CN103764639A - 用于制备脂肪酸衍生物的方法 - Google Patents
用于制备脂肪酸衍生物的方法 Download PDFInfo
- Publication number
- CN103764639A CN103764639A CN201280042257.2A CN201280042257A CN103764639A CN 103764639 A CN103764639 A CN 103764639A CN 201280042257 A CN201280042257 A CN 201280042257A CN 103764639 A CN103764639 A CN 103764639A
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- Prior art keywords
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- hydroxyl
- rudimentary
- methyl
- azaadamantane
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 29
- 235000014113 dietary fatty acids Nutrition 0.000 title claims abstract description 14
- 239000000194 fatty acid Substances 0.000 title claims abstract description 14
- 229930195729 fatty acid Natural products 0.000 title claims abstract description 14
- 150000004665 fatty acids Chemical class 0.000 title claims abstract description 14
- 239000007800 oxidant agent Substances 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- BCJCJALHNXSXKE-UHFFFAOYSA-N azado Chemical group C1C(C2)CC3CC1N([O])C2C3 BCJCJALHNXSXKE-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 claims abstract description 9
- -1 benzyl ester Chemical class 0.000 claims description 63
- 239000001301 oxygen Substances 0.000 claims description 26
- 229910052760 oxygen Inorganic materials 0.000 claims description 26
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 16
- 125000000623 heterocyclic group Chemical group 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 230000000903 blocking effect Effects 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 7
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 7
- 229920006395 saturated elastomer Polymers 0.000 claims description 6
- 125000004104 aryloxy group Chemical group 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000004043 oxo group Chemical group O=* 0.000 claims description 4
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 4
- 229910052701 rubidium Inorganic materials 0.000 claims description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 3
- SFXINVPZIZMFHM-UHFFFAOYSA-N azadol(r) Chemical compound C1C(C2)CC3CC1N(O)C2C3 SFXINVPZIZMFHM-UHFFFAOYSA-N 0.000 claims description 3
- ORWXHNXGXZJPKA-UHFFFAOYSA-N C1C(C2)CC3CC2N(O)C1(C)C3 Chemical compound C1C(C2)CC3CC2N(O)C1(C)C3 ORWXHNXGXZJPKA-UHFFFAOYSA-N 0.000 claims description 2
- 239000006227 byproduct Substances 0.000 abstract description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 239000002585 base Substances 0.000 description 27
- 239000000243 solution Substances 0.000 description 23
- 239000000203 mixture Substances 0.000 description 22
