CN112174823B - 一种合成2,2-二甲基-3-氧杂环丁酮的中间体及其制备方法和应用 - Google Patents
一种合成2,2-二甲基-3-氧杂环丁酮的中间体及其制备方法和应用 Download PDFInfo
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- CN112174823B CN112174823B CN201910585048.6A CN201910585048A CN112174823B CN 112174823 B CN112174823 B CN 112174823B CN 201910585048 A CN201910585048 A CN 201910585048A CN 112174823 B CN112174823 B CN 112174823B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 56
- YFOSTDMTAXUXED-UHFFFAOYSA-N 2,2-dimethyloxetan-3-one Chemical compound CC1(C)OCC1=O YFOSTDMTAXUXED-UHFFFAOYSA-N 0.000 title abstract description 10
- 230000002194 synthesizing effect Effects 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 175
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 claims abstract description 31
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 10
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 claims abstract description 5
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 claims abstract description 5
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract 5
- 238000006243 chemical reaction Methods 0.000 claims description 99
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 28
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 19
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- -1 lithium aluminum hydride Chemical compound 0.000 claims description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical group ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 6
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims description 6
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 5
- JXRGUPLJCCDGKG-UHFFFAOYSA-N 4-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=C(S(Cl)(=O)=O)C=C1 JXRGUPLJCCDGKG-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 claims description 3
- RPNNPZHFJPXFQS-UHFFFAOYSA-N methane;rhodium Chemical compound C.[Rh] RPNNPZHFJPXFQS-UHFFFAOYSA-N 0.000 claims description 3
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 claims description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- 229950009390 symclosene Drugs 0.000 claims description 3
- 239000012448 Lithium borohydride Substances 0.000 claims description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 claims description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 2
- 229910052782 aluminium Inorganic materials 0.000 claims description 2
- 150000008064 anhydrides Chemical class 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- 239000007800 oxidant agent Substances 0.000 claims description 2
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims 2
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-Tetramethylpiperidine Substances CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 claims 1
- 239000005711 Benzoic acid Substances 0.000 claims 1
- 235000010233 benzoic acid Nutrition 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 15
- 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 abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 5
- 150000002576 ketones Chemical class 0.000 abstract description 5
- KTNRUPLVDJJAEZ-UHFFFAOYSA-N 2-oxo-3-phenylmethoxybutanoic acid Chemical compound OC(=O)C(=O)C(C)OCC1=CC=CC=C1 KTNRUPLVDJJAEZ-UHFFFAOYSA-N 0.000 abstract description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 3
- 238000010511 deprotection reaction Methods 0.000 abstract description 3
