KR100864266B1 - 7-치환된 항에스트로겐을 제조하기 위한 방법 및 중간체 - Google Patents
7-치환된 항에스트로겐을 제조하기 위한 방법 및 중간체 Download PDFInfo
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- KR100864266B1 KR100864266B1 KR1020037005110A KR20037005110A KR100864266B1 KR 100864266 B1 KR100864266 B1 KR 100864266B1 KR 1020037005110 A KR1020037005110 A KR 1020037005110A KR 20037005110 A KR20037005110 A KR 20037005110A KR 100864266 B1 KR100864266 B1 KR 100864266B1
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- South Korea
- Prior art keywords
- formula
- compound
- group
- alkyl
- copper
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- 238000000034 method Methods 0.000 title claims abstract description 42
- 230000008569 process Effects 0.000 title claims description 13
- 238000004519 manufacturing process Methods 0.000 title claims description 7
- 239000000543 intermediate Substances 0.000 title abstract description 17
- 230000001833 anti-estrogenic effect Effects 0.000 title description 3
- 229940046836 anti-estrogen Drugs 0.000 title description 2
- 239000000328 estrogen antagonist Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 83
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 claims abstract description 41
- 229960002258 fulvestrant Drugs 0.000 claims abstract description 41
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 23
- 238000005899 aromatization reaction Methods 0.000 claims abstract description 17
- 239000002243 precursor Substances 0.000 claims abstract description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 36
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 239000001257 hydrogen Substances 0.000 claims description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 12
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical class [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 claims description 11
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical group [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 10
- 238000005859 coupling reaction Methods 0.000 claims description 10
- 239000011777 magnesium Substances 0.000 claims description 10
- 229910052749 magnesium Inorganic materials 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 9
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 8
- 125000004423 acyloxy group Chemical group 0.000 claims description 8
- 150000001879 copper Chemical class 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- -1 alkali metal salt Chemical class 0.000 claims description 6
- 230000008878 coupling Effects 0.000 claims description 6
- 238000010168 coupling process Methods 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- 230000003647 oxidation Effects 0.000 claims description 6
- 238000007254 oxidation reaction Methods 0.000 claims description 6
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 6
- 125000004429 atom Chemical group 0.000 claims description 5
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical group Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 5
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- 150000003462 sulfoxides Chemical class 0.000 claims description 5
- 239000012345 acetylating agent Substances 0.000 claims description 4
- 230000003197 catalytic effect Effects 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 229910052802 copper Inorganic materials 0.000 claims description 4
- 239000010949 copper Substances 0.000 claims description 4
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical group [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 claims description 4
- 230000001590 oxidative effect Effects 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 3
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims description 3
- 229910001507 metal halide Inorganic materials 0.000 claims description 3
- 150000005309 metal halides Chemical class 0.000 claims description 3
- 229910021645 metal ion Inorganic materials 0.000 claims description 3
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims description 2
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 2
- 229910021590 Copper(II) bromide Inorganic materials 0.000 claims description 2
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims description 2
- 150000008065 acid anhydrides Chemical group 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 230000020176 deacylation Effects 0.000 claims description 2
