TWI557133B - 抗病毒核苷酸類似物的製備方法 - Google Patents
抗病毒核苷酸類似物的製備方法 Download PDFInfo
- Publication number
- TWI557133B TWI557133B TW101136508A TW101136508A TWI557133B TW I557133 B TWI557133 B TW I557133B TW 101136508 A TW101136508 A TW 101136508A TW 101136508 A TW101136508 A TW 101136508A TW I557133 B TWI557133 B TW I557133B
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- TW
- Taiwan
- Prior art keywords
- compound
- propyl
- ethyl
- adenine
- methoxy
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 28
- 230000000840 anti-viral effect Effects 0.000 title description 2
- 125000003729 nucleotide group Chemical group 0.000 title description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 45
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- 239000000203 mixture Substances 0.000 claims description 29
- 229930024421 Adenine Natural products 0.000 claims description 22
- 229960000643 adenine Drugs 0.000 claims description 22
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 22
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 22
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 21
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 17
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical group C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 4
- 229940011051 isopropyl acetate Drugs 0.000 claims description 4
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 239000013078 crystal Substances 0.000 claims description 3
- 238000010956 selective crystallization Methods 0.000 claims description 3
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims description 2
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical group C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 claims description 2
- WFPZOAOJEXDUGP-UHFFFAOYSA-N 2,5-dimethyl-3-piperazin-1-ylpyrazine Chemical compound CC1=CN=C(C)C(N2CCNCC2)=N1 WFPZOAOJEXDUGP-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- 229960004132 diethyl ether Drugs 0.000 claims description 2
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 2
- 229940090181 propyl acetate Drugs 0.000 claims description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims 1
- FDSGHYHRLSWSLQ-UHFFFAOYSA-N dichloromethane;propan-2-one Chemical compound ClCCl.CC(C)=O FDSGHYHRLSWSLQ-UHFFFAOYSA-N 0.000 claims 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-M phenolate Chemical compound [O-]C1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-M 0.000 claims 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 25
- 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 24
- 229940126142 compound 16 Drugs 0.000 description 24
- 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 23
- 229940125758 compound 15 Drugs 0.000 description 23
- 239000000243 solution Substances 0.000 description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 19
- 229940125797 compound 12 Drugs 0.000 description 19
