CN113024396A - 一种奥司他韦的制备方法及其中间体 - Google Patents
一种奥司他韦的制备方法及其中间体 Download PDFInfo
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- CN113024396A CN113024396A CN201911353220.1A CN201911353220A CN113024396A CN 113024396 A CN113024396 A CN 113024396A CN 201911353220 A CN201911353220 A CN 201911353220A CN 113024396 A CN113024396 A CN 113024396A
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- oseltamivir
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- VSZGPKBBMSAYNT-RRFJBIMHSA-N oseltamivir Chemical compound CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 VSZGPKBBMSAYNT-RRFJBIMHSA-N 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 229960003752 oseltamivir Drugs 0.000 title abstract description 24
- 150000001875 compounds Chemical class 0.000 claims abstract description 76
- 238000000034 method Methods 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 10
- 238000007142 ring opening reaction Methods 0.000 claims description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- 230000009471 action Effects 0.000 claims description 9
- 229960002194 oseltamivir phosphate Drugs 0.000 claims description 9
- 238000005984 hydrogenation reaction Methods 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 claims description 5
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 5
- 239000012346 acetyl chloride Substances 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- 238000006640 acetylation reaction Methods 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 239000001632 sodium acetate Substances 0.000 claims description 3
- 235000017281 sodium acetate Nutrition 0.000 claims description 3
- 230000000397 acetylating effect Effects 0.000 claims description 2
- 230000021736 acetylation Effects 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- 238000006264 debenzylation reaction Methods 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000006501 nitrophenyl group Chemical group 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 96
- 238000003756 stirring Methods 0.000 description 25
- 238000004128 high performance liquid chromatography Methods 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 239000007788 liquid Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- -1 aziridine compound Chemical class 0.000 description 11
