JP5133937B2 - 7−置換抗エストロゲンの製造法及び製造中間体 - Google Patents
7−置換抗エストロゲンの製造法及び製造中間体 Download PDFInfo
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- JP5133937B2 JP5133937B2 JP2009113404A JP2009113404A JP5133937B2 JP 5133937 B2 JP5133937 B2 JP 5133937B2 JP 2009113404 A JP2009113404 A JP 2009113404A JP 2009113404 A JP2009113404 A JP 2009113404A JP 5133937 B2 JP5133937 B2 JP 5133937B2
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- 238000000034 method Methods 0.000 title claims description 32
- 238000004519 manufacturing process Methods 0.000 title claims description 20
- 230000008569 process Effects 0.000 title claims description 19
- 230000001833 anti-estrogenic effect Effects 0.000 title description 4
- 229940046836 anti-estrogen Drugs 0.000 title description 3
- 239000000328 estrogen antagonist Substances 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 67
- 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 description 38
- 229960002258 fulvestrant Drugs 0.000 claims description 38
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 30
- 125000006239 protecting group Chemical group 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 18
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 18
- 238000005899 aromatization reaction Methods 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 12
- 230000003647 oxidation Effects 0.000 claims description 8
- 238000007254 oxidation reaction Methods 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 125000004423 acyloxy group Chemical group 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 150000001879 copper Chemical class 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 4
- -1 alkali metal salt Chemical class 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 150000003462 sulfoxides Chemical class 0.000 claims description 4
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims description 3
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 claims description 2
- 229910021645 metal ion Inorganic materials 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims 1
- 230000020176 deacylation Effects 0.000 claims 1
- 238000005947 deacylation reaction Methods 0.000 claims 1
- 229910001507 metal halide Inorganic materials 0.000 claims 1
- 150000005309 metal halides Chemical class 0.000 claims 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
- 239000000543 intermediate Substances 0.000 description 13
- 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
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 10
- 150000003431 steroids Chemical class 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
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical group [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 8
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 8
- 239000011777 magnesium Substances 0.000 description 8
- 229910052749 magnesium Inorganic materials 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 239000003153 chemical reaction reagent 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
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 150000004795 grignard reagents Chemical class 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 6
- 239000002184 metal Substances 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
- 239000012535 impurity Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000000047 product 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
- 239000012345 acetylating agent Substances 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
- 238000005859 coupling reaction Methods 0.000 description 4