- 238000002360 preparation method Methods 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 13
- WCDLCPLAAKUJNY-UHFFFAOYSA-N 4-[4-[3-(1h-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl]phenyl]morpholine Chemical compound C1COCCN1C1=CC=C(C2=CN3N=CC(=C3N=C2)C2=CNN=C2)C=C1 WCDLCPLAAKUJNY-UHFFFAOYSA-N 0.000 description 12
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000002585 base Substances 0.000 description 9
- 239000002002 slurry Substances 0.000 description 9
- 238000000926 separation method Methods 0.000 description 8
- HVLLSGMXQDNUAL-UHFFFAOYSA-N triphenyl phosphite Chemical compound C=1C=CC=CC=1OP(OC=1C=CC=CC=1)OC1=CC=CC=C1 HVLLSGMXQDNUAL-UHFFFAOYSA-N 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 7
- 235000015497 potassium bicarbonate Nutrition 0.000 description 7
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 7
- 239000011736 potassium bicarbonate Substances 0.000 description 7
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 7
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 238000006317 isomerization reaction Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 4
- 235000019799 monosodium phosphate Nutrition 0.000 description 4
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 3
- QNAYBMKLOCPYGJ-UWTATZPHSA-N L-Alanine Natural products C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 3
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 229960003767 alanine Drugs 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
- 239000000543 intermediate Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- 244000025254 Cannabis sativa Species 0.000 description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical group ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- HQFQTTNMBUPQAY-UHFFFAOYSA-N cyclobutylhydrazine Chemical compound NNC1CCC1 HQFQTTNMBUPQAY-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 230000002140 halogenating effect Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- -1 phenoxyphosphino Chemical group 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 2
- MWDNZMWVENFVHT-UHFFFAOYSA-L (2-decoxy-2-oxoethyl)-[2-[2-[(2-decoxy-2-oxoethyl)-dimethylazaniumyl]ethylsulfanyl]ethyl]-dimethylazanium;dichloride Chemical compound [Cl-].[Cl-].CCCCCCCCCCOC(=O)C[N+](C)(C)CCSCC[N+](C)(C)CC(=O)OCCCCCCCCCC MWDNZMWVENFVHT-UHFFFAOYSA-L 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- GJFNRSDCSTVPCJ-UHFFFAOYSA-N 1,8-bis(dimethylamino)naphthalene Chemical compound C1=CC(N(C)C)=C2C(N(C)C)=CC=CC2=C1 GJFNRSDCSTVPCJ-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- OEBXWWBYZJNKRK-UHFFFAOYSA-N 1-methyl-2,3,4,6,7,8-hexahydropyrimido[1,2-a]pyrimidine Chemical compound C1CCN=C2N(C)CCCN21 OEBXWWBYZJNKRK-UHFFFAOYSA-N 0.000 description 1
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- GTLNHPVVGKLBQP-UHFFFAOYSA-N C(C(C)C)N1C2(N(CCN(CC1)CCN2CC(C)C)CC(C)C)P Chemical compound C(C(C)C)N1C2(N(CCN(CC1)CCN2CC(C)C)CC(C)C)P GTLNHPVVGKLBQP-UHFFFAOYSA-N 0.000 description 1
