WO2023286078A1 - Procédé amélioré pour préparer un intermédiaire de morboxavir morboxil - Google Patents
Procédé amélioré pour préparer un intermédiaire de morboxavir morboxil Download PDFInfo
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- WO2023286078A1 WO2023286078A1 PCT/IN2022/050629 IN2022050629W WO2023286078A1 WO 2023286078 A1 WO2023286078 A1 WO 2023286078A1 IN 2022050629 W IN2022050629 W IN 2022050629W WO 2023286078 A1 WO2023286078 A1 WO 2023286078A1
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- compound
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- 238000000034 method Methods 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- FIDLLEYNNRGVFR-CTNGQTDRSA-N (3R)-2-[(11S)-7,8-difluoro-6,11-dihydrobenzo[c][1]benzothiepin-11-yl]-11-hydroxy-5-oxa-1,2,8-triazatricyclo[8.4.0.03,8]tetradeca-10,13-diene-9,12-dione Chemical compound OC1=C2N(C=CC1=O)N([C@@H]1COCCN1C2=O)[C@@H]1C2=C(SCC3=C1C=CC(F)=C3F)C=CC=C2 FIDLLEYNNRGVFR-CTNGQTDRSA-N 0.000 title claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims description 76
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 65
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 35
- 239000000203 mixture Substances 0.000 claims description 28
- 239000002904 solvent Substances 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 22
- UDJFFSGCRRMVFH-UHFFFAOYSA-N pyrido[2,3-d]pyrimidine Chemical compound N1=CN=CC2=CC=CN=C21 UDJFFSGCRRMVFH-UHFFFAOYSA-N 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 10
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 claims description 10
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 10
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 10
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 6
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 5
- XLLIQLLCWZCATF-UHFFFAOYSA-N 2-methoxyethyl acetate Chemical compound COCCOC(C)=O XLLIQLLCWZCATF-UHFFFAOYSA-N 0.000 claims description 5
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 5
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 5
- 239000012320 chlorinating reagent Substances 0.000 claims description 5
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 5
- 229940035429 isobutyl alcohol Drugs 0.000 claims description 5
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 5
- 229940011051 isopropyl acetate Drugs 0.000 claims description 5
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 5
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 3
- -1 Oxalyl chloride Cyanuric Chloride Chemical compound 0.000 claims description 3
- 238000011065 in-situ storage Methods 0.000 claims description 3
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- APTNXGQTESXKBG-UHFFFAOYSA-N n,n-diethylethanamine;n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(CC)CC.CCN(C(C)C)C(C)C APTNXGQTESXKBG-UHFFFAOYSA-N 0.000 claims description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- SCZNXLWKYFICFV-UHFFFAOYSA-N 1,2,3,4,5,7,8,9-octahydropyrido[1,2-b]diazepine Chemical compound C1CCCNN2CCCC=C21 SCZNXLWKYFICFV-UHFFFAOYSA-N 0.000 claims 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- HJTRSKVIYMCKJU-AWEZNQCLSA-N (3R)-11-phenylmethoxy-5-oxa-1,2,8-triazatricyclo[8.4.0.03,8]tetradeca-10,13-diene-9,12-dione Chemical compound O=C1C=CN2N[C@@H]3COCCN3C(=O)C2=C1OCC1=CC=CC=C1 HJTRSKVIYMCKJU-AWEZNQCLSA-N 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 20
- 235000019439 ethyl acetate Nutrition 0.000 description 20
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 16
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- 239000007787 solid Substances 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 description 6
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 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 description 4
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 3
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 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