- 238000001816 cooling Methods 0.000 description 11
- 238000010438 heat treatment Methods 0.000 description 11
- 238000000926 separation method Methods 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
- PGZUMBJQJWIWGJ-ONAKXNSWSA-N oseltamivir phosphate Chemical compound OP(O)(O)=O.CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 PGZUMBJQJWIWGJ-ONAKXNSWSA-N 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- 238000005070 sampling Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 2
- 239000004593 Epoxy Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 208000002979 Influenza in Birds Diseases 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 206010064097 avian influenza Diseases 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- MZTXMZRYPLRCSW-AQNXPRMDSA-N ethyl (3r,4s,5r)-5-(benzylamino)-4-hydroxy-3-pentan-3-yloxycyclohexene-1-carboxylate Chemical compound C1C(C(=O)OCC)=C[C@@H](OC(CC)CC)[C@@H](O)[C@@H]1NCC1=CC=CC=C1 MZTXMZRYPLRCSW-AQNXPRMDSA-N 0.000 description 2
- 206010022000 influenza Diseases 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000003541 multi-stage reaction Methods 0.000 description 2
- LPNBBFKOUUSUDB-UHFFFAOYSA-N p-toluic acid Chemical compound CC1=CC=C(C(O)=O)C=C1 LPNBBFKOUUSUDB-UHFFFAOYSA-N 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 229940061367 tamiflu Drugs 0.000 description 2
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical group CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- QBTROWHSMGZXCV-RQURQNPSSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecoxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OCCCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 QBTROWHSMGZXCV-RQURQNPSSA-N 0.000 description 1
- MOQCFMZWVKQBAP-UHFFFAOYSA-N 1-[3,5-bis(trifluoromethyl)benzoyl]-n-(4-chlorophenyl)piperidine-3-carboxamide Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C(=O)N2CC(CCC2)C(=O)NC=2C=CC(Cl)=CC=2)=C1 MOQCFMZWVKQBAP-UHFFFAOYSA-N 0.000 description 1
