JP2010539101A - インテグラーゼ阻害剤の調製のためのプロセスおよび中間体 - Google Patents
インテグラーゼ阻害剤の調製のためのプロセスおよび中間体 Download PDFInfo
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- JP2010539101A JP2010539101A JP2010524261A JP2010524261A JP2010539101A JP 2010539101 A JP2010539101 A JP 2010539101A JP 2010524261 A JP2010524261 A JP 2010524261A JP 2010524261 A JP2010524261 A JP 2010524261A JP 2010539101 A JP2010539101 A JP 2010539101A
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- 238000000034 method Methods 0.000 title claims abstract description 53
- 238000002360 preparation method Methods 0.000 title claims description 14
- 239000000543 intermediate Substances 0.000 title abstract description 8
- 239000002850 integrase inhibitor Substances 0.000 title description 2
- 229940124524 integrase inhibitor Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 198
- 150000003839 salts Chemical class 0.000 claims abstract description 58
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 28
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 16
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 16
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 14
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims description 8
- 239000001103 potassium chloride Substances 0.000 claims description 8
- 235000011164 potassium chloride Nutrition 0.000 claims description 8
- WVUCPRGADMCTBN-UHFFFAOYSA-M potassium;3-ethoxy-3-oxopropanoate Chemical compound [K+].CCOC(=O)CC([O-])=O WVUCPRGADMCTBN-UHFFFAOYSA-M 0.000 claims description 8
- -1 1-imidazolyl Chemical group 0.000 claims description 7
- 239000001569 carbon dioxide Substances 0.000 claims description 7
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 7
- NWYYWIJOWOLJNR-RXMQYKEDSA-N l-valinol Chemical compound CC(C)[C@H](N)CO NWYYWIJOWOLJNR-RXMQYKEDSA-N 0.000 claims description 7
- YAOZCMANASAVFN-UHFFFAOYSA-N 3-chloro-2-fluorobenzaldehyde Chemical compound FC1=C(Cl)C=CC=C1C=O YAOZCMANASAVFN-UHFFFAOYSA-N 0.000 claims description 5
- 150000002690 malonic acid derivatives Chemical class 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- LULXBAGMGMJJRW-UHFFFAOYSA-N n,2-bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)CC(=O)N[Si](C)(C)C LULXBAGMGMJJRW-UHFFFAOYSA-N 0.000 claims description 3
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- YZMVLKJJJCMVGX-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline-2,4-dione Chemical class C1=CC=C2NC(=O)CC(=O)C2=C1 YZMVLKJJJCMVGX-UHFFFAOYSA-N 0.000 abstract description 5
- 102100034343 Integrase Human genes 0.000 abstract 1
- 108010061833 Integrases Proteins 0.000 abstract 1
- 125000004429 atom Chemical group 0.000 abstract 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract 1