- 150000002148 esters Chemical class 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 229940098779 methanesulfonic acid Drugs 0.000 description 3
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- UJJLJRQIPMGXEZ-SCSAIBSYSA-N tetrahydrofuran-2-carboxylic acid Chemical compound OC(=O)[C@H]1CCCO1 UJJLJRQIPMGXEZ-SCSAIBSYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- MFSHZGFPADYOTO-UHFFFAOYSA-N chloromethyl methyl carbonate Chemical compound COC(=O)OCCl MFSHZGFPADYOTO-UHFFFAOYSA-N 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 1
- HFGHRUCCKVYFKL-UHFFFAOYSA-N 4-ethoxy-2-piperazin-1-yl-7-pyridin-4-yl-5h-pyrimido[5,4-b]indole Chemical compound C1=C2NC=3C(OCC)=NC(N4CCNCC4)=NC=3C2=CC=C1C1=CC=NC=C1 HFGHRUCCKVYFKL-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- NJTZSWLQBQJUHK-UHFFFAOYSA-N CCCP(=O)=O Chemical compound CCCP(=O)=O NJTZSWLQBQJUHK-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- UZVGSSNIUNSOFA-UHFFFAOYSA-N dibenzofuran-1-carboxylic acid Chemical compound O1C2=CC=CC=C2C2=C1C=CC=C2C(=O)O UZVGSSNIUNSOFA-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 208000037797 influenza A Diseases 0.000 description 1
- 208000037798 influenza B Diseases 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- AYOOGWWGECJQPI-NSHDSACASA-N n-[(1s)-1-(5-fluoropyrimidin-2-yl)ethyl]-3-(3-propan-2-yloxy-1h-pyrazol-5-yl)imidazo[4,5-b]pyridin-5-amine Chemical compound N1C(OC(C)C)=CC(N2C3=NC(N[C@@H](C)C=4N=CC(F)=CN=4)=CC=C3N=C2)=N1 AYOOGWWGECJQPI-NSHDSACASA-N 0.000 description 1
- VOVZXURTCKPRDQ-CQSZACIVSA-N n-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3r)-3-hydroxypyrrolidin-1-yl]-5-(1h-pyrazol-5-yl)pyridine-3-carboxamide Chemical compound C1[C@H](O)CCN1C1=NC=C(C(=O)NC=2C=CC(OC(F)(F)Cl)=CC=2)C=C1C1=CC=NN1 VOVZXURTCKPRDQ-CQSZACIVSA-N 0.000 description 1
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
- DVCFNCQPOANJGU-UHFFFAOYSA-N oxolane-2-carbonyl chloride Chemical group ClC(=O)C1CCCO1 DVCFNCQPOANJGU-UHFFFAOYSA-N 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- ITFBHIXXJXZODU-UHFFFAOYSA-N pyrido[2,1-f][1,2,4]triazine-6,8-dione Chemical compound N=1N2C(C=NC=1)=CC(CC2=O)=O ITFBHIXXJXZODU-UHFFFAOYSA-N 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- KMIOJWCYOHBUJS-HAKPAVFJSA-N vorolanib Chemical compound C1N(C(=O)N(C)C)CC[C@@H]1NC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C KMIOJWCYOHBUJS-HAKPAVFJSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
Definitions
- the present invention relates to an improved process for the preparation of
- Baloxavir morboxil is chemically known as ( ⁇ (12aR)-12-[(llS)-7,8-Difluoro-6,ll- dihydrodibenzo[b,e]thiepinll-yl]-6,8-dioxo-3,4,6,8,12,12a-hexahydro-l//- [ 1 ,4] oxazino [3 ,4-c]pyrido [2,1-f] [1 ,2,4] triazin-7 -yl ⁇ oxy )methylmethyl carbonate of Formula (II).
- Baloxavir morboxil is an antiviral drug developed by Shionogi Co. and Roche for the treatment of influenza A and influenza B infections. It is a prodrug that is converted (by hydrolysis) to Baloxavir, the active form that exerts anti -influenza virus activity.
- WO 2017221869 A1 and CN 112079848 A1 also disclose a process for the preparation of ( 12aR)-3,4, 12, 12a-tetrahydro-7-(phenylmethoxy)- IH-[ 1 ,4] oxazino[3,4-c] pyrido[2,l-f][l,2,4]triazine-6,8-dione of Formula (I) by reacting 3,4,12,12a-tetrahydro-7-(phenylmethoxy) oxazino[3,4-c]pyrido [l,2,4]triazine-6,8-dione hemihydrate of Formula (Ilia) with (R)-2- tetrahydrofuroic acid of formula (IV) in the presence of propanephosphonic acid anhydride (T3P) and triethylamine in ethyl acetate and ethanol to produce (12aR)- 3,4,
- the main objective of the present invention is to provide a simple and cost effective process for the preparation of (12aR)-3,4,12,12a-tetrahydro-7- (phcnylmcthoxy)- oxazino[3,4-c]pyrido[2,l-f][l,2,4] triazine-6,8-dione of Formula (I) which is a key intermediate for the preparation of Baloxavir morboxil of Formula (II) with high purity and good yield on a commercial scale.