- PHMMLQFGWPEXLW-UHFFFAOYSA-N C(C)(C)N1C2(N(CCN(CC1)CCN2C(C)C)C(C)C)P Chemical compound C(C)(C)N1C2(N(CCN(CC1)CCN2C(C)C)C(C)C)P PHMMLQFGWPEXLW-UHFFFAOYSA-N 0.000 description 1
- KZQDKDRMSDVWEY-UHFFFAOYSA-N C1=CC=CC=C1[PH2](C=1C=CC=CC=1)C1=CC=CC=C1 Chemical class C1=CC=CC=C1[PH2](C=1C=CC=CC=1)C1=CC=CC=C1 KZQDKDRMSDVWEY-UHFFFAOYSA-N 0.000 description 1
- KXJJNUPBAWFPKY-UHFFFAOYSA-N CC(C(=O)O)(O)C.C(CCCCCCCCC)(=O)O Chemical compound CC(C(=O)O)(O)C.C(CCCCCCCCC)(=O)O KXJJNUPBAWFPKY-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- QEGCPIMZHQJQAO-UHFFFAOYSA-N bromo(triphenyl)-$l^{5}-phosphane Chemical class C=1C=CC=CC=1P(C=1C=CC=CC=1)(Br)C1=CC=CC=C1 QEGCPIMZHQJQAO-UHFFFAOYSA-N 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 150000001983 dialkylethers Chemical class 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000006345 epimerization reaction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- KPADFPAILITQBG-UHFFFAOYSA-N non-4-ene Chemical compound CCCCC=CCCC KPADFPAILITQBG-UHFFFAOYSA-N 0.000 description 1
- FVZVCSNXTFCBQU-UHFFFAOYSA-N phosphanyl Chemical group [PH2] FVZVCSNXTFCBQU-UHFFFAOYSA-N 0.000 description 1
- ACVYVLVWPXVTIT-UHFFFAOYSA-M phosphinate Chemical compound [O-][PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-M 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- YAQKNCSWDMGPOY-JEDNCBNOSA-N propan-2-yl (2s)-2-aminopropanoate;hydrochloride Chemical compound Cl.CC(C)OC(=O)[C@H](C)N YAQKNCSWDMGPOY-JEDNCBNOSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- FWMUJAIKEJWSSY-UHFFFAOYSA-N sulfur dichloride Chemical compound ClSCl FWMUJAIKEJWSSY-UHFFFAOYSA-N 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
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- C07F9/02—Phosphorus compounds
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- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6509—Six-membered rings
- C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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Description
本發明案主張在2011年10月7日申請之美國臨時專利申請案號61/544,950之優先權利益,將其完整內容以引用方式併入本文。
本發明是有關抗病毒核苷酸類似物的製備方法。
美國專利號7,390,791和7,803,788(將各者的完整內容以引用方式併入本文)說明可用於治療的膦酸酯核苷酸類似物之特定前藥。一種此前藥為9-{(R)-2-[((S)-{[(S)-1-(異丙氧基羰基)乙基]胺基}苯氧基膦基)甲氧基]丙基}腺嘌呤(化合物16):
此化合物亦由化學摘要名稱已知為L-丙胺酸,N-[(S)-[[(1R)-2-(6-胺基-9H-嘌呤-9-基)-1-甲基乙氧基]甲基]苯氧基膦基]-1-甲基乙酯。美國專利號7,390,791和7,803,788亦揭示此化合物的單反丁烯二酸鹽形式及其製備方法(參見例如實例4)。
化合物12、化合物13(其中X為鹵基)和化合物15:
為可用於製備化合物16之合成中間物。化合物15經描述為磷中心上的非鏡像異構物之混合物。組成化合物15之混合物的兩種非鏡像異構物在此顯示為化合物15a和15b。異構物15a在結構上與化合物16相同。
目前對用於製備化合物12、13、15和16之改良方法有需求。特別對用於製備具有高非鏡像異構性純度的化合物13、15和16之改良方法有需求。此等改良方法可比目前可行之方法提供更高的產量、更容易執行或使用更低成本或更低毒性的試劑。
本發明說明一種使用結晶誘發之動態析離(crystallization-induced dynamic resolution)而分離出9-{(R)-2-[((S)-{[(S)-1-(異丙氧基羰基)乙基]胺基}苯氧基膦基)甲氧基]丙基}腺嘌呤(化合物16)之改良方法;用於製備具有高非鏡像異構性純度的化合物13和15之改良方法
;及用於製備化合物12之之改良方法。
據此,在一個具體例中,其係提供一種包含使含有下列者之溶液接受供選擇性結晶出9-{(R)-2-[((S)-{[(S)-1-(異丙氧基羰基)乙基]胺基}苯氧基膦基)甲氧基]丙基}腺嘌呤的條件之方法:a)適合的溶劑;b)適合的鹼;c)非鏡像異構性混合物9-{(R)-2-[((R,S)-{[(S)-1-(異丙氧基羰基)乙基]胺基}苯氧基膦基)甲氧基]丙基}腺嘌呤,及隨意的d)一或多個9-{(R)-2-[((S)-{[(S)-1-(異丙氧基羰基)乙基]胺基}苯氧基膦基)甲氧基]丙基}腺嘌呤晶種。
