CN101790509A - 制备含有7α-(ξ-烷基氨基-ω-全氟烷基)烷基侧链的雌激素拮抗性11β-氟-17α-烷基雌甾-1,3,5(10)-三烯-3,17-二醇的方法以及α-烷基(氨基)-ω-全氟(烷基)烷烃和它们的制备方法 - Google Patents
制备含有7α-(ξ-烷基氨基-ω-全氟烷基)烷基侧链的雌激素拮抗性11β-氟-17α-烷基雌甾-1,3,5(10)-三烯-3,17-二醇的方法以及α-烷基(氨基)-ω-全氟(烷基)烷烃和它们的制备方法 Download PDFInfo
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- CN101790509A CN101790509A CN200880104489A CN200880104489A CN101790509A CN 101790509 A CN101790509 A CN 101790509A CN 200880104489 A CN200880104489 A CN 200880104489A CN 200880104489 A CN200880104489 A CN 200880104489A CN 101790509 A CN101790509 A CN 101790509A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 38
- 238000000034 method Methods 0.000 title claims abstract description 36
- 125000000217 alkyl group Chemical group 0.000 title claims abstract description 34
- 150000001335 aliphatic alkanes Chemical class 0.000 title claims abstract description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 title claims abstract description 10
- 238000004519 manufacturing process Methods 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 62
- 229910052731 fluorine Inorganic materials 0.000 claims description 58
- 239000011737 fluorine Substances 0.000 claims description 58
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 46
- 239000000203 mixture Substances 0.000 claims description 35
- 229910052799 carbon Inorganic materials 0.000 claims description 24
- 125000004432 carbon atom Chemical group C* 0.000 claims description 24
- 150000001412 amines Chemical class 0.000 claims description 18
- 239000000328 estrogen antagonist Substances 0.000 claims description 14
- 239000011541 reaction mixture Substances 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- -1 trimethyl silyl Lithamide Chemical compound 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- POXSDSRWVJZWCN-UHFFFAOYSA-N triphenylphosphanium;iodide Chemical compound I.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 POXSDSRWVJZWCN-UHFFFAOYSA-N 0.000 claims description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- 238000007239 Wittig reaction Methods 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 238000005984 hydrogenation reaction Methods 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 150000001336 alkenes Chemical class 0.000 claims description 2
- 150000003973 alkyl amines Chemical class 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 230000008878 coupling Effects 0.000 claims description 2
- 238000010168 coupling process Methods 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 abstract description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 230000001076 estrogenic effect Effects 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- 238000013375 chromatographic separation Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 102000015694 estrogen receptors Human genes 0.000 description 3
- 108010038795 estrogen receptors Proteins 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 125000005010 perfluoroalkyl group Chemical group 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 235000009518 sodium iodide Nutrition 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- XNMQEEKYCVKGBD-UHFFFAOYSA-N 2-butyne Chemical compound CC#CC XNMQEEKYCVKGBD-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- KDKYADYSIPSCCQ-UHFFFAOYSA-N but-1-yne Chemical group CCC#C KDKYADYSIPSCCQ-UHFFFAOYSA-N 0.000 description 2