- 238000005947 deacylation reaction Methods 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000000101 thioether group Chemical group 0.000 claims description 2
- 239000002699 waste material Substances 0.000 claims description 2
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims 1
- 229910052783 alkali metal Inorganic materials 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 125000006239 protecting group Chemical group 0.000 abstract description 15
- 125000003118 aryl group Chemical group 0.000 abstract description 2
- 125000001188 haloalkyl group Chemical group 0.000 abstract description 2
- 125000003342 alkenyl group Chemical group 0.000 abstract 1
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 abstract 1
- 125000003710 aryl alkyl group Chemical group 0.000 abstract 1
- 125000000962 organic group Chemical group 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 150000003431 steroids Chemical class 0.000 description 9
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 239000007818 Grignard reagent Substances 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 150000004795 grignard reagents Chemical class 0.000 description 6
- 125000002524 organometallic group Chemical group 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 150000001993 dienes Chemical class 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 239000003999 initiator Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 2
- 0 C*C(C1)C([C@]2C(*)(CC3)C(C)(*)C(*)C2)C3C(CC2)C1=CC2=O Chemical compound C*C(C1)C([C@]2C(*)(CC3)C(C)(*)C(*)C2)C3C(CC2)C1=CC2=O 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 229960001603 tamoxifen Drugs 0.000 description 2
- 239000010936 titanium Substances 0.000 description 2
- 229910052719 titanium Inorganic materials 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- BVAUHWMMAVAPFK-TUQRKZLWSA-O C[C@](CC1)(C(CC2)C([C@H](CCCCCCCCC[SH+]CCCC(C(F)(F)F)(F)F)Cc3c4)C1c3ccc4O)[C@H]2O Chemical compound C[C@](CC1)(C(CC2)C([C@H](CCCCCCCCC[SH+]CCCC(C(F)(F)F)(F)F)Cc3c4)C1c3ccc4O)[C@H]2O BVAUHWMMAVAPFK-TUQRKZLWSA-O 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- GUMZVBJNPFEQDA-UHFFFAOYSA-J [I-].[I-].[I-].[I-].[Ce+4] Chemical compound [I-].[I-].[I-].[I-].[Ce+4] GUMZVBJNPFEQDA-UHFFFAOYSA-J 0.000 description 1
- 229910001508 alkali metal halide Inorganic materials 0.000 description 1
- 150000008045 alkali metal halides Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 125000005333 aroyloxy group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 description 1
- 150000004699 copper complex Chemical class 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000006196 deacetylation Effects 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- LMPDLIQFRXLCMO-UHFFFAOYSA-L dipotassium;hydrogen phosphate;phosphoric acid Chemical compound [K+].[K+].OP(O)(O)=O.OP([O-])([O-])=O LMPDLIQFRXLCMO-UHFFFAOYSA-L 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 102000015694 estrogen receptors Human genes 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- 230000001076 estrogenic effect Effects 0.000 description 1
- 229940087861 faslodex Drugs 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000002902 organometallic compounds Chemical class 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000004763 sulfides Chemical class 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical group CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
- C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
보호기 R12는 아실기, 예컨대 아세틸이 바람직하다.
Claims (34)
- 아실화제 존재하에서 하기 화학식(III)의 화합물의 방향족화 단계를 포함하고, 이후에 필요하거나 원하는 경우,(i) 임의의 아세틸기 R을 제거하는 단계,(ii) 전구체 기 R4'를 기 R4로 전환시키거나, 또는 기 R4'가 기 R4인 경우 기 R4'를 다른 그러한 기로 전환시키는 단계중 하나 이상을 수행하여 중간체인 하기 화학식(II)의 화합물을 제조하는 방법:화학식(II)[상기 식 중,X는 S, SO, SO2, O, NR6, N(O)R6, (PO)R6, COO-, NR7SO2, CONR6, CSNR6, NR7CO, NR7C(NR8)NR6, NR7CS, NR7CONR6, SO2NR6 또는 CO이고, 여기서 R6은 수소 또는 C1-6알킬이며, R7은 수소 또는 C1-6알킬이고, R8은 시아노, 수소 또는 니트로이며,n은 3 내지 14의 정수이고,R은 수소 또는 아세틸이며,R1은 할로C1-10알킬, C1-10알킬, C2-10알케닐, C3-10시클로알킬, 카르복시C1-10알킬, C1-10알콕시카르보닐C1-10알킬, 페닐, 페닐(C1-10)알킬 또는 디(C1-6알킬)아미노이고,R2는 수소, C1-6알킬 또는 히드록시이며,R3은 수소, C1-6알킬, C2-6알케닐 또는 C2-6알키닐이고,R4는 히드록시, C1-10알카노일옥시, 카르복시C1-10알카노일옥시 또는 벤조일옥시이며,R5는 C1-6알킬이다]화학식(III)[상기 식 중, R1, R2, R3, n, X 및 R5는 화학식(II)에 관하여 정의한 바와 같고, R4'는 기 R4이거나, 또는 이것의 전구체 기이다]
- 제1항에 있어서, 아실화제가 산 무수물인 방법.