在另一具體例中,其係提供一種製備非鏡像異構性純度至少約90%的化合物13之方法,其係藉由將化合物12之甲苯溶液:
以亞硫醯氯處理,以提供化合物13,其中X=Cl。
在另一具體例中,其係提供一種製備9-{(R)-2-[((R,S)-{[(S)-1-(異丙氧基羰基)乙基]胺基}苯氧基膦基)甲氧基]丙基}腺嘌呤(化合物15)之方法,該化合物15為非鏡像異構性純度至少約90%的化合物16,該方法包含將非鏡像異構性純度至少約90%的化合物13(其中X為鹵基):
在提供化合物15之條件下以胺11處理:
該化合物15為非鏡像異構性純度至少約90%的化合物16(亦即異構物15a)。
在另一具體例中,其係提供一種製備化合物12之方法
該方法包含將PMPA:
在適合的鹼存在下以亞磷酸三苯酯處理,以提供化合物12。
亦提供本文所揭示之新穎方法及中間物。
在本文所列示用於基團、取代基及範圍之特定值僅以例證為目的;該等不排除在用於基團及取代基之限定範圍內的其他限定值或其他值。
藉由結晶誘發之動態析離來製備化合物16
在一個具體例中,其係提供一種結晶誘發之動態析離9-{(R)-2-[((R,S)-{[(S)-1-(異丙氧基羰基)乙基]胺基}苯氧基膦基)甲氧基]丙基}腺嘌呤(化合物15)之方法:
以提供9-{(R)-2-[((S)-{[(S)-1-(異丙氧基羰基)乙基]胺基}苯氧基膦基)甲氧基]丙基}腺嘌呤(化合物16)。該方法包含在亦提供選擇性結晶出9-{(R)-2-[((S)-{[(S)-1-(異丙氧基羰基)乙基]胺基}苯氧基膦基)甲氧基]丙基}腺嘌呤的條件下使含有下列者之溶液接受供磷中心差向異構化的條件:a)適合的溶劑;b)適合的鹼;c)9-{(R)-2-[((R,S)-{[(S)-1-(異丙氧基羰基)乙基]胺基}苯氧基膦基)甲氧基]丙基}腺嘌呤;及隨意的d)一或多個9-{(R)-2-[((S)-{[(S)-1-(異丙氧基羰基)乙基]胺基}苯氧基膦基)甲氧基]丙基}腺嘌呤晶種。
結晶可在任何適合的溶劑中進行。例如,其可在非質子性有機溶劑中或其混合物中進行。例如,非質子性有機溶劑可包含乙酸乙酯、乙酸甲酯、乙酸丙酯、乙酸異丙酯、二***、二異丙醚、四氫呋喃、二氯甲烷、丙酮、甲基乙基酮、甲基第三丁基醚、甲苯、或乙腈、或其混合物。在一個具體例中,溶劑包含乙腈。
析離(resolution)可在任何適合的鹼存在下進行。例如,析離可在選自下列者之鹼存在下進行:1,5-二氮雜雙環[4.3.0]壬-5-烯(DBN)、1,8-二氮雜雙環[5.4.0]十一碳-7-烯(DBU)、7-甲基-1,5,7-三氮雜雙環[4.4.0]癸-5-烯(MTBD)、四甲基胍、Verkade鹼(例如,2,8,9-三異丙基-2,5,8,9-四氮雜-1-磷雙環[3.3.3]十一烷和2,8,9-三異丁基-2,5,8,9-四氮雜-1-磷雙環[3.3.3]十一烷)、金屬碳酸鹽(例如,MxCO3)、金屬苯氧化物(M+ -OPh)、及與氟離子來源(例如,R4N+ -F、TASF(二氟三甲基矽酸參(二甲基胺基)鋶)或TBAT(三苯基二氟矽酸四丁基銨)組合之PhOTMS、及其混合物,其中各M為適合的金屬,諸如鹼金屬或鹼土金屬,及各R為例如(C1-C6)烷基。在一個特定的具體例中,鹼為DBU。
析離可在任何適合的溫度下進行,例如從約0℃至約50℃之範圍內的溫度。在一個特定的具體例中,析離係在約20℃之溫度下進行。
在一個特定的具體例中,析離係在酚存在下進行。
化合物16在起始非鏡像異構性混合物中的百分比可
在從約0%至約99%之範圍內之任何值。在本發明的一個具體例中,化合物16在起始非鏡像異構性混合物中的百分比可在從約0%至約20%之範圍內。在一個具體例中,化合物16在起始非鏡像異構性混合物中的百分比可在從約20%至約99%之範圍內。在一個具體例中,化合物16在起始非鏡像異構性混合物中的百分比可在從約50%至約99%之範圍內。在一個具體例中,最終化合物16具有至少約90%,約95%,約97%,或約99%非鏡像異構性純度。在一個具體例中,最終化合物16含有少於1%之任何非鏡像異構性雜質。在一個具體例中,最終化合物16不含有任何可檢測出之非鏡像異構性雜質。
具有高非鏡像異構性純度的化合物13之製備
非鏡像異構性純度至少約90%的化合物13(其中X為鹵基)可藉由將化合物12以適合的鹵化劑處理而製得。例如,化合物13可藉由將化合物12以鹵化劑處理而製得,諸如亞硫醯氯(SOCl2)、草醯氯(C2O2Cl2)、三氯化磷(PCl3)、氯三苯基磷烷鹽、亞硫醯溴(SOBr2)、草醯溴(C2O2Br2)、三溴化磷(PBr3)或溴三苯基磷烷鹽。反應可在適合的有機溶劑中在適合的溫度下(例如,在從約-20℃至
約100℃之範圍內的溫度)進行。適合的溶劑包括四氫呋喃、2-甲基四氫呋喃、二氯甲烷、乙腈、甲苯、氯苯、1,2-二氯乙烷、1,4-二烷、環丁碸、及三氯乙烯、及其混合物。
在一個具體例中,將化合物12在從約22℃至約110℃之溫度下在甲苯中以亞硫醯氯處理,以提供非鏡像異構性純度至少約90%的化合物13a:
在一個具體例中,最終化合物13a具有至少約90%,約95%,約97%,或約99%非鏡像異構性純度。在一個具體例中,最終化合物13a含有少於1%之任何非鏡像異構性雜質。在一個具體例中,最終化合物13a不含有任何可檢測出之非鏡像異構性雜質。
具有高非鏡像異構性純度的化合物15之製備
化合物15可藉由將非鏡像異構性純度至少約90%的化合物13(其中X為鹵基)在提供化合物15的條件下以胺
11處理而製得,該化合物15為非鏡像異構性純度至少約90%的特定異構物15a,在本文亦以化合物16代表。例如,化合物15可藉由將化合物13在適合的溫度下(例如,在從約-78℃至約25℃之範圍內的溫度)在適合的有機溶劑中以胺11處理而製得。適合的溶劑包括有機溶劑,諸如四氫呋喃、2-甲基四氫呋喃、二氯甲烷、1,2-二氯乙烷、三氯乙烯、1,4-二烷、乙腈、甲苯、氯苯、環丁碸、及乙酸異丙酯、及其混合物。反應可便利地在適合的鹼存在下進行,諸如三乙胺((C2H5)3N)、N,N-二異丙基乙胺([(CH3)2CH]2NC2H5)或1,8-雙(二甲基胺基)-萘(質子海綿,C14H18N2)。在反應之後,可將所得材料以含有適合的清洗試劑之水溶液清洗,該清洗試劑諸如磷酸二氫鈉(NaH2PO4)、碳酸氫鉀(KHCO3)、檸檬酸(C6H8O7)或碳酸氫鈉(NaHCO3)。可將所得有機溶液經適合的乾燥劑乾燥,例如硫酸鈉、硫酸鎂或氯化鈣,以提供化合物15,其為非鏡像異構性純度至少約90%的化合物16。
在一個具體例中,將非鏡像異構性純度至少約90%的化合物13(其中X為氯)在三乙胺的存在下在-25℃至25℃之溫度下在二氯甲烷中以胺11處理。接著將所得反應混合物以含有磷酸二氫鈉(NaH2PO4)和碳酸氫鉀(KHCO3)之水溶液清洗且經硫酸鈉乾燥,以提供化合物15,其為非鏡像異構性純度至少約90%的化合物16。在一個具體例中,起始化合物13及所得化合物15具有至少約95%或97%非鏡像異構性純度。在一個具體例中,最終化合物15含有至
