WO2022257895A1 - 一种用于制备氟维司群的中间体及其制备方法 - Google Patents
一种用于制备氟维司群的中间体及其制备方法 Download PDFInfo
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- WO2022257895A1 WO2022257895A1 PCT/CN2022/097214 CN2022097214W WO2022257895A1 WO 2022257895 A1 WO2022257895 A1 WO 2022257895A1 CN 2022097214 W CN2022097214 W CN 2022097214W WO 2022257895 A1 WO2022257895 A1 WO 2022257895A1
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- 238000002360 preparation method Methods 0.000 title claims abstract description 97
- 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 title claims abstract description 29
- 229960002258 fulvestrant Drugs 0.000 title claims abstract description 29
- 150000001875 compounds Chemical class 0.000 claims abstract description 262
- 238000006243 chemical reaction Methods 0.000 claims abstract description 134
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 25
- 239000001257 hydrogen Substances 0.000 claims abstract description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 17
- 125000005257 alkyl acyl group Chemical group 0.000 claims description 30
- 125000005251 aryl acyl group Chemical group 0.000 claims description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 20
- 239000011777 magnesium Substances 0.000 claims description 19
- 125000003118 aryl group Chemical group 0.000 claims description 18
- 238000007259 addition reaction Methods 0.000 claims description 15
- 238000005899 aromatization reaction Methods 0.000 claims description 15
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 239000000460 chlorine Substances 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- 229910052749 magnesium Inorganic materials 0.000 claims description 11
- 150000004795 grignard reagents Chemical class 0.000 claims description 9
- 150000002431 hydrogen Chemical group 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 229910052744 lithium Inorganic materials 0.000 claims description 8
- 229910052751 metal Inorganic materials 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- 229910052708 sodium Inorganic materials 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- 239000007818 Grignard reagent Substances 0.000 claims description 6
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
- 238000007254 oxidation reaction Methods 0.000 claims description 5
- GRPYAHAFRYQIEX-UHFFFAOYSA-N 1-bromo-9-chlorononane Chemical compound ClCCCCCCCCCBr GRPYAHAFRYQIEX-UHFFFAOYSA-N 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- 238000003747 Grignard reaction Methods 0.000 claims description 4
- 229910052740 iodine Chemical group 0.000 claims description 4
- 239000011630 iodine Chemical group 0.000 claims description 4
- JMGRNJZUQCEJDB-UHFFFAOYSA-N 1,9-dichlorononane Chemical compound ClCCCCCCCCCCl JMGRNJZUQCEJDB-UHFFFAOYSA-N 0.000 claims description 3
- MCUDHXVIWDEUGP-UHFFFAOYSA-N 1-chloro-9-iodononane Chemical compound ClCCCCCCCCCI MCUDHXVIWDEUGP-UHFFFAOYSA-N 0.000 claims description 2
- 150000002736 metal compounds Chemical class 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 238000000746 purification Methods 0.000 abstract description 4
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 76
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 40
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 38
- 239000000243 solution Substances 0.000 description 34
- 238000003756 stirring Methods 0.000 description 32
- 238000004128 high performance liquid chromatography Methods 0.000 description 23
- -1 N,N-dimethyl formaldehyde amide Chemical class 0.000 description 19
- 239000012074 organic phase Substances 0.000 description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 239000007858 starting material Substances 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 16
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 239000003960 organic solvent Substances 0.000 description 15
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 13
- 239000003153 chemical reaction reagent Substances 0.000 description 13
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 13
- 229940045803 cuprous chloride Drugs 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000010791 quenching Methods 0.000 description 11
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 9
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 7
- 230000009471 action Effects 0.000 description 7
- 150000001879 copper Chemical class 0.000 description 7
- 229910052802 copper Inorganic materials 0.000 description 7
- 239000010949 copper Substances 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 6
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 5
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 3
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 3
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 3
- PGXRMXFWANSLOV-UHFFFAOYSA-N 1,1,2,2,3-pentafluoropentane-1-thiol Chemical group CCC(F)C(F)(F)C(F)(F)S PGXRMXFWANSLOV-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 239000005909 Kieselgur Substances 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 229910000365 copper sulfate Inorganic materials 0.000 description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 2
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 2
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 description 2
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 125000000000 cycloalkoxy group Chemical group 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 125000005366 cycloalkylthio group Chemical group 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000004210 ether based solvent Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000011160 research 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
- 125000001424 substituent group Chemical group 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- YLBSXJWDERHYFY-UHFFFAOYSA-N (2-methylbenzoyl) 2-methylbenzoate Chemical compound CC1=CC=CC=C1C(=O)OC(=O)C1=CC=CC=C1C YLBSXJWDERHYFY-UHFFFAOYSA-N 0.000 description 1
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- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 1
- NOGFHTGYPKWWRX-UHFFFAOYSA-N 2,2,6,6-tetramethyloxan-4-one Chemical compound CC1(C)CC(=O)CC(C)(C)O1 NOGFHTGYPKWWRX-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
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- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- NQUVCRCCRXRJCK-UHFFFAOYSA-N 4-methylbenzoyl chloride Chemical compound CC1=CC=C(C(Cl)=O)C=C1 NQUVCRCCRXRJCK-UHFFFAOYSA-N 0.000 description 1
- USJDOLXCPFASNV-UHFFFAOYSA-N 9-bromononan-1-ol Chemical compound OCCCCCCCCCBr USJDOLXCPFASNV-UHFFFAOYSA-N 0.000 description 1
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- ARFTURSGEFYLGB-UHFFFAOYSA-N CC[Zn]CC.C1CCOC1 Chemical compound CC[Zn]CC.C1CCOC1 ARFTURSGEFYLGB-UHFFFAOYSA-N 0.000 description 1
- 229940102550 Estrogen receptor antagonist Drugs 0.000 description 1
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- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
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- VAPFAAVJYYWRHJ-UHFFFAOYSA-M [Br-].CC(C)[Mg+].C1CCOC1 Chemical compound [Br-].CC(C)[Mg+].C1CCOC1 VAPFAAVJYYWRHJ-UHFFFAOYSA-M 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
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- 125000002252 acyl group Chemical group 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
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- 230000009286 beneficial effect Effects 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
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- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
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- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
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- 230000000977 initiatory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 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
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- NPAGDVCDWIYMMC-IZPLOLCNSA-N nandrolone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 NPAGDVCDWIYMMC-IZPLOLCNSA-N 0.000 description 1
- 229960004719 nandrolone Drugs 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 150000002902 organometallic compounds Chemical class 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 125000005440 p-toluyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C(*)=O)C([H])([H])[H] 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
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- CHWRSCGUEQEHOH-UHFFFAOYSA-N potassium oxide Chemical compound [O-2].[K+].[K+] CHWRSCGUEQEHOH-UHFFFAOYSA-N 0.000 description 1
- 229910001950 potassium oxide Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000006479 redox reaction Methods 0.000 description 1
- 238000013341 scale-up Methods 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
- 238000004904 shortening Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 150000003431 steroids Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- QCIWZIYBBNEPKB-UHFFFAOYSA-N tert-butyl(dimethyl)silane Chemical group C[SiH](C)C(C)(C)C QCIWZIYBBNEPKB-UHFFFAOYSA-N 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic System
- C07F1/02—Lithium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic System
- C07F1/04—Sodium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic System
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic System
- C07F3/02—Magnesium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic System
- C07F3/06—Zinc compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
- C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
- C07J1/0074—Esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
Definitions
- the invention relates to an intermediate used for preparing fulvestrant and a preparation method thereof.
- Fulvestrant (formula I) is an estrogen receptor antagonist.
- AstraZeneca's fulvestrant injection was approved by the FDA, and its global sales in 2018 exceeded US$1 billion.
- fulvestrant is mainly carried out by introducing a side chain into the C7 position of the steroid core.
- the introduction method of the side chain is roughly divided into two strategies: alkylation and Grignard reagent addition.
- the alkylation route uses estradiol as a raw material. After protection, it is necessary to first oxidize C-6 to form an alcohol, and then oxidize to form a ketone. After the alkylation reaction, it is necessary to reduce the ketone to an alkyl group to obtain the parent structure of fulvestrant, and the reaction operation is relatively cumbersome.
- the Grignard addition route uses dehydronandrolone acetate as a raw material, and undergoes two steps of Grignard addition and aromatization to obtain the parent structure of fulvestrant.
- patents WO2002032922 and WO2006015081 disclose that when R is Grignard reagents for the addition route.
- WO2006015081 and CN103965280B also disclose that when R is OTBS, a relatively short-chain Grignard reagent is added to dehydronandrolone acetate.