- 125000004185 ester group Chemical group 0.000 abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 238000010534 nucleophilic substitution reaction Methods 0.000 abstract description 3
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 abstract description 3
- 230000003647 oxidation Effects 0.000 abstract description 3
- 238000007254 oxidation reaction Methods 0.000 abstract description 3
- 238000006798 ring closing metathesis reaction Methods 0.000 abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
- 239000007788 liquid Substances 0.000 description 37
- 239000000243 solution Substances 0.000 description 36
- 238000004440 column chromatography Methods 0.000 description 29
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 238000010828 elution Methods 0.000 description 26
- 238000003756 stirring Methods 0.000 description 25
- 239000004576 sand Substances 0.000 description 23
- 239000007858 starting material Substances 0.000 description 23
- 239000012074 organic phase Substances 0.000 description 22
- IFBHFJLYXAGPBL-UHFFFAOYSA-N 2,2-dimethyloxetan-3-ol Chemical compound CC1(C)OCC1O IFBHFJLYXAGPBL-UHFFFAOYSA-N 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 230000008034 disappearance Effects 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 239000005457 ice water Substances 0.000 description 15
- 238000001816 cooling Methods 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 14
- 239000003921 oil Substances 0.000 description 13
- 239000008346 aqueous phase Substances 0.000 description 12
- 238000004821 distillation Methods 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- 238000010992 reflux Methods 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 239000012295 chemical reaction liquid Substances 0.000 description 10
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- 238000001514 detection method Methods 0.000 description 8
- 238000010791 quenching Methods 0.000 description 8
- 238000000967 suction filtration Methods 0.000 description 8
- OBTZDIRUQWFRFZ-UHFFFAOYSA-N 2-(5-methylfuran-2-yl)-n-(4-methylphenyl)quinoline-4-carboxamide Chemical compound O1C(C)=CC=C1C1=CC(C(=O)NC=2C=CC(C)=CC=2)=C(C=CC=C2)C2=N1 OBTZDIRUQWFRFZ-UHFFFAOYSA-N 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
- 239000012230 colorless oil Substances 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 238000005984 hydrogenation reaction Methods 0.000 description 7
- 238000012544 monitoring process Methods 0.000 description 7
- 230000001105 regulatory effect Effects 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 239000012065 filter cake Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- ROADCYAOHVSOLQ-UHFFFAOYSA-N 3-oxetanone Chemical compound O=C1COC1 ROADCYAOHVSOLQ-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- QWGRWMMWNDWRQN-UHFFFAOYSA-N 2-methylpropane-1,3-diol Chemical compound OCC(C)CO QWGRWMMWNDWRQN-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- FSNCEEGOMTYXKY-JTQLQIEISA-N Lycoperodine 1 Natural products N1C2=CC=CC=C2C2=C1CN[C@H](C(=O)O)C2 FSNCEEGOMTYXKY-JTQLQIEISA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- JARKCYVAAOWBJS-UHFFFAOYSA-N hexanal Chemical compound CCCCCC=O JARKCYVAAOWBJS-UHFFFAOYSA-N 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 2
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 2
- SLCVBVWXLSEKPL-UHFFFAOYSA-N neopentyl glycol Chemical compound OCC(C)(C)CO SLCVBVWXLSEKPL-UHFFFAOYSA-N 0.000 description 2