- 229910052794 bromium Inorganic materials 0.000 abstract 1
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 67
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 48
- 238000006243 chemical reaction Methods 0.000 description 46
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 29
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 238000004128 high performance liquid chromatography Methods 0.000 description 24
- 239000012074 organic phase Substances 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- 239000002002 slurry Substances 0.000 description 22
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 15
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 14
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- 238000001914 filtration Methods 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 229960000583 acetic acid Drugs 0.000 description 11
- 239000012071 phase Substances 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 229940125773 compound 10 Drugs 0.000 description 10
- 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 10
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- 239000012362 glacial acetic acid Substances 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 7
- 0 Cc1cccc(C(*)C2C=C(*)C(O*)=CC2O)c1[I+] Chemical compound Cc1cccc(C(*)C2C=C(*)C(O*)=CC2O)c1[I+] 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 229940126214 compound 3 Drugs 0.000 description 6
- 229940125898 compound 5 Drugs 0.000 description 6
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 6
- 229910001629 magnesium chloride Inorganic materials 0.000 description 6
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 4
- LJIOTBMDLVHTBO-CUYJMHBOSA-N (2s)-2-amino-n-[(1r,2r)-1-cyano-2-[4-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]phenyl]cyclopropyl]butanamide Chemical compound CC[C@H](N)C(=O)N[C@]1(C#N)C[C@@H]1C1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)N2CCN(C)CC2)C=C1 LJIOTBMDLVHTBO-CUYJMHBOSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- 229940126543 compound 14 Drugs 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- BHKKSKOHRFHHIN-MRVPVSSYSA-N 1-[[2-[(1R)-1-aminoethyl]-4-chlorophenyl]methyl]-2-sulfanylidene-5H-pyrrolo[3,2-d]pyrimidin-4-one Chemical compound N[C@H](C)C1=C(CN2C(NC(C3=C2C=CN3)=O)=S)C=CC(=C1)Cl BHKKSKOHRFHHIN-MRVPVSSYSA-N 0.000 description 3
- OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- ZNSPHKJFQDEABI-NZQKXSOJSA-N Nc1nc(O[C@H](c2ccc(Cl)cc2-c2ccccc2)C(F)(F)F)cc(n1)N1CCC2(CN[C@@H](C2)C(O)=O)CC1 Chemical compound Nc1nc(O[C@H](c2ccc(Cl)cc2-c2ccccc2)C(F)(F)F)cc(n1)N1CCC2(CN[C@@H](C2)C(O)=O)CC1 ZNSPHKJFQDEABI-NZQKXSOJSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 229940125758 compound 15 Drugs 0.000 description 3