- the pentafluoropentanethiol fragment can only be introduced after the tert-butyldimethylsilane protecting group is hydrolyzed and converted into a leaving group, which increases the length of the synthetic route and the difficulty of purification.
- the existing methods for preparing fulvestrant require repeated oxidation-reduction reactions on the carrier skeleton, or repeated protection and deprotection reactions on the side chains, resulting in cumbersome reaction routes, difficult purification, and low synthesis efficiency. . Therefore, there is a need to develop a more efficient synthetic route to prepare fulvestrant.
- fulvestrant preparation method Aiming at the shortcomings of the existing fulvestrant preparation method, through the unremitting efforts of the inventors, a new intermediate and synthesis method for the preparation of fulvestrant were invented, as well as a preparation method for synthesizing fulvestrant through the intermediate,
- the method has short synthesis route, mild and safe reaction conditions, simple and convenient operation and purification, high reaction selectivity and high synthesis efficiency, and is suitable for large-scale production of fulvestrant.
- the present invention provides a compound represented by formula V,
- R 1 is hydrogen or a hydroxyl protecting group.
- R 1 is hydrogen, C 1 -C 6 alkyl, C 1 -C 10 alkyl acyl, aryl acyl or (C 1-10 alkyl or aryl) 3 silyl groups.
- R 1 is C 1 -C 10 alkyl acyl or aryl acyl.
- R 1 is acetyl
- the present invention also provides a preparation method of the compound shown in formula V, which includes the following steps: adding the compound shown in formula VI to the compound shown in formula VII to obtain the compound shown in formula V; Said addition reaction is preferably carried out under the catalysis of copper reagent;
- R 1 is hydrogen or a hydroxyl protecting group
- M is MgCl, MgBr, MgI, Mg 1/2 , ZnCl, ZnBr, ZnI, Zn 1/2 , MnCl, Li or Na.
- the R in the preparation method of the compound shown in formula V, can be hydrogen, C 1 -C 6 alkyl, C 1 -C 10 alkyl acyl, aryl Acyl or (C 1 - 10 alkyl or aryl) 3 silyl; M is MgCl or MgBr.
- the R 1 in the preparation method of the compound represented by formula V, can be C 1 -C 10 alkyl acyl or aryl acyl; M is MgCl or MgBr.
- the R 1 in the preparation method of the compound represented by formula V, can be acetyl; M is MgBr.
- the addition reaction produces a group of diastereomer mixtures.
- the ratio of the diastereomer V-7 ⁇ :V-7 ⁇ may be 100 ⁇ 1:1.
- the diastereomer mixture can be directly subjected to the next step reaction, or can be purified to obtain a single isomer before the next step reaction.
- organic solvent can be the conventional solvent of this type of reaction in this area, also can be C 6 -C 10 alkane solvent (such as normal hexane, normal heptane), aromatic hydrocarbon solvent (such as toluene), ether solvent (such as tetrahydrofuran , 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane) in one or more.
- the amount of the organic solvent used may be a conventional amount used in this type of reaction in the art, for example, the molar concentration of the compound represented by the formula VI in the organic solvent may be 0.001-5 mol/L.
- the molar concentration of the compound shown in the formula VI in the organic solvent can be further preferably 0.005, 0.01, 0.05, 0.1, 0.5, 1.0 or 5.0 mol/L.
- the copper reagent can be one or more of cuprous chloride, cuprous bromide, cuprous iodide, cuprous trifluoromethanesulfonate .
- the amount of the copper reagent used may be a conventional amount used in this type of reaction in the art, for example, the molar ratio of the copper reagent to the compound represented by formula VI may be 0.001 ⁇ 1:1.
- the molar ratio of the copper reagent to the compound shown in formula VI can be further preferably 0.01:1, 0.05:1, 0.1:1, 0.3 :1, 0.5:1 or 1:1.
- the molar ratio of the compound represented by the formula VII to the compound represented by the formula VI may be 1 ⁇ 10:1.
- the molar ratio of the compound shown in the described formula VII to the compound shown in the described formula VI is further preferably 5:1, 4:1, 3: 1. 2:1 or 1:1.
- the process of the addition reaction can be monitored by conventional testing methods in the art (such as TLC, HPLC, GC or NMR, preferably HPLC) , generally when the compound shown in formula VI no longer reacts as the reaction end point.
- the reaction temperature of the addition reaction may be a conventional temperature of this type of reaction in the art, for example, -50-50°C.
- the reaction temperature of the addition reaction is further preferably -30°C, -20°C, -10°C, 0°C, 10°C or 20°C.
- the present invention also provides a compound as shown in formula VII,
- M is MgCl, MgBr, MgI, Mg 1/2 , ZnCl, ZnBr, ZnI, Zn 1/2 , MnCl, Li or Na.
- M is MgCl or MgBr.
- M is MgBr.
- the present invention also provides a preparation method of the compound shown in formula VII, which includes the following steps: reacting the compound shown in formula VIII with a metal, or performing an exchange reaction with a metal organic compound to prepare the compound shown in formula VII compound,
- X is chlorine, bromine or iodine
- M is MgCl, MgBr, MgI, Mg 1/2 , ZnCl, ZnBr, ZnI, Zn 1/2 , MnCl, Li or Na.
- X is chlorine or bromine
- M is MgCl or MgBr.
- the X is bromine
- M is MgBr.
- the compound shown in the formula VIII reacts with metal magnesium to prepare the compound shown in the formula VII, and the metal magnesium It can be one or more of magnesium powder and magnesium chips.
- the Grignard reaction can be carried out in an organic solvent.
- the organic solvent can be a conventional solvent for this type of reaction in the art, for example, it can be one of ether solvents (such as tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, diethyl ether, dioxane) or more.
- the amount of the organic solvent used may be a conventional amount used in this type of reaction in the art, for example, the molar concentration of the compound represented by the formula VIII in the organic solvent may be 0.001-5 mol/L.
- the molar concentration of the compound shown in the formula VIII in the organic solvent can be further preferably 0.005, 0.01, 0.05, 0.1, 0.5, 1.0 or 5.0 mol/L.
- the molar ratio of the metal magnesium to the compound represented by the formula VIII may be 0.5-10:1.
- the molar ratio of the described metal magnesium to the compound shown in the described formula VIII is further preferably 0.5:1, 0.8:1, 0.9:1, 0.95: 1, 1:1, 1.5:1, 2:1, 3:1 or 5:1.
- the reaction temperature of the Grignard reaction can be a conventional temperature of this type of reaction in the art, for example, -20-80°C.
- the reaction temperature of the Grignard reaction is further preferably -10°C, 0°C, 10°C, 20°C, 30°C, 40°C, 50°C or 80°C °C.
- the present invention also provides a compound as shown in formula III,
- R 1 is hydrogen or a hydroxyl protecting group
- R 2 is a hydroxyl protecting group
- R 1 is hydrogen, C 1 -C 6 alkyl, C 1 -C 10 alkyl acyl, aryl acyl or (C 1-10 alkyl or Aryl) 3 silyl;
- R 2 is C 1 -C 10 alkyl acyl or aryl acyl.
- R 1 is C 1 -C 10 alkylacyl or aryl acyl
- R 2 is C 1 -C 10 alkyl acyl or aryl acyl.
- R 1 is acetyl
- R 2 is acetyl or propionyl.
- the present invention also provides a preparation method of the compound shown in formula III, which comprises the following steps: preparing the compound shown in formula III through aromatization reaction and phenolic hydroxyl protection reaction of the compound shown in formula V;
- the aromatization reaction is preferably carried out under the action of copper salt;
- R 1 is hydrogen or a hydroxyl protecting group
- R 2 is a hydroxyl protecting group
- the R in the preparation method of the compound shown in formula III, can be hydrogen, C 1 -C 6 alkyl, C 1 -C 10 alkyl acyl, aryl Acyl or (C 1 -10 alkyl or aryl) 3 silyl;
- R 2 is C 1 -C 10 alkyl acyl or aryl acyl.
- the R 1 in the preparation method of the compound shown in formula III, can be selected from C 1 -C 10 alkyl acyl or aryl acyl; R 2 is C 1 -C 10 alkyl acyl or aryl acyl.
- the aromatization reaction can be carried out in an organic solvent.
- organic solvent can be the conventional solvent of this type of reaction in this area, can also be nitrile solvent (such as normal acetonitrile, propionitrile, butyronitrile, benzonitrile), amide solvent (such as N,N-dimethyl formaldehyde amide, N,N-dimethylacetamide), sulfone solvents (such as dimethyl sulfoxide, sulfolane), aromatic hydrocarbon solvents (such as toluene), ether solvents (such as tetrahydrofuran, 2-methyltetrahydrofuran, methyl One or more of tert-butyl ether, dioxane).