- FIYYMXYOBLWYQO-UHFFFAOYSA-N ortho-iodylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I(=O)=O FIYYMXYOBLWYQO-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical group COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 2
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 description 1
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 1
- 229940035437 1,3-propanediol Drugs 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- JFBZPFYRPYOZCQ-UHFFFAOYSA-N [Li].[Al] Chemical compound [Li].[Al] JFBZPFYRPYOZCQ-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000003287 bathing Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002062 molecular scaffold Substances 0.000 description 1
- 150000002921 oxetanes Chemical class 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
- C07C69/708—Ethers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
-
- 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
- C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
- C07C45/57—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom
- C07C45/59—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom in five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D305/04—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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Abstract
本发明公开了一种合成2,2‑二甲基‑3‑氧杂环丁酮的中间体及其制备方法和应用,包括以下步骤:以2‑氧代‑3‑苄氧基‑丁酸酯(化合物II)为原料,与酮保护试剂反应生成缩酮化合物III;化合物III经过酯基还原生成化合物IV;化合物IV经过脱保护生成化合物V;化合物V与甲基溴化镁/甲基氯化镁经过亲核取代反应生成化合物VI;化合物VI经过关环得到氧杂环丁烷化合物VII;化合物VII脱除苄基保护基得到化合物VIII;最后化合物VIII经过羟基氧化生成化合物I(2,2‑二甲基‑3‑氧杂环丁酮)。该方法操作方便,收率稳定,适合大规模生产。
Description
技术领域
本发明涉及药物中间体合成领域,具体地说涉及一种合成2,2-二甲基-3-氧杂环丁酮的中间体及其制备方法和应用。
背景技术
氧杂环丁烷是高能含氧非芳族杂环化合物,其独有的环状刚性结构能在增加药物分子代谢稳定性的同时保持或降低药物分子的亲脂性,其作为具有显著生物活性的新潜在药效团具有重要意义。
3-位取代的氧杂环丁烷,因其是非手性的并且它们作为分子砌块连接到分子支架中不会产生新的立体中心,因此这类氧杂环丁烷类化合物是一类有吸引力的分子模块,具有显著的优势,可以改善作为候选药物的小分子化合物的性质。3-氧杂环丁酮是3-位取代的氧杂环丁烷类化合物中的一类,其是医药合成的一种重要中间体,文献AngewandteChemie,International Edition(2010),49(48):9052报道了3-氧杂环丁酮可以合成衍生出多种小分子化合物(scheme1),这些小分子砌块可以应用于多种靶点的药物分子设计中。
Scheme1文献报道的氧杂环丁烷-3-酮的应用
2,2-二甲基-3-氧杂环丁酮是3-氧杂环丁酮的类似化合物,同样其也可以衍生出一系列的具有药效活性的小分子化合物,可应用于多种靶点的药物分子设计中,具有广阔的市场前景。
文献Bulletin of the Chemical Society of Japan,62(6),2032-9;1989报道了化合物VIII的合成方法:
丙酮和己醛通过光照[2+2]环加成反应,合成得到2,2-二甲基-3-羟基-氧杂环丁烷(化合物VIII),此方法收率很低,仅为8%,并且用到了光照条件,对设备要求比较高,不适合大规模生产。
发明内容
发明目的:现有技术中关于2,2-二甲基-3-氧杂环丁酮的合成鲜有报道,本发明的目的是开发设计出一种操作方便,收率稳定,适合大规模生产的2,2-二甲基-3-氧杂环丁酮的合成工艺。
以2-氧代-3-苄氧基-丁酸酯(化合物II)为原料,与酮保护试剂反应生成缩酮化合物III;化合物III经过酯基还原生成化合物IV;化合物IV经过脱保护生成化合物V;化合物V与甲基溴化镁/甲基氯化镁经过亲核取代反应生成化合物VI;化合物VI经过关环得到氧杂环丁烷化合物VII;化合物VII脱除苄基保护基得到化合物VIII;最后化合物VIII经过羟基氧化生成化合物I(2,2-二甲基-3-氧杂环丁酮)。
一方面,本方明公开了结构式(III)的化合物:
其中:R1为甲基、乙基或者异丙基;
R2,R3同时为甲基、乙基或者R2和R3组合为-CH2CH2-/-CH2CH2CH2-/-CH2CH(CH3)CH2-/-CH2C(CH3)2CH2-。
另一方面,本发明公开了一种化合物III的制备方法,包括:
其中:R1为甲基、乙基或者异丙基;酸1选用对甲苯磺酸;
R2,R3同时为甲基、乙基或者R2和R3组合为-CH2CH2-/-CH2CH2CH2-/-CH2CH(CH3)CH2-/-CH2C(CH3)2CH2-;
优选的,化合物II制备化合III的步骤中,酮保护试剂为原甲酸三甲酯、原甲酸三乙酯、甲醇、乙醇、乙二醇、丙二醇、2-甲基-1,3-丙二醇或者2,2-二甲基-1,3-丙二醇;化合物II、酮保护试剂和酸1的摩尔比范围为1∶1~5∶0.01~0.1;反应温度范围为60~110℃。
另一方面,本发明公开了化合物III制备化合物V的方法,其特征在于,包括:
其中:R1为甲基、乙基或者异丙基;
R2,R3同时为甲基、乙基或者R2和R3组合为-CH2CH2-/-CH2CH2CH2-/-CH2CH(CH3)CH2-/-CH2C(CH3)2CH2-。
另一方面,本发明公开了化合物III制备化合物VI的方法,包括:
其中:R1为甲基、乙基或者异丙基;
R2,R3同时为甲基、乙基或者R2和R3组合为-CH2CH2-/-CH2CH2CH2-/-CH2CH(CH3)CH2-/-CH2C(CH3)2CH2-。
另一方面,本发明公开了化合物III制备化合物I的方法,其特征在于,包括:
其中:R1为甲基、乙基或者异丙基;
R2,R3同时为甲基、乙基或者R2和R3组合为-CH2CH2-/-CH2CH2CH2-/-CH2CH(CH3)CH2-/-CH2C(CH3)2CH2-。
优选的,化合物III制备化合物IV的步骤中,还原剂1选自四氢铝锂、硼氢化钠、硼氢化钾、硼氢化锂或者红铝;化合物Ⅲ与还原剂1的摩尔比为1∶0.5~1∶3;反应温度的范围为-10~50℃;