- 229930188620 butyrolactone Natural products 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125961 compound 24 Drugs 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- UIZVMOZAXAMASY-UHFFFAOYSA-N hex-5-en-1-ol Chemical compound OCCCCC=C UIZVMOZAXAMASY-UHFFFAOYSA-N 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000006317 isomerization reaction Methods 0.000 description 2
- 230000002045 lasting effect Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 2
- REPWBKQJAMXHFL-UHFFFAOYSA-N phenylphosphane;hydrobromide Chemical class [Br-].[PH3+]C1=CC=CC=C1 REPWBKQJAMXHFL-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000000935 solvent evaporation Methods 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- KDAJXWIPFWEZRO-UHFFFAOYSA-N 1-fluoro-5-iodopentane Chemical class FCCCCCI KDAJXWIPFWEZRO-UHFFFAOYSA-N 0.000 description 1
- JCTGUJIBPLBUOA-UHFFFAOYSA-N 2,3,3,4,4-pentafluoro-1-phenylhexan-2-ol Chemical compound FC(C(C(O)(CC1=CC=CC=C1)F)(F)F)(CC)F JCTGUJIBPLBUOA-UHFFFAOYSA-N 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 238000006859 Swern oxidation reaction Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 230000000368 destabilizing effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000005816 fluoropropyl group Chemical group [H]C([H])(F)C([H])([H])C([H])([H])* 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- BNSOYWDFFBDEFB-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O BNSOYWDFFBDEFB-UHFFFAOYSA-L 0.000 description 1
- HMRCZKQIOFZACX-UHFFFAOYSA-N lithium;trimethylsilylazanide Chemical compound [Li+].C[Si](C)(C)[NH-] HMRCZKQIOFZACX-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 150000004714 phosphonium salts Chemical class 0.000 description 1
- 235000007715 potassium iodide Nutrition 0.000 description 1
- 229960004839 potassium iodide Drugs 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000007342 radical addition reaction Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C211/15—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/20—Preparation of halogenated hydrocarbons by replacement by halogens of halogen atoms by other halogen atoms
- C07C17/202—Preparation of halogenated hydrocarbons by replacement by halogens of halogen atoms by other halogen atoms two or more compounds being involved in the reaction
- C07C17/208—Preparation of halogenated hydrocarbons by replacement by halogens of halogen atoms by other halogen atoms two or more compounds being involved in the reaction the other compound being MX
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
- C07C17/263—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions
- C07C17/2635—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions involving a phosphorus compound, e.g. Wittig synthesis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C21/00—Acyclic unsaturated compounds containing halogen atoms
- C07C21/02—Acyclic unsaturated compounds containing halogen atoms containing carbon-to-carbon double bonds