- the amount of the organic solvent used may be a conventional amount used in this type of reaction in the art, for example, the molar concentration of the compound represented by the formula V in the organic solvent may be 0.001-5 mol/L.
- the molar concentration of the compound shown in the formula V in the organic solvent can be further preferably 0.005, 0.01, 0.05, 0.1, 0.5, 1.0 or 5.0 mol/L.
- the copper salt can be copper chloride, copper bromide, copper iodide, copper sulfate, copper acetate, copper nitrate, copper trifluoromethanesulfonate one or more.
- the amount of the copper salt used may be a conventional amount used in this type of reaction in the art, for example, the molar ratio of the copper salt to the compound represented by formula V may be 0.5-10:1.
- the molar ratio of the copper salt to the compound shown in formula V can be further preferably 0.5:1, 0.8:1, 0.9:1, 1 :1, 2:1, 3:1 or 5:1.
- the acylating agent can be an alkyl acylating agent (such as acetic anhydride, acetyl chloride, propionic anhydride, propionyl chloride) or an aryl acylating agent (such as benzoyl chloride, benzoic anhydride, p-toluyl chloride, p One or more of methyl benzoic anhydride).
- the amount of the acylating reagent used may be a conventional amount used in this type of reaction in the art, for example, the molar ratio of the acylating reagent to the compound represented by formula V may be 1-10:1.
- the amount of the acylating agent can be the conventional amount of this type of reaction in the art, for example, the acylating agent and the compound shown in formula V
- the molar ratio of the compounds may further preferably be 1:1, 2:1, 3:1, 5:1 or 8:1.
- the process of the aromatization reaction can be carried out by conventional testing methods in the art (such as TLC, HPLC, GC or NMR, preferably HPLC)
- TLC TLC, HPLC, GC or NMR, preferably HPLC
- the end point of the reaction is generally when the compound represented by the formula V no longer reacts.
- the reaction temperature of the aromatization reaction may be a conventional temperature of this type of reaction in the art, for example, -20-60°C.
- the reaction temperature of the aromatization reaction can be further preferably -10°C, 0°C, 10°C, 20°C, 30°C, 40°C, 50°C or 60°C.
- the present invention also provides a preparation method of fulvestrant as shown in formula I, specifically, comprising the following steps,
- R 1 is hydrogen or a hydroxyl protecting group
- R 2 is a hydroxyl protecting group
- M is MgCl, MgBr, MgI, Mg 1/2 , ZnCl, ZnBr, ZnI, Zn 1/2 , MnCl, Li or Na.
- the compound shown in formula V obtains the compound shown in formula III through aromatization reaction and phenolic hydroxyl protection reaction;
- the aromatization reaction is preferably carried out under the effect of copper salt;
- the copper salt is preferably chlorine
- the phenolic hydroxyl protection reaction is completed under the action of an acylating reagent, and the Described acylating reagent is acetic anhydride or propionic anhydride;
- the compound shown in the formula III and the compound shown in the formula IV obtain the compound shown in the formula II through a substitution reaction; the substitution reaction is preferably carried out under the action of a base; the base is preferably sodium hydroxide, hydrogen One or more of potassium oxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate;
- the compound shown in formula II is obtained through oxidation reaction as the compound shown in formula I;
- the oxidation reaction is preferably carried out under the effect of oxidant;
- the R in the preparation method of the compound shown in formula I, can be hydrogen, C 1 -C 6 alkyl, C 1 -C 10 alkyl acyl, aryl Acyl or (C 1 - 10 alkyl or aryl) 3 silyl;
- R 2 is C 1 -C 10 alkyl acyl or aryl acyl;
- M is MgCl or MgBr.
- the R 1 in the preparation method of the compound shown in formula I, can be C 1 -C 10 alkyl acyl or aryl acyl;
- R 2 is C 1 -C 10 alkyl acyl or aryl acyl;
- M is MgCl or MgBr.
- the R 1 in the preparation method of the compound shown in formula I, can be acetyl; R 2 is acetyl or propionyl; M is MgBr.
- the preparation method of fulvestrant as shown in formula I includes the following steps,
- the present invention also provides a method for preparing fulvestrant through the following formula, comprising: 1,9-dichlorononane, 1-chloro-9-bromononane or 1-chloro-9-iodo The steps of preparing fulvestrant from nonane,
- 1,9-dichlorononane or 1-chloro-9-bromononane can be purchased;
- 1-Chloro-9-bromononane can also be prepared by chlorination of 9-bromo-1-nonanol.
- compound IV can be purchased, or prepared according to document WO2008044033.
- the present invention also provides a method for preparing fulvestrant, the method first prepares the compound represented by formula V or formula III according to the method provided above in the present invention, and then passes formula V according to known methods. or a compound represented by formula III to prepare fulvestrant, the method can refer to literature: WO2002032922; WO2006015081; Organic Process Research & Development 2010, 14, 544-552.
- the present invention adopts the metal reagent VII containing chlorine at the terminal (especially the Grignard reagent VIIA containing chlorine at the terminal) to carry out the addition reaction, and the product V obtained after aromatization can directly use chlorine as the leaving group to introduce pentafluoro Pentanthiol fragments, thereby avoiding the use of protecting groups and the transformation of functional groups in the prior art, and shortening the steps of the fulvestrant synthesis route.
- the conditions of the present invention are mild, and there are no ultra-low temperature (such as less than -40°C) and ultra-high temperature (such as greater than 80°C) reaction conditions.
- the synthesis operation process of the present invention is simple, qualified products can be obtained without column chromatography, and it is easy to realize industrial scale-up production.
- the hydroxy protecting group of the present invention is a suitable group known in the art for hydroxy protecting, see the hydroxy protecting group in the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. TW Greene & P. GM Wuts).
- the hydroxyl protecting group can be (C 1-10 alkyl or aryl) 3 silyl, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl , tert-butyldiphenylsilyl, etc.; can be C 1-10 alkyl or substituted alkyl, such as: methyl, tert-butyl, allyl, benzyl, methoxymethyl, ethoxyethyl Base, 2-tetrahydropyranyl (THP), etc.; can be (C 1-10 alkyl or aryl) acyl, for example: formyl, acetyl, benzoyl, p-tol
- Alkyl refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms.
- Non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethyl Propyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl Base-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl , 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpenty
- Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from alkyl, alkenyl, Alkynyl, alkyloxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy , heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, or oxo; non-limiting examples include, but are not limited to, methyloxymethyl, ethyloxymethyl, benzyl, p-methyl Oxybenzyl, p-methylbenzyl, 2-tetrahydropyranyl, etc.
- Aryl means a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, more preferably benzene and naphthyl, most preferably phenyl.
- Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkyl ylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio or heterocycle Alkylthio.