优选的,化合物IV制备化合物V的步骤中,酸2选自盐酸、硫酸、三氟乙酸或者对甲苯磺酸;化合物IV与酸2的摩尔比范围为1∶1~1∶10;反应温度范围为0~100℃;
优选的,化合物V制备化合物VI的步骤中,化合物V和甲基溴化镁/甲基氯化镁的摩尔比范围为1∶2~1∶6;反应温度范围为-80~50℃;
优选的,化合物VI制备化合物VII的步骤中,所述的碱1选自叔丁醇钾、氢氧化钠、氢氧化钾、正丁基锂,二异丙基氨基锂或者氢化钠;所述的磺酰氯/磺酸酐为:对甲苯磺酰氯、甲基磺酰氯、对硝基苯磺酰氯、甲磺酸酐或者三氟甲磺酸酐;反应温度范围为-20~60℃;
优选的,化合物VII制备化合物VIII的步骤中,所述的催化剂1选为钯碳、氢氧化钯碳,铑碳或者铂碳;还原剂2选自氢气;反应温度范围为0~60℃;
优选的,化合物VIII制备化合物I的步骤中,氧化试剂选自草酰氯+二甲基亚砜、三氟乙酸+二甲基亚砜、戴斯-马丁试剂、2-碘酰基苯甲酸、三氯异氰尿酸+2,2,6,6-四甲基-哌啶氮氧化物;反应温度范围为-80~40℃。
另一方面,本发明提供了化合物II制备化合物I的方法,包括:
其中:R1为甲基、乙基或者异丙基;酸1选用对甲苯磺酸;
R2,R3同时为甲基、乙基或者R2和R3组合为-CH2CH2-/-CH2CH2CH2-/-CH2CH(CH3)CH2-/-CH2C(CH3)2CH2-。
有益效果
以2-氧代-3-苄氧基-丁酸酯(化合物II)为原料,与酮保护试剂反应生成缩酮化合物III;化合物III经过酯基还原生成化合物IV;化合物IV经过脱保护生成化合物V;化合物V与甲基溴化镁/甲基氯化镁经过亲核取代反应生成化合物VI;化合物VI经过关环得到氧杂环丁烷化合物VII;化合物VII脱除苄基保护基得到化合物VIII;最后化合物VIII经过羟基氧化生成化合物I(2,2-二甲基-3-氧杂环丁酮)。该方法操作方便,收率稳定,适合大规模生产。
说明书中涉及到的反应试剂的缩写如下所示:
LAH:氢化铝锂;
TEMPO:2,2,6,6-四甲基-哌啶氮氧化物;
DMSO:二甲基亚砜;
DMP:戴斯-马丁试剂;
IBX:2-碘酰基苯甲酸;
PE:石油醚;
THF:四氢呋喃;
DCM:二氯甲烷;
MeOH:甲醇;
EtOH:乙醇;
EA:乙酸乙酯;
TsCl:对甲苯磺酰氯;
TCCA:三氯异氰尿酸。
具体实施方式
下面结合具体实施例,进一步阐明本发明,本实施例在以本发明技术方案为前提下进行实施,应理解这些实施例仅用于说明本发明而不用于限制本发明的范围。
实施例1
化合物III-1的制备
将化合物II-1(190.00g,0.804mol,1.0eq.),乙二醇(59.89g,0.804mol,1.0eq.)溶于甲苯(1200mL)中,加入对甲苯磺酸(9.50g,0.0552mol,0.068eq.);加热至回流搅拌反应4h,TLC监测原料消失。减压浓缩除去溶剂,向残留物中加入EA,用饱和食盐水洗涤、干燥、浓缩、制砂柱层析纯化(PE/EA洗脱),得化合物III-1为淡黄色液体150.1g,收率为67%。1HNMR(400MHz,CDCl3):δ(ppm)7.30-7.39(m,5H);4.70-4.73(d,J=12Hz,1H);4.52-4.55(d,J=12Hz,1H);4.22-4.27(m,2H);3.95-4.02(m,5H);1.49(s,3H);1.29-1.32(t,J=4Hz,3H)。
化合物IV-1的制备
氮气氛围,冰水浴下,分批向500mL THF中加入LAH(14.23g,0.375mo1,0.7eq.)。搅拌10min后,向其中滴加化合物III-1(150.1g,0.535mo1,1.0eq.),滴完室温下搅拌反应1h,TLC检测原料消失。往反应液中滴加15.00g水、15.00g 15%NaOH水溶液和30.00g水淬灭反应,过滤,滤饼用THF洗涤,滤液浓缩、制砂柱层析(PE/EA洗脱),得化合物IV-1为无色油状物100.2g,收率为78.6%。
化合物V的制备
将6N HCl(250mL)加入到化合物IV-1(100.2g,0.421mo1,1.0eq.)中,室温搅拌过夜反应。TLC检测原料消失,结束反应,向反应液中加入水(500mL),用EA萃取,合并有机相,浓缩制砂柱层析纯化(PE/EA洗脱),得化合物V为淡黄色油状物80.01g,收率为97.8%。1HNMR(400MHz,CDCl3):δ(ppm)7.33-7.42(m,5H);4.70-4.73(d,J=12Hz,1H);4.58-4.61(d,J=12Hz,1H);3.81-3.95(m,3H);2.26(s,3H);2.17(s,1H)。化合物VI的制备
将化合物V(80.00g,0.432mol,1.0eq.)溶于THF(500mL),冰水浴下,向其中滴加CH3MgBr(750mL,1.732mol,4.0eq.);加毕室温搅拌反应13h;TLC检测原料不再变化,结束反应,将反应液缓慢倒入稀盐酸(800mL)中淬灭反应,调节pH=6-7,分液;水相用EA提取,合并有机相浓缩制砂柱层析纯化(PE/EA洗脱),得化合物VI为浅红色油状物69.01g,收率为80%。1HNMR(400MHz,CDCl3):δ(ppm)7.31-7.39(m,5H);4.77-4.80(d,J=4Hz,1H);4.66-4.69(d,J=4Hz,1H);3.79-3.94(m,2H);3.30-3.32(t,J=4Hz,1H);2.40(s,2H);1.27-1.29(d,J=8Hz,6H)。
化合物VII的制备
将化合物VI(69.01g,0.328mol,1.0eq.)溶于THF(600mL)中,氮气保护,降温至-20℃,滴加n-BuLi(131mL,0.328mol,1.0eq.),控制T<0℃;滴毕,0℃搅拌反应1h,再滴加TsCl(62.53g,0.328mol,1.0eq.)的THF(200mL)溶液,控制T<0℃;滴毕,0℃搅拌反应50min,再滴加n-BuLi(158mL,0.394mol,1.2eq.),控制T<5℃。滴毕,自然升至室温,加热回流搅拌反应4h。降至室温,将反应液倒入到饱和的氯化铵(800mL)中,分液,水相用EA萃取,合并有机相,浓缩、制砂柱层析纯化(PE/EA洗脱),得化合物VII为淡黄色液体50.01g,收率:79%,直接投入下一步。1HNMR(400MHz,CDCl3):δ(ppm)7.30-7.40(m,5H);4.42-4.52(m,3H);4.33-4.36(t,J=6Hz,1H);4.21-2.24(d,J=6Hz,1H);1.46(s,3H);1.461.46(s,3H)。
化合物VIII的制备
在2L氢化釜中,化合物VII(50.01g,0.26mol,1.0eq.),HOAc(2.00g),溶于MeOH中,加入Pd(OH)2/C(5.01g),3.5MPa氢气,50℃搅拌反应18h,TLC监测显示原料消失,反应结束,反应液冷却后,抽滤除去催化剂,浓缩,水泵减压蒸馏收集75-82℃的馏分,得化合物VIII为无色液体19.01g,收率:71%。1HNMR(400MHz,CDCl3):δ(ppm)4.60-4.64(t,J=8Hz,1H);4.40-4.45(q,J=8Hz,1H);4.25-4.27(t,J=8Hz,1H);2.58-2.59(d,J=8Hz,1H);1.40(s,6H)。
化合物I的制备
将化合物VIII(9.01g,88.12mmol,1.0eq.)溶于DCM(100mL)中,加入KOAc(10.81g,110.15mol,1.25eq.)及TEMPO(0.55g,3.52mmol,0.04eq.),冰水浴下T<5℃,分批向其中加入TCCA(9.22g,39.6mol,0.45eq.),控制T<10℃。滴完搅拌反应2h,GC检测显示原料反应完全。结束反应,向反应液中加入K2CO3(8.52g,61.68mol,0.7eq.),搅拌30min,抽滤、滤饼用DCM洗涤、合并滤液,水泵减压蒸馏收集58-70℃的馏分,得化合物I为无色液体4.01g,收率为45%。1HNMR(400MHz,CDCl3):δ(ppm)5.25(s,2H);1.51(s,6H)。