- the present invention provides an improved process for the preparation of (12aR)-3,4,12,12a-tetrahydro-7-(phenylmethoxy)- [2,1-f] [1,2,4] triazine-6,8-dione of Formula (I), comprising the steps of:
- Formula (VI) c) separating the compound of Formula (V) from the mixture obtained in above step b); d) deprotecting the compound of Formula (V) in presence of a base in suitable solvent to produce compound of Formula (I).
- Another present invention provides a process for the preparation of 3,4,12,12a- tetrahydro-7-(phenylmethoxy)- 1 H-[ 1 ,4]oxazino[3 ,4-c]pyrido triazine-6,8-dione compound of Formula (III), comprising the step of converting the compound of Formula (VI)
- the present invention provides an improved process for the preparation of (12aR)-3,4,12,12a-tetrahydro-7-(phenylmethoxy)-l//-[l,4]oxazino[3,4-c]pyrido [2,1-f] [1,2,4] triazine-6,8-dione of Formula (I), comprising the steps of: a) reacting a compound of Formula (IV) with chlorinating agent in presence of a base in a solvent to produce acid chloride compound of Formula (IVa), b) reacting the compound of Formula (IVa) in situ with compound of Formula (III) in presence of a base in a solvent to produce to produce mixture of compound of Formula (V) and compound of Formula (VI), c) separating the compound of Formula (V) from the mixture obtained in above step b), d) deprotecting the compound of Formula (V) in presence of a base in suitable solvent to produce compound of Formula (I).
- the chlorinating agent used in step a) is selected from thionyl Chloride Oxalyl chloride Cyanuric Chloride, Phosphorus oxychloride, Phosphorus trichloride, phosphorus pentachloride or mixtures thereof.
- the solvent used in step a) is an organic solvent, for example an aprotic polar solvent comprises dimethylformamide, dimethylsulfoxide, acetonitrile, dichloromethane or mixture thereof; ketone solvent comprises acetone, methylisobutylketone, 2-pentanone, ethylmethylketone, diethylketone; ester comprises ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate or mixture thereof.
- the reaction may be performed usually from 0 ° C to a boiling point of used solvent for 30 min to 48hours and then compound of formula (IVa) can be obtained by a usual procedure. The obtained compound (IVa) can be used in the next reaction directly without isolation.
- the base used in step b) is an organic or inorganic base.
- the organic base is selected from diisopropylamine, diisopropylethylamine triethylamine, dimethylamine, trimethyl amine, pyridine preferably triethylamine;
- the inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, or mixture thereof or mixtures thereof.
- the solvent used in step b) is an organic solvent, for example an aprotic polar solvent comprises dimethylformamide, dimethylsulfoxide, acetonitrile, dichloromethane or mixture thereof preferable dichloromethane; alcohol comprises methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, tert- butylalcohol, isoamylalcohol, 2-methoxyethanol or mixture thereof; ketone comprises acetone, methylisobutylketone, 2-pentanone, ethylmethylketone, diethylketone; ester comprises ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate or mixture thereof.
- an aprotic polar solvent comprises dimethylformamide, dimethylsulfoxide, acetonitrile, dichloromethane or
- Step c) performs in a suitable solvent selected from dichloromethane and ethylacetetate or mixture thereof.
- reaction may be performed from -30 C to 60 ° C for 30 min to 48hours and then compound of formula (V) can be obtained by a usual procedure.
- the base used in step d) is 1,8-Diazabicyclo [5.4.0] undec-7-ene (DBU)
- the solvent used in step d) is organic solvent, for example alcohol comprises methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, tert- butylalcohol, isoamylalcohol, 2 -methoxy ethanol or mixture thereof preferable methanol; ketone comprises acetone, methylisobutylketone, 2-pentanone, ethylmethylketone, diethylketone; ester comprises ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate or mixture thereof preferable ethyl acetate.
- alcohol comprises methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, tert- butylalcohol, isoamylalcohol,
- reaction may be performed from -30 C to 60 ° C for 30 min to 48hours and then compound of formula (I) can be obtained by a usual procedure.
- Another present invention provides a process for the preparation of 3,4,12,12a- ) triazine-6,8-dione compound of Formula (III), comprising the step of converting compound of Formula (VI) to compound of Formula (III) in presence of base and suitable solvent.
- the base used in above step is 1,8-Diazabicyclo [5.4.0] undec-7-ene (DBU)
- the solvent used in above step is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, isoamylalcohol, 2- methoxy ethanol or mixture thereof preferable methanol.