- Embodiment 1 preparation compound VIIIa
- Embodiment 2 Preparation of compound VIIa
- Embodiment 3 preparation compound VIIa
- Embodiment 4 preparation compound VIIb
- Embodiment 5 preparation compound VIIc
- Embodiment 7 preparation compound VIIe
- Embodiment 8 preparation compound VIIf
- Embodiment 9 preparation compound VIIg
- Embodiment 10 preparation compound Va
- Embodiment 11 preparation compound Va
- Embodiment 12 preparation compound Va
- Embodiment 13 Preparation of compound Va
- Embodiment 17 preparation compound Vb
- Embodiment 18 Preparation of compound Vc
- Embodiment 19 Preparation of compound Vd
- Embodiment 20 Preparation of compound Ve
Abstract
本发明涉及一种氟维司群的中间体及其制备方法。具体而言,本发明涉及一种如式V所示的化合物及其制备方法,其中R 1为氢或羟基保护基。本发明还涉及一种经由如式V所示的化合物合成氟维司群的制备方法,该方法具有反应步骤简短,反应条件温和安全,选择性高,操作和纯化简便,合成效率高等优点,适于大规模生产。
Description
本申请要求申请日为2021年6月9日的中国专利申请2021106443179的优先权。本申请引用上述中国专利申请的全文。
本发明涉及一种用于制备氟维司群的中间体及其制备方法。
氟维司群(如式I所示)是一种雌激素受体拮抗剂。2002年4月,阿斯利康的氟维司群注射液被FDA批准上市,2018年时其全球销售额已经超过了10亿美元。
现有技术对氟维司群的合成主要通过对甾体母核的C7位引进侧链的方式来进行,侧链的引入方法大致上分为烷基化和格氏试剂加成两种策略。
如专利CN102827048、CN102993257、CN110938107、CN102993259、WO2009013310、WO2009039700、US9315540中所公开,烷基化路线以雌二醇为原料,经保护后,需要先对C-6氧化形成醇,再氧化形成酮。进行烷基化反应后,又需要将酮还原为烷基,以获得氟维司群母体结构,反应操作比较繁琐。
格氏加成路线以脱氢诺龙醋酸酯为原料,经过格氏加成和芳构化两步反应得到氟维司群母体结构。在格氏试剂的结构上,专利WO2002032922、WO2006015081公开了当R为
的格氏试剂进行加成的路线。虽然路线十分简洁,但是在其相应的文献Organic Process Research&Development 2010,14,544-552中提到,当结构中同时含有硫和溴时,其格氏试剂的前体溴代物不稳定,易于降解,且少量杂质的存在也会导致格氏试剂的引发困难,因此对物料的保存和纯度的要求非常高。
WO2006015081和CN103965280B还公开了当R为OTBS时,相对而言短链的格氏试剂对脱氢诺龙醋酸酯加成的方案。但是在该情况下,需要将叔丁基二甲基硅烷保护基水解脱除并转化为离去基团后,才能引入五氟戊硫醇片段,从而增加了合成路线的长度和纯化的难度。
综上,现有制备氟维司群的方法需要对载体骨架进行反复的氧化还原反应,或者对侧链进行反复的保护和去保护反应,导致反应路线比较繁琐,纯化困难,合成效率低等缺点。因此,需要开发一种更高效的合成路线来制备氟维司群。
发明内容
针对现有氟维司群制备方法的缺点,经过发明人的不懈努力,发明了一种制备氟维司群的新中间体和合成方法,以及经由该中间体合成氟维司群的制备方法,该方法合成路线简短,反应条件温和安全,操作和纯化简便,反应选择性高,合成效率高,适于大规模生产氟维司群。
本发明提供一种如式V所示的化合物,
其中,R
1为氢或羟基保护基。
本发明一个优选的实施方案,式V所示的化合物中,R
1为氢、C
1-C
6烷基、C
1-C
10烷基酰基、芳基酰基或(C
1-10烷基或芳基)
3硅烷基。
本发明一个更优选的实施方案,式V所示的化合物中,R
1为C
1-C
10烷基酰基或芳基 酰基。
本发明一个更优选的实施方案,式V所示的化合物中,R
1为乙酰基。
本发明还提供一种如式V所示的化合物的制备方法,其包括如下步骤:将式VI所示的化合物与式VII所示的化合物经过加成反应得到如式V所示的化合物;所述加成反应优选在铜试剂的催化下进行;
其中,R
1为氢或羟基保护基;M为MgCl、MgBr、MgI、Mg
1/2、ZnCl、ZnBr、ZnI、Zn
1/2、MnCl、Li或Na。
本发明一个优选的实施方案,所述的如式V所示化合物的制备方法中,所述的R
1可为氢、C
1-C
6烷基、C
1-C
10烷基酰基、芳基酰基或(C
1-
10烷基或芳基)
3硅烷基;M为MgCl或MgBr。
本发明一个更优选的实施方案,所述的如式V所示化合物的制备方法中,所述的R
1可为C
1-C
10烷基酰基或芳基酰基;M为MgCl或MgBr。
本发明一个更优选的实施方案,所述的如式V所示化合物的制备方法中,所述的R
1可为乙酰基;M为MgBr。
所述的如式V所示化合物的制备方法中,所述的加成反应产生一组非对映异构体混合物。作为示例地,所述非对映异构体V-7α:V-7β的比例可为100~1:1。所述非对映异构体混合物可以直接进行下一步反应,也可以经过纯化后得到单一的异构体再进行下一步反应。
所述的如式V所示化合物的制备方法中,所述的加成反应可在有机溶剂中进行。所述的有机溶剂可为本领域该类反应的常规溶剂,还可为C
6-C
10烷烃溶剂(如正己烷、正 庚烷)、芳烃类溶剂(如甲苯)、醚类溶剂(如四氢呋喃、2-甲基四氢呋喃、甲基叔丁基醚、二噁烷)中的一种或多种。所述的有机溶剂的用量可为本领域该类反应的常规用量,例如所述的式VI所示的化合物在所述的有机溶剂中的摩尔浓度可为0.001~5mol/L。
所述的如式V所示化合物的制备方法中,所述的式VI所示的化合物在所述的有机溶剂中的摩尔浓度可进一步优选为0.005、0.01、0.05、0.1、0.5、1.0或5.0mol/L。
所述的如式V所示化合物的制备方法中,所述的铜试剂可为氯化亚铜、溴化亚铜、碘化亚铜、三氟甲磺酸亚铜中的一种或多种。所述的铜试剂的用量可为本领域该类反应的常规用量,例如所述的铜试剂与所述的如式VI所示的化合物的摩尔比例可为0.001~1:1。
所述的如式V所示化合物的制备方法中,所述的铜试剂与所述的如式VI所示的化合物的摩尔比例可进一步优选为0.01:1、0.05:1、0.1:1、0.3:1、0.5:1或1:1。
所述的如式V所示的化合物的制备方法中,所述的式VII所示的化合物与所述的式VI所示的化合物的摩尔比例可为1~10:1。
所述的如式V所示的化合物的制备方法中,所述的式VII所示的化合物与所述的式VI所示的化合物的摩尔比例进一步优选为5:1、4:1、3:1、2:1或1:1。
所述的如式V所示的化合物的制备方法中,所述的加成反应的进程可以采用本领域中的常规测试方法(如TLC、HPLC、GC或NMR,较佳地为HPLC)进行监控,一般以所述的如式VI所示的化合物不再反应时作为反应终点。
所述的如式V所示的化合物的制备方法中,所述的加成反应的反应温度可为本领域该类反应的常规温度,例如为-50~50℃。
所述的如式V所示的化合物的制备方法中,所述的加成反应的反应温度进一步优选为-30℃、-20℃、-10℃、0℃、10℃或20℃。
本发明还提供一种如式VII所示的化合物,
其中,M为MgCl、MgBr、MgI、Mg
1/2、ZnCl、ZnBr、ZnI、Zn
1/2、MnCl、Li或Na。
本发明一个优选的实施方案,M为MgCl或MgBr。
本发明一个更优选的实施方案,M为MgBr。
本发明还提供一种如式VII所示的化合物的制备方法,其包括如下步骤:将如式VIII所述的化合物与金属反应,或者与金属有机化合物发生交换反应制得如式VII所示的化合物,
其中,X为氯、溴或碘;M为MgCl、MgBr、MgI、Mg
1/2、ZnCl、ZnBr、ZnI、Zn
1/2、MnCl、Li或Na。
本发明一个优选的实施方案,所述的如式VII所示化合物的制备方法中,所述的X为氯或溴,M为MgCl或MgBr。
本发明一个更优选的实施方案,所述的如式VII所示化合物的制备方法中,所述的X为溴,M为MgBr。
本发明一个优选的实施方案,所述的如式VII所示化合物的制备方法中,如式VIII所述的化合物与金属镁发生格式反应制得如式VII所示的化合物,所述的金属镁可为镁粉、镁屑中的一种或多种。
所述的如式VII所示化合物的制备方法中,所述的格氏反应可在有机溶剂中进行。所述的有机溶剂可为本领域该类反应的常规溶剂,例如,可为醚类溶剂(如四氢呋喃、2-甲基四氢呋喃、甲基叔丁基醚、乙醚、二噁烷)中的一种或多种。所述的有机溶剂的用量可为本领域该类反应的常规用量,例如所述的式VIII所示的化合物在所述的有机溶剂中的摩尔浓度可为0.001~5mol/L。