实施例2
化合物III-2的制备
将化合物II-2(100.1g,0.40mol,1.0eq.),乙二醇(24.82g,0.40mol,1.0eq.)溶于甲苯(1200mL)中,加入对甲苯磺酸(0.689g,0.004mol,0.01eq.);加热至回流搅拌反应8h,TLC监测原料消失。减压浓缩除去溶剂,向残留物中加入EA,用饱和食盐水洗涤、干燥、浓缩、制砂柱层析纯化(PE/EA洗脱),得化合物III-2为淡黄色液体72.17g,收率为61.3%。(ESI-TOF)m/z:[M+H]+calcd for C16H22O5:294;found:295。
化合物IV-1的制备
氮气氛围,冰水浴0℃下,将化合物III-2(70g,0.238mol,1.0eq.)的乙醚溶液(200mL)在冰水浴中降温到5℃左右,滴加红铝的甲苯溶液(138.1g,0.476mol,2.0eq.),放气,放热,10℃下反应2h,反应结束,将反应液缓慢倒入500mL冰水中,分液,水层用乙酸乙酯提取,合并有机层,饱和氯化钠洗一次,无水硫酸钠干燥,过滤,滤液浓缩、制砂柱层析(PE/EA洗脱),得化合物IV-1为无色油状物44.23g,收率为78%。
化合物V的制备
将三氟乙酸(80mL)加入到化合物IV-1(44.23g,0.186mo1,1.0eq.)中,室温搅拌反应8h。TLC检测原料消失,结束反应,将反应液倒入冰水中,饱和碳酸氢钠调节pH至6-7用EA萃取,合并有机相,浓缩制砂柱层析纯化(PE/EA洗脱),得化合物V为淡黄色油状物30.81g,收率为85.3%。
化合物VI的制备
将化合物V(30.32g,0.156mol,1.0eq.)溶于THF(500mL),冰水浴下,向其中滴加2.0M CH3MgCl(156mL,0.312mol,2.0eq.);加毕室温搅拌反应16h;TLC检测原料不再变化,结束反应,将反应液缓慢倒入稀盐酸(500mL)中淬灭反应,调节pH=6-7,分液;水相用EA提取,合并有机相浓缩制砂柱层析纯化(PE/EA洗脱),得化合物VI为浅红色油状物24.70g,收率为75.3%。1HNMR(400MHz,CDCl3):δ(ppm)7.31-7.39(m,5H);4.77-4.80(d,J=4Hz,1H);4.66-4.69(d,J=4Hz,1H);3.79-3.94(m,2H);3.30-3.32(t,J=4Hz,1H);2.40(s,2H);1.27-1.29(d,J=8Hz,6H)。
化合物VII的制备
将化合物VI(20.01g,0.0952mol,1.0eq.)溶于THF(200mL)中,冷却至0℃,分批加入NaH(3.52g,0.095mol,1.0eq.),滴加甲磺酸酐(16.58g,0.0952mol,1.0eq.)的100mLTHF溶液,再分批加入NaH(3.52g,0.095mol,1.0eq.),加入完毕后,升温至室温,搅拌反应1h,加热至60℃,搅拌反应12h,加入1L水,分液,水相用EA萃取,有机相合并,用饱和食盐水洗涤后干燥,浓缩,柱层析纯化得化合物VII为黄色液体14.70g,收率为80.3%。1HNMR(400MHz,CDCl3):δ(ppm)7.30-7.40(m,5H);4.42-4.52(m,3H);4.33-4.36(t,J=6Hz,1H);4.21-2.24(d,J=6Hz,1H);1.46(s,3H);1.461.46(s,3H)。
化合物VIII的制备
在500mL氢化釜中,化合物VII(14.01g,0.0728mol,1.0eq.)溶于MeOH中,加入Pd(OH)2/C(10.00g),2.5MPa氢气,50℃搅拌反应26h,TLC监测显示原料消失,反应结束,反应液冷却后,抽滤除去催化剂,浓缩,水泵减压蒸馏收集75-82℃的馏分,得化合物VIII为无色液体4.89g,收率:65.8%。1HNMR(400MHz,CDCl3):δ(ppm)4.60-4.64(t,J=8Hz,1H);4.40-4.45(q,J=8Hz,1H);4.25-4.27(t,J=8Hz,1H);2.58-2.59(d,J=8Hz,1H);1.40(s,6H)。
化合物I的制备
将化合物VIII(4.89g,0.0479mol,1.0eq.)溶于EA(100mL)中,加入IBX(40.23g,0.144mol,3.0eq.),加完搅拌反应2h,GC检测显示原料反应完全。结束反应,冷却,抽滤、滤饼用EA洗涤、合并滤液,浓缩后水泵减压蒸馏收集58-70℃的馏分,得化合物I为无色液体3.12g,收率为65%。1HNMR(400MHz,CDCl3):δ(ppm)5.25(s,2H);1.51(s,6H)。
实施例3
化合物III-3的制备
将化合物II-3(100.1g,0.450mol,1.0eq.),原甲酸三甲酯(95.51g,0.90mol,2.0eq.)溶于MeOH(800mL)中,加入对甲苯磺酸(2.32g,0.0135mol,0.03eq.);加热至回流搅拌反应6h,TLC监测原料消失。减压浓缩除去溶剂,向残留物中加入EA,用饱和食盐水洗涤、干燥、浓缩、制砂柱层析纯化(PE/EA洗脱),得化合物III-3为淡黄色液体80.05g,收率为66.3%。(ESI-TOF)m/z:[M+H]+calcd for C16H22O5:268;found:269。
化合物IV-3的制备
0℃氮气保护下,将LAH(5.65g,0.149mol,0.5eq.)悬浮于THF(500mL)中,滴加化合物III-3(80.05g,0.298mol,1.0e.q.)的THF溶液(300mL)放气放热,10℃下反应4h,反应结束,0℃下依次滴加水(5.65g),15%的氢氧化钠水溶液(5.65g),水(16.96g),搅拌30min,抽滤,滤饼再用THF打浆3次,过滤,合并滤液,滤液浓缩、制砂柱层析(PE/EA洗脱),得化合物IV-3为无色油状物61.08g,收率为85.3%。
化合物V的制备
将6N HCl(347mL)加入到化合物IV-3(50.10g,0.208mo1,1.0eq.)中,室温搅拌过夜反应。TLC检测原料消失,结束反应,向反应液中加入水(500mL),用EA萃取,合并有机相,浓缩制砂柱层析纯化(PE/EA洗脱),得化合物V为淡黄色油状物37.77g,收率为93.5%。1HNMR(400MHz,CDCl3):δ(ppm)7.33-7.42(m,5H);4.70-4.73(d,J=12Hz,1H);4.58-4.61(d,J=12Hz,1H);3.81-3.95(m,3H);2.26(s,3H);2.17(s,1H)。
化合物VI的制备
将化合物V(30.01g,0.155mol,1.0eq.)溶于THF(500mL),-80℃下,向其中滴加2.0M CH3MgCl(464mL,0.927mol,6.0eq.);加毕此温度下搅拌反应2h后,升至室温搅拌反应10h;TLC检测原料不再变化,结束反应,将反应液缓慢倒入稀盐酸中淬灭反应,调节pH=6-7,分液;水相用EA提取,合并有机相浓缩制砂柱层析纯化(PE/EA洗脱),得化合物VI为浅红色油状物21.67g,收率为66.5%。1HNMR(400MHz,CDCl3):δ(ppm)7.31-7.39(m,5H);4.77-4.80(d,J=4Hz,1H);4.66-4.69(d,J=4Hz,1H);3.79-3.94(m,2H);3.30-3.32(t,J=4Hz,1H);2.40(s,2H);1.27-1.29(d,J=8Hz,6H)。
化合物VII的制备