- C07C21/18—Acyclic unsaturated compounds containing halogen atoms containing carbon-to-carbon double bonds containing fluorine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/20—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic unsaturated carbon skeleton
- C07C211/24—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic unsaturated carbon skeleton the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
- C07C211/29—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C33/40—Halogenated unsaturated alcohols
- C07C33/42—Halogenated unsaturated alcohols acyclic
- C07C33/423—Halogenated unsaturated alcohols acyclic containing only double bonds as unsaturation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
- C07C45/292—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups with chromium derivatives
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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Abstract
H(R)N-(CH2)i-C2F5(II)本发明涉及制备含有7α-(ξ-烷基氨基-ω-全氟烷基)烷基侧链的通式(I)的雌激素拮抗性11β-氟-17α-烷基雌甾-1,3,5(10)-三烯-3,17-二醇的新方法和通式(II)的α-烷基(氨基)-ω-全氟(烷基)烷烃、它们的制备方法以及此目的所需的中间体。
Description
本发明涉及制备含有7α-(ξ-烷基氨基-ω-全氟烷基)烷基侧链的通式I的雌激素拮抗性11β-氟-17α-烷基雌甾-1,3,5(10)-三烯-3,17-二醇的新方法和通式II的α-烷基(氨基)-ω-全氟(烷基)烷烃、它们的制备方法以及此目的所需的中间体。
更具体地,本发明涉及制备通式I化合物的方法
其中
R17α为可以部分或完全氟化的具有1-4个碳原子的烷基,或者是具有2-4个碳原子的炔基
R17β为氢原子、具有1-4个碳原子的烷基或具有1-4个碳原子的烷酰基,
h为1-6的整数
R为具有1-3个碳原子的烷基,且
i为6-9的整数。
本发明进一步涉及通式II的α-烷基(氨基)-ω-全氟(烷基)烷烃
H(R)N-(CH2)i-C2F5 (II)
其中,
R为具有1-3个碳原子的烷基,且
i为6-9的整数,
以及它们的制备方法。
本发明还涉及在通式II的α-烷基(氨基)-ω-全氟(烷基)烷烃的制备中所需的中间体。这些中间体为通式VII、IX的化合物以及化合物16b、20、24、25、26、27和28。
通式I化合物为具有强抗雌激素活性的化合物。更具体地,它们是雌激素拮抗剂,其由于将天然雌激素从它们的受体上竞争性替代和/或通过使雌激素受体失去稳定性显示它们的抗雌激素活性。在后一种情况下,也称作选择性雌激素受体去稳定剂(SERDs)。有时,同样的缩写也被理解为表示术语选择性雌激素受体负调节物。在两种情况下,即在选择性雌激素拮抗剂和SERDs的情况下,结果均为抑制雌激素刺激物的传递。
而且,通式I化合物优选为完全的抗雌激素,这是为了表示这些化合物如果有任何雌激素残留作用的话,仅具有减退的(vanishing)雌激素残留作用。
WO 03/045972中第一次描述了这些通式I化合物以及它们的制备。在该案中,通式III化合物
其中
R17α为可以部分或完全氟化的具有1-4个碳原子的烷基,或者为具有2-4个碳原子的炔基
R17β为氢原子、具有1-4个碳原子的烷基或具有1-4个碳原子的烷酰基,
h为1-6的整数
且
Hal为卤素原子
与通式II的α-烷基(氨基)-ω-全氟(烷基)烷反应
H(R)N-(CH2)i-C2F5 (II)
其中
R为具有1-3个碳原子的烷基,且
i为6-9的整数
以获得通式I化合物。
特别地,R为甲基,i为5且Hal为溴原子、氯原子或碘原子。
通式II化合物尤其可以通过本领域技术人员公知的方法从α-羟基-ω-全氟(烷基)烷烃开始制备(参见路线1)。
路线1
在WO 99/33855A1中已描述了用于此目的作为起始化合物所需的α-羟基-ω-全氟(烷基)烷烃的可能的制备路线(参见路线2)。
路线2
上述制备α-羟基-ω-全氟(烷基)烷烃(该化合物用于制备通式II化合物)的方法(路线2)的一个缺点是需要对中间体进行色谱纯化的步骤以制备足够纯度的相应的α-羟基-ω-全氟(烷基)烷烃。
而且,由化合物4a-b与1,1,1,2,2-五氟-5-碘戊烷所制备的格式试剂的反应需要严格的控制和专家操作的过程,而且,尽管在实验室规模实施适当的控制是有可能的,但将这些反应改变到工业规模则产生巨大的技术困难。
除路线2以外,α-羟基-ω-全氟(烷基)烷烃也可以经由路线3中所示的路线从α-羟基-ω-烯类开始制备。[i]
路线3
为此目的,将全氟烷基(通常使用相应的全氟烷基碘化物)加成至α-羟基-ω-烯的末端双键上。
上述制备α-羟基-ω-全氟(烷基)烷烃(该化合物用于制备通式II化合物)的方法(路线3)的一个缺点为在这种情况下所使用的原料(α-羟基-ω-烯烃)仅在少数情况下(例如丙烯醇(m=1)或5-己烯-1-醇(m=4))可以在市场上大量购得用于工业规模的合成,即以kg级别的量购得。在大量6-庚烯-1-醇(m=5)的可得性上已发现特别的问题,根据路线3,6-庚烯-1-醇(m=5)将必须被用作通式I化合物的具体抗雌激素(当i=7时)制备的起始化合物。因此,根据路线3某些胺的制备不适合于将实验室合成放大至工业规模(kg量)。
而且,已知在为了引入末端全氟烷基基团而将全氟烷基卤化物(例如五氟乙基碘化物,CF3CF2I)向末端双键的加成中,不仅形成所需的直链产物而且还形成一定比例的支链异构体(引入另外的立构中心)(参照路线4)。
路线4
为了满足活性药物成分合成所需的纯度要求,自由基加成产物必须被纯化以除去合成过程中不需要的异构体。这伴随着较高的成本,而且连同(例如6-庚烯-1-醇(m=5)的)有限可得性一起,将该制备路线转化成工业规模产生严重问题-尤其是对于化合物1的制备。
因此,本发明的目的是提供制备通式II的α-烷基(氨基)-ω-全氟(烷基)烷烃的改进方法,此方法无需使用仅具有有限可得性的α-羟基-ω-烯烃。应该可能使用廉价的、市场上可购得的原料。具体地,起始化合物应在kg级别上(即在工业规模上)可得,从而也可能将本发明制备通式II化合物的方法转化为工业规模。