少約90%,約95%,約97%,或約99%非鏡像異構性純度的化合物16。在一個具體例中,最終化合物15含有少於1%之任何非鏡像異構性雜質。
化合物12之製備
化合物12可如例如美國專利號7,390,791中所述而製得或可如本文所述而製得。在一個具體例中,其係提供一種製備化合物12之方法,其包含將PMPA在適合的鹼存在下以亞磷酸三苯酯處理,以提供化合物12。反應可便利地在適合的溶劑中進行,諸如乙腈、N-甲基吡咯啶酮(NMP)、二氯乙烷、吡啶、乙酸烷酯(例如,乙酸乙酯)、或二烷基醚(例如,二***)、或其混合物。反應亦可便利地在適合的鹼存在下進行,諸如三烷基胺(例如,三乙胺)、2-甲基咪唑、二甲基胺基吡啶(DMAP)、1,5-二氮雜雙環[4.3.0]壬-5-烯(DBN)、1,8-二氮雜雙環[5.4.0]十一碳-7-烯(DBU)、或吡啶、或其混合物。反應亦可便利地在適合的溫度下進行,諸如從約20℃至約120℃之溫度(例如,從約20℃至約82℃)。在一個特定的具體例中,將PMPA在約80℃下在三乙胺和二甲胺基吡啶的存在下在乙腈中以亞磷酸三苯酯處理,以提供化合物12。
以下為非限制性例證實例。
a.化合物11之製備。將L-丙胺酸異丙酯鹽酸鹽(化合物10)(1公斤,5.97莫耳,1.0當量)及碳酸氫鉀(1.45公斤,14.5莫耳,2.43當量)在DCM(4公斤)中攪動10至14小時,以最大攪動維持罐溫度介於19℃與25℃之間。接著將混合物過濾且以DCM(2公斤)沖洗。將濾液經4埃分子篩床乾燥,直到溶液的水含量0.05%為止。接著將含有化合物11的所得貯存溶液冷卻至-20℃之罐溫度且保存以供進一步使用。
b.化合物13a之製備。將化合物12(1公斤,2.75莫耳,1.00當量)以10等份經2小時添加在60℃下在乙腈(5.5公斤)中的亞硫醯氯(0.72公斤,6.02莫耳,2.19當量)之溶液中。接著將罐溫度調整至70℃且攪拌1至3小
時,直到認為反應完成為止。接著將罐溫度調整至40℃且施以真空。將混合物蒸餾至乾燥,維持40℃之最大夾套溫度。接著將乾燥之殘餘物溶解在二氯甲烷(30公斤)中且將罐溫度調整至19℃至25℃。保持含有化合物13a之所得漿液以供進一步使用。
c.化合物15之製備。將含有化合物13a(1.0當量)之漿液經最少2小時添加至-25℃下的L-丙胺酸異丙酯11(4.82當量)之貯存溶液中,維持罐溫度-10℃。接著將混合物保持在-10℃之溫度下至少30分鐘,接著使用水濕性pH紙檢查pH。若pH<4,則以三乙胺調整至pH 4-7。接著將罐溫度調整至室溫(19℃至25℃)。在單獨的容器中製備在水(16公斤)中的磷酸二氫鈉(2.2公斤,18莫耳,6.90當量)之溶液。將一半的磷酸二氫鈉溶液裝入膦醯胺酸鹽反應器中且劇烈攪拌。將層沉降且分溶。將有機層再以剩餘一半的磷酸二氫鈉溶液清洗。在單獨的容器中製備在水(5.5公斤)中的碳酸氫鉀(1.1公斤,11莫耳,4.22當量)之溶液。將一半的碳酸氫鉀溶液裝入有機相中且劇烈攪拌。將層沉降且分溶。將有機層再以剩餘一半的碳酸氫鉀溶液清洗,接著以最後的水(3.3公斤)洗液清洗。接著保留且蒸餾有機相至約6公升體積。分析所得溶液的水含量。若水含量>1.0%,則可重複裝入DCM且蒸餾至約6公升。當溶液的水含量少於或約1.0%時,則在排出在DCM中的貯存溶液之前,將罐溫度調整至19℃至25℃,以提供非鏡像異構性混合物9-{(R)-2-[((R,S)-{[(S)-1-
(異丙氧基羰基)乙基]胺基}苯氧基膦基)甲氧基]丙基}腺嘌呤(化合物15)。1H NMR(400 MHz,CDCl3):δ 1.20-1.33(m,12H),3.62-3.74(m,1H),3.86-4.22(m,5H),4.30-4.44(m,1H),4.83-5.10(m,1H),6.02(br s,3H),7.18-7.34(m,5H),7.98-8.02(m,1H),8.32-8.36(m,1H);31P NMR(162 MHz,CDCl3):δ.21.5,22.9。
將乙腈中的22重量%之9-{(R)-2-[((R,S)-{[(S)-1-(異丙氧基羰基)乙基]胺基}苯氧基膦基)甲氧基]丙基}腺嘌呤(化合物15)溶液(2.3公斤溶液,0.51公斤化合物15,1.1莫耳,1當量)裝入配備有頂置攪拌器、蒸餾裝置及氮入口的容器中。將混合物在45℃至55℃之溫度範圍內在100至300毫巴下蒸餾而濃縮成30至35重量%之最終濃度。接著移除蒸餾裝置且將溶液冷卻至20℃。將溶液以2.0%之化合物16接種且容許在20℃下攪拌1小時。添加酚(9.9公克,0.11莫耳,0.1當量)及DBU(16公克,0.11莫
耳,0.1當量)且將混合物再攪拌24小時,或直到剩餘在溶液中的化合物16之重量百分比少於12%為止。接著將漿液冷卻至0℃且在0℃下再攪拌18小時。將漿液過濾且在0℃下以1:1之乙酸異丙酯:乙腈溶液(1.5公升)清洗。將固體在50℃之真空烘箱中乾燥,得到成為白色固體的0.40公斤化合物16(80%產率)。1H NMR(400 MHz,CDCl3):δ 1.21(m,9H),1.28(d,J=7.0 Hz,3H),3.65(dd,J=13.1,10.7,1H)4.00(m,4H),4.33(dd,J=14.4,3.1 Hz,1H),5.00(m,1H)6.00(bs,2H),6.99(m,2H),7.07(m,1H),7.19(m,2H),7.97(s,1H),8.33(s,1H)。31P NMR(162 MHz,CDCl3):δ.20.8。
將亞硫醯氯(3.0毫升,41毫莫耳,1.5當量)添加至周圍溫度下在甲苯(60毫升)中的化合物12(10.0公克,27.5毫莫耳,1.00當量)之漿液中。將漿液加熱至70℃且攪動48至96小時,直到以HPLC認為完成反應及非鏡像異構性富集為止(目標:>97.0%之轉化率,化合物12轉化成化合物13a,及>90:10之非鏡像異構比的化合物13a)。將混合物以真空蒸餾而濃縮至乾燥且將乾燥之殘餘物溶解在甲苯(50毫升)中。保持含有化合物13a之所得漿液在周圍溫度下以供進一步使用。
)-{[(S)-1-(異丙氧基羰基)乙基]胺基}苯氧基膦基)甲氧基]丙基}腺嘌呤(化合物15)之製備