- 제2항에 있어서, 아실화제가 아세틸화제인 방법.
- 제1항 내지 제3항 중 어느 하나의 항에 있어서, R4'가 기 OR10이고, 여기서 R10이 알칼리 가수분해에 의해 제거 가능한 아세틸기인 방법.
- 삭제
- 제4항에 있어서, 임의의 단계 (i) 및 (ii)는 단일 탈아실화 단계로 함께 수행하는 것인 방법.
- 제1항 내지 제3항 중 어느 하나의 항에 있어서, 화학식(III)의 화합물의 방향족화는 R이 아세틸인 화학식(II)의 화합물을 생성시키기 위해 아세트산 무수물의 존재 하에 수행하는 것인 방법.
- 제1항 내지 제3항 중 어느 하나의 항에 있어서, 방향족화는 구리염을 사용하여 수행하는 것인 방법.
- 제8항에 있어서, 구리염이 브롬화구리(II)인 방법.
- 제8항에 있어서, 방향족화 반응은 알칼리 금속염의 존재 하에 수행하는 것인 방법.
- 제8항에 있어서, 티오우레아는 방향족화 후 구리 폐기물을 침전시키는 데 사용하는 것인 방법.
- 제12항에 있어서, 화학식(V)의 화합물에서 Z가 화학식 R11-M(여기서, M은 금속 이온이고, R11은 할로겐 원자임)의 금속 할로겐화물인 방법.
- 제13항에 있어서, M이 마그네슘인 방법.
- 제12항에 있어서, 커플링 반응은 촉매량의 구리(I)염의 존재 하에 수행하는 것인 방법.
- 제15항에 있어서, 구리(I)염이 염화구리(I)인 방법.
- 제1항 내지 제3항 중 어느 하나의 항에 있어서, 화학식(II)의 화합물에서 X는 S이고, 이 S는 이후에 기 SO로 산화되는 것인 방법.
- 제17항에 있어서, 상기 산화는 과산화수소 또는 과요오드산염을 사용하여 수 행하는 것인 방법.
- 제1항에 정의된 바와 같은 화학식(III)의 화합물.
- 삭제
- 제22항에 있어서, 화학식(V)의 화합물에서 Z가 화학식 R11-M(여기서, M은 금속 이온이고, R11은 할로겐 원자임)의 금속 할로겐화물인 방법.
- 제23항에 있어서, M이 마그네슘인 방법.
- 제22항에 있어서, 커플링 반응은 촉매량의 구리(I)염의 존재 하에 수행하는 것인 방법.
- 제25항에 있어서, 구리(I)염이 염화구리(I)인 방법.
- (a) 제28항에 정의된 바와 같은 화학식(VII)의 화합물과 화학식(X)의 화합물을, 구리(I)염의 첨가에 의해, 모두가 용해되는 에테르 용매 중에서 커플링시킴으로써 하기 화학식(VIII)의 생성물을 형성시키는 단계,(b) A-고리의 방향족화 단계,(c) 아세틸기 R12의 제거 단계, 및(d) 설파이드기를 설폭사이드로 산화시켜서 풀베스트란트를 형성시키는 단계를 포함하여 하기 화학식(I)의 풀베스트란트, 이것의 약학적으로 허용 가능한 염 또는 에스테르, 또는 이들 중 어느 하나의 수화물을 제조하는 방법:화학식(I)화학식(VIII)
- 하기 화학식(III)의 화합물의 방향족화 단계를 포함하고, 이후에 필요하거나 원하는 경우,(i) 임의의 아세틸기 R을 제거하는 단계,(ii) 전구체 기 R4'를 기 R4로 전환시키거나, 또는 기 R4'가 기 R4인 경우 기 R4'를 다른 그러한 기로 전환시키는 단계중 하나 이상을 수행하여 중간체인 하기 화학식(II)의 화합물을 제조하는 방법:화학식(II)[상기 식 중,X는 S 이며,n은 9 이고,R은 수소 또는 아세틸이며,R1은 -(CH2)3CF2CF3 이고,R2는 수소, C1-6알킬 또는 히드록시이며,R3은 수소, C1-6알킬, C2-6알케닐 또는 C2-6알키닐이고,R4는 히드록시, C1-10알카노일옥시, 카르복시C1-10알카노일옥시 또는 벤조일옥시이며,R5는 C1-6알킬이다]화학식(III)[상기 식 중, R1, R2, R3, n, X 및 R5는 화학식(II)에 관하여 정의한 바와 같고, R4'는 기 R4이거나, 또는 이것의 전구체 기이다]
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GB0025221D0 (en) | 2000-10-14 | 2000-11-29 | Astrazeneca Ab | New process |