通过本发明的制备通式II化合物的方法达到此目的。
在此方法中,通式V的Wittig试剂
Hal1-(CH2)p-P+(Ar)3(Hal2)- (V)
其中
Hal1和Hal2各自独立地为卤素原子,
Ar为芳族基团,特别是苯基、邻、间或对甲苯基基团,
且
p为3-6的整数,
与式VI的4,4,5,5,5-五氟戊醛
H(O)C-(CH2)2-C2F5 (VI)
在非常强的碱的存在下在Wittig反应中发生反应以生成通式VII的烯烃
Hal1-(CH2)(p-1)-C=C-(CH2)2-C2F5 (VII)
其中
p如上所定义,
通式VII的卤代烯烃与通式VIII的烷基胺偶联
HN(R)(Rb) (VIII)
其中
R如通式II中所定义,且
Rb为氢原子或苄基,
以得到通式IX化合物
(Rb)(R)N-(CH2)(p-1)-C=C-(CH2)2-C2F5 (IX)
并且
然后使双键氢化(当Rb为苄基时,另外将苄基消除)以得到通式II化合物。
H(R)N-(CH2)i-C2F5 (II)
其中
R和i各自如上所定义。
所使用的式V的Wittig试剂是烷基部分(CH2)p中具有3-6个碳原子的化合物。
被用作另一原料的式VI的4,4,5,5,5-五氟戊醛通过已知方法从4,4,5,5,5-五氟戊醇可以获得。
通式VII和IX的化合物以及8,8,9,9,9-五氟壬-4-烯-1-醇、8,8,9,9,9-五氟壬-4-烯基甲苯-4-磺酸酯和8,8,9,9,9-五氟壬-4-烯基甲磺酸酯以E和Z异构体以及E和Z异构体的任意混合物存在。
通式I和III的化合物中,R17α和R17β特别地为甲基、乙基、正丙基、正丁基、异丁基和叔丁基,其中R17β此外也可以为氢、乙酰基、丙酰基和丁酰基,且其中在这种情况下,相应的异构体可以被包括在内。此外,R17α可以为乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基和3-丁炔基以及三氟甲基、五氟乙基、七氟丙基和九氟丁基,其中在这种情况下,相应的异构体也被包括在内。R17β特别地为氢、CH3或CH3C(O)-。R17α优选代表甲基、乙炔基和三氟甲基。在本发明的一个实施方案中,R在具体化合物中为甲基。
在本发明的另一个实施方案中,i在具体化合物中为7。
本发明的另一个变体设想Hal1在具体化合物中为氯原子。
而且,Hal1在具体化合物中可以为溴原子或碘原子。
Ar在具体化合物中主要为苯基基团。
所使用的强碱可以为,例如,叔丁醇钾、正丁基锂或三甲基甲硅烷基氨基锂(lithium trimethylsilylamide)。
本发明提供合成通式II化合物的方法,该方法允许这些化合物以基于易得的大量化学制品的有效方法制备。
使用该合成得到异构纯形式的化合物II,以便于它们可以直接且不进行进一步纯化即被用于与通式III化合物反应获得相应的通式I化合物的反应中。
可以以实验室规模和工业规模同样地进行该反应。
因此,本发明也涉及在工业规模上制备通式I化合物的方法
其中
R17α为可以部分或完全氟化的具有1-4个碳原子的烷基,或者为具有2-4个碳原子的炔基
R17β为氢原子、具有1-4个碳原子的烷基或具有1-4个碳原子的烷酰基,
h为1-6的整数
R为具有1-3个碳原子的烷基,且
i为6-9的整数,
其中如上(即根据权利要求1-7之一)制备的通式II化合物任选地不从反应混合物中分离而直接与通式III化合物以本身已知的方式反应以生成通式I化合物。
根据已被描述的方法,例如WO 03/045972中的类似化合物的方法(方法变体2.2,27页),类似地进行该反应本身。
根据本发明,如路线5中所示制备通式II化合物(1a-d):
路线5
除此合成路线(使用N-甲基苄胺)之外,同样可以使用N-甲胺使α-氯-ω-全氟(烷基)烷烃16烷基化:
路线6
特别是对于α-官能团化ω-全氟壬烷系列的制备,可以经由以下合成路线制备化合物24,同样地从4,4,5,5,5-五氟戊-1-醇开始进行
路线7
4,4,5,5,5-五氟戊-1-醇14通过已知方法被转化为甲苯磺酸酯19。新的鏻盐20的制备可以通过使19与碘化钠和三苯基膦在一道工序中发生反应容易地实现。四氢呋喃-2-醇23或者通过丁内酯21的还原,或者通过1,4-丁烯二醇22的金属催化的双键异构化的文献方法进行制备。23与20在Wittig反应中发生反应生成新的醇8,8,9,9,9-五氟壬-4-烯-1-醇24。
化合物24中的羟基可以通过本领域技术人员所熟悉的方法被替换为更好的离去基团,例如氯原子、溴原子、碘原子或者甲磺酰基或甲苯磺酰基。然后,所得化合物可以如路线5和6中或以下的综述路线8中所示被转化为作为通式II化合物代表的化合物1。
总之,这样经由不同的合成路线合成α-烷基(氨基)-ω-全氟(烷基)烷1是可能的-在以下的综述路线中再一次展示这些路线。
路线8
所有的合成路线均基于使用4,4,5,5,5-五氟戊醇作为原料,该原料由几家供应商以相对大的量供应。
通式II、VII和IX的中间体和单个化合物16b、20、24、25、26、27和28是新的。
因此,它们均属于本发明的范围之内。它们的用途,特别是在制备抗雌激素中的用途,尤其是在制备通式I的抗雌激素中的用途,同样形成本发明的部分主题。
以下的实施例被用作本发明更为详细的解释。
实施例
根据文献方法类似地制备(4-氯丁基)三苯基溴化鏻[ii]。
4,4,5,5,5-五氟戊-1-醛(或相关的化合物)已在文献中被描述[参见例如iii或iv]。这里,通过在标准条件下氧化4,4,5,5,5-五氟戊-1-醇制备4,4,5,5,5-五氟戊-1-醛(通过与重铬酸吡啶鎓反应或TEMPO氧化制备二氯甲烷溶液[参见例如v]-由于低沸点,4,4,5,5,5-五氟戊-1-醛的二氯甲烷溶液直接被用于Wittig反应中)。五氟戊醇的Swern氧化是有问题的[vi]。
根据文献方法通过丁内酯的还原或者1,4-丁烯二醇的金属催化的双键异构化类似地制备四氢呋喃-2-醇[vii]。4,4,5,5,5-五氟戊基甲苯-4-磺酸酯已在专利文献中被描述[viii]。
实施例1:
1-氯-8,8,9,9,9-五氟壬-4-烯(16b)(E/Z混合物)的制备
最初将1072.1g(4-氯丁基)三苯基溴化鏻加入1200ml THF中。在冷却至-25℃下,将252.5g KOtBu在1900ml THF中的溶液缓慢加入,从而使内部温度部不上升至高于-20℃。加入完毕后,在该温度下持续搅拌30min以使去质子化完全,然后(同样地在不高于-20℃的温度下)将溶解于2000ml二氯甲烷中的约390g 4,4,5,5,5-五氟戊-1-醛缓慢加入。加入完毕后,首先在冷却条件下将该混合物再搅拌一小时,然后通过移除冷水浴使该反应混合物温热至室温。
对于后处理,首先将该反应混合物减压浓缩至约2000ml的残留体积,然后加入3800ml环己烷。将这样所得的悬浮液通过1200g硅胶短柱过滤,并在减压下将粗产物的溶液分离。最后在约3-5mbar的压力和75-78℃下,将残渣减压蒸馏。得到210.6g(理论的34%)1-氯-8,8,9,9,9-五氟壬-4-烯(E/Z混合物)无色液体。
1H NMR(400MHz;CDCl3):1.80-1.95(m;2H);2.05-2.35(m;4H);2.35-2.50(m;2H);3.60(tr,7.0Hz;2H);5.40-5.55(m;2H)ppm.