將在甲苯(50毫升)中含有非鏡像異構性純度至少90%的化合物13a(1.00當量)之漿液經最少45分鐘添加至-25℃下在DCM(80毫升)中的L-丙胺酸異丙酯11(4.50當量)之溶液中,維持內部溫度-20℃。接著將混合物保持在-20℃之溫度下至少30分鐘且使用水濕性pH紙檢查pH。若pH<4,則以三乙胺調整至pH 4至7。將罐溫度調整至室溫(19℃至25℃)。將混合物轉移至分液漏斗中且依序以10% w/v之磷酸二氫鈉水溶液(2 x 50毫升)、15% w/v之碳酸氫鉀水溶液(2 x 20毫升)及水(50毫升)清洗。將最終有機層經無水硫酸鈉乾燥,過濾且在真空中濃縮成黏的琥珀色油。將油溶解在甲苯/乙腈(4:1)(50毫升)中,將溶液以9-{(R)-2-[((R,S)-{[(S)-1-(異丙氧基羰基)乙基]胺基}苯氧基膦基)甲氧基]丙基}腺嘌呤(約1毫克,99:1之非鏡像異構比)接種且在周圍溫度下攪拌2小時。將所得漿液過濾,將濾餅以甲苯/乙腈(4:1)(15毫升)清洗且在40℃之真空烘箱中乾燥16小時,得到成為白色固體的產物9-{(R)-2-[((R,S)-{[(S)-1-(異丙氧基羰基)乙基]胺基}苯氧基膦基)甲氧基]丙基}腺嘌呤(化合物15)(10.0公克,76.4%,有利於化合物16的97.5:2.5之非鏡像異構比)。1H NMR(400 MHz,CDCl3):δ 1.20-1.33(m,12H),3.62-3.74(m,1H),3.86-4.22(m,5H),4.30-4.44(m,1H),4.83-5.10(m,1H),6.02(br s,3H),7.18-7.34(m,5H),7.98-
8.02(m,1H),8.32-8.36(m,1H);31P NMR(162 MHz,CDCl3):δ.21.5,22.9。
將PMPA(100.0公克,0.35莫耳,1當量)裝入配備有頂置攪拌器、回流冷凝器及氮入口的容器中,接著裝入乙腈(800毫升)。將三乙胺(71.0公克,0.70莫耳,2當量)裝入容器中,接著裝入DMAP(42.6公克,0.35莫耳,1當量)及亞磷酸三苯酯(162.1公克,0.52莫耳,1.5當量)。將混合物加熱至80℃且在80℃下攪動48小時,或直到以31P NMR認為反應完成為止(取得直接來自反應的樣品且添加含有在D2O中的10% H3PO2之***物。所形成之中間物為PMPA無水物且為7至8 ppm;產物為12.3至12.6 ppm。當少於5%之無水物存在時,則認為反應完成)。將反應混合物蒸餾至約1.5體積之乙腈且以乙酸乙酯(200毫升)和水(300毫升)稀釋。將水層分開且以乙酸乙酯(200毫升)清洗兩次。將水層再裝入容器中且將pH使用12.1M HCl(21.0毫升)調整至pH 3。接著將反應以0.05%化合物12接種且容許在25℃下攪拌。經20分鐘添加額外的12.1M HCl(7.0毫升),直到達成pH 2為止。容許在周圍溫度下攪拌30分鐘而結晶且接著經2小時冷卻至10℃。一旦在10℃時,容許在10℃下攪拌2.5小時而結晶。將漿液過濾且以pH 1.5之水(200公克)清洗。在真空烘箱中乾燥之後,獲得成為白色固體的102.2公克化合物12(81%
產率)。1H NMR(400 MHz,D2O):δ 1.31(d,J=6.1 Hz,3H),3.59(dd,J=14.0,9.0 Hz,1H),3.85(dd,J=14.0,9.0 Hz,1H),4.1(m,1H),4.3(dd,J=15.0,9.0 Hz,1H),4.5(dd,J=15.0,2 Hz,1H),6.75(d,J=7 Hz,2H),7.15(t,J=7 Hz,1H),7.25(t,J=7 Hz,2H),8.26(s,1H),8.35(s,1H)。31P NMR(162 MHz,D2O):δ.14.8。
將所有刊物、專利及專利文件以引用方式併入本文,如同個別以引用方式併入。本發明已參考各種特定且較佳的具體例和技術予以說明。然而,應瞭解可進行許多變化及修改,但是仍在本發明的精神和範圍內。
Claims (8)
- 一種方法,其包括使含有下列者之溶液:a)適合的溶劑;b)適合的鹼;及c)9-{(R)-2-[((R,S)-{[(S)-1-(異丙氧基羰基)乙基]胺基}苯氧基膦基)甲氧基]丙基}腺嘌呤,接受供選擇性結晶出9-{(R)-2-[((S)-{[(S)-1-(異丙氧基羰基)乙基]胺基}苯氧基膦基)甲氧基]丙基}腺嘌呤的條件。
- 根據申請專利範圍第1項之方法,其中該溶液另外包含一或多個9-{(R)-2-[((S)-{[(S)-1-(異丙氧基羰基)乙基]胺基}苯氧基膦基)甲氧基]丙基}腺嘌呤晶種。
- 根據申請專利範圍第1或2項之方法,其中該溶劑包含非質子性有機溶劑。
- 根據申請專利範圍第1-2項中任一項之方法,其中該溶劑包含乙酸乙酯、乙酸甲酯、乙酸丙酯、乙酸異丙酯、二***、二異丙醚、四氫呋喃、二氯甲烷、丙酮、甲基乙基酮、甲基第三丁基醚、甲苯、或乙腈、或其混合物。
- 根據申請專利範圍第4項之方法,其中該溶劑包含乙腈。
- 根據申請專利範圍第1-2項中任一項之方法,其中該鹼為1,5-二氮雜雙環[4.3.0]壬-5-烯、1,8-二氮雜雙環[5.4.0]十一碳-7-烯、7-甲基-1,5,7-三氮雜雙環[4.4.0]癸-5- 烯、四甲基胍、Verkade鹼、金屬碳酸鹽、金屬苯氧化物、或與氟離子來源組合之PhOTMS、或其混合物。
- 根據申請專利範圍第6項之方法,其中該鹼為1,8-二氮雜雙環[5.4.0]十一碳-7-烯。
- 根據申請專利範圍第1-2項中任一項之方法,其中該溶液另外包含酚。
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Families Citing this family (50)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3070088A1 (en) | 2011-08-16 | 2016-09-21 | Gilead Sciences, Inc. | Tenofovir alafenamide hemifumarate |
BR112014011340A2 (pt) * | 2011-10-07 | 2017-06-13 | Gilead Sciences Inc | métodos para a preparação de análogos de nucleotídeos antivirais |
CN103665043B (zh) | 2012-08-30 | 2017-11-10 | 江苏豪森药业集团有限公司 | 一种替诺福韦前药及其在医药上的应用 |
CA2914381A1 (en) | 2013-06-07 | 2014-12-11 | Cipla Limited | An efficient process for separation of diastereomers of 9-[(r)-2-[[(r,s)-[[(s)-1-(isopropoxycarbonyl)ethyl]amino]-phenoxyphosphinyl] methoxy]propyl]adenine |
CN104628773B (zh) * | 2013-11-06 | 2018-10-23 | 杭州和泽医药科技有限公司 | (r)-9-[2-(磷酰苯酚基甲氧基)丙基]腺嘌呤的制备方法 |