- reaction may be performed from -30 C to 60 ° C for 30 min to 48hours and then compound of formula (III) can be obtained by a usual procedure.
- Example- 1 Preparation of (12a/?)-3,4,12,12a-tetrahydro-7-(phenylmethoxy)-12- [l,2,4]triazine-6,8-dione of Formula (V).
- reaction mixture was washed with water (2000 ml), separated the organic layer and concentrated at below 40°C, resulting residue was purified in mixture of dichloromethane and ethyl acetate to produce compound of Formula (V) (118 g, wet) as a solid. Also, the filtrate and the washing solutions were combined to obtain as ethyl acetate solution of compound of formula (V), which was used for isolation of compound of Formula (VI) and preparation of compound (III).
- Example-2 Isolation of (12aS)-3,4,12,12a-tetrahydro-7-(phenylmethoxy)-12- [[(2/?)-tetrahydro-2-furanyl]carbonyl]-lH-[l,4]oxazino[3,4-c]pyrido[2,l]
- Example-4 Preparation of (12a5)-3, 4, 12,12a-tetrahydro-7-(phenylmethoxy)- -[l,4]oxazino [3,4-c]pyrido[2,l-/][l,2,4]triazine-6,8-dione of Formula (VII).
- Example-6 Preparation of 7-(hexyloxy)-3, 4, 12, 12a-tetrahydro-(12aR)-
- Example-7 Preparation of triazine-6,8-dione,12-[(llS)-7,8-difluoro-6,ll-dihydrodibenzo[b,e]thiepin-ll- yl]-7-(hexyloxy)-3,4,12,12a-tetrahydro-(12aR)-,methanesulfonate (X).
- Example-8 Preparation of 12-[(llS)-7,8-difluoro-6,ll-dihydrodibenzo[b,e] thiepin-ll-yl]-3,4,12,12a-tetrahydro-7-hydroxy-(12aR)lH-[l,4]Oxazino[3,4- c]pyrido[2,l-f][l,2,4]triazine-6,8-dione (XI) (Baloxavir)
- Example-9 Preparation ( ⁇ (12aR)-12-[(lls)-7,8-difluoro -dihydro dibenzo-[B,E]-thiepinll-yl]-6,8-dioxo-3,4,6,8,12,12a-hexahydro-lh-[l,4]- oxazino[3,4-c]pyrido[2,l-f][l,2,4]triazin-7-yl ⁇ oxy)methyl methyl carbonate of Formula (II) (Baloxavir morboxil):
- Route of synthesis-I of Route of synthesis- II of (12aR)-3,4, 12,12a-tetrahydro-7-(phenylmethoxy)-l//- [1,4] oxazino from the compound of Formula (VI) in the present invention Route of synthesis-III of Baloxavir morboxil of Formula-(II) in the present invention.
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Abstract
La présente invention concerne un procédé amélioré pour préparer du (12aR)-3,4,12,12a-tétrahydro-7-(phénylméthoxy)-1H-[1,4]oxazino[3,4-c] pyrido[2,1-f] [1,2,4]triazine-6,8-dione de formule (I). La formule I qui est un intermédiaire clé dans la synthèse de Baloxavir Morboxil de formule (II).
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WO2016175224A1 (fr) * | 2015-04-28 | 2016-11-03 | 塩野義製薬株式会社 | Dérivé de pyridone polycyclique substitué et promédicaments de celui-ci |
WO2017221869A1 (fr) * | 2016-06-20 | 2017-12-28 | 塩野義製薬株式会社 | Méthodes de production de dérivés substitués de pyridone polycyclique et cristal correspondant |
CN112679522A (zh) * | 2020-12-29 | 2021-04-20 | 南京友杰医药科技有限公司 | 一种巴洛沙韦中间体的制备方法 |
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WO2016175224A1 (fr) * | 2015-04-28 | 2016-11-03 | 塩野義製薬株式会社 | Dérivé de pyridone polycyclique substitué et promédicaments de celui-ci |
WO2017221869A1 (fr) * | 2016-06-20 | 2017-12-28 | 塩野義製薬株式会社 | Méthodes de production de dérivés substitués de pyridone polycyclique et cristal correspondant |
CN112679522A (zh) * | 2020-12-29 | 2021-04-20 | 南京友杰医药科技有限公司 | 一种巴洛沙韦中间体的制备方法 |
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