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 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
- 125000004429 atom Chemical group 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 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
- 239000012044 organic layer Substances 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-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 group [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical group [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 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 group [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 150000001805 chlorine compounds Chemical group 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000006196 deacetylation Effects 0.000 description 2
- 238000003381 deacetylation reaction Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000001033 ether group Chemical group 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 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
- 239000002243 precursor Substances 0.000 description 2
- 238000001953 recrystallisation Methods 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 Chemical group 0.000 description 2
- 229910052719 titanium Chemical group 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- 239000011701 zinc Chemical group 0.000 description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- 125000006619 (C1-C6) dialkylamino 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
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 description 1
- 0 C[C@@]1(CC2)[C@@](*)CCC1C(C(CCCCCCCCCSCCCC(C(F)(F)F)(F)F)Cc1c3)C2c1ccc3O* Chemical compound C[C@@]1(CC2)[C@@](*)CCC1C(C(CCCCCCCCCSCCCC(C(F)(F)F)(F)F)Cc1c3)C2c1ccc3O* 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 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
- 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
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 125000005333 aroyloxy group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- ITZXULOAYIAYNU-UHFFFAOYSA-N cerium(4+) Chemical class [Ce+4] ITZXULOAYIAYNU-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 150000004699 copper complex Chemical class 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229940045803 cuprous chloride Drugs 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug 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
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 230000003301 hydrolyzing effect Effects 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
- 125000000449 nitro group Chemical group [O-][N+](*)=O 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
- 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
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 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
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 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
- 239000012453 solvate Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 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
- 125000000101 thioether group Chemical group 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
- 239000002699 waste material Substances 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)
Description
フルベストラント (ファスロデックス(登録商標)、ZD9238、ICI 182,780)(Wakeling AE. J. Steroid Biochemistry 1990c; 37:771-5, WakelingAE, et al. J. Endocrinology 1987;112:R7-10 及びWakeling AE et al. J. Steroid Biochemistry 1988;3:141-7) は、このようなステロイド誘導体の特別な例であり、現在利用可能なタモキシフェンのような抗エストロゲン薬に伴う部分アゴニスト即ちエストロゲン様活性をまったく持たない新しいクラスに属する、初めての強力な純粋抗エストロゲン薬である。
nは3から14の整数であり;
Rは水素またはヒドロキシ保護基であり、