将化合物VI(20.01g,0.0952mol,1.0eq.)溶于THF(200mL)中,冷却至0℃,分批加入叔丁醇钾(21.36g,0.19mol,2.0eq.),保温20min,分批加入对甲苯磺酰氯(18.13g,0.095mol,1.0eq.),加入完毕后,升温至室温,搅拌反应1.5h,冷却至0℃,加入1L水,分液,水相用EA萃取,有机相合并,用饱和食盐水洗涤后干燥,浓缩制砂,柱层析纯化得化合物VII为黄色液体14.33g,收率为78.3%。1HNMR(400MHz,CDCl3):δ(ppm)7.30-7.40(m,5H);4.42-4.52(m,3H);4.33-4.36(t,J=6Hz,1H);4.21-2.24(d,J=6Hz,1H);1.46(s,3H);1.461.46(s,3H)。
化合物VIII的制备
在500mL氢化釜中,化合物VII(14.01g,0.0728mol,1.0eq.)溶于甲醇中,加入Pd/C(2.00g),3.5MPa氢气,60℃搅拌反应26h,TLC监测显示原料消失,反应结束,反应液冷却后,抽滤除去催化剂,浓缩,水泵减压蒸馏收集75-82℃的馏分,得化合物VIII为无色液体4.63g,收率:62.3%。1HNMR(400MHz,CDCl3):δ(ppm)4.60-4.64(t,J=8Hz,1H);4.40-4.45(q,J=8Hz,1H);4.25-4.27(t,J=8Hz,1H);2.58-2.59(d,J=8Hz,1H);1.40(s,6H)。
化合物I的制备
氮气氛围下,100mLDCM冷却至-80℃,加入草酰氯(8.62g,0.068mol,1.5eq.),滴加入DMSO(7.08g,0.0906mol,2.0eq.),加完-80℃下搅拌30min后,滴加入化合物VIII(4.63g,0.0453mol,1.0eq.)的20mLDCM溶液,加完此温度下搅拌1h后,GC检测显示原料反应完全。往反应液中加入TEA(27.51g,0.272mol,4eq.),反应液升温至室温搅拌反应2h。往反应液中加入水,分液,DCM萃取水相、合并有机相,稀盐酸洗涤,无水硫酸钠干燥后,浓缩,水泵减压蒸馏收集58-70℃的馏分,得化合物I为无色液体3.19g,收率为70.3%。1HNMR(400MHz,CDCl3):δ(ppm)5.25(s,2H);1.51(s,6H)。
实施例4
化合物III-4的制备
将化合物II-3(94.23g,0.424mol,1.0eq.),原甲酸三乙酯(313.95g,2.11mol,5.0eq.)溶于EtOH(800mL)中,加入对甲苯磺酸(7.31g,0.0424mol,0.1eq.);加热至回流搅拌反应6h,TLC监测原料消失。减压浓缩除去溶剂,向残留物中加入EA,用饱和食盐水洗涤、干燥、浓缩、制砂柱层析纯化(PE/EA洗脱),得化合物III-4为淡黄色液体85.82g,收率为68.3%。(ESI-TOF)m/z:[M+H]+calcd for C16H24O5:296;found:297。
化合物IV-4的制备
化合物III-4(80.05g,0.27mol,1.0e.q.)溶于500mL甲醇中,冰水浴5℃左右,氮气保护下将NaBH4(30.64g,0.81mol,3.0e.q.)分批加入,放气,放热,10℃下反应1h,反应结束,0℃下加入200mL饱和氯化铵溶液中淬灭反应,浓缩,残留物用乙酸乙酯和水各300mL分液,水层用乙酸乙酯提取,合并有机层,有机层无水硫酸钠干燥后过滤,滤液浓缩、制砂柱层析(PE/EA洗脱),得化合物IV-4为无色油状物54.56g,收率为75.3%。
化合物V的制备
化合物IV-4(50.10g,0.186mo1,1.0eq.)溶于500mL MeOH中,0℃滴加入5mL浓硫酸,加完室温搅拌过夜反应。TLC检测原料消失,结束反应,向反应液中加入水(800mL),用EA萃取,合并有机相,饱和碳酸氢钠洗涤,无水硫酸钠干燥后,浓缩制砂柱层析纯化(PE/EA洗脱),得化合物V为淡黄色油状物31.25g,收率为86.5%。1HNMR(400MHz,CDCl3):δ(ppm)7.33-7.42(m,5H);4.70-4.73(d,J=12Hz,1H);4.58-4.61(d,J=12Hz,1H);3.81-3.95(m,3H);2.26(s,3H);2.17(s,1H)。
化合物VI的制备
将化合物V(30.01g,0.155mol,1.0eq.)溶于THF(500mL),冰水浴下,向其中滴加2.0M CH3MgBr(310mL,0.62mol,4.0eq.);加毕室温搅拌反应10h;TLC检测原料不再变化,结束反应,将反应液缓慢倒入稀盐酸中淬灭反应,调节pH=6-7,分液;水相用EA提取,合并有机相浓缩制砂柱层析纯化(PE/EA洗脱),得化合物VI为浅红色油状物22.98g,收率为70.5%。1HNMR(400MHz,CDCl3):δ(ppm)7.31-7.39(m,5H);4.77-4.80(d,J=4Hz,1H);4.66-4.69(d,J=4Hz,1H);3.79-3.94(m,2H);3.30-3.32(t,J=4Hz,1H);2.40(s,2H);1.27-1.29(d,J=8Hz,6H)。
化合物VII的制备
将化合物VI(20.01g,0.0952mol,1.0e.q.)溶于200mL THF中,冷却至0℃,分批加入NaH(3.51g,0.0952mol,1.0e.q.),滴加三氟甲磺酸酐(26.86g,0.0952mol,1.0e.q.)的50mL THF溶液,再分批加入NaH(3.51g,0.0952mol,1.0e.q.),加入完毕后,升温至室温,搅拌反应1h,加热至60℃,搅拌反应16h,加入1L水,分液,水相用EA萃取,有机相合并,用饱和食盐水洗涤后干燥,浓缩制砂,柱层析纯化得化合物VII为黄色液体13.96g,收率为76.3%。1HNMR(400MHz,CDCl3):δ(ppm)7.30-7.40(m,5H);4.42-4.52(m,3H);4.33-4.36(t,J=6Hz,1H);4.21-2.24(d,J=6Hz,1H);1.46(s,3H);1.461.46(s,3H)。
化合物VIII的制备
在500mL氢化釜中,化合物VII(13.01g,0.0676mol,1.0eq.)溶于MeOH中,加入Pt/C(1.3g),3.5MPa氢气,40℃搅拌反应16h,TLC监测显示原料消失,反应结束,反应液冷却后,抽滤除去催化剂,浓缩,水泵减压蒸馏收集75-82℃的馏分,得化合物VIII为无色液体4.73g,收率:68.6%。1HNMR(400MHz,CDCl3):δ(ppm)4.60-4.64(t,J=8Hz,1H);4.40-4.45(q,J=8Hz,1H);4.25-4.27(t,J=8Hz,1H);2.58-2.59(d,J=8Hz,1H);1.40(s,6H)。
化合物I的制备
将化合物VIII(4.73g,0.0463mol,1.0eq.)溶于EA(100mL)中,加入DMP(78.6g,0.185mol,4.0eq.),加完室温搅拌反应5h,GC检测显示原料反应完全。结束反应,冷却,抽滤、滤饼用EA洗涤、合并滤液,水泵减压蒸馏收集58-70℃的馏分,得化合物I为无色液体3.08g,收率为66.5%。1HNMR(400MHz,CDCl3):δ(ppm)5.25(s,2H);1.51(s,6H)。
实施例5
化合物III-5的制备
将化合物II-3(100.1g,0.45mol,1.0eq.),1,3-丙二醇(51.37g,0.675mol,1.5eq.)溶于甲苯(1200mL)中,加入对甲苯磺酸(1.55g,0.009mol,0.02eq.);加热至回流搅拌反应8h,TLC监测原料消失。减压浓缩除去溶剂,向残留物中加入EA,用饱和食盐水洗涤、干燥、浓缩、制砂柱层析纯化(PE/EA洗脱),得化合物III-5为淡黄色液体79.85g,收率为63.3%。(ESI-TOF)m/z:[M+H]+calcd for C15H20O5:280;found:281。
化合物IV-5的制备