- 235000002639 sodium chloride Nutrition 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- 150000003839 salts Chemical class 0.000 description 13
- 229910052799 carbon Inorganic materials 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 239000012230 colorless oil Substances 0.000 description 9
- 230000003647 oxidation Effects 0.000 description 9
- 238000007254 oxidation reaction Methods 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 229960003328 benzoyl peroxide Drugs 0.000 description 8
- FAHUKNBUIVOJJR-UHFFFAOYSA-N 1-(4-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine Chemical compound C1=CC(F)=CC=C1C1C2=CC=CN2CCN1 FAHUKNBUIVOJJR-UHFFFAOYSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000006859 Swern oxidation reaction Methods 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000005708 Sodium hypochlorite Substances 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 235000010724 Wisteria floribunda Nutrition 0.000 description 4
- 230000003213 activating effect Effects 0.000 description 4
- 125000005907 alkyl ester group Chemical group 0.000 description 4
- 230000006837 decompression Effects 0.000 description 4
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 239000003125 aqueous solvent Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- JQCSUVJDBHJKNG-UHFFFAOYSA-N 1-methoxy-ethyl Chemical group C[CH]OC JQCSUVJDBHJKNG-UHFFFAOYSA-N 0.000 description 2
- SZNYYWIUQFZLLT-UHFFFAOYSA-N 2-methyl-1-(2-methylpropoxy)propane Chemical compound CC(C)COCC(C)C SZNYYWIUQFZLLT-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 150000005215 alkyl ethers Chemical class 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical group 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
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 229910001385 heavy metal Inorganic materials 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 2
- 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 2
- 150000003180 prostaglandins Chemical class 0.000 description 2
- WGJJROVFWIXTPA-OALUTQOASA-N prostanoic acid Chemical compound CCCCCCCC[C@H]1CCC[C@@H]1CCCCCCC(O)=O WGJJROVFWIXTPA-OALUTQOASA-N 0.000 description 2
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- RWSOTUBLDIXVET-UHFFFAOYSA-O sulfonium Chemical compound [SH3+] RWSOTUBLDIXVET-UHFFFAOYSA-O 0.000 description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
- FFJCNSLCJOQHKM-CLFAGFIQSA-N (z)-1-[(z)-octadec-9-enoxy]octadec-9-ene Chemical compound CCCCCCCC\C=C/CCCCCCCCOCCCCCCCC\C=C/CCCCCCCC FFJCNSLCJOQHKM-CLFAGFIQSA-N 0.000 description 1
- NKJOXAZJBOMXID-UHFFFAOYSA-N 1,1'-Oxybisoctane Chemical compound CCCCCCCCOCCCCCCCC NKJOXAZJBOMXID-UHFFFAOYSA-N 0.000 description 1