实施例2:
苄基甲基(8,8,9,9,9-五氟壬-4-烯-1-基)胺(17b)(E/Z混合物)的制备
最初将3.0g碘化钠与8.0g无水碳酸钠一起加入。然后,将25.2g 1-氯-8,8,9,9,9-五氟壬-4-烯(E/Z混合物)溶解于126ml DMF中的溶液加入。加入20.2ml N-甲基苄胺后,将该反应混合物加热至内部温度约为70℃以使反应完全(约7h)。
对于后处理,加入126ml甲基叔丁基醚和126ml水。进行相分离,首先,每次用63ml甲基叔丁基醚萃取水相2次。然后,每次用63ml水洗涤合并的有机相3次,然后浓缩至干燥。最后通过经由100g硅胶塞的过滤将少量的杂质除去。得到25g(理论的70%)微黄色液体形式的苄基甲基(8,8,9,9,9-五氟壬-4-烯-1-基)胺(E/Z混合物)。
1H NMR(400MHz;CDCl3):1.55-1.70(m;2H);1.95-2.15(m;4H);2.2(s,3H);2.30-2.45(m;2H);3.5(s,2H);5.25-5.50(m;2H);7.20-7.35(m;5H)ppm.
实施例3:
甲基(8,8,9,9,9-五氟壬基)胺(1)的制备(由氢化和去苄基化)
将264g苄基甲基(8,8,9,9,9-五氟壬-4-烯-1-基)胺(E/Z混合物)溶解于2600ml甲醇中。加入10.6g Pd/C(10%)后,在氢环境中在1bar压力下搅拌该反应混合物直至氢吸附停止。
对于后处理,将该反应混合物过滤,每次用100ml甲醇洗涤残渣3次,并将滤液减压浓缩。将残渣置于2500ml甲基叔丁基醚和2500ml水中。在冰浴冷却下,使用250ml NaOH(50%)使pH>12。进行相分离。每次用250ml MTBE萃取水相3次。每次用250ml水洗涤合并的有机相3次,然后浓缩。得到169.6g(理论的87%)甲基(8,8,9,9,9-五氟壬基)胺无色液体。可以通过减压蒸馏(在4mbar和90℃下)除去少量杂质。
1H NMR(400MHz;CDCl3):1.1(br s;NH);1.3-1.7(m;10H);1.9-2.1(m;2H);2.4(s;3H);2.6(tr;7.2Hz;2H)ppm.
实施例4:
甲基(8,8,9,9,9-五氟壬-4-烯-1-基)胺(18b)(E/Z混合物)的制备
将5g 1-氯-8,8,9,9,9-五氟壬-4-烯(E/Z混合物)溶解于25ml乙醇中,然后与60ml甲胺水溶液(40%强度)混合并在高压釜中在80℃夹套温度下加热16h。冷却至室温后,加入50ml MTBE和20ml水,并进行相分离。每次用30ml MTBE再萃取水相2次,并用20ml NaOH(1摩尔浓度)洗涤。然后在旋转蒸发器上将有机相浓缩至10ml,并用约10ml 10%硫酸调节至pH<2。用15ml己烷洗涤该产物水溶液,然后每次用20ml己烷和MTBE的混合物(3∶1)萃取产物3次。加入28ml 1摩尔浓度NaOH溶液将该水相的pH调节至>12,并用MTBE萃取该产物三次。将合并的有机相浓缩生成3.35g(理论的68%)甲基(8,8,9,9,9-五氟壬-4-烯-1-基)胺(E/Z混合物)橙色油。
1H NMR(400MHz,CDCl3):1.1(br s;NH);1.6(五重峰;7.3Hz;2H);2.0-2.2(m;4H);2.3-2.4(m;2H);2.5(s;3H);2.6(t;7.3Hz;2H);5.3-5.6(m;2H)ppm.