化合物III-5(70.05g,0.25mol,1.0e.q.)溶于500mL甲醇中,冰水浴5℃左右,氮气保护下将KBH4(30.64g,0.81mol,3.0eq.)分批加入,放气,放热,10℃下反应1h,反应结束,0℃下加入200mL饱和氯化铵溶液中淬灭反应,浓缩,残留物用乙酸乙酯和水各300mL分液,水层用乙酸乙酯提取,合并有机层,有机层无水硫酸钠干燥后过滤,滤液浓缩、制砂柱层析(PE/EA洗脱),得化合物IV-5为无色油状物49.39g,收率为78.3%。
化合物V的制备
化合物IV-5(45.01g,0.178mol,1.0eq.)溶于400mL EtOH和100mL水中,室温下加入对甲苯磺酸(33.93g,0.178mol,1.0eq.),加完加热至回流搅拌反应4h,GC显示原料反应完,反应液冷却后,将反应液倒入500mL水中,EA萃取,合并有机相,饱和碳酸氢钠洗涤,无水硫酸钠干燥后,浓缩制砂,柱层析纯化(PE/EA洗脱),得化合物V为淡黄色油状物28.76g,收率83.2%。
化合物VI的制备
将化合物V(25.01g,0.129mol,1.0eq.)溶于THF(200mL),冰水浴下,向其中滴加2.0M CH3MgBr(258mL,0.516mol,4.0eq.);加毕加热至50℃搅拌反应1h;TLC检测原料不再变化,结束反应,将反应液缓慢倒入饱和氯化铵中淬灭反应,调节pH=6-7,分液;水相用EA提取,合并有机相浓缩制砂柱层析纯化(PE/EA洗脱),得化合物VI为浅红色油状物20.48g,收率为75.5%。1HNMR(400MHz,CDCl3):δ(ppm)7.31-7.39(m,5H);4.77-4.80(d,J=4Hz,1H);4.66-4.69(d,J=4Hz,1H);3.79-3.94(m,2H);3.30-3.32(t,J=4Hz,1H);2.40(s,2H);1.27-1.29(d,J=8Hz,6H)。
化合物VII的制备
将化合物VI(20.01g,0.095mol,1.0e.q.)溶于200mL THF中,冷却至0℃,滴加2.5MLDA(0.285mol,3.0eq.)114mL THF溶液,保温30min,滴加甲基磺酰氯(10.85g,0.0947mol,1.0eq.)的100mL THF溶液,加入完毕后,升温至50℃,搅拌反应18h,降至室温加入600mL水,分液,水相用EA萃取,有机相合并,用饱和食盐水洗涤后干燥,浓缩制砂柱层析纯化得化合物VII黄色液体15.58g,收率为85.3%。1HNMR(400MHz,CDCl3):δ(ppm)7.30-7.40(m,5H);4.42-4.52(m,3H);4.33-4.36(t,J=6Hz,1H);4.21-2.24(d,J=6Hz,1H);1.46(s,3H);1.461.46(s,3H)。
化合物VIII的制备
在500mL氢化釜中,化合物VII(13.01g,0.0676mol,1.0eq.)溶于MeOH中,加入Pd(OH)2/C(1.3g),3.0MPa氢气,40℃搅拌反应18h,TLC监测显示原料消失,反应结束,反应液冷却后,抽滤除去催化剂,浓缩,水泵减压蒸馏收集75-82℃的馏分,得化合物VIII为无色液体4.53g,收率:65.6%。1HNMR(400MHz,CDCl3):δ(ppm)4.60-4.64(t,J=8Hz,1H);4.40-4.45(q,J=8Hz,1H);4.25-4.27(t,J=8Hz,1H);2.58-2.59(d,J=8Hz,1H);1.40(s,6H)。
化合物I的制备
将化合物VIII(4.01g,0.0392mol,1.0eq.)溶于EA(500mL)中,加入IBX(43.87g,0.157mol,4.0eq.),加完40℃搅拌反应5h,GC检测显示原料反应完全。结束反应,冷却,抽滤、滤饼用EA洗涤、合并滤液,水泵减压蒸馏收集58-70℃的馏分,得化合物I为无色液体2.69g,收率为68.5%。1HNMR(400MHz,CDCl3):δ(ppm)5.25(s,2H);1.51(s,6H)。
实施例6
化合物III-6的制备
将化合物II-3(100.1g,0.45mol,1.0eq.),2-甲基-1,3-丙二醇(81g,0.90mol,2.0eq.)溶于甲苯(1200mL)中,加入对甲苯磺酸(1.55g,0.009mol,0.02eq.);加热至回流搅拌反应8h,TLC监测原料消失。减压浓缩除去溶剂,向残留物中加入EA,用饱和食盐水洗涤、干燥、浓缩、制砂柱层析纯化(PE/EA洗脱),得化合物III-6为淡黄色液体95.19g,收率为68.6%。(ESI-TOF)m/z:[M+H]+calcd for C16H22O5:294;found:295。
化合物IV-6的制备
化合物III-6(50.05g,0.162mol,1.0eq.)溶于500mL MeOH中,冰水浴5℃左右,氮气保护下将LiBH4(14.13g,0.648mol,4.0eq.)分批加入,放气,放热,10℃下反应1h,反应结束,0℃下加入250mL饱和氯化铵溶液淬灭反应,浓缩,残留物用EA和水各300mL分液,水层用乙酸乙酯提取,合并有机层,有机层无水硫酸钠干燥后过滤,滤液浓缩、制砂柱层析(PE/EA洗脱),得化合物IV-6为无色油状物33.74g,收率为74.3%。
化合物V的制备
化合物IV-6(30.01g,0.107mol,1.0eq.)溶于400mL乙醇和100mL水中,室温下加入对甲苯磺酸(24.35g,0.128mol,1.2eq.),加完加热至回流搅拌反应4h,GC显示原料反应完,反应液冷却后,将反应液倒入500mL水中,EA萃取,合并有机相,饱和碳酸氢钠洗涤,无水硫酸钠干燥后,浓缩制砂,柱层析纯化(PE/EA洗脱),得化合物V为淡黄色油状物17.71g,收率85.2%。
化合物VI的制备
将化合物V(15.01g,0.077mol,1.0eq.)溶于THF(200mL),冰水浴下,向其中滴加2.0M CH3MgBr(193mL,0.386mol,5.0eq.);加毕室温搅拌反应10h;TLC检测原料不再变化,结束反应,将反应液缓慢倒入稀盐酸中淬灭反应,调节pH=6-7,分液;水相用EA提取,合并有机相浓缩制砂柱层析纯化(PE/EA洗脱),得化合物VI为浅红色油状物12.71g,收率为78.5%。1HNMR(400MHz,CDCl3):δ(ppm)7.31-7.39(m,5H);4.77-4.80(d,J=4Hz,1H);4.66-4.69(d,J=4Hz,1H);3.79-3.94(m,2H);3.30-3.32(t,J=4Hz,1H);2.40(s,2H);1.27-1.29(d,J=8Hz,6H)。
化合物VII的制备
将化合物VI(10.01g,0.0476mol,1.0e.q.)溶于200mL THF中,冷却至0℃,滴加2.5M LDA(0.119mol,2.5eq.)48mL THF溶液,保温30min,滴加对硝基苯磺酰氯(15.81g,0.0713mol,1.5eq.)的100mL THF溶液,加入完毕后,升温至50℃,搅拌反应18h,加入600mL水,分液,水相用EA萃取,有机相合并,用饱和食盐水洗涤后干燥,浓缩制砂柱层析纯化得化合物VII黄色液体7.35g,收率为80.3%。1HNMR(400MHz,CDCl3):δ(ppm)7.30-7.40(m,5H);4.42-4.52(m,3H);4.33-4.36(t,J=6Hz,1H);4.21-2.24(d,J=6Hz,1H);1.46(s,3H);1.461.46(s,3H)。
化合物VIII的制备
在500mL氢化釜中,化合物VII(7.01g,0.0364mol,1.0eq.)溶于MeOH中,加入Pd/C(1g),3.0MPa氢气,50℃搅拌反应18h,TLC监测显示原料消失,反应结束,反应液冷却后,抽滤除去催化剂,浓缩,水泵减压蒸馏收集75-82℃的馏分,得化合物VIII为无色液体2.17g,收率:61.5%。1HNMR(400MHz,CDCl3):δ(ppm)4.60-4.64(t,J=8Hz,1H);4.40-4.45(q,J=8Hz,1H);4.25-4.27(t,J=8Hz,1H);2.58-2.59(d,J=8Hz,1H);1.40(s,6H)。