所述的如式VII所示化合物的制备方法中,所述的式VIII所示的化合物在所述的有机溶剂中的摩尔浓度可进一步优选为0.005、0.01、0.05、0.1、0.5、1.0或5.0mol/L。
所述的如式VII所示的化合物的制备方法中,所述的金属镁与所述的式VIII所示的化合物的摩尔比例可为0.5~10:1。
所述的如式VII所示的化合物的制备方法中,所述的金属镁与所述的式VIII所示的化合物的摩尔比例进一步优选为0.5:1、0.8:1、0.9:1、0.95:1、1:1、1.5:1、2:1、3:1或5:1。
所述的如式VII所示的化合物的制备方法中,所述的格氏反应的反应温度可为本领域该类反应的常规温度,例如为-20~80℃。
所述的如式VII所示的化合物的制备方法中,所述的格氏反应的反应温度进一步优选为-10℃、0℃、10℃、20℃、30℃、40℃、50℃或80℃。
本发明还提供一种如式III所示的化合物,
其中,R
1为氢或羟基保护基;R
2为羟基保护基。
本发明一个优选的实施方案,式III所示的化合物中,R
1为氢、C
1-C
6烷基、C
1-C
10烷基酰基、芳基酰基或(C
1-10烷基或芳基)
3硅烷基;R
2为C
1-C
10烷基酰基或芳基酰基。
本发明一个更优选的实施方案,式III所示的化合物中,R
1为C
1-C
10烷基酰基或芳基酰基;R
2为C
1-C
10烷基酰基或芳基酰基。
本发明一个更优选的实施方案,式III所示的化合物中,R
1为乙酰基;R
2为乙酰基或丙酰基。
本发明还提供一种如式III所示的化合物的制备方法,其包括如下步骤:将如式V所示的化合物通过芳构化反应和酚羟基保护反应制得如式III所示的化合物;所述芳构化反应优选在铜盐的作用下进行;
其中,R
1为氢或羟基保护基;R
2为羟基保护基。
本发明一个优选的实施方案,所述的如式III所示化合物的制备方法中,所述的R
1可为氢、C
1-C
6烷基、C
1-C
10烷基酰基、芳基酰基或(C
1-
10烷基或芳基)
3硅烷基;R
2为C
1-C
10烷基酰基或芳基酰基。
本发明一个更优选的实施方案,所述的如式III所示化合物的制备方法中,所述的R
1可为选为C
1-C
10烷基酰基或芳基酰基;R
2为C
1-C
10烷基酰基或芳基酰基。
本发明一个更优选的实施方案,所述的如式III所示化合物的制备方法中,所述的R
1可为乙酰基;R
2为乙酰基或丙酰基。
本发明一个更优选的实施方案,所述的如式III所示化合物的制备方法中,所述的R
1可为乙酰基;R
2为乙酰基。
所述的如式III所示化合物的制备方法中,所述的芳构化反应可在有机溶剂中进行。所述的有机溶剂可为本领域该类反应的常规溶剂,还可为腈类溶剂(如正乙腈、丙腈、丁腈、苯腈)、酰胺类溶剂(如N,N-二甲基甲酰胺、N,N-二甲基乙酰胺)、砜类溶剂(如二甲基亚砜、环丁砜)、芳烃类溶剂(如甲苯)、醚类溶剂(如四氢呋喃、2-甲基四氢呋喃、甲基叔丁基醚、二噁烷)中的一种或多种。所述的有机溶剂的用量可为本领域该类反应的常规用量,例如所述的式V所示的化合物在所述的有机溶剂中的摩尔浓度可为0.001~5mol/L。
所述的如式III所示化合物的制备方法中,所述的式V所示的化合物在所述的有机溶剂中的摩尔浓度可可进一步优选为0.005、0.01、0.05、0.1、0.5、1.0或5.0mol/L。
所述的如式III所示化合物的制备方法中,所述的铜盐可为氯化铜、溴化铜、碘化铜、硫酸铜、醋酸铜、硝酸铜、三氟甲磺酸铜中的一种或多种。所述的铜盐的用量可为本领域该类反应的常规用量,例如所述的铜盐与所述的如式V所示的化合物的摩尔比例可为0.5~10:1。
所述的如式III所示化合物的制备方法中,所述的铜盐与所述的如式V所示的化合物的摩尔比例可进一步优选为0.5:1、0.8:1、0.9:1、1:1、2:1、3:1或5:1。
所述的如式III所示化合物的制备方法中,所述的酚羟基保护反应在酰化试剂作用下完成。所述的酰化试剂可以烷基酰化试剂(如乙酸酐、乙酰氯、丙酸酐、丙酰氯)或芳基酰化试剂(如苯甲酰氯、苯甲酸酐、对甲基苯甲酰氯、对甲基苯甲酸酐)中的一种或多种。所述的酰化试剂的用量可为本领域该类反应的常规用量,例如所述的酰化试剂与所述的如式V所示的化合物的摩尔比例可为1~10:1。
所述的如式III所示化合物的制备方法中,所述的酰化试剂的用量可为本领域该类反应的常规用量,例如所述的酰化试剂与所述的如式V所示的化合物的摩尔比例可可进一步优选为1:1、2:1、3:1、5:1或8:1。
所述的如式III所示的化合物的制备方法中,所述的芳构化反应的进程可以采用本领域中的常规测试方法(如TLC、HPLC、GC或NMR,较佳地为HPLC)进行监控,一般以所述的如式V所示的化合物不再反应时作为反应终点。
所述的如式III所示的化合物的制备方法中,所述的芳构化反应的反应温度可为本领域该类反应的常规温度,例如为-20~60℃。
所述的如式III所示的化合物的制备方法中,所述的芳构化反应的反应温度可进一步优选为-10℃、0℃、10℃、20℃、30℃、40℃、50℃或60℃。
本发明还提供一种如式I所示的氟维司群的制备方法,具体来说,包含如下步骤,
其中,R
1为氢或羟基保护基;R
2为羟基保护基;M为MgCl、MgBr、MgI、Mg
1/2、 ZnCl、ZnBr、ZnI、Zn
1/2、MnCl、Li或Na。
1)如式VI所示的化合物和式VII所示的化合物经过加成反应得到如式V所示的化合物;所述加成反应优选在铜试剂的作用下进行;所述铜试剂优选为氯化亚铜、溴化亚铜、碘化亚铜、三氟甲磺酸亚铜中的一种或多种;
2)如式V所示的化合物经过芳构化反应和酚羟基保护反应得到如式III所示的化合物;所述芳构化反应优选在铜盐的作用下进行;所述铜盐优选为氯化铜、溴化铜、碘化铜、硫酸铜、醋酸铜、硝酸铜、三氟甲磺酸铜中的一种或多种;所述的酚羟基保护反应在酰化试剂作用下完成,所述的酰化试剂为乙酸酐或丙酸酐;
3)如式III所示的化合物和式IV所示的化合物经过取代反应得到如式II所示的化合物;所述取代反应优选在碱的作用下进行;所述碱优选为氢氧化钠、氢氧化钾、氢氧化锂、碳酸钠、碳酸钾、碳酸铯中的一种或多种;
4)如式II所示的化合物经过氧化反应得到如式I所示的化合物;所述氧化反应优选在氧化剂的作用下进行;所述氧化剂优选为双氧水、间氯过氧苯甲酸、过氧叔丁醇、过氧乙酸中的一种或多种;
本发明一个优选的实施方案,所述的如式I所示化合物的制备方法中,所述的R
1可为氢、C
1-C
6烷基、C
1-C
10烷基酰基、芳基酰基或(C
1-
10烷基或芳基)
3硅烷基;R
2为C
1-C
10烷基酰基或芳基酰基;M为MgCl或MgBr。
本发明一个更优选的实施方案,所述的如式I所示化合物的制备方法中,所述的R
1可为C
1-C
10烷基酰基或芳基酰基;R
2为C
1-C
10烷基酰基或芳基酰基;M为MgCl或MgBr。
本发明一个更优选的实施方案,所述的如式I所示化合物的制备方法中,所述的R
1可为乙酰基;R
2为乙酰基或丙酰基;M为MgBr。
本发明的一个更优选实施方案,所述的如式I所示的氟维司群的制备方法中,包含如下步骤,
1)如式VIa所示的化合物和式VIIa所示的化合物经过格氏加成反应得到如式Va所示的化合物;
2)如式Va所示的化合物经过芳构化反应和通过乙酸酐对酚羟基保护反应得到如式IIIa所示的化合物;
3)如式IIIa所示的化合物和式IV所示的化合物经过取代反应得到如式II所示的化合物;
4)如式II所示的化合物经过氧化反应得到如式I所示的化合物。
进一步优选的,包含如下步骤,
1)如式VIa所示的化合物和式VIIa所示的化合物在氯化亚铜的作用下经过格氏加成反应得到如式Va所示的化合物;
2)如式Va所示的化合物在溴化铜和溴化锂的作用下经过芳构化反应和通过乙酸酐对酚羟基保护反应得到如式IIIa所示的化合物;
3)如式IIIa所示的化合物和式IV所示的化合物在氢氧化钠的作用下经过取代反应得到如式II所示的化合物;
4)如式II所示的化合物在双氧水和过氧乙酸的作用下经过氧化反应得到如式I所示的化合物;
另一方面,本发明还提供了经过如式一种制备氟维司群的方法,包括经1,9-二氯壬烷、1-氯-9-溴壬烷或1-氯-9-碘壬烷制备氟维司群的步骤,
其中,1,9-二氯壬烷或1-氯-9-溴壬烷可购得;
1-氯-9-溴壬烷也可以通过9-溴-1-壬醇的氯代制得。
1-氯-9-碘壬烷的制备可参考文献:J.Org.Chem.1963,28,1254-1259。
另外,化合物IV可购得,或依据文献WO2008044033制得。
化合物VI的合成可参考文献:Canadian Journal of Chemistry 1984,62,2740–2747。即采用四氯苯醌氧化诺龙得到脱氢诺龙,然后对羟基进行保护制得;
也可以对脱氢诺龙醋酸酯脱保护后,再更换其他保护基制得;
如果可以购得,也可使用上述反应步骤中的部分产物依更短路线制得式V所示化合物;例如可通过购买前述式VI,而后依照上述方法中提供的步骤制得式V所示的化合物。
另一方面,本发明还提供了一种制备氟维司群的方法,该方法先依照本发明前述提供的方法制得式V或式III所示的化合物,而后依照已知的方法经式V或式III所示的化合物制得氟维司群,所述方法可参照文献:WO2002032922;WO2006015081;Organic Process Research&Development 2010,14,544-552。