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CA2574967A1 (en) | 2004-07-27 | 2006-02-09 | Sicor, Inc. | A process for the preparation of 7.alpha.-alkylated 19-norsteroids |
WO2009039700A1 (en) * | 2007-09-24 | 2009-04-02 | Xi'an Libang Pharmaceutical Co., Ltd. | Process for the manufacture of 7-alpha-[9-(4,4,5,5,5-penta fluoropentvlsulphinvl) nonvllestra-l,3,5-(10)- triene-3,17-beta-diol |
EP2070942A1 (de) * | 2007-12-13 | 2009-06-17 | Bayer Schering Pharma Aktiengesellschaft | Verfahren zur Aromatisierung von 19-Nor-androst-4-en-3-onen zu Estra-1,3,5(10)-trienen |
CN101525364B (zh) * | 2008-03-07 | 2012-12-12 | 杭州九源基因工程有限公司 | 一种氟维司群的晶型及其制备方法 |
US8063249B1 (en) | 2008-04-25 | 2011-11-22 | Olema Pharmaceuticals, Inc. | Substituted triphenyl butenes |
CN102391341B (zh) * | 2011-08-09 | 2013-05-22 | 福建省微生物研究所 | 制备6,7-脱氢-17β-烃酰氧基诺龙的方法 |
CN102600064A (zh) * | 2012-03-31 | 2012-07-25 | 西安力邦制药有限公司 | 氟维司群或其衍生物缓释制剂及其制备方法 |
US9315540B2 (en) | 2012-10-22 | 2016-04-19 | Intas Pharmaceuticals Ltd. | Process for the preparation of fulvestrant |
CN103788164A (zh) * | 2012-10-31 | 2014-05-14 | 正大天晴药业集团股份有限公司 | 一种氟维司群的制备方法 |
CN103965280B (zh) * | 2014-05-21 | 2016-04-20 | 天津孚音生物科技发展有限公司 | 一种氟维司群中间体的制备方法 |
WO2015181116A1 (en) | 2014-05-26 | 2015-12-03 | Crystal Pharma, S.A.U. | Process and intermediades for the preparation of 7-alkylated steroids |
CN104387435B (zh) * | 2014-12-10 | 2017-05-10 | 天津孚音生物科技发展有限公司 | 一种化合物及其制备方法与应用 |
KR101640747B1 (ko) | 2015-05-20 | 2016-07-19 | 이금운 | 확장 가능형 끼움식 엘이디 조명 등기구 |
CN107488205A (zh) * | 2016-06-13 | 2017-12-19 | 重庆圣华曦药业股份有限公司 | 一种氟维司群有关物质的制备方法及其在制剂中的检测方法 |
CN110818764A (zh) * | 2018-08-07 | 2020-02-21 | 重庆圣华曦药业股份有限公司 | 一种应用加料监测系统制备氟维斯群中间体的方法 |
CN111018936B (zh) * | 2019-11-12 | 2021-10-29 | 广州曼翔医药有限公司 | 一种氟维司群有关物质e的合成方法 |
CN116041412A (zh) * | 2023-01-13 | 2023-05-02 | 香港中文大学(深圳) | 氟维司群衍生物及其制备方法、应用和治疗乳腺癌的药物 |
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