- QOOQLKSEGVNYLA-UHFFFAOYSA-N 1-$l^{1}-oxidanylbutane Chemical group CCCC[O] QOOQLKSEGVNYLA-UHFFFAOYSA-N 0.000 description 1
- HXKKHQJGJAFBHI-UHFFFAOYSA-N 1-aminopropan-2-ol Chemical class CC(O)CN HXKKHQJGJAFBHI-UHFFFAOYSA-N 0.000 description 1
- WENISBCJPGSITQ-UHFFFAOYSA-N 1-azatricyclo[3.3.1.13,7]decane Chemical class C1C(C2)CC3CC1CN2C3 WENISBCJPGSITQ-UHFFFAOYSA-N 0.000 description 1
- QSSXJPIWXQTSIX-UHFFFAOYSA-N 1-bromo-2-methylbenzene Chemical compound CC1=CC=CC=C1Br QSSXJPIWXQTSIX-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- CMCBDXRRFKYBDG-UHFFFAOYSA-N 1-dodecoxydodecane Chemical compound CCCCCCCCCCCCOCCCCCCCCCCCC CMCBDXRRFKYBDG-UHFFFAOYSA-N 0.000 description 1
- FDCJDKXCCYFOCV-UHFFFAOYSA-N 1-hexadecoxyhexadecane Chemical compound CCCCCCCCCCCCCCCCOCCCCCCCCCCCCCCCC FDCJDKXCCYFOCV-UHFFFAOYSA-N 0.000 description 1
- AOPDRZXCEAKHHW-UHFFFAOYSA-N 1-pentoxypentane Chemical compound CCCCCOCCCCC AOPDRZXCEAKHHW-UHFFFAOYSA-N 0.000 description 1
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 1
- PLNNBRYFKARCEV-UHFFFAOYSA-N 2-[(2-hydroxyphenyl)methoxymethyl]phenol Chemical compound OC1=CC=CC=C1COCC1=CC=CC=C1O PLNNBRYFKARCEV-UHFFFAOYSA-N 0.000 description 1
- ULQQGOGMQRGFFR-UHFFFAOYSA-N 2-chlorobenzenecarboperoxoic acid Chemical compound OOC(=O)C1=CC=CC=C1Cl ULQQGOGMQRGFFR-UHFFFAOYSA-N 0.000 description 1
- SGJUFIMCHSLMRJ-UHFFFAOYSA-N 2-hydroperoxypropane Chemical compound CC(C)OO SGJUFIMCHSLMRJ-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- QCHPKSFMDHPSNR-UHFFFAOYSA-N 3-aminoisobutyric acid Chemical compound NCC(C)C(O)=O QCHPKSFMDHPSNR-UHFFFAOYSA-N 0.000 description 1
- SAWMBRUFQYQNLJ-UHFFFAOYSA-N 3-ethyl-3-(3-ethyloctan-3-yloxy)octane Chemical compound CCCCCC(CC)(CC)OC(CC)(CC)CCCCC SAWMBRUFQYQNLJ-UHFFFAOYSA-N 0.000 description 1
- XHWSCQCJAPLELI-UHFFFAOYSA-N 4-(3,4-dimethoxyphenoxy)-1,2-dimethoxybenzene Chemical compound C1=C(OC)C(OC)=CC=C1OC1=CC=C(OC)C(OC)=C1 XHWSCQCJAPLELI-UHFFFAOYSA-N 0.000 description 1
- BMFMQGXDDJALKQ-BYPYZUCNSA-N Argininic acid Chemical class NC(N)=NCCC[C@H](O)C(O)=O BMFMQGXDDJALKQ-BYPYZUCNSA-N 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical group C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- 108010037003 Buserelin Proteins 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 241000370738 Chlorion Species 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical class NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical class NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 241000208202 Linaceae Species 0.000 description 1