R1はハロC1-10アルキル、C1-10アルキル、C2-10アルケニル、C2-10シクロアルキル、カルボキシC1-10アルキル、C1-10アルコキシカルボニルC1-10アルキル、アリール(フェニルなど)、アリール(C1-10)アルキル(例えばフェニル(C1-10)アルキル)又はジ(C1-6アルキル)アミノであり;
R2は水素、C1-6アルキル又はヒドロキシであり、
R3は水素、C1-6アルキル、C2-6アルケニル又はC2-6アルキニルであり;
R4はヒドロキシ、C1-10アルカノイルオキシ、カルボキシC1-10アルカノイルオキシ又はアロイルオキシ(例えばベンゾイルオキシ)であり;
R5はC1-6アルキルである);
該方法が式(III)の化合物
従ってさらなる実施態様において、本発明は式(XIII)の化合物の製造法を提供し、
これらの化合物は、式(IV)の化合物
適切なZ脱離基は、ハロ、メシラート及びトシラートなどの慣用基であるが、特に好ましい実施態様において、Zは、Mが金属イオンでありR11がハロゲン原子である式R11-Mのハロゲン化金属である。
好ましくは、R11は塩素、臭素及びヨウ素から選択される。好ましいハロR11は臭素である。従って好ましい実施態様において、式(V)の化合物は有機金属試薬であり、とりわけグリニャール試薬である。
Zが脱離基である式(V)の化合物及び式(VI)の化合物は、既知化合物(例えばWO93/06124の実施例4cを参照のこと)であるか、あるいは慣用法により既知化合物より製造できるものであるかのいずれかである。
とりわけ、前記化合物(II)、(III)、(IV)、(V)及び(VI)において、R1はハロアルキル基であり、とりわけ式-(CH2)3CF2CF3基である。
好ましくは、R3は水素である。
適切なR4基の特別な例は、ヒドロキシであるか又はアセトキシなどのアルカノイルオキシである。これらの化合物の中でとりわけR4はヒドロキシでありR4'はアセトキシである。
これらの化合物の中ではまた、好ましくは、nは9である。
このましいX基は、S、SO又はSO2である。しかしながら本出願の目的のための特に好ましいX基はSである。
1.高価な"ジエノン"中間体から7ステップがある。
2.出発物質から最終生成物までの間に結晶性中間体が存在しない。従って、ステップ間における単離と精製が困難である。
3.収率が低いため、重量比で1のフルベストラントを生成するために約11のジエノンを必要とする。
4.ジエノンステロイドの7位に側鎖を加えるステップは、好ましいα位が不必要なβ位と比較して1.9:1と優位に生成する。
1.ジエノン中間体からはただの4ステップがあるだけである。
2.フルベストラントの場合、中間体で結晶化できるものは無く、これが単離と精製を困難にしているが、最終生成物が得られるまで全反応を溶液中で実施することができ、最終生成物は溶液から晶出させることができる。
3.収率が大幅に改善し、重量比で1のフルベストラントを生成するために約2のジエノンを必要とする。
4.α/β比は約2.5:1に改善されている。
酸化ステップの後、再結晶による精製の前の最終ステップとして、不必要なフルベストラントのβ体を除く。
(1)A環の芳香化
(2)保護基R12の除去
(3)スルフィドのスルホキシドへの酸化によるフルベストラントの生成。
好ましいR12保護基はアセチルなどのアシル基である。
前記のように、A環の芳香化は無水酢酸などのアセチル化剤の存在下で適切に行なわれる。このアセチル化剤はフェノール環をその場で保護し、さらに、式(IX)の中間体を生成する
酸化ステップもまた、当業者により公知の技術を用いて実施できる。スルホンの生成を防ぐために反応剤と条件の選択には注意を必要とする。スルフィドからスルホキシドへの酸化のために当業界に公知のいずれの反応剤も使用できるが、例えば、過酸化水素、過酸(過ヨウ素酸塩又は3-クロロ過安息香酸あるいは過酢酸など)、白金又はハロゲン及び次亜塩素酸ナトリウムなどの活性ハロゲン供給源の存在下におけるガス状酸素並びにセリウム(IV)塩が使用できる。過度の酸化の恐れを防ぐために一般的に酸化はできるだけ穏やかな条件で実施する。好ましい方法において、2.0モル当量の過酸化水素を用いる。
特に、式(X)の化合物は式(XI)の化合物である
有機金属試薬(XI)は式(XII)のハロゲン化アルキル
本発明はさらに、フルベストラントあるいはその薬剤学的に受容できる塩又はエステル、あるいはこれらのいずれかの水和物の製造法であって、以下のステップを含む製造法を提供する
(a)前記で定義の式(IX)の化合物と前記で定義の式(XI)の化合物とを、第一銅塩を添加し、全てを適切な溶媒に溶解し、カップリングさせる式(VIII)の化合物の生成
(c) 保護基R12の除去、そして
(d) スルフィド基のスルホキシドへの酸化によるフルベストラントの生成。
グリニャール開始剤の製造法
相対量及び相対重量という用語は臭化物の重量を指す。
実施例2
フルベストラントEASの製造法
相対量という用語はジエノンの重量を指す。
実施例3
フルベストラントPHSの製造法
相対量という用語はフルベストラントEASの重量を指す。
実施例4
フルベストラントの製造法
相対量という用語はフルベストラントPHSの重量を指す。
Claims (16)
- 式(II)の中間化合物
nは9であり;
Rは水素又はヒドロキシ保護基であり;
R1は−(CH2)3CF2CF3であり;
R2は水素、C1−6アルキル又はヒドロキシであり;
R3は水素、C1−6アルキル、C2−6アルケニル又はC2−6アルキニルであり;
R4はヒドロキシ、C1−10アルカノイルオキシ、カルボキシC1−10アルカノイルオキシ又はベンゾイルオキシであり;
R5はC1−6アルキルである)
の製造法であって、式(III)の化合物
(i)任意のヒドロキシ保護基Rの除去;
(ii)R4’のR4への変換、あるいはR4’がR4である場合、異なるこのような基への変換。 - Rがアシル基である請求項1に記載の方法。
- Rがアセチル基である請求項1に記載の方法。
- R10がアルカリ加水分解で除去可能なアシル基である、請求項1〜3のいずれか一項に記載の方法。
- R及びR10が共にアセチルであり、随意ステップ(i)及び(ii)を共に単一の脱アシルステップにより行なう、請求項1〜4のいずれか一項に記載の方法。
- 式(III)の化合物の芳香化を無水酢酸の存在下で行なってRがアセチルである式(II)の化合物を製造する、請求項1〜5のいずれか一項に記載の方法。
- 銅塩を用いて芳香化を行なう、請求項1〜6のいずれか一項に記載の方法。
- 芳香化反応をアルカリ金属塩の存在下で行なう、請求項7に記載の方法。
- 式(V)の化合物において、Zは式R11−Mのハロゲン化金属であり、ここでMは金属イオンでありR11はハロゲン原子である、請求項9に記載の方法。
- 式(II)の化合物において、Xを次いで酸化してSOにする、請求項1〜10のいずれか一項に記載の方法。
- 請求項1で定義の式(III)の化合物。
- R12がアセチル基である請求項13に記載の化合物。
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GB0025221D0 (en) | 2000-10-14 | 2000-11-29 | Astrazeneca Ab | New process |
GB0123961D0 (en) | 2001-10-05 | 2001-11-28 | Astrazeneca Ab | Process and intermediates |
TW200617019A (en) * | 2004-07-27 | 2006-06-01 | Sicor Inc | A process for the preparation of 7α-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 |
CA2884806A1 (en) | 2012-10-22 | 2014-05-01 | Intas Pharmaceuticals Limited | An improved 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 |
CN116535454A (zh) * | 2023-04-28 | 2023-08-04 | 香港中文大学(深圳) | 氟维司群类化合物及其制备方法和应用 |
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