- 229940125876 compound 15a Drugs 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 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 2
- FJFFPLISNMPUFF-DUSLRRAJSA-N 6-[(3-chloro-2-fluorophenyl)methyl]-1-[(2s)-1-hydroxy-3-methylbutan-2-yl]-7-methoxy-2,4-dioxoquinoline-3-carboxylic acid Chemical compound COC1=CC=2N([C@H](CO)C(C)C)C(=O)C(C(O)=O)C(=O)C=2C=C1CC1=CC=CC(Cl)=C1F FJFFPLISNMPUFF-DUSLRRAJSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- SIOVKLKJSOKLIF-UHFFFAOYSA-N bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)OC(C)=N[Si](C)(C)C SIOVKLKJSOKLIF-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 238000006473 carboxylation reaction Methods 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 229910052500 inorganic mineral Chemical class 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- DBTNVRCCIDISMV-UHFFFAOYSA-L lithium;magnesium;propane;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-].C[CH-]C DBTNVRCCIDISMV-UHFFFAOYSA-L 0.000 description 2
- 239000011707 mineral Chemical class 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000011833 salt mixture Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 150000003460 sulfonic acids Chemical class 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- SIOVKLKJSOKLIF-HJWRWDBZSA-N trimethylsilyl (1z)-n-trimethylsilylethanimidate Chemical compound C[Si](C)(C)OC(/C)=N\[Si](C)(C)C SIOVKLKJSOKLIF-HJWRWDBZSA-N 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- KPGXRSRHYNQIFN-UHFFFAOYSA-N 2-oxoglutaric acid Chemical compound OC(=O)CCC(=O)C(O)=O KPGXRSRHYNQIFN-UHFFFAOYSA-N 0.000 description 1
- MCCFZRKWSJPXFP-UHFFFAOYSA-N 7-methoxy-2,4-dioxo-1H-quinoline-3-carboxylic acid Chemical compound COC1=CC=C2C(C(C(NC2=C1)=O)C(=O)O)=O MCCFZRKWSJPXFP-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- GAEBDCHFRFIUQB-UHFFFAOYSA-N COc(cc1OC)c(C(c2cccc(Cl)c2F)O)cc1Br Chemical compound COc(cc1OC)c(C(c2cccc(Cl)c2F)O)cc1Br GAEBDCHFRFIUQB-UHFFFAOYSA-N 0.000 description 1
- RWDBTYMKLCELOD-UHFFFAOYSA-N COc1c(Cc(cccc2Cl)c2F)cc(C([n]2cncc2)=O)c(OC)c1 Chemical compound COc1c(Cc(cccc2Cl)c2F)cc(C([n]2cncc2)=O)c(OC)c1 RWDBTYMKLCELOD-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 241000694440 Colpidium aqueous Species 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical group OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 229940099797 HIV integrase inhibitor Drugs 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- XCOBLONWWXQEBS-KPKJPENVSA-N N,O-bis(trimethylsilyl)trifluoroacetamide Chemical compound C[Si](C)(C)O\C(C(F)(F)F)=N\[Si](C)(C)C XCOBLONWWXQEBS-KPKJPENVSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 150000008043 acidic salts Chemical class 0.000 description 1