- JXRGUPLJCCDGKG-UHFFFAOYSA-N 4-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=C(S(Cl)(=O)=O)C=C1 JXRGUPLJCCDGKG-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 229940126656 GS-4224 Drugs 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 102000005348 Neuraminidase Human genes 0.000 description 1
- 108010006232 Neuraminidase Proteins 0.000 description 1
- 229940123424 Neuraminidase inhibitor Drugs 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 1
- PEZBJHXXIFFJBI-UHFFFAOYSA-N ethanol;phosphoric acid Chemical compound CCO.OP(O)(O)=O PEZBJHXXIFFJBI-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 208000037797 influenza A Diseases 0.000 description 1
- 208000037798 influenza B Diseases 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- DYUWTXWIYMHBQS-UHFFFAOYSA-N n-prop-2-enylprop-2-en-1-amine Chemical group C=CCNCC=C DYUWTXWIYMHBQS-UHFFFAOYSA-N 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- JXOHGGNKMLTUBP-HSUXUTPPSA-N shikimic acid Chemical compound O[C@@H]1CC(C(O)=O)=C[C@@H](O)[C@H]1O JXOHGGNKMLTUBP-HSUXUTPPSA-N 0.000 description 1
- JXOHGGNKMLTUBP-JKUQZMGJSA-N shikimic acid Natural products O[C@@H]1CC(C(O)=O)=C[C@H](O)[C@@H]1O JXOHGGNKMLTUBP-JKUQZMGJSA-N 0.000 description 1
- 239000002911 sialidase inhibitor Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- WGRQANOPCQRCME-PMACEKPBSA-N teneligliptin Chemical compound O=C([C@H]1NC[C@H](C1)N1CCN(CC1)C1=CC(=NN1C=1C=CC=CC=1)C)N1CCSC1 WGRQANOPCQRCME-PMACEKPBSA-N 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C229/48—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups and carboxyl groups bound to carbon atoms of the same non-condensed ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/52—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
- C07D203/26—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
-
- 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)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及一种奥司他韦(式Ⅰ化合物)的制备方法及其中间体,所述方法通过下面的路线制备,该方法操作便捷安全,收率较高,对环境污染小,适宜工业生产,有很好的经济效应。
Description
技术领域
本发明属于医药技术领域,具体涉及一种奥司他韦的合成方法及其中间体。
技术背景
磷酸奥司他韦是由瑞士罗氏(Roche)制药公司研发的一款高效的、高选择性的流感病毒神经氨酸酶抑制剂药物,于1999年被美国FDA批准上市,2004年7月在我国上市,商品名为达菲,很快成了世界卫生组织和我国防控禽流感的治疗用药和国家战略储备药物。临床上主要用于预防和治疗甲型、乙型流感等由神经氨酸酶引起的疾病。到目前为止,奥司他韦(或者奥司他韦磷酸盐,也称达菲)是公认的抗禽流感最为有效的药物,因此,它的合成非常重要。