- 235000004431 Linum usitatissimum Nutrition 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- ZRKWMRDKSOPRRS-UHFFFAOYSA-N N-Methyl-N-nitrosourea Chemical compound O=NN(C)C(N)=O ZRKWMRDKSOPRRS-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical class C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 1
- 206010057040 Temperature intolerance Diseases 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical class OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- QYKIQEUNHZKYBP-UHFFFAOYSA-N Vinyl ether Chemical compound C=COC=C QYKIQEUNHZKYBP-UHFFFAOYSA-N 0.000 description 1
- XXFXTBNFFMQVKJ-UHFFFAOYSA-N [diphenyl(trityloxy)methyl]benzene Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)OC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 XXFXTBNFFMQVKJ-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- DORMTBIPKNPJPY-UHFFFAOYSA-N acetic acid;iodobenzene Chemical compound CC(O)=O.IC1=CC=CC=C1 DORMTBIPKNPJPY-UHFFFAOYSA-N 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
- C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyrane Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
公开了一种用于制造式(I)表示的脂肪酸衍生物的方法。所述方法包括在氮杂金刚烷-N-烃氧基衍生物存在下,使式(II)的化合物与辅助氧化剂反应的步骤。根据所述方法,通过利用容易得到的廉价的辅助氧化剂,无需专门的设备,可合成期望的脂肪酸衍生物,并且抑制不期望的副产物的产生。
Description
发明背景
发明领域。
本发明涉及一种用于制造可用作药物或药物的合成中间体的脂肪酸衍生物的新方法。
脂肪酸衍生物为存在于人和其它哺乳动物的组织和器官中的有机羧酸并且具有多种多样的生物学活性。在自然界发现的一些脂肪酸衍生物包括具有如式(A)所示的前列腺烷酸骨架作为其通用结构的那些:
在制备脂肪酸衍生物(例如具有以上前列腺烷酸骨架的前列腺素衍生物)中,羟基的氧化是重要的反应步骤之一。已经知道许多氧化羟基的方法。
常规用于前列腺素合成的Swern氧化需要可在非常低的反应温度(-70至-40℃)下操作的专门的制造设备。此外,当脂肪酸衍生物在分子中具有羧基时,由于副反应,不期望的副产物可能为多数产物(参见,例如,US2006-0036108A,尤其是,对比实施例1,该文献通过引用结合到本文中)。为了避免该问题,需要在Swern氧化前保护羧基和在氧化后使保护基团脱保护,结果是,由于这些另外的步骤使得制造过程变得长久和冗余。
通过Swern氧化得到的酮的α位可被氯取代和/或甲硫基被由氯代二甲基氯化锍产生的氯离子和二甲基锍离子取代,所述氯代二甲基氯化锍为用于Swern氧化的活性氧化物类或反应试剂(二甲基亚砜和草酰氯)。
尤其是,当所得到的酮的α位具有高酸性或者酮结构倾向于转化为烯醇形式时,容易产生副产物,像α-氯代衍生物。
有时通过使用柱层析法非常难以从期望的产物除去副产物像氯代或甲硫基衍生物。当/如果通过结晶纯化不是非常有效时,必须重复结晶。此外,在得到终产物的接下来的过程步骤中,那些副产物偶尔抑制反应,尤其是催化氢化和水解。此外,Swern氧化共同产生强恶臭的二甲基硫醚,因此,需要设备(例如废气洗涤器、活性碳吸附塔等)用于防止恶臭。
使用重金属试剂(例如铬酸)的传统氧化方法可用于氧化具有羧基的化合物。然而,大多数重金属有毒并且有时不适合作为药物的工业生产方法。
Dess-Martin氧化也可用于氧化具有羧基的化合物,然而,报道了该氧化试剂的热敏感性和冲击敏感性(Chem. Eng. News,1990年7月16日,3,该文献通过引用结合到本文中)。此外,该氧化试剂不容易在市场上作为工业原料得到。因此,Dess-Martin氧化不适于工业制造。
TEMPO氧化也用于氧化羟基。该反应可在相对温和的条件下容易进行,因此,无需使用例如超低温反应器和废气洗涤器的设备。已知作为一种可生产具有高纯度和高生产效率的产物的方法(US 2006-0036108A,该文献通过引用结合到本文中)。然而,本领域已知TEMPO氧化的一些问题。例如,TEMPO的被氧化形式(即,TEMPO的活性形式)在结构上不稳定,因此,反应需要相对大量的催化剂。此外,当使用TEMPO氧化大体积基材时,可能几乎不能实现足够的反应性。为了促进反应,对每1摩尔当量的羟基,通常向反应中加入1.0-2.0摩尔当量的卤化物盐,例如溴化钠、溴化钾、四丁基溴化铵或四丁基氯化铵。然而,那些卤化物盐可导致产生副产物,例如溴化物类似物。
在以上讨论的情况下,期望可抑制产生副产物的用于氧化羟基的工业上适用的方法。
发明概述
本发明的一个目的是提供一种用于制造脂肪酸衍生物的新方法,所述方法在相对温和的条件下可容易进行。