WO2015079455A2 (en) * | 2013-11-27 | 2015-06-04 | Laurus Labs Private Limited | A recycling process for preparing tenofovir alafenamide diastereomers |
EP3077404B1 (en) * | 2014-01-14 | 2020-10-07 | Mylan Laboratories Ltd. | Purification of tenofovir alafenamide and its intermediates |
TWI660965B (zh) | 2014-01-15 | 2019-06-01 | 美商基利科學股份有限公司 | 泰諾福韋之固體形式 |
CN105518011B (zh) * | 2014-04-21 | 2018-07-27 | 四川海思科制药有限公司 | 氨基磷酸酯类衍生物制备方法及其中间体和中间体的制备方法 |
WO2015197006A1 (zh) * | 2014-06-25 | 2015-12-30 | 四川海思科制药有限公司 | 一种取代的氨基酸硫酯类化合物、其组合物及应用 |
CN105399771B (zh) | 2014-07-21 | 2020-11-24 | 江苏豪森药业集团有限公司 | 替诺福韦前药晶型及其制备方法和用途 |
CN108148094A (zh) * | 2014-11-12 | 2018-06-12 | 四川海思科制药有限公司 | 一种替诺福韦艾拉酚胺富马酸盐晶型c及其制备方法和用途 |
CN104817593B (zh) * | 2015-04-27 | 2016-11-16 | 广州同隽医药科技有限公司 | 半富马酸替诺福韦艾拉酚胺关键中间体的合成工艺 |
KR20180044303A (ko) | 2015-08-05 | 2018-05-02 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | 균질한 올리고머의 제조를 위한 키랄 시약 |
TWI616452B (zh) * | 2015-08-26 | 2018-03-01 | Preparation method of nucleoside analog and intermediate thereof | |
CN105330700A (zh) * | 2015-12-17 | 2016-02-17 | 中国药科大学 | 富马酸替诺福韦艾拉酚胺杂质的制备方法 |
WO2017118928A1 (en) | 2016-01-06 | 2017-07-13 | Lupin Limited | Process for the separation of diastereomers of tenofovir alafenamide |
CZ2016156A3 (cs) * | 2016-03-17 | 2017-09-27 | Zentiva, K.S. | Způsob přípravy diastereomerně čistého Tenofoviru Alafenamidu nebo jeho solí |
CN107286190A (zh) * | 2016-04-13 | 2017-10-24 | 刘沛 | 核苷之烃氧基苄基氨基磷酸/膦酸酯衍生物的制备及其医药用途 |
EP3455218A4 (en) | 2016-05-10 | 2019-12-18 | C4 Therapeutics, Inc. | C3 CARBON-BASED GLUTARIMIDE DEGRONIMERS FOR TARGET PROTEIN REDUCTION |
WO2017197036A1 (en) | 2016-05-10 | 2017-11-16 | C4 Therapeutics, Inc. | Spirocyclic degronimers for target protein degradation |
EP3454856A4 (en) | 2016-05-10 | 2019-12-25 | C4 Therapeutics, Inc. | HETEROCYCLIC DEGRONIMERS FOR TARGET PROTEIN REDUCTION |
CN106565785B (zh) * | 2016-11-09 | 2019-11-12 | 周雨恬 | 一种具有抗hbv/hiv活性的核苷氨基磷酸酯类化合物及其盐和用途 |
CN106946935B (zh) * | 2017-04-28 | 2020-01-07 | 福建广生堂药业股份有限公司 | 一种非对映异构体核苷衍生物的制备方法 |
US10590136B2 (en) * | 2017-10-04 | 2020-03-17 | Celgene Corporation | Processes for the preparation of cis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide |
CN109942633B (zh) * | 2017-12-20 | 2021-08-31 | 上海新礼泰药业有限公司 | 替诺福韦艾拉酚胺中间体的制备方法 |
CN109942632B (zh) * | 2017-12-20 | 2021-08-31 | 上海博志研新药物研究有限公司 | 替诺福韦艾拉酚胺中间体的制备方法 |
CN110092803A (zh) * | 2018-01-31 | 2019-08-06 | 北京睿创康泰医药研究院有限公司 | 替诺福韦艾拉酚胺富马酸盐工艺杂质的制备及其应用 |
CN108409788B (zh) * | 2018-03-12 | 2020-05-08 | 科兴生物制药股份有限公司 | 一种富马酸替诺福韦艾拉酚胺的制备方法 |
CN110305163A (zh) * | 2018-03-27 | 2019-10-08 | 北京济美堂医药研究有限公司 | 替诺福韦艾拉酚胺半富马酸盐的制备方法 |
CN108467410B (zh) * | 2018-04-09 | 2021-04-09 | 重庆三圣实业股份有限公司 | 一种taf中间体的制备方法及产品和应用 |
CN108484672A (zh) * | 2018-05-23 | 2018-09-04 | 中国药科大学制药有限公司 | 磷丙替诺福韦的手性拆分方法 |
CN108822149B (zh) * | 2018-06-01 | 2020-08-11 | 成都苑东生物制药股份有限公司 | 一种富马酸替诺福韦艾拉酚胺关键中间体的制备方法 |
CN110283208B (zh) * | 2018-06-22 | 2022-07-08 | 南京济群医药科技股份有限公司 | 一种替诺福韦艾拉酚胺的手性拆分方法 |
CN109081853A (zh) * | 2018-09-03 | 2018-12-25 | 南京正大天晴制药有限公司 | 一种磷丙替诺福韦有关物质的制备方法 |