奥司他韦的分子式为C16H28N2O4,化学名为:(3R,4R,5S)-4-乙酰胺-5-胺基-3-(1-丙氧乙酯)-1-环己烯-1-羧酸乙酯,结构式如下所示:
目前报道奥司他韦合成路线的文献非常多,但大多数路线由于使用较为昂贵的试剂或工艺不易放大,没有进行工业化生产。
根据市场原料供应情况,工业化生产主流路线是从草莽酸合成制备奥司他韦关键中间体(式Ⅵ化合物),再由式Ⅵ化合物进行多步骤反应制备得到奥司他韦。
由式Ⅵ化合物进行多步骤反应制备得到奥司他韦,报道的主要合成路线如下:
路线一、1998年,J.Org.Chem.1998,63,4545-4550公开由美国Gilead公司和瑞士Roche公司联合研发,该合成方法包括式Ⅵ化合物经叠氮开环、氨基乙酰化和叠氮还原得到奥司他韦。其合成路线如下:
该方法从式IV化合物为起始物料,得到磷酸奥司他韦,需要经过5步化学反应,总收率为26%。该方法的缺点是使用剧毒易爆的化学品叠氮化钠,生产上存在着安全隐患,并且收率较低。
路线二、专利CN100545145C公开由瑞士Roche公司改进得合成路线,该合成路线包括式Ⅵ化合物经叔丁胺开环环氧化合物、双烯丙基胺开环氮丙啶化合物、脱叔丁基和烯丙基保护得到奥司他韦,其合成路线如下:
该方法从式IV化合物为起始物料,得到磷酸奥司他韦,需要经过6步化学反应,总收率为60%,收率大大提高的提高了,但该路线需要经历两步脱保护反应,且在脱叔丁基时使用了腐蚀性很强三氟乙酸,容易对反应釜造成腐蚀;并且在脱烯丙基时使用了催化剂醋酸钯,该催化剂不能直接回收循环再利用,生产成本较高。
路线三、专利CN103304437B是由广州同隽医药科技有限公司申请,该专利公开了一种奥司他韦的合成方法,该方法包括式Ⅵ化合物经三氟化硼/乙腈开环环氧化合物、钠氢合环氮丙啶、叔丁胺开环乙酰氮丙啶化合物和脱叔丁基保护得到奥司他韦,其合成路线如下:
该方法从式IV化合物为起始物料,得到磷酸奥司他韦,需要经过5步化学反应,总收率为62%。该方法的缺点是在合环氮丙啶步骤中使用钠氢,一方面工业化生产大量使用钠氢存在安全隐患,另一方面反应条件苛刻且难以控制,易产生较大且难以纯化去除的副产物,影响奥司他韦成品质量。
而目前流感在全球范围内均时有爆发,对能有效应对流感药物-奥司他韦的需求量有增无减,因此开发一种更安全、高效、经济的奥司他韦制备方法迫在眉睫。
发明内容
本发明旨在提供了一种新的奥司他韦制备方法及其中间体,该方法工艺简洁,安全高效、经济环保等优点,适于工业化放大。
第一方面,本发明提供了一种磷酸奥司他韦的制备方法,该方法包括以下步骤:
(a)将式IV化合物在酸的存在下经二苄胺开环得到式III化合物;
(b)将步骤a)得到的式III化合物在有机碱或无机碱的作用下,经乙酰化试剂作用进行乙酰化反应得到式II化合物;
(c)将步骤b)得到的式II化合物在钯催化剂的作用下,进行氢化脱苄反应得到式I化合物;
(d)将式I化合物在乙醇溶液中,用磷酸处理得到磷酸奥司他韦;
优选地,步骤a)所述的酸为苯磺酸、对甲苯磺酸。
优选地,步骤b)所述的有机碱为乙酸钠、三乙胺、二异丙基乙胺,所述的无机碱为碳酸钾。
优选地,步骤b)所述的乙酰化试剂为醋酸酐、乙酰氯。
优选地,步骤c)的反应溶剂为乙醇、四氢呋喃、乙酸乙酯。
另一方面,本发明提供了一种奥司他韦中间体,如式(III)所示化合物和式(II)所示化合物:
以上两种中间体可以用来制备奥司他韦。
第三方面,本发明还提供了一种合成奥司他韦起始物式IV化合物的制备方法,该方法包括:
(1)以式Ⅵ化合物为原料,经苄胺开环得到式V化合物;
(2)式Ⅴ化合物在式Ⅶ化合物的作用下合环制备得到式IV化合物;
式Ⅶ化合物的结构式如下:
其中R基代表甲基、苯基、甲基苯基、硝基苯基。
优选地,步骤1)所述的式Ⅵ化合物在氯化镁的作用下,苄胺开环得式V化合物。
优选地,步骤2)所述的反应溶剂为甲苯、四氢呋喃。
本发明的合成路线,最优合成路线如下:
本发明相对现有技术取得的有益效果:
1)本发明由式Ⅵ化合物制备得到奥司他韦,经过5步化学反应,总收率为62%,操作简便。
2)本发明有效避免使用了有安全隐患的试剂,各步骤原料成本低廉,催化氢化反应选择Pd/C作为催化剂,可回收利用,进一步降低了成本。
3)整条路线使用的溶剂单一,便于回收,对环保经济。
4)本发明提供的奥司他韦合成路线,采用苄胺对环氧化物式VI化合物开环,后使用二苄胺对氮丙啶式IV化合物进行开环,在后续的合成过程中只需要一步就能脱掉保护基得到奥司他韦,简化反应步骤。
5)本发明提供的奥司他韦合成路线各步骤反应条件温和,操作便捷安全,适宜工业生产,有很好的经济效应。
具体实施方式
以下实施例举例说明本发明,但并非限制本发明。
实例1(3R,4S,5R)-5-(苄氨基)-4-羟基-3-(戊烷-3-基氧基)环己-1-烯羧酸乙酯(Ⅴ)的合成:
向500mL四口瓶加入150mL甲苯,17g无水氯化镁和6g苄胺,在20℃~30℃搅拌2小时。向体系滴加式Ⅵ化合物的甲苯溶液(50g式Ⅵ化合物溶解在150mL甲苯中),升温至50℃~60℃搅拌反应16小时后,开始取样送HPLC跟踪至式Ⅵ化合物转化完全。降温至20℃~30℃,体系加入100mL 10%柠檬酸水溶液,搅拌30分钟,静置分液。甲苯相再用50mL水洗一次,分液后,甲苯相浓缩至无馏分得黄色油状物(68g,收率95%):LC-MS:362[M+1]+。