- 150000007929 acylimidazolides Chemical class 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 150000001559 benzoic acids Chemical class 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 230000021523 carboxylation Effects 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- MGNCLNQXLYJVJD-UHFFFAOYSA-N cyanuric chloride Chemical compound ClC1=NC(Cl)=NC(Cl)=N1 MGNCLNQXLYJVJD-UHFFFAOYSA-N 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000005828 desilylation reaction Methods 0.000 description 1
- 238000005906 dihydroxylation reaction Methods 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 239000012156 elution solvent Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003084 hiv integrase inhibitor Substances 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 150000002680 magnesium Chemical class 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 238000006263 metalation reaction Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
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- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
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- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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Abstract
Description
本出願は、米国特許法§119(e)の下、2007年9月11日に出願された米国仮特許出願第60/971,395号からの優先権を主張し、この仮出願の内容は、本明細書中でその全体を援用する。
特許文献1は、HIVインテグラーゼ阻害剤として有用な幾つかの4−オキソキノロン化合物を開示している。それらの化合物は抗HIV薬として有用であると報じられている。
現在、国際特許出願公開公報WO第2004/046115号および国際特許出願公開公報WO第2005/113508号で報じられている4−オキソキノロン化合物を調製するための改善された方法に対するニーズが存在する。具体的には、もっと簡単もしくはもっと安価に実行することができ、高められた収量をもたらす、または有毒な試薬もしくは高価な試薬の使用を排除する、新たな合成方法に対するニーズが存在する。
別な具合に記述されていない限り、以下の定義が用いられる:ハロはフルオロ、クロロ、ブロモまたはヨードである。アルキルは直鎖状および分枝鎖状の両方の基を表すが、プロピルなどの個々のラジカルへの言及は、直鎖ラジカルおよび具体的に言及されているイソプロピルなどの分枝鎖異性体のみを包含する。
氷浴中において予め冷却されていたトリフルオロ酢酸(33.13g)にトリエチルシラン(6.83g)を加えた。温度を15℃以下に維持しながら、その混合物に化合物3(10g)を加えた。2時間撹拌した後、MTBEを加えてその生成物を沈殿させた。生じたスラリーをろ過し、得られた生成物を付加的なMTBEで洗った。乾燥させた後、9.12gの化合物4が単離された:
イミダゾール(0.42g)および1,1’−カルボニルジイミダゾール(5.49g)を環境温度において30mLのTHF中でスラリー化した。化合物4(10g)を一度に加え、生じた混合物を、HPLCにより反応が完了するまで、環境温度で撹拌した。結果として生じたスラリーをろ過し、得られた固体をMTBEで洗った。その固体を乾燥させることにより、化合物5aがもたらされた:
イミダゾール(0.42g)および1,1’−カルボニルジイミダゾール(5.49g)を環境温度において30mLのTHF中でスラリー化した。化合物5a(10g)を一度に加え、生じた混合物を環境温度で4時間撹拌して化合物5aのスラリーを形成した。別のフラスコ内において、8.91gのマロン酸モノエチルエステルカリウム塩を40mLのTHF中でスラリー化した。塩化マグネシウム(4.40g)を加え、結果として生じたスラリーを55℃に90分間温めた。化合物5aのスラリーを塩化マグネシウム/マロン酸モノエチルエステルカリウム塩混合物へ移し、55℃で夜通し撹拌した。その後、得られた混合物を室温に冷却し、80mLの28重量%H3PO4水溶液を1滴ずつ加えることによりクエンチした。生じた相を分離し、有機相をNaHSO4、KHCO3およびNaCl水溶液で連続的に洗った。その有機相を濃縮してオイル状にした後、エタノールを用いて共蒸発させた。結果として生じた固体を30mLのエタノールおよび6mLの水に溶解した。冷却することにより、化合物6aが結晶化された。得られた固体をろ過により単離し、その生成物をエタノール水溶液で洗った。乾燥後、化合物6aが得られた:
化合物6a(20g)を6.6gのジメチルホルムアミドジメチルアセタール、66gのトルエンおよび0.08gの氷酢酸と共に撹拌した。生じた混合物を90℃に4時間温めた。その後、得られた混合物を環境温度に冷却し、5.8gの(S)−2−アミノ−3−メチル−1−ブタノールを加えた。得られた混合物を環境温度で1時間撹拌した後、濃縮して濃厚なオイルにした。ジメチルホルムアミド(36g)、塩化カリウム(1.8g)およびビス(トリメチルシリル)アセトアミド(29.6g)を加え、得られた混合物を90℃に1時間温めた。その混合物を室温に冷却し、200gのジクロロメタンで希釈した。希塩酸(44g、約1N)を加え、得られた混合物を環境温度で20分間撹拌した。生成された相を分離し、有機相を水、重炭酸ナトリウム水溶液および水で連続的に洗った。溶媒をアセトニトリルに換え、体積を160mLに調整した。その混合物を透明になるまで加熱し、僅かに冷却し、種を入れ、冷却して化合物9aを結晶化させた。得られた生成物をろ過により単離し、付加的な冷たいアセトニトリルで洗った。真空乾燥することにより、化合物9aがもたらされた:
化合物9a(6.02g)を36mLのイソプロパノールおよび24mLの水中においてスラリー化した。水酸化カリウム水溶液(2.04gの45重量%溶液)を加え、その混合物を40℃に温めた。3時間後、1.13gの氷酢酸を加え、得られた混合物に10mgの化合物10を用いて種入れした。その混合物を氷浴中において2時間冷却し、生じた固体をろ過により単離した。そのケーキをイソプロパノール水溶液で洗い、乾燥させることにより、化合物10がもたらされた:
1.残存する化合物6aのHPLCによるANは、ベースラインのアーチファクトにより誇大化されている。歩調を合わせたHPLC(HPLC in step)は、化合物8aに対して相対的に僅か2%の化合物6aを示している。実験により、試薬をもっと多く加え、且つ、反応時間を延ばしても、典型的には、観測される化合物6aのレベルがそれ以上には下がらないことが実証された。
溶出溶媒:100%の酢酸エチル、
シリル化された化合物9aのRf:0.85、化合物9aのRf:0.50。
化合物14を無水テトラヒドロフラン:ジオキサン(5:0.9)と化合させ、均一溶液が達成されるまで、その混合物を窒素雰囲気下において撹拌する。得られた溶液を−3℃に冷却し、テトラヒドロフラン中における1.3当量のi−PrMgCl・LiClを加える。HPLC分析法による判定でモノ−グリニャールの形成が完了するまで、その反応混合物を0℃で撹拌する。次に、テトラヒドロフラン中における1.1当量の3−クロロ−2−フルオロベンズアルデヒドの溶液を加える。HPLCにより化合物15aの形成が完了するまで、この混合物を0℃で撹拌する。次に、テトラヒドロフラン中における付加的なi−PrMgCl・LiCl溶液(2.5当量)を加え、その反応混合物を約20℃に温める。この第2グリニャール中間体への変換が完了した後、反応混合物を3℃に冷却する。その反応混合物に無水CO2(g)を約5℃で充填する。反応混合物を約20℃に調整する。HPLCによりカルボキシル化反応が完了した後、その反応混合物を約10℃に冷却し、水を充填して反応をクエンチし、続いて、濃塩酸を加えることによりpHを3以上にならないように調整する。その後、その反応混合物を約20℃に温める。生じた相を分離する。有機相をイソプロピルアルコールおよび水の混合物に溶媒交換し、結果として生じたスラリーを約0℃に冷却する。その生成物をろ過により単離し、イソプロピルアルコールおよび水の混合物で洗い、約40℃で乾燥させることにより、化合物3がもたらされる。
トリフルオロ酢酸(10当量)を反応器に充填し、0℃に冷却する。温度を<15℃に維持しながらトリエチルシラン(1.5当量)を加え、得られた混合物を充分に撹拌する。温度を<15℃に維持しながら、その充分に撹拌された混合物に化合物3を小分けして加える。HPLCにより反応が完了したと判定されたときに、温度を45℃以上にならないように維持しながら、メタノール中における5当量の酢酸ナトリウム(13体積)の溶液を加えることにより化合物4を沈殿させる。得られたスラリーを温めて還流させ、2〜3時間撹拌する。そのスラリーを約0℃に冷却した後、その温度で2〜3時間撹拌する。得られた生成物をろ過により単離し、メタノールで洗い、約40℃で乾燥させることにより、化合物4がもたらされる。
化合物6aをジメチルホルムアミド(1.9体積)、N,N−ジメチルホルムアミドジメチルアセタール(1.1当量)および氷酢酸(0.026当量)と化合させ、その後、約65℃に温める。その反応をHPLCでモニタリングする。反応が完了したら、その混合物を約22℃に冷却し、その後、(S)−2−アミノ−3−メチル−1−ブタノール(1.1当量)およびトルエン(1.2体積)を加える。その反応をHPLCでモニタリングする。反応が完了したら、その混合物を濃縮する。得られた残渣を塩化カリウム(0.5当量)およびN,O−ビス(トリメチルシリル)アセトアミド(2.5当量)と化合させ、約100℃に温める。その反応をHPLCでモニタリングする。反応が完了したら、その混合物を冷却し、ジクロロメタン(6体積)を加える。塩酸水溶液を加えて生成物を脱シリル化する。この反応をTLCによりモニタリングする。反応が完了したら、有機相を水、重炭酸ナトリウム水溶液および水で洗う。溶媒をアセトニトリルに換え、得られた混合物を温めて溶液を形成する。その混合物に種入れし、冷却して化合物9aを結晶化させる。その生成物をろ過し、冷たいアセトニトリルで洗い、40℃以下で乾燥させることにより、化合物9aがもたらされる。
Claims (28)
- 前記式15の化合物または該化合物の塩をもたらすべく、前記式14の化合物をメタル化し、3−クロロ−2−フルオロベンズアルデヒドで処理することにより、該式14の化合物が該式15の化合物または該化合物の塩に変換される、請求項7記載の方法。
- 前記式3の化合物をもたらすべく前記式15の化合物をメタル化し、且つ、二酸化炭素で処理することにより、該式15の化合物が該式3の化合物に変換される、請求項9記載の方法。
- Rcがハロまたは1−イミダゾリルである、請求項12記載の方法。
- 前記式4の化合物が1,1’−カルボニルジイミダゾールで処理することにより前記式5aの化合物に変換される、請求項14記載の方法。