化合物I的制备
将化合物VIII(2.01g,0.0196mol,1.0eq.)溶于EA(500mL)中,加入IBX(27.42g,0.0979mol,5.0eq.),加完40℃搅拌反应5h,GC检测显示原料反应完全。结束反应,冷却,抽滤、滤饼用EA洗涤、合并滤液,水泵减压蒸馏收集58-70℃的馏分,得化合物I为无色液体1.25g,收率为63.5%。1HNMR(400MHz,CDCl3):δ(ppm)5.25(s,2H);1.51(s,6H)。
实施例7
化合物III-7的制备
将化合物II-3(100.1g,0.45mol,1.0eq.),2,2-二甲基-1,3-丙二醇(84.44g,0.81mol,1.8eq.)溶于甲苯(1200mL)中,加入对甲苯磺酸(4.28g,0.0225mol,0.05eq.);加热至回流搅拌反应8h,TLC监测原料消失。减压浓缩除去溶剂,向残留物中加入EA,用饱和食盐水洗涤、干燥、浓缩、制砂柱层析纯化(PE/EA洗脱),得化合物III-7为淡黄色液体97.96g,收率为70.6%。(ESI-TOF)m/z:[M+H]+calcd for C17H24O5:308;found:309。
化合物IV-7的制备
化合物III-7(50.05g,0.162mol,1.0e.q.)溶于500mL甲醇中,冰水浴5℃左右,氮气保护下将LiBH4(17.66g,0.81mol,5.0e.q.)分批加入,放气,放热,10℃下反应1h,反应结束,0℃下加入250mL氯化铵溶液淬灭反应,浓缩,残留物用乙酸乙酯和水各300mL分液,水层用乙酸乙酯提取,合并有机层,有机层无水硫酸钠干燥后过滤,滤液浓缩、制砂柱层析(PE/EA洗脱),得化合物IV-7为无色油状物35.15g,收率为77.4%。
化合物V的制备
化合物IV-7(30.01g,0.107mol,1.0eq.)溶于400mL乙醇和100mL水中,室温下加入对甲苯磺酸(20.35g,0.107mol,1.0eq.),加完加热至回流搅拌反应5h,GC显示原料反应完,反应液冷却后,将反应液倒入500mL水中,EA萃取,合并有机相,饱和碳酸氢钠洗涤,无水硫酸钠干燥后,浓缩制砂,柱层析纯化(PE/EA洗脱),得化合物V为淡黄色油状物17.08g,收率82.2%。
化合物VI的制备
将化合物V(15.01g,0.077mol,1.0eq.)溶于THF(200mL),冰水浴下,向其中滴加2.0M CH3MgBr(155mL,0.309mol,4.0eq.);加毕室温搅拌反应10h;TLC检测原料不再变化,结束反应,将反应液缓慢倒入稀盐酸中淬灭反应,调节pH=6-7,分液;水相用EA提取,合并有机相浓缩制砂柱层析纯化(PE/EA洗脱),得化合物VI为浅红色油状物11.25g,收率为69.5%。1HNMR(400MHz,CDCl3):δ(ppm)7.31-7.39(m,5H);4.77-4.80(d,J=4Hz,1H);4.66-4.69(d,J=4Hz,1H);3.79-3.94(m,2H);3.30-3.32(t,J=4Hz,1H);2.40(s,2H);1.27-1.29(d,J=8Hz,6H)。
化合物VII的制备
将化合物VI(10.01g,0.0476mol,1.0e.q.)溶于200mL DMSO中,冷却至0℃,加入氢氧化钠(3.8g,0.095mol,2.0eq.),保温30min,滴加对硝基苯磺酰氯(10.60g,0.0476mol,1.0eq.)的100mL THF溶液,加入完毕后,升温至50℃,搅拌反应18h,加入600mL水,分液,水相用EA萃取,有机相合并,用饱和食盐水洗涤后干燥,浓缩制砂柱层析纯化得化合物VII黄色液体7.18g,收率为78.5%。1HNMR(400MHz,CDCl3):δ(ppm)7.30-7.40(m,5H);4.42-4.52(m,3H);4.33-4.36(t,J=6Hz,1H);4.21-2.24(d,J=6Hz,1H);1.46(s,3H);1.461.46(s,3H)。
化合物VIII的制备
在500mL氢化釜中,化合物VII(7.01g,0.0364mol,1.0eq.)溶于MeOH中,加入铑碳(1g),3.0MPa氢气,50℃搅拌反应10h,TLC监测显示原料消失,反应结束,反应液冷却后,抽滤除去催化剂,浓缩,水泵减压蒸馏收集75-82℃的馏分,得化合物VIII为无色液体2.47g,收率:66.5%。1HNMR(400MHz,CDCl3):δ(ppm)4.60-4.64(t,J=8Hz,1H);4.40-4.45(q,J=8Hz,1H);4.25-4.27(t,J=8Hz,1H);2.58-2.59(d,J=8Hz,1H);1.40(s,6H)。化合物I的制备
将化合物VIII(2.01g,0.0196mol,1.0eq.)溶于EA(500mL)中,加入IBX(32.9g,0.117mol,6.0eq.),加完室温搅拌反应5h,GC检测显示原料反应完全。结束反应,冷却,抽滤、滤饼用EA洗涤、合并滤液,水泵减压蒸馏收集58-70℃的馏分,得化合物I为无色液体1.30g,收率为66.5%。1HNMR(400MHz,CDCl3):δ(ppm)5.25(s,2H);1.51(s,6H)。
Claims (9)
1.一种化合物III制备化合物V的方法,其特征在于,包括:
其中:R1为甲基、乙基或者异丙基;
R2,R3同时为甲基、乙基或者R2和R3组合为-CH2CH2-/-CH2CH2CH2-/-CH2CH(CH3)CH2-/-CH2C(CH3)2CH2-。
2.一种权利要求1中的化合物III制备化合物VI的方法,包括:
其中:R1为甲基、乙基或者异丙基;
R2,R3同时为甲基、乙基或者R2和R3组合为-CH2CH2-/-CH2CH2CH2-/-CH2CH(CH3)CH2-/-CH2C(CH3)2CH2-。
3.一种权利要求1中的化合物III制备化合物I的方法,其特征在于,包括:
其中:R1为甲基、乙基或者异丙基;
R2,R3同时为甲基、乙基或者R2和R3组合为-CH2CH2-/-CH2CH2CH2-/-CH2CH(CH3)CH2-/-CH2C(CH3)2CH2-。
4.根据权利要求1-3中任一项所述的制备方法,其特征在于:化合物III制备化合物IV的步骤中,还原剂1选自四氢铝锂、硼氢化钠、硼氢化钾、硼氢化锂或者红铝;化合物Ⅲ与还原剂1的摩尔比为1∶0.5~1∶3;反应温度的范围为-10~50℃。
5.根据权利要求1-3中任一项所述的制备方法,其特征在于:化合物IV制备化合物V的步骤中,酸2选自盐酸,硫酸,三氟乙酸或者对甲苯磺酸;化合物IV与酸2的摩尔比范围为1∶1~1∶10;反应温度范围为0~100℃。
6.根据权利要求2-3中任一项所述的制备方法,其特征在于:化合物V制备化合物VI的步骤中,化合物V和甲基溴化镁/甲基氯化镁的摩尔比范围为1∶2~1∶6;反应温度范围为-80~50℃。
7.根据权利要求3所述的制备方法,其特征在于:化合物VI制备化合物VII的步骤中,所述的碱1选自叔丁醇钾、氢氧化钠、氢氧化钾、正丁基锂、二异丙基氨基锂或者氢化钠;所述的磺酰氯/磺酸酐为:对甲苯磺酰氯、甲基磺酰氯、对硝基苯磺酰氯、甲磺酸酐或者三氟甲磺酸酐;反应温度范围为-20~60℃。
8.根据权利要求3所述的制备方法,其特征在于:化合物VII制备化合物VIII的步骤中,所述的催化剂1选自钯碳、氢氧化钯碳,铑碳或者铂碳;还原剂2选为氢气;反应温度范围为0~60℃。
9.根据权利要求3所述的制备方法,其特征在于:化合物VIII制备化合物I的步骤中,氧化试剂选自草酰氯+二甲基亚砜、三氟乙酸+二甲基亚砜、戴斯-马丁试剂、2-碘酰基苯甲酸、三氯异氰尿酸+2,2,6,6-四甲基-哌啶氮氧化物;反应温度范围为-80~40℃。
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