实例2(1R,5R,6R)-7-苄基-5-(戊基-3-基氧基)-7-氮杂双环[4.1.0]庚-3-烯-3-羧酸乙酯(Ⅳ)的合成:
方法1)向250mL四口瓶加入100mL甲苯和34g式Ⅴ化合物,控温0℃~10℃滴加12g甲基磺酰氯。滴毕,搅拌30分钟后,控温0℃~10℃滴加20g三乙胺。滴毕,回温至15℃~25℃搅拌30分钟。再升温至65℃~75℃保温搅拌4小时后,开始取样送HPLC跟踪至式Ⅴ化合物转化完全。降温至15℃~25℃,加入30mL水搅拌30分钟,静置分液。甲苯相用20mL饱和碳酸氢钠洗两次。浓缩甲苯相得黄色油状物(30g,收率92%):LC-MS:344[M+1]+。
方法2)向25mL四口瓶加入10mL甲苯和3.4g式Ⅴ化合物,控温0℃~10℃滴加1.9g苯磺酰氯。滴毕,搅拌30分钟后,控温0℃~10℃滴加2g三乙胺。滴毕,回温至15℃~25℃搅拌30分钟。再升温至65℃~75℃保温搅拌4小时后,开始取样送HPLC跟踪至式Ⅴ化合物转化完全。降温至15℃~25℃,加入5mL水搅拌10分钟,静置分液。甲苯相用5mL饱和碳酸氢钠洗两次。浓缩甲苯相得黄色油状物(3.1g,收率95%)。
方法3)向25mL四口瓶加入10mL甲苯和3.4g式Ⅴ化合物,控温0℃~10℃滴加2g对甲苯磺酰氯。滴毕,搅拌30分钟后,控温0℃~10℃滴加2g三乙胺。滴毕,回温至15℃~25℃搅拌30分钟。再升温至65℃~75℃保温搅拌4小时后,开始取样送HPLC跟踪至式Ⅴ化合物转化完全。降温至15℃~25℃,加入5mL水搅拌30分钟,静置分液。甲苯相用5mL饱和碳酸氢钠洗两次。浓缩甲苯相得黄色油状物(3.1g,收率95%)。
方法4)向25mL四口瓶加入10mL四氢呋喃和3.4g式Ⅴ化合物,控温(-5)℃~5℃滴加2.3g对硝基苯磺酰氯。滴毕,搅拌30分钟后,控温(-5)℃~5℃滴加2g三乙胺。滴毕,回温至15℃~25℃搅拌30分钟。再升温至65℃~75℃保温搅拌4小时后,开始取样送HPLC跟踪至式Ⅴ化合物转化完全。浓缩蒸去四氢呋喃,降温至15℃~25℃,加入15mL乙酸乙酯和5mL水搅拌30分钟,静置分液。乙酸乙酯相用5mL饱和碳酸氢钠洗两次。浓缩乙酸乙酯相得黄色油状物(2.7g,收率90%)。
方法5)向500mL四口瓶加入300mL甲苯,30g三苯基膦和34g式Ⅴ化合物,控温(-5)℃~5℃向体系滴加19g偶氮二甲酸二乙酯。滴毕,升温至120℃回流3小时后,开始取样送HPLC跟踪至式Ⅴ化合物转化完全。降温至15℃~25℃,加入60mL 2N盐酸搅拌15分钟,分液。向水相加入300mL甲苯,控温0℃~10℃滴加50mL 10%氢氧化钠溶液,分液。甲苯相再用60mL水洗一次,浓缩甲苯相得黄色油状物(31g,收率95%)。
实例3(3R,4R,5S)-4-(苄基氨基)-5-(二苄基氨基)-3-(戊基-3-基氧基)环己-1-烯甲酸乙酯(Ⅲ)的合成:
方法1)向1000mL四口瓶加入120mL甲苯,60g式Ⅳ化合物和46g二苄胺,分批加入34g苯甲酸。升温至115℃~120℃保温搅拌3小时后,开始取样送HPLC跟踪至式Ⅳ化合物转化完全。降温至30℃以下,加入300mL甲苯,控温0℃~10℃滴加90mL 10%氢氧化钠水溶液,分液。用90mL水洗2次,浓缩甲苯相得棕色油状物(86g,收率92%):LC-MS:541[M+1]+。1H NMR(400MHz,CDCl3)δ7.34–7.20(m,15H),6.77(s,1H),4.26(dd,J=14.2,7.3Hz,3H),4.05(s,1H),3.78(dd,J=13.3,7.1Hz,3H),3.46(d,J=13.7Hz,3H),3.03(s,1H),2.92–2.81(m,2H),2.76–2.65(m,1H),2.43–2.30(m,1H),1.87–1.43(m,5H),1.35(t,J=7.1Hz,3H),0.96(t,J=7.4Hz,3H),0.89(t,J=7.5Hz,3H)。
方法2)向1000mL四口瓶加入120mL甲苯,60g式Ⅳ化合物和46g二苄胺,分批加入37g对甲苯甲酸。升温至115℃~120℃保温搅拌3小时后,开始取样送HPLC跟踪至式Ⅳ化合物转化完全。降温至30℃以下,加入300mL甲苯,控温0℃~10℃滴加90mL 10%氢氧化钠水溶液,分液。用90mL水洗2次,浓缩甲苯相得棕色油状物(84g,收率90%)。
实例4(3R,4R,5S)-4-(N-苄基乙酰胺基)-5-(二苄基氨基)-3-(戊烷-3-基氧基)环己-1-烯甲酸乙酯(Ⅱ)的合成:
方法1)向1000mL四口瓶加入85g式Ⅲ化合物,80g醋酸酐和30g醋酸钠,升温至110℃~115℃保温搅拌3小时后,开始取样送HPLC跟踪至式Ⅲ化合物转化完全。降温至30℃以下,加入500mL甲苯,控温(-5)℃~5℃滴加240mL 20%的氢氧化钠溶液。升温至15℃~25℃,分液。用100mL水洗两次,浓缩甲苯相得棕色油状物(93g,收率100%):LC-MS:583[M+1]+。