实施例5:
甲基(8,8,9,9,9-五氟壬基)胺(1)的制备(由氢化)
将1.5g甲基(8,8,9,9,9-五氟壬-4-烯-1-基)胺(E/Z混合物)溶解于15mlMTBE中,并与1.5ml乙酸混合。加入80mg Pd/C(10%)后,在氢环境中在1bar压力下搅拌该反应混合物直至氢吸附停止。对于后处理,将该反应混合物过滤,洗涤残渣并加入15ml水。之后,用约2ml 50%NaOH将pH调节至>12,并进行相分离。然后,每次用7.5ml MTBE再萃取水相2次,并用7.5ml水再萃取合并的有机相。将溶剂除去生成1.42g(理论的92%)甲基(8,8,9,9,9-五氟壬基)胺微黄色油。
1H NMR(400MHz;CDCl3):1.1(br s;NH);1.3-1.7(m;10H);1.9-2.1(m;2H);2.4(s;3H);2.6(tr;7.2Hz;2H)ppm.
实施例6:
(4,4,5,5,5-五氟戊基)三苯基碘化鏻(20)的制备
将100g 4,4,5,5,5-五氟戊基甲苯-4-磺酸酯溶解于300ml乙腈中,并与86.8g三苯基膦和49.6g碘化钠混合。将该悬浮液加热至90℃持续8h。之后,将固体滤出,并用300ml乙腈洗涤残渣。滤液重蒸馏至约600ml乙酸乙酯中,产物作为固体沉淀出来。将结晶滤出,并用200ml乙酸乙酯洗涤并在干燥箱中干燥。得到151g淡黄色结晶。
1H NMR(400MHz;DMSO-d6):1.70-1.80(m;2H);2.35-2.55(m;2H);3.65-3.75(m;2H);7.70-7.95(m;15H)ppm.
实施例7:
8,8,9,9,9-五氟壬-4-烯-1-醇(24)(E/Z混合物)的制备
将2.97g(4,4,5,5,5-五氟戊基)三苯基碘化鏻悬浮于2.4ml THF中,然后在冷却条件下将溶解于2.4ml THF中的665mg KOtBu加入。30min后,将570mg四氢呋喃-2-醇在1.2ml THF中的溶液逐滴加入,并在冷却条件下再搅拌该混合物30min,然后在3h中温热至室温。通过加入5ml水使该反应终止,并加入10ml MTBE后除去有机相。然后,每次用5ml MTBE再萃取水相2次,并将有机相减压浓缩。将粗物质与10ml己烷混合,将固体抽滤出来,并用10ml己烷洗涤滤饼。然后,在旋转蒸发器上将该混合物浓缩,并在硅胶上对该产物进行色谱分离。得到830mg(理论的66%)8,8,9,9,9-五氟壬-4-烯-1-醇(E/Z混合物)无色油。
1H NMR(400MHz;CDCl3):1.35(br s;OH);1.65(五重峰;7.0Hz;2H);2.0-2.2(m;4H);2.3-2.4(m;2H);3.65(tr;7.0Hz;2H);5.3-5.55(m;2H)ppm.
实施例8:
1-溴-8,8,9,9,9-五氟壬-4-烯(26)(E/Z混合物)的制备
将5g 1-氯-8,8,9,9,9-五氟壬-4-烯(E/Z混合物)与10.26g溴化钠悬浮于25ml DMF中,然后加热至130℃持续5h。加入30ml乙酸乙酯和50ml水后,进行相分离,然后每次用50ml水洗涤有机相4次,并经硫酸钠干燥。将溶剂除去,并在硅胶上对该粗产物进行色谱分离。得到4.33g无色油。
1H NMR(400MHz;CDCl3):1.85-2.00(m;2H);2.05-2.20(m;4H);2.20-2.40(m;2H);3.40(tr;7.0Hz;2H);5.35-5.50(m;2H)ppm.
实施例9:
1-碘-8,8,9,9,9-五氟壬-4-烯(27)(E/Z混合物)的制备
将10g 1-氯-8,8,9,9,9-五氟壬-4-烯(E/Z混合物)与33.12g碘化钾悬浮于50ml DMF中,并在130℃持续搅拌2h。对于该反应混合物的后处理,加入75ml己烷和50ml水,并进行相分离。再次用己烷萃取水相,并用50ml和25ml水洗涤合并的有机相2次。将溶剂除去,并在硅胶上对该粗产物进行色谱分离。得到8.47g无色油。
1H NMR(400MHz;CDCl3):1.80-1.95(m;2H);2.00-2.25(m;4H);2.30-2.45(m;2H);3.20(tr,7.0Hz;2H);5.35-5.50(m;2H)ppm.