本发明的有益效果是:
1)本发明采用末端含氯的金属试剂VII(特别是末端含氯的格式试剂VIIA)进行加成反应,所得的产物V经过芳构化之后可以直接以氯为离去基团,引入五氟戊硫醇片段,从而避免了现有技术中对保护基的使用和官能团的转化,缩短了氟维司群合成路线的步骤。
2)本发明采用末端含氯的格氏试剂VIIA进行加成反应时反应选择性高,产生的非对映异构体比例可以达到9:1。
3)本发明的条件温和,不存在超低温(如小于-40℃)和超高温(如大于80℃)的 反应条件。
4)本发明的合成操作过程简单,可以不通过柱层析得到合格产品,易于实现工业化放大生产。
5)本发明的氟维司群的合成效率具有显著优势。
本发明所使用的术语,除有相反的表述外,具有如下的含义:
本发明的羟基保护基是本领域已知的适当的用于羟基保护的基团,参见文献(“Protective Groups in Organic Synthesis”,5
Th Ed.T.W.Greene&P.G.M.Wuts)中的羟基保护基团。作为示例地,所述的羟基保护基可以是(C
1-10烷基或芳基)
3硅烷基,例如:三乙基硅基,三异丙基硅基,叔丁基二甲基硅基,叔丁基二苯基硅基等;可以是C
1-10烷基或取代烷基,例如:甲基,叔丁基,烯丙基,苄基,甲氧基甲基,乙氧基乙基,2-四氢吡喃基(THP)等;可以是(C
1-10烷基或芳香基)酰基,例如:甲酰基,乙酰基,苯甲酰基,对甲基苯甲酰基等;可以是(C
1-6烷基或C
6-10芳基)磺酰基;也可以是(C
1-6烷氧基或C
6-10芳基氧基)羰基。
“烷基”指饱和的脂族烃基团,包括1至10个碳原子的直链和支链基团,优选包括1至6个碳原子。非限制性实施例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或未取代的,当被取代时,取代基可以在任何可使用的连接点上被取代,优选为一个或多个以下基团,独立地选自烷基、烯基、炔基、烷基氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷基氧基、杂环烷基氧基、环烷硫基、杂环烷硫基或氧代;非限制性实施例包括但不限于甲基氧基甲基、乙基氧基甲基、苄基、对甲氧基苄基、对甲基苄基、2-四氢吡喃基等。
“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,优选为6至10元,更优选苯基和萘基,最优选苯基。芳基可以是取代的或未取代的,当被取代时,取代基优选为一个或多个以下基团,独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基或杂环烷硫基。
缩写表:
缩写 | 全称 |
MTBE | 甲基叔丁基醚 |
Ac | 乙酰基 |
TBS | 叔丁基二甲基硅基 |
Bz | 苯甲酰基 |
Bn | 苄基 |
MOM | 甲基氧基甲基 |
THP | 2-四氢吡喃基 |
TsO - | 对甲基苯磺酸根 |
HPLC | 液相色谱 |
下表为实施例中所涉及的化合物的结构式
以下将结合具体实例详细地解释本发明,使得本专业技术人员更全面地理解本发明,具体实例仅用于说明本发明的技术方案,并不以任何方式限定本发明。
实施例1:制备化合物VIIIa
将化合物IXa(50g)和氯化亚砜(50mL)加入500ml三口瓶中。控制内温在20℃以下,滴加入吡啶(10mL),反应继续在20℃反应48h。TLC显示原料反应完全。将反应液冰水中猝灭,MTBE萃取,有机相用饱和碳酸氢钠洗涤,干燥浓缩后得52.6g化合物VIIIa,收率97%。
1H NMR(400MHz,Chloroform-d)δ3.53(td,J=6.7,0.9Hz,2H),3.41(td,J=6.9,0.8Hz,2H),1.85(p,J=7.0Hz,2H),1.81–1.72(m,2H),1.43(dq,J=12.9,6.8Hz,4H),1.32(d,J=4.5Hz,6H)。
实施例2:制备化合物VIIa
将镁屑(6.42g)加入反应瓶中,加入无水四氢呋喃(380mL)。20℃下加入化合物VIIIa(46.1g)。滴加完毕后,反应继续在室温下搅拌2h,得到化合物VIIa,备用。
实施例3:制备化合物VIIa
将化合物VIIIa(46.1g)加入反应瓶中,加入无水四氢呋喃(380mL)。降温至0℃,滴加异丙基溴化镁四氢呋喃溶液(1.0eq)。滴加完毕后,反应继续搅拌2h,得到化合物VIIa,备用。
实施例4:制备化合物VIIb
将镁屑(6g)加入反应瓶中,加入无水四氢呋喃(380mL)。20℃下加入化合物VIIIb(48g)。滴加完毕后,反应继续在室温下搅拌2h,得到化合物VIIb,备用。
实施例5:制备化合物VIIc
将镁屑(6g)加入反应瓶中,加入无水四氢呋喃(380mL)。20℃下加入化合物VIIIc(32.7g)。滴加完毕后,反应继续在室温下搅拌2h,得到化合物VIIb,备用。
实施例6:制备化合物VIId
将镁屑(6.42g)加入反应瓶中,加入无水四氢呋喃(380mL)。20℃下加入化合物VIIIa(46.1g)。滴加完毕后,反应继续在室温下搅拌2h,得到化合物VIIa。将VIIa溶液降温至0℃,加入无水ZnCl
2四氢呋喃溶液(1.0eq),继续搅拌2h,得到化合物VIId,备用。
实施例7:制备化合物VIIe
将化合物VIIIa(46.1g)加入反应瓶中,加入无水四氢呋喃(380mL)。降温至-30℃,滴加二乙基锌四氢呋喃溶液(0.5eq)。滴加完毕后,反应继续搅拌2h,得到化合物VIIe,备用。
实施例8:制备化合物VIIf
将化合物VIIIa(46.1g)加入反应瓶中,加入无水四氢呋喃(380mL)。降温至-30℃,滴加特丁基锂四氢呋喃溶液(2.5eq)。滴加完毕后,反应继续搅拌2h,得到化合物VIIf。-30℃下保存备用。
实施例9:制备化合物VIIg
将镁屑(6.42g)加入反应瓶中,加入无水四氢呋喃(380mL)。20℃下加入化合物VIIIa(46.1g)。滴加完毕后,反应继续在室温下搅拌2h,得到化合物VIIa。将VIIa溶液降温至0℃,加入无水二氯化锰四氢呋喃溶液(1.0eq),继续搅拌2h,得到化合物VIIg,备用。
实施例10:制备化合物Va
将化合物VIa(20g)和氯化亚铜(1.42g)加入反应瓶中,加入四氢呋喃(120mL), -20℃下,滴入化合物VIIa的四氢呋喃溶液(1.3eq.),滴加完毕后,反应继续在-20℃搅拌2h,HPLC显示原料转化完全。加入乙酸淬灭反应,加入水稀释,乙酸乙酯萃取,有机相用饱和碳酸氢钠洗涤,干燥后浓缩得28.0g化合物Va,收率92%。非对映异构体比例7α:7β=9:1。
MS(ESI)m/z:477(M+H
+)。
1H NMR(400MHz,Chloroform-d)δ5.82(s,1H),4.61(t,1H),3.52(t,2H),2.52(dd,J=14Hz,J=2Hz,1H),2.38~2.42(m,1H),2.21~2.29(m,3H),2.15~2.21(m,1H),2.03(s,3H),1.96~2.02(m,1H),1.85~1.88(m,1H),1.68~1.79(m,5H),1.46~1.60(m,4H),0.95~1.42(m,18H)。
实施例11:制备化合物Va
将化合物VIa(20g)和氯化亚铜(1.42g)加入反应瓶中,加入四氢呋喃(120mL),-20℃下,滴入化合物VIIb的四氢呋喃溶液(1.3eq.),滴加完毕后,反应继续在-20℃搅拌2h,HPLC显示原料转化完全。加入乙酸淬灭反应,加入水稀释,乙酸乙酯萃取,有机相用饱和碳酸氢钠洗涤,干燥后浓缩得25.2g化合物Va,收率83%。非对映异构体比例7α:7β=8:1。
MS(ESI)m/z:477(M+H
+)。
1H NMR(400MHz,Chloroform-d)δ5.82(s,1H),4.61(t,1H),3.52(t,2H),2.52(dd,J=14Hz,J=2Hz,1H),2.38~2.42(m,1H),2.21~2.29(m,3H),2.15~2.21(m,1H),2.03(s,3H),1.96~2.02(m,1H),1.85~1.88(m,1H),1.68~1.79(m,5H),1.46~1.60(m,4H),0.95~1.42(m,18H)。
实施例12:制备化合物Va
将化合物VIa(20g)和氯化亚铜(1.42g)加入反应瓶中,加入四氢呋喃(120mL),-10℃下,滴入化合物VIIc的四氢呋喃溶液(1.3eq.),滴加完毕后,反应继续在-10℃搅拌2h,HPLC显示原料转化完全。加入乙酸淬灭反应,加入水稀释,乙酸乙酯萃取,有机相用饱和碳酸氢钠洗涤,干燥后浓缩得22.7g化合物Va,收率75%。非对映异构体比例7α:7β=7:1。
MS(ESI)m/z:477(M+H
+)。
1H NMR(400MHz,Chloroform-d)δ5.82(s,1H),4.61(t,1H),3.52(t,2H),2.52(dd,J=14Hz,J=2Hz,1H),2.38~2.42(m,1H),2.21~2.29(m,3H),2.15~2.21(m,1H),2.03(s,3H),1.96~2.02(m,1H),1.85~1.88(m,1H),1.68~1.79(m,5H),1.46~1.60(m,4H),0.95~1.42(m,18H).