方法2)向100mL四口瓶加入40mL二氯甲烷,3.2g三乙胺和8.5g式Ⅲ化合物,控温0℃~10℃向体系滴加1.5g乙酰氯。滴毕,升温至35℃~40℃保温搅拌3小时后,开始取样送HPLC跟踪至式Ⅲ化合物转化完全。降温至30℃以下,向体系滴加15mL水,搅拌30分钟,分液。二氯甲烷相用10mL饱和碳酸氢钠洗一次,浓缩二氯甲烷得棕色油状物(9.4g,收率100%)。
方法3)向100mL四口瓶加入40mL二氯甲烷,4.1g三乙胺和8.5g式Ⅲ化合物,控温0℃~10℃向体系滴加1.5g乙酰氯。滴毕,升温至35℃~40℃保温搅拌3小时后,开始取样送HPLC跟踪至式Ⅲ化合物转化完全。降温至30℃以下,向体系滴加15mL水,搅拌30分钟,分液。二氯甲烷相用10mL饱和碳酸氢钠洗一次,浓缩二氯甲烷得棕色油状物(9.4g,收率100%)。
方法4)向100mL四口瓶加入40mL甲苯,4.4g碳酸钾和8.5g式Ⅲ化合物,控温0℃~10℃向体系滴加1.5g乙酰氯。滴毕,升温至50℃~60℃保温搅拌2小时后,开始取样送HPLC跟踪至式Ⅲ化合物转化完全。降温至30℃以下,向体系滴加15mL水,搅拌30分钟,分液。甲苯相用10mL饱和碳酸氢钠洗一次,浓缩甲苯得棕色油状物(9.3g,收率100%)。
棕色油状物可通过以下操作精制纯化:
向1000mL四口瓶加入200mL乙醇和93g棕色油状物,控温15℃~25℃滴加25g 30%HCl-乙醇溶液。在15℃~25℃保温搅拌30分钟后,缓慢滴加250mL正庚烷。保温搅拌30分钟后,2个小时降温至(-15)℃~(-10)℃。在(-15)℃~(-10)℃保温搅拌1小时后,过滤,用50mL(-15)℃乙醇:正庚烷=1:1的混合溶剂淋洗,得类白色固体。
将固体加入400mL甲苯,滴加50mL保护碳酸氢钠,搅拌30分钟,静置分液。浓缩甲苯相得到棕色油状物。(80g,收率86%):LC-MS:583[M+1]+。1H NMR(600MHz,CDCl3)δ7.33(dt,J=16.7,7.9Hz,10H),7.11(d,J=7.1Hz,3H),6.94–6.86(m,2H),6.57(s,1H),5.41(d,J=15.5Hz,1H),4.26(q,J=7.1Hz,2H),4.00(dd,J=11.2,8.7Hz,1H),3.77(d,J=12.9Hz,2H),3.62(d,J=8.5Hz,1H),3.45(d,J=12.9Hz,2H),3.21(d,J=15.3Hz,2H),3.04(dd,J=17.4,4.0Hz,1H),2.43(dd,J=10.3,7.0Hz,1H),2.34(dd,J=11.9,5.7Hz,1H),2.19(s,3H),1.33(t,J=7.1Hz,3H),1.19(dd,J=14.0,7.2Hz,1H),1.14–1.06(m,1H),1.04–0.93(m,2H),0.60(d,J=16.4Hz,6H)。
实例5(3R,4R,5S)-4-乙酰氨基-5-氨基-3-(戊烷-3-基氧基)环己-1-烯甲酸乙酯磷酸盐(Ⅰ)的合成:
方法1)向1L氢化瓶加入400mL乙酸乙酯、20g醋酸、80g式Ⅱ化合物和8g Pd/C,氮气置换3次,氢气置换5次。氢化瓶保持压力3~5bar,温度50℃~60℃,反应16小时后,开始取样送HPLC跟踪至式Ⅱ化合物转化完全,将体系过滤后,浓缩得棕色油状物。
方法2)向1L氢化瓶加入400mL四氢呋喃、20g醋酸、80g式Ⅱ化合物和6g Pd/C,氮气置换3次,氢气置换5次。氢化瓶保持压力3~5bar,温度35℃~45℃,反应8小时后,开始取样送HPLC跟踪至式Ⅱ化合物转化完全,将体系过滤后,浓缩得棕色油状物。
方法3)向1L氢化瓶加入400mL乙醇、80g式Ⅱ化合物和4g Pd/C,氮气置换3次,氢气置换5次。氢化瓶保持压力1~3.5bar,温度15℃~25℃,反应3小时后,开始取样送HPLC跟踪至式Ⅱ化合物转化完全,将体系过滤后,浓缩得棕色油状物。
棕色油状物成盐精制纯化:
将棕色油状物用400mL乙醇溶解后,转移至500mL的恒压滴液漏斗中备用。
向1000mL四口瓶加入240mL乙醇和19g 85%的磷酸,升温至48℃~52℃。将恒压滴液漏斗中的体系缓慢滴入磷酸乙醇溶液中,滴毕,在50±2℃保温搅拌2小时。16小时匀速降温至(-19)℃~(-15)℃,保温搅拌2时后,过滤,烘干得白色固体(38.5g,收率90%),纯度99.2%:LC-MS:313[M+1]+。
Claims (7)
2.根据权利要求1所述的制备方法,其特征在于,步骤a)所述的酸为苯磺酸、对甲苯磺酸。
3.根据权利要求1所述的制备方法,其特征在于,步骤b)所述的有机碱为乙酸钠、三乙胺、二异丙基乙胺,所述的无机碱为碳酸钾。
4.根据权利要求1所述的制备方法,其特征在于,步骤b)所述的乙酰化试剂为醋酸酐、乙酰氯。
5.根据权利要求1所述的制备方法,其特征在于,步骤c)的反应溶剂为乙醇、四氢呋喃、乙酸乙酯。
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