实施例10:
8,8,9,9,9-五氟壬-4-烯基甲磺酸酯(25)(E/Z混合物)的制备
将100mg 8,8,9,9,9-五氟壬-4-烯-1-醇溶解于2.8ml二氯甲烷中。然后,加入0.17ml三乙胺和107mg甲基磺酰氯,并将该反应混合物在室温下持续搅拌18h。加入7.2ml二氯甲烷,并用5ml水和10ml盐水溶液萃取该反应混合物。有机相经硫酸钠干燥,并将有机溶剂蒸发生成110mg淡黄色油。
1H-NMR(400MHz;CDCl3):1.75-1.90(m;2H);2.00-2.25(m;4H);2.30-2.40(m;2H);3.00(s;3H);4.25(tr;6.4Hz;2H);5.35-5.50(m;2H)ppm.
实施例11:
8,8,9,9,9-五氟壬-4-烯基甲苯-4-磺酸酯(28)(E/Z混合物)的制备
将100mg 8,8,9,9,9-五氟壬-4-烯-1-醇溶解于2.8ml二氯甲烷中。然后,加入0.17ml三乙胺和107mg甲苯-4-磺酰氯,并将该反应混合物在室温下持续搅拌18h。加入7.2ml二氯甲烷,并用5ml水和10ml盐水溶液萃取该反应混合物。有机相经硫酸钠干燥,并将有机溶剂蒸发生成156mg淡黄色油。
1H-NMR(400MHz;CDCl3):1.65-1.75(m;2H);1.95-2.15(m;4H);2.20-2.30(m;2H);2.45(s;3H);4.05(tr;7.0Hz;2H);5.30-5.45(m;2H);7.35(d;8.1Hz;2H)7.80(d;8.1Hz;2H)ppm.
文献
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Claims (24)
1.制备通式II的α-烷基(氨基)-ω-全氟(烷基)烷烃的方法
H(R)N-(CH2)i-C2F5(II)
其中
R为具有1-3个碳原子的烷基,且
i为6-9的整数,
其特征在于通式V的Wittig试剂
Hal1-(CH2)p-P+(Ar)3(Hal2)-(V)
其中
Hal1和Hal2各自独立地为卤素原子,
Ar为芳族基团,特别是苯基、邻、间或对甲苯基基团,且
p为3-6的整数,
与式VI的4,4,5,5,5-五氟戊醛
H(O)C-(CH2)2-C2F5(VI)
在强碱的存在下在Wittig反应中发生反应以生成通式VII的烯烃
Hal1-(CH2)(p-1)-C=C-(CH2)2-C2F5(VII)
其中
p如上所定义,
通式VII的卤代烯烃与通式VIII的烷基胺偶联
HN(R)(Rb)(VIII)
其中
R如通式II中所定义,且
Rb为氢原子或苄基,
以得到通式IX化合物
(Rb)(R)N-(CH2)(p-1)-C=C-(CH2)2-C2F5(IX)
并且
然后使双键氢化(当Rb为苄基时,将苄基消除)以得到通式II化合物。
H(R)N-(CH2)i-C2F5(II)
其中
R和i各自如上所定义。
2.权利要求1的方法,其中R在具体化合物中为甲基。
3.权利要求1或2的方法,其中i在具体化合物中为7。
4.上述权利要求之一的方法,其中Hal1在具体化合物中为氯原子。
5.上述权利要求之一的方法,其中Hal1在具体化合物中为溴原子或碘原子。
6.上述权利要求之一的方法,其中Ar在具体化合物中为苯基基团。
7.上述权利要求之一的方法,其中所述强碱为叔丁醇钾、正丁基锂或三甲基甲硅烷基氨基锂。
8.通式VII化合物
Hal1-(CH2)(p-1)-C=C-(CH2)2-C2F5(VII)
其中
Hal1和p各自如权利要求1中所定义。
9.a)权利要求8的1-氯-8,8,9,9,9-五氟壬-4-烯(E和Z异构体以及E和Z异构体的任意混合物)
b)权利要求8的1-溴-8,8,9,9,9-五氟壬-4-烯(E和Z异构体以及E和Z异构体的任意混合物)
c)权利要求8的1-碘-8,8,9,9,9-五氟壬-4-烯(E和Z异构体以及E和Z异构体的任意混合物)。
10.权利要求8或9的通式VII化合物,其作为中间体用于合成通式I的抗雌激素。
11.通式IX化合物
(Rb)(R)N-(CH2)(p-1)-C=C-(CH2)2-C2F5(IX)
其中
R和Rb以及p各自如权利要求1中所定义。
12.权利要求11的苄基甲基(8,8,9,9,9-五氟壬-4-烯-1-基)胺(E和Z异构体以及E和Z异构体的任意混合物)。
13.权利要求11的甲基(8,8,9,9,9-五氟壬-4-烯-1-基)胺(E和Z异构体以及E和Z异构体的任意混合物)。
14.权利要求11、12或13的通式IX化合物,其作为中间体用于合成通式I的抗雌激素。
15.通式II化合物
H(R)N-(CH2)i-C2F5(II)
其中
R为具有有1-3个碳原子的烷基,且
i为6-9的整数。
16.权利要求15的甲基(8,8,9,9,9-五氟壬-1-基)胺。