实施例13:制备化合物Va
将化合物VIa(20g)和氯化亚铜(1.42g)加入反应瓶中,加入四氢呋喃(120mL),-10℃下,滴入化合物VIId的四氢呋喃溶液(1.3eq.),滴加完毕后,反应继续在-10℃搅拌2h,HPLC显示原料转化完全。加入乙酸淬灭反应,加入水稀释,乙酸乙酯萃取,有机相用饱和碳酸氢钠洗涤,干燥后浓缩得11.0g化合物Va,收率38%。
实施例14:制备化合物Va
将化合物VIa(20g)和氯化亚铜(1.42g)加入反应瓶中,加入四氢呋喃(120mL),-10℃下,滴入化合物VIIe的四氢呋喃溶液(1.3eq.),滴加完毕后,反应继续在-10℃搅拌2h,HPLC显示原料转化完全。加入乙酸淬灭反应,加入水稀释,乙酸乙酯萃取,有机相用饱和碳酸氢钠洗涤,干燥后浓缩得10.0g化合物Va,收率33%。
实施例15:制备化合物Va
将化合物VIa(20g)和氯化亚铜(1.42g)加入反应瓶中,加入四氢呋喃(120mL),-10℃下,滴入化合物VIIf的四氢呋喃溶液(1.3eq.),滴加完毕后,反应继续在-10℃搅拌2h,HPLC显示原料转化完全。加入乙酸淬灭反应,加入水稀释,乙酸乙酯萃取,有机相用饱和碳酸氢钠洗涤,干燥后浓缩得8.0g化合物Va,收率26%。
实施例16:制备化合物Va
将化合物VIa(20g)和氯化亚铜(1.42g)加入反应瓶中,加入四氢呋喃(120mL),-10℃下,滴入化合物VIIg的四氢呋喃溶液(1.3eq.),滴加完毕后,反应继续在-10℃搅拌2h,HPLC显示原料转化完全。加入乙酸淬灭反应,加入水稀释,乙酸乙酯萃取,有机相用饱和碳酸氢钠洗涤,干燥后浓缩得18.0g化合物Va,收率60%。
实施例17:制备化合物Vb
将化合物VIb(2g)和氯化亚铜(263mg)加入反应瓶中,加入四氢呋喃(15mL),-30℃下,滴入化合物VIIa的四氢呋喃溶液(1.5eq.),滴加完毕后,反应继续在-30℃搅拌2h,HPLC显示原料转化完全。加入乙酸淬灭反应,加入水稀释,乙酸乙酯萃取,有机相用饱和碳酸氢钠洗涤,干燥后浓缩得2.24g化合物Vb,收率78%。非对映异构体比例7α:7β=9:1。
MS(ESI)m/z:539(M+H
+)。
实施例18:制备化合物Vc
将化合物VIc(2g)和溴化亚铜(280mg)加入反应瓶中,加入四氢呋喃(15mL),0℃下,滴入化合物VIIa的四氢呋喃溶液(1.5eq.),滴加完毕后,反应继续在0℃搅拌1h,HPLC显示原料转化完全。加入乙酸淬灭反应,加入水稀释,乙酸乙酯萃取,有机相用饱和碳酸氢钠洗涤,干燥后浓缩得2.13g化合物Vc,收率70%。非对映异构体比例7α:7β=5:1。
MS(ESI)m/z:479(M+H
+)。
实施例19:制备化合物Vd
将化合物VId(2g)和碘化亚铜(306mg)加入反应瓶中,加入四氢呋喃(15mL),-10℃下,滴入化合物VIIa的四氢呋喃溶液(1.2eq.),滴加完毕后,反应继续在-10℃搅拌2h,HPLC显示原料转化完全。加入乙酸淬灭反应,加入水稀释,乙酸乙酯萃取,有机相用饱和碳酸氢钠洗涤,干燥后浓缩得2.35g化合物Vd,收率81%。非对映异构体比例7α:7β=8:1。
MS(ESI)m/z:525(M+H
+)。
实施例20:制备化合物Ve
将化合物VIe(2g)和三氟甲磺酸亚铜(244mg)加入反应瓶中,加入2-甲基四氢呋喃(15mL),-30℃下,滴入化合物VIIb的四氢呋喃溶液(1.3eq.),滴加完毕后,反应继续在-30℃搅拌2h,HPLC显示原料转化完全。加入乙酸淬灭反应,加入水稀释,乙 酸乙酯萃取,有机相用饱和碳酸氢钠洗涤,干燥后浓缩得2.28g化合物Ve,收率80%。非对映异构体比例7α:7β=9:1。
MS(ESI)m/z:549(M+H
+)。
实施例21:制备化合物Vf
将化合物VIf(2g)和氯化亚铜(122mg)加入反应瓶中,加入四氢呋喃(15mL),-20℃下,滴入化合物VIIa的四氢呋喃溶液(1.3eq.),滴加完毕后,反应继续在-20℃搅拌2h,HPLC显示原料转化完全。加入乙酸淬灭反应,加入水稀释,乙酸乙酯萃取,有机相用饱和碳酸氢钠洗涤,干燥后浓缩得2.25g化合物Vf,收率77%。非对映异构体比例7α:7β=9:1。
MS(ESI)m/z:519(M+H
+)。
实施例22:制备化合物Vg
将化合物VIg(20g)和氯化亚铜(1.42g)加入反应瓶中,加入四氢呋喃(120mL),-10℃下,滴入化合物VIIa的四氢呋喃溶液(2.5eq.),滴加完毕后,反应继续在-10℃搅拌2h,HPLC显示原料转化完全。加入乙酸淬灭反应,加入水稀释,乙酸乙酯萃取,有机相用饱和碳酸氢钠洗涤,干燥后浓缩得18.6g化合物Vg,收率58%。非对映异构体比例7α:7β=8:1。
实施例23:制备化合物IIIa
将溴化铜(5.62g)和溴化锂(1.55g)加入反应瓶中,随后加入乙腈(15mL)和乙酸酐(1.23g),反应在20℃搅拌30min后,滴加入化合物Va(5g)的乙腈(15mL)溶液,反应继续在20℃搅拌3h,HPLC监控显示原料转化完全。将反应液滴加入硫脲的甲苯和水的混合液中,搅拌30min,加入碳酸氢钠,搅拌10min,垫硅藻土过滤,用甲苯洗涤,滤液分层后有机相用饱和氯化钠溶液洗涤,干燥后浓缩得4.87g化合物IIIa,收率:90%。
MS(ESI)m/z:517(M+H
+)。
1H NMR(400MHz,Chloroform-d)δ7.27(d,J=9.6Hz,1H),6.87(dd,J=8.4Hz,J=2.4 Hz,1H),6.78(d,J=2.4Hz,1H),4.70(t,J=8.4Hz,1H),3.53(t,J=6.8Hz,2H),2.90(t,J=16.8Hz,J=5.2Hz,1H),2.75(d,J=16.8Hz,1H),2.29~2.37(m,1H),2.28(s,3H),2.20~2.26(m,1H),2.06(s,3H),1.84~1.87(m,1H),1.72~1.79(m,3H),1.59~1.68(m,3H),1.37~1.55(m,8H),1.18~1.48(m,18H),0.82(s,1H)。
实施例24:制备化合物IIIb
将溴化铜(3.71g)和溴化锂(1.02g)加入反应瓶中,随后加入乙腈(10mL)和丙酸酐(0.77g),反应在20℃搅拌30min后,滴加入化合物Va(3.3g)的乙腈(10mL)溶液,反应继续在20℃搅拌3h,HPLC监控显示原料转化完全。将反应液滴加入硫脲的甲苯和水的混合液中,搅拌30min,加入碳酸氢钠,搅拌10min,垫硅藻土过滤,用甲苯洗涤,滤液分层后有机相用饱和氯化钠溶液洗涤,干燥后浓缩得3.24g化合物IIIb,收率:88%。
MS(ESI)m/z:531(M+H
+)。
1H NMR(400MHz,Chloroform-d)δ7.28(d,J=8.8Hz,1H),6.84(dd,J=8.4Hz,J=2.4Hz,1H),6.78(d,J=2.4Hz,1H),4.67(t,J=8.4Hz,1H),3.52(t,J=6.8Hz,2H),2.90(dd,J=16.8Hz,J=5.2Hz,1H),2.75(d,J=16.8Hz,1H),2.56(q,J=15.2Hz,2H),2.19~2.39(m,3H),2.06(s,3H),1.83~1.87(m,1H),1.72~1.79(m,3H),1.62~1.67(m,1H),1.39~1.58(m,8H),1.17~1.27(m,14H),0.82(s,3H)。
