 2017-06-13 | 上海众强药业有限公司 | The preparation of Wei Patawei and its derivative |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107674064B (en) | 2020-03-27 |
| CN107573380B (en) | 2020-06-02 |
| CN107674063B (en) | 2020-03-27 |
| CN107674062B (en) | 2020-03-27 |
| CN107674064A (en) | 2018-02-09 |
| CN107573355A (en) | 2018-01-12 |
| CN107674063A (en) | 2018-02-09 |
| CN107573380A (en) | 2018-01-12 |
| CN107573355B (en) | 2020-03-17 |
| CN107805256B (en) | 2020-03-31 |
| CN107759577A (en) | 2018-03-06 |
| CN110698489A (en) | 2020-01-17 |
| CN107805256A (en) | 2018-03-16 |
| CN107674062A (en) | 2018-02-09 |
| CN110698489B (en) | 2022-02-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107759577B (en) | GS5816 intermediate, preparation method and application | |
| CN102985416A (en) | Process of preparing a thrombin specific inhibitor | |
| CN106749259A (en) | A kind of synthetic method of cyclopenta pyrimido azoles | |
| CN108424389A (en) | A kind of preparation method of Ivabradine impurity | |
| CN110551144B (en) | Preparation method of amoxicillin | |
| CN111072660B (en) | Simple preparation method of rilibatan | |
| EP2643308B1 (en) | Process for the preparation of taurolidine and its intermediates thereof | |
| WO2019049824A1 (en) | Protected l-carnosine derivative, l-carnosine, and method for producing crystalline l-carnosine zinc complex | |
| KR101935636B1 (en) | A method for preparation of (S)-N1-(2-aminoethyl)-3-(4-alkoxyphenyl)propane-1,2-diamine trihydrocholoride | |
| CN105418477B (en) | The method for reducing diastereoisomer impurity content in Lei Dipawei intermediate | |
| CN112375055A (en) | Preparation method of eptifibatide key raw material L-high arginine | |
| CN104402813B (en) | Novel method for synthesizing sorafenib | |
| CN107573345B (en) | Preparation method of erigeron and intermediate thereof | |
| CN109574860B (en) | Method for preparing vilanterol | |
| CN114591299A (en) | Paroviride intermediate and preparation and application thereof | |
| US20230348412A1 (en) | Method for preparing glp-1 receptor agonist | |
| CN107602454B (en) | Sulfonamide compound and preparation method and application thereof | |
| CN105017251B (en) | A kind of Preparation Method And Their Intermediate of nk 1 receptor antagonist | |
| CN113583021B (en) | Synthesis method of spiropiperidine rifamycin | |
| CN109970620A (en) | A method of preparing onglyza intermediate | |
| CN111943894A (en) | Synthesis method of 4, 7-diazaspiro [2.5] octane compound | |
| CN114805220A (en) | Preparation method of quinazolinone compound | |
| CN118851972A (en) | Industrial preparation method of antiviral ketoamide derivative intermediate | |
| CN115232020A (en) | Method for synthesizing N, N-diethyl-2-hydroxyphenylacetamide and analogue thereof and application thereof | |
| CN113072466A (en) | Synthetic method of dapoxetine impurity |
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 | ||
| CB03 | Change of inventor or designer information | ||
| CB03 | Change of inventor or designer information |
Inventor after: Ying Shuhuan Inventor after: Pi Hongjun Inventor after: Gong Xudong Inventor after: Yu Chongchong Inventor after: Wang Tingting Inventor before: Ying Shuhuan Inventor before: Pi Hongjun Inventor before: Gong Xudong Inventor before: Yu Chongchong |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| 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. |