17.权利要求15或16的通式II化合物,其作为中间体用于合成通式I的抗雌激素。
18.(4,4,5,5,5-五氟戊基)三苯基碘化鏻。
19.权利要求18的(4,4,5,5,5-五氟戊基)三苯基碘化鏻,其作为中间体用于合成通式I的抗雌激素。
20.8,8,9,9,9-五氟壬-4-烯-1-醇(E和Z异构体以及E和Z异构体的任意混合物)。
21.权利要求20的8,8,9,9,9-五氟壬-4-烯-1-醇(E和Z异构体以及E和Z异构体的任意混合物),其作为中间体用于合成通式I的抗雌激素。
22.a)8,8,9,9,9-五氟壬-4-烯基甲苯-4-磺酸酯(E和Z异构体以及E和Z异构体的任意混合物)
b)8,8,9,9,9-五氟壬-4-烯基甲磺酸酯(E和Z异构体以及E和Z异构体的任意混合物)。
23.权利要求22的a)8,8,9,9,9-五氟壬-4-烯基甲苯-4-磺酸酯(E和Z异构体以及E和Z异构体的任意混合物)和b)8,8,9,9,9-五氟壬-4-烯基甲磺酸酯(E和Z异构体以及E和Z异构体的任意混合物),它们作为中间体用于合成通式I的抗雌激素。
24.在工业规模上制备通式I化合物的方法
其中
R17α为可以部分或完全氟化的具有1-4个碳原子的烷基,或者是具有2-4个碳原子的炔基
R17β为氢原子、具有1-4个碳原子的烷基或具有1-4个碳原子的烷酰基,
h为1-6的整数
R为具有1-3个碳原子的烷基,且
i为6-9的整数,
其特征在于根据权利要求1-7之一制备的通式II化合物任选地不从反应混合物中分离而直接与通式III化合物以本身已知的方式反应以生成通式I化合物。
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CN109988209A (zh) * | 2019-05-14 | 2019-07-09 | 浙江工业大学 | 烯烃化雌二醇类化合物及其制备与应用 |
CN113620923A (zh) * | 2021-07-16 | 2021-11-09 | 扬州工业职业技术学院 | 一种低温电解液添加剂的制备方法及应用 |
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KR101172157B1 (ko) * | 2010-05-27 | 2012-08-07 | 전남대학교산학협력단 | 미토콘드리아 영상을 위한 방사성 약물의 제조 방법 |
MY180345A (en) * | 2013-02-25 | 2020-11-28 | The Scripps Res Institue | Oxidation of alkanes to alcohols |
KR101359321B1 (ko) * | 2013-10-17 | 2014-03-13 | 주식회사 인텍 | 벨크로 인서팅 타입의 필터교환 방식 범용 합성수지 마스크, 이의 사출성형장치 및 제작방법 |
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CN108727170A (zh) * | 2017-04-21 | 2018-11-02 | 信越化学工业株式会社 | 1-卤代-6,9-十五碳二烯和制备(7z,10z)-7,10-十六碳二烯醛的方法 |
CN108727170B (zh) * | 2017-04-21 | 2021-10-26 | 信越化学工业株式会社 | 1-卤代-6,9-十五碳二烯和制备(7z,10z)-7,10-十六碳二烯醛的方法 |
CN109988209A (zh) * | 2019-05-14 | 2019-07-09 | 浙江工业大学 | 烯烃化雌二醇类化合物及其制备与应用 |
CN113620923A (zh) * | 2021-07-16 | 2021-11-09 | 扬州工业职业技术学院 | 一种低温电解液添加剂的制备方法及应用 |
CN113620923B (zh) * | 2021-07-16 | 2023-03-14 | 扬州工业职业技术学院 | 一种低温电解液添加剂的制备方法及应用 |
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US20090062558A1 (en) | 2009-03-05 |
CA2697713A1 (en) | 2009-03-05 |
EP2197831A1 (en) | 2010-06-23 |
JP2010536910A (ja) | 2010-12-02 |
KR20100055441A (ko) | 2010-05-26 |
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