- 前記式5’の化合物が対応するモノアルキルマロナート塩で処理することにより前記式6の化合物に変換される、請求項16記載の方法。
- Rがエチルである、請求項16記載の方法。
- 前記式5’の化合物がマロン酸モノエチルエステルカリウム塩で処理することにより前記式6の化合物に変換される、請求項18記載の方法。
- 前記式6の化合物がN,N−ジメチルホルムアミドジメチルアセタールで処理することにより前記式7の化合物に変換される、請求項20記載の方法。
- 上記N,N−ジメチルホルムアミドジメチルアセタールでの処理が約100±50℃の温度において酢酸の存在下で実施される、請求項21記載の方法。
- 前記式7の化合物が(S)−2−アミノ−3−メチル−1−ブタノールで処理することにより前記式8の化合物に変換される、請求項23記載の方法。
- 前記式8の化合物が塩化カリウムおよびN,O−ビストリメチルシリルアセトアミドで処理することにより前記式9の化合物に変換される、請求項25記載の方法。
- 前記式9の化合物が塩基で処理することにより前記式10の化合物に変換される、請求項27記載の方法。
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JP2015524822A (ja) * | 2012-08-03 | 2015-08-27 | ギリアード サイエンシーズ, インコーポレイテッド | インテグラーゼインヒビターを調製するためのプロセスおよび中間体 |
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US20090093467A1 (en) * | 2007-06-29 | 2009-04-09 | Gilead Sciences, Inc. | Therapeutic compositions and methods |
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AR068403A1 (es) | 2007-09-11 | 2009-11-18 | Gilead Sciences Inc | Proceso e intermediarios para la preparacion de inhibidores de integrasa |
WO2011004389A2 (en) | 2009-06-18 | 2011-01-13 | Matrix Laboratories Ltd | An improved process for the preparation of elvitegravir |
CN102212032B (zh) * | 2011-04-20 | 2013-07-31 | 复旦大学 | 一种5-羟基喹诺酮类衍生物及其制备方法和用途 |
WO2013082476A1 (en) | 2011-11-30 | 2013-06-06 | Emory University | Antiviral jak inhibitors useful in treating or preventing retroviral and other viral infections |
CZ304983B6 (cs) * | 2012-10-12 | 2015-03-11 | Zentiva, K.S. | Způsob výroby a nové intermediáty syntézy elvitegraviru |
CZ304984B6 (cs) * | 2012-10-12 | 2015-03-11 | Zentiva, K.S. | Zlepšený způsob výroby a nové intermediáty syntézy elvitegraviru |
MY164352A (en) | 2012-12-21 | 2017-12-15 | Gilead Sciences Inc | Polycyclic-carbamoylpyridone compounds and their pharmaceutical use |
NO2865735T3 (ja) | 2013-07-12 | 2018-07-21 | ||
SI3019503T1 (sl) | 2013-07-12 | 2017-11-30 | Gilead Sciences, Inc. | Policiklične karbamoilpiridonske spojine in njihova uporaba za zdravljenje HIV infekcij |
TWI744723B (zh) | 2014-06-20 | 2021-11-01 | 美商基利科學股份有限公司 | 多環型胺甲醯基吡啶酮化合物之合成 |
NO2717902T3 (ja) | 2014-06-20 | 2018-06-23 | ||
TW201613936A (en) | 2014-06-20 | 2016-04-16 | Gilead Sciences Inc | Crystalline forms of(2R,5S,13aR)-8-hydroxy-7,9-dioxo-n-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide |
TWI695003B (zh) | 2014-12-23 | 2020-06-01 | 美商基利科學股份有限公司 | 多環胺甲醯基吡啶酮化合物及其醫藥用途 |
SI3466490T1 (sl) | 2015-04-02 | 2020-12-31 | Gilead Sciences, Inc. | Policiklične spojine karbamoilpiridona in njihova farmacevtska uporaba |
CN111733133B (zh) * | 2020-07-22 | 2020-12-01 | 华夏源(上海)生命科技有限公司 | 一种促进表皮干细胞分化和生长的方法 |
CN111944761B (zh) * | 2020-08-23 | 2021-03-26 | 泉州伟业生物医学科技有限公司 | 促进表皮干细胞分化和生长的方法 |
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