实施例25:制备化合物II
将化合物IIIa(4.38g)和化合物IV(4.5g)加入反应瓶中,加入DMF(25mL)。20℃下加入40%的氢氧化钠(8.4g)。反应继续在20℃搅拌2h,HPLC显示原料转化完全。加入乙酸猝灭反应,加入水稀释,MTBE萃取,有机相依次用饱和碳酸氢钠溶液和饱和氯化钠溶液洗涤,干燥后浓缩得到4.51g化合物II,收率:90%。
MS(ESI)m/z:591(M+H
+)。
1H NMR(400MHz,Chloroform-d)δ7.15(d,J=8.4Hz,1H),6.63(dd,J=8.8Hz,J=2.4Hz,1H),6.55(d,J=2.4Hz,1H),4.67(s,1H),3.75(t,J=7.6Hz,1H),2.86(dd,J=16.8Hz,J=5.2Hz,1H),2.71(d,J=16.8Hz,1H),2.59(t,J=6Hz,2H),2.50(t,J=7.2Hz,2H),2.28~2.34(m,2H), 2.11~2.23(m,3H),1.84~1.92(m,3H),1.72~1.75(m,1H),1.53~1.65(m,4H),1.17~1.50(m,24H)。
实施例26:制备化合物II
将化合物IIIb(3g)和化合物IV(3.08g)加入反应瓶中,加入DMF(20mL)。20℃下加入40%的氢氧化钠(5.25g)。反应继续在20℃搅拌2h,HPLC显示原料转化完全。加入乙酸猝灭反应,加入水稀释,MTBE萃取,有机相依次用饱和碳酸氢钠溶液和饱和氯化钠溶液洗涤,干燥后浓缩得到2.77g化合物II,收率:83%。
MS(ESI)m/z:591(M+H
+)。
1H NMR(400MHz,Chloroform-d)δ7.15(d,J=8.4Hz,1H),6.63(dd,J=8.8Hz,J=2.4Hz,1H),6.55(d,J=2.4Hz,1H),4.67(s,1H),3.75(t,J=7.6Hz,1H),2.86(dd,J=16.8Hz,J=5.2Hz,1H),2.71(d,J=16.8Hz,1H),2.59(t,J=6Hz,2H),2.50(t,J=7.2Hz,2H),2.28~2.34(m,2H),2.11~2.23(m,3H),1.84~1.92(m,3H),1.72~1.75(m,1H),1.53~1.65(m,4H),1.17~1.50(m,24H)。
实施例27:制备化合物I
将化合物II(4.31g)溶于乙酸乙酯(15mL)中,依次加入乙酸(2.63g)和17.5%的双氧水(3.12g),反应在20℃继续搅拌10h,HPLC显示原料转化完全。加入亚硫酸钠溶液猝灭反应。加入乙酸乙酯萃取。有机相依次用饱和碳酸氢钠和氯化钠溶液洗涤,干燥后浓缩,乙酸乙酯重结晶得到3.52g化合物I,收率:80%。纯度:99.7%。
MS(ESI)m/z:607(M+H
+)。
1H NMR(400MHz,Chloroform-d)δ7.11(d,J=8.4Hz,1H),6.63(d,J=8.4Hz,1H),6.55(s,1H),3.74(t,J=8.5Hz,1H),2.90-2.53(m,6H),2.35-2.03(m,7H),1.99-1.83(m,1H),1.80-1.67(m,3H),1.60(qt,J=8.5,3.3Hz,2H),1.53-1.11(m,19H),1.08-0.95(m,1H),0.77(s,3H)。
由于已根据其特殊的实施方案描述了本发明,某些修饰和等价变化对于本领域普通技术人员是显而易见的且包括在本发明的范围内。
Claims (26)
- 根据权利要求1所述的如式V所示的化合物,其特征在于,R 1为氢、苄基、C 1-C 6烷基、C 1-C 10烷基酰基、芳基酰基或(C 1-10烷基或芳基) 3硅烷基。
- 根据权利要求1所述的如式V所示的化合物,其特征在于,R 1为C 1-C 10烷基酰基或芳基酰基。
- 根据权利要求1所述的如式V所示的化合物,其特征在于,R 1为乙酰基。
- 根据权利要求5所述的如式V所示的化合物的制备方法,其特征在于,R 1为氢、苄基、C 1-C 6烷基、C 1-C 10烷基酰基、芳基酰基或(C 1-10烷基或芳基) 3硅烷基;M为MgCl或MgBr。
- 根据权利要求5所述的如式V所示的化合物的制备方法,其特征在于,R 1为C 1-C 10烷基酰基或芳基酰基;M为MgCl或MgBr。
- 根据权利要求5所述的如式V所示的化合物的制备方法,其特征在于,R 1为乙酰基;M为MgBr。
- 根据权利要求13所述的如式III所示的化合物,其特征在于,R 1为苄基、C 1-C 6烷基、C 1-C 10烷基酰基、芳基酰基或(C 1-10烷基或芳基) 3硅烷基;R 2为C 1-C 10烷基酰基或芳基酰基。
- 根据权利要求13所述的如式III所示的化合物,其特征在于,R 1为乙酰基,R 2为乙酰基或丙酰基。
- 根据权利要求16所述的如式III所示的化合物的制备方法,其特征在于,R 1为氢、苄基、C 1-C 6烷基、C 1-C 10烷基酰基、芳基酰基或(C 1-10烷基或芳基) 3硅烷基;R 2为C 1-C 10烷基酰基或芳基酰基。
- 根据权利要求16所述的如式III所示的化合物的制备方法,其特征在于,R 1为C 1-C 10烷基酰基或芳基酰基;R 2为C 1-C 10烷基酰基或芳基酰基。
- 根据权利要求16所述的如式III所示的化合物的制备方法,其特征在于,R 1为乙酰基;R 2为乙酰基或丙酰基。
- 根据权利要求20所述的如式I所示的化合物的制备方法,其特征在于,R 1为氢、苄基、C 1-C 6烷基、C 1-C 10烷基酰基、芳基酰基或(C 1-10烷基或芳基) 3硅烷基;R 2为C 1-C 10烷基酰基或芳基酰基;M为MgCl或MgBr。
- 根据权利要求20所述的如式I所示的化合物的制备方法,其特征在于,R 1为C 1-C 10烷基酰基或芳基酰基;R 2为C 1-C 10烷基酰基或芳基酰基;M为MgCl或MgBr。
- 根据权利要求20所述的如式I所示的化合物的制备方法,其特征在于,R 1为乙酰基;R 2为乙酰基或丙酰基;M为MgBr。
- 一种氟维司群的制备方法,其特征在于:其包括权利要求5-8、10-12或16-19中任一项所述的如式VII、VIIA、V、III所示的化合物的制备方法,或经权利要求1-4中任一项所述的如式V所示的化合物、或经权利要求9-11所述的如式VII或VIIA所示化合物、或经权利要求13-15中任一项所述的如式III所示的化合物中的任一化合物制备氟维司群的步骤。
- 一种氟维司群的制备方法,其特征在于,包括经1,9-二氯壬烷、1-氯-9-溴壬烷或 1-氯-9-碘壬烷制备氟维司群的步骤。
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