CN111484527A (zh) * | 2019-01-25 | 2020-08-04 | 上海清松制药有限公司 | 一种替诺福韦艾拉酚胺中间体的制备方法 |
CN111943981A (zh) * | 2019-05-14 | 2020-11-17 | 博瑞生物医药泰兴市有限公司 | 一种磷丙替诺福韦的制备方法 |
CN112175003B (zh) * | 2019-07-01 | 2022-02-15 | 上海医药工业研究院 | 一种苯基氢膦酸酯及其中间体的制备方法 |
US20220257619A1 (en) | 2019-07-18 | 2022-08-18 | Gilead Sciences, Inc. | Long-acting formulations of tenofovir alafenamide |
CN112390824B (zh) * | 2019-08-19 | 2022-07-05 | 鲁南制药集团股份有限公司 | 一种替诺福韦艾拉酚胺中间体的制备方法 |
CN110981911A (zh) * | 2019-10-08 | 2020-04-10 | 浙江车头制药股份有限公司 | 一种替诺福韦艾拉酚胺的制备方法 |
CN111171076A (zh) * | 2019-12-26 | 2020-05-19 | 合肥启旸生物科技有限公司 | 一种替诺福韦二聚体的制备方法 |
KR20220156884A (ko) | 2020-03-20 | 2022-11-28 | 길리애드 사이언시즈, 인코포레이티드 | 4'-c-치환된-2-할로-2'-데옥시아데노신 뉴클레오시드의 프로드러그 및 이의 제조 및 사용 방법 |
KR20210125298A (ko) | 2020-04-08 | 2021-10-18 | 주식회사 파마코스텍 | 테노포비어 알라펜아미드 헤미타르트레이트의 신규한 제조방법 |
AU2021377614A1 (en) | 2020-11-11 | 2023-06-22 | Gilead Sciences, Inc. | METHODS OF IDENTIFYING HIV PATIENTS SENSITIVE TO THERAPY WITH gp120 CD4 BINDING SITE-DIRECTED ANTIBODIES |
KR20220141457A (ko) | 2021-04-13 | 2022-10-20 | 경동제약 주식회사 | 신규 결정형의 테노포비어 알라펜아미드 말레산염 및 이를 포함하는 약제학적 조성물 |
TW202400172A (zh) | 2022-04-06 | 2024-01-01 | 美商基利科學股份有限公司 | 橋聯三環胺甲醯基吡啶酮化合物及其用途 |
US20240034724A1 (en) | 2022-07-01 | 2024-02-01 | Gilead Sciences, Inc. | Therapeutic compounds useful for the prophylactic or therapeutic treatment of an hiv virus infection |
US20240083984A1 (en) | 2022-08-26 | 2024-03-14 | Gilead Sciences, Inc. | Dosing and scheduling regimen for broadly neutralizing antibodies |
US20240226130A1 (en) | 2022-10-04 | 2024-07-11 | Gilead Sciences, Inc. | 4'-thionucleoside analogues and their pharmaceutical use |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1443189A (zh) * | 2000-07-21 | 2003-09-17 | 吉里德科学公司 | 核苷酸膦酸酯类似物前药及其筛选和制备方法 |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050239054A1 (en) * | 2002-04-26 | 2005-10-27 | Arimilli Murty N | Method and compositions for identifying anti-HIV therapeutic compounds |
PT2258376T (pt) * | 2004-07-27 | 2019-05-31 | Gilead Sciences Inc | Análogos fosfonatados de compostos inibidores do vih |
CN101448838B (zh) | 2006-03-29 | 2012-07-04 | 吉里德科学公司 | 制备hiv蛋白酶抑制剂的方法 |
PL2038290T3 (pl) * | 2006-07-07 | 2014-03-31 | Gilead Sciences Inc | Modulatory receptora Toll-podobnego 7 |
WO2008011116A2 (en) * | 2006-07-21 | 2008-01-24 | Gilead Sciences, Inc. | Aza-peptide protease inhibitors |
BRPI0714880A2 (pt) * | 2006-07-24 | 2013-05-21 | Gilead Sciences Inc | inibidores da transcriptase reversa do hiv |
KR20100041798A (ko) * | 2007-06-29 | 2010-04-22 | 한국화학연구원 | 신규 hiv 역전사효소 억제제 |
EP3070088A1 (en) | 2011-08-16 | 2016-09-21 | Gilead Sciences, Inc. | Tenofovir alafenamide hemifumarate |
BR112014011340A2 (pt) | 2011-10-07 | 2017-06-13 | Gilead Sciences Inc | métodos para a preparação de análogos de nucleotídeos antivirais |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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