本发明人已集中地研究并且发现在氮杂金刚烷-N-烃氧基衍生物存在下,使用辅助氧化剂,通过氧化合成的中间体,可有效生产脂肪酸衍生物。根据本发明的方法,通过利用容易得到的廉价的辅助氧化剂,无需专门的设备,可合成期望的脂肪酸衍生物,并且抑制不期望的副产物的产生。
因此,本发明提供了一种用于制造式(I)表示的脂肪酸衍生物的方法:
A为-CH3、-CH2OH、-COCH2OH、-COOH或它们的官能衍生物;
B为单键、-CH2-、-CH2-CH2-、-CH=CH-或-C≡C-、-CH2-CH2-CH2-、-CH=CH-CH2-、-CH2-CH=CH-、-C≡C-CH2-或-CH2-C≡C-;
Ra为二价饱和或不饱和的低级-中等脂族烃基,其未被取代或被卤素原子、低级烷基、低级烷氧基、氧代、芳基或杂环基团取代,条件是所述脂族烃基的一个或多个碳原子可任选被氧、氮或硫原子代替;和
Rb为氢原子;饱和或不饱和的低级-中等脂族烃基,其未被取代或被以下取代:卤素、氧代、羟基、低级烷氧基、低级烷酰基氧基、环(低级)烷基、环(低级)烷氧基、芳基、芳氧基、杂环或杂环氧基;环(低级)烷基;环(低级)烷氧基;芳基;芳氧基;杂环;或杂环氧基,
所述方法包括在氮杂金刚烷-N-烃氧基衍生物存在下,使式(II)的化合物与辅助氧化剂反应的步骤:
A、B、Ra和Rb与以上相同。
发明详述
在以上Ra和Rb的定义中,在Ra和Rb的定义中术语"不饱和的"旨在包括在主链和/或侧链的碳原子之间单独、分开或连续地存在的至少一个或多个双键和/或叁键。根据通常的命名法,在两个连续位置之间的不饱和键用两个位置的较低数字表示,而在两个远侧位置之间的不饱和键用两个位置表示。
术语"低级-中等脂族烃"是指具有1-14个碳原子的直链或支链的烃,其中侧链优选具有1-3个碳原子。优选的Ra具有1-10个,更优选6-10个碳原子,而优选的Rb具有1-10个,更优选1-8个碳原子。
术语"卤素"包括氟、氯、溴和碘原子。
除非另外说明,否则术语"低级"是指具有1-6个碳原子的基团。
术语"低级烷基"是指具有1-6个碳原子的直链或支链饱和烃基,例如,甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基和己基。
术语"低级烷氧基"是指低级烷基-O-,其中所述低级烷基如上所述。
术语"低级烷酰基氧基"是指式RCO-O-表示的基团,其中RCO-为通过氧化如上所述的低级烷基形成的酰基,例如,乙酰基。
术语"低级环烷基"是指通过含有3个或更多个如上所述的碳原子的低级烷基环化形成的基团,例如,环丙基、环丁基、环戊基和环己基。
术语"环(低级)烷氧基"是指式“环烷基-O-”表示的基团,其中环烷基如上所述。
术语"芳基"包括芳族烃环(优选单环基团),其可被取代,例如,苯基、甲苯基和二甲苯基。在这种情况下,取代基的实例包括卤素和卤素取代的低级烷基,其中卤素原子和低级烷基如上所述。
术语"芳氧基"是指式ArO-表示的基团,其中Ar为如上所述的芳基。
术语"杂环"包括单环至三环(优选单环)杂环基团,其为5-14元(优选5-10元)环,具有任选被取代的碳原子和1-4个(优选1-3个)1种或2种类型的选自氮、氧和硫原子的杂原子。杂环基团的实例包括呋喃基、噻吩基、吡咯基、噁唑基、异噁唑基、噻唑基、异噻唑基、咪唑基、吡唑基、呋咱基、吡喃基、吡啶基、哒嗪基、嘧啶基、吡嗪基、2-吡咯啉基、吡咯烷基、2-咪唑啉基、咪唑烷基、2-吡唑啉基、吡唑烷基、哌啶子基、哌嗪基、吗啉代、吲哚基、苯并噻吩基、喹啉基、异喹啉基、嘌呤基、喹唑啉基、咔唑基、吖啶基、菲啶基、苯并咪唑基、苯并咪唑酮基、苯并噻唑基、吩噻嗪基。在这种情况下,取代基的实例包括卤素和卤素取代的低级烷基,其中卤素原子和低级烷基如上所述。
术语"杂环-氧基"是指式HcO-表示的基团,其中Hc为如上所述的杂环基团。
术语A的"官能衍生物"包括盐,优选药学上可接受的盐、醚、酯和酰胺。
合适的"药学上可接受的盐"的实例包括常用的无毒盐,以及具有无机碱的盐,例如,碱金属盐(钠盐、钾盐等);碱土金属盐(钙盐、镁盐等);铵盐;具有有机碱的盐,例如,胺盐(例如甲基胺盐、二甲基胺盐、环己基胺盐、苄基胺盐、哌啶盐、乙二胺盐、乙醇胺盐、二乙醇胺盐、三乙醇胺盐、三(羟甲基氨基)乙烷盐、单甲基-单乙醇胺盐、赖氨酸盐、普鲁卡因盐和咖啡碱盐);碱性氨基酸盐(例如精氨酸盐和赖氨酸盐);四烷基铵盐等。这些盐可例如由相应的酸和碱根据常规的方式或盐交换来制造。
醚的实例包括烷基醚,例如,低级烷基醚,例如甲基醚、乙基醚、丙基醚、异丙基醚、丁基醚、异丁基醚、叔丁基醚、戊基醚和1-环丙基乙基醚;和中等或高级烷基醚,例如辛基醚、二乙基己基醚、月桂基醚和鲸蜡基醚;不饱和醚,例如油基醚和亚麻基醚;低级烯基醚,例如乙烯基醚、烯丙基醚;低级炔基醚,例如乙炔基醚和丙炔基醚;羟基(低级)烷基醚,例如羟基乙基醚和羟基异丙基醚;低级烷氧基(低级)烷基醚,例如甲氧基甲基醚和1-甲氧基乙基醚;任选被取代的芳基醚,例如苯基醚、甲苯磺酰基醚、叔丁基苯基醚、水杨基醚、3,4-二甲氧基苯基醚和苯甲酰氨基苯基醚;和芳基(低级)烷基醚,例如苄基醚、三苯甲基醚和二苯甲基醚。
酯的实例包括脂族酯,例如,低级烷基酯,例如甲基酯、乙基酯、丙基酯、异丙基酯、丁基酯、异丁基酯、叔丁基酯、戊基酯和1-环丙基乙基酯;低级烯基酯,例如乙烯基酯和烯丙基酯;低级炔基酯,例如乙炔基酯和丙炔基酯;羟基(低级)烷基酯,例如羟乙基酯;和低级烷氧基(低级)烷基酯,例如甲氧基甲基酯和1-甲氧基乙基酯,以及例如任选被取代的芳基酯,例如苯基酯、甲苯磺酰基酯、叔丁基苯基酯、水杨基酯、3,4-二甲氧基苯基酯和苯甲酰氨基苯基酯;和芳基(低级)烷基酯,例如苄基酯、三苯甲基酯和二苯甲基酯。
A的酰胺为式-CONR'R"表示的基团,其中R'和R"独立地表示氢原子、低级烷基、芳基、烷基磺酰基或芳基磺酰基、低级烯基或低级炔基。酰胺的实例包括单低级烷基酰胺或二低级烷基酰胺,例如甲基酰胺、乙基酰胺和二甲基酰胺;芳基酰胺,例如酰基苯胺和酰基甲苯胺;和烷基磺酰基酰胺或芳基磺酰基酰胺,例如甲基磺酰基酰胺、乙基磺酰基酰胺和甲苯基磺酰基酰胺。
A的优选实例包括-COOH及其药学上可接受的盐、酯和酰胺。
优选的B为-CH2-CH2-,其提供所谓的13,14-二氢类型衍生物的结构。
优选的Ra为具有1-10个碳原子,更优选6-10个碳原子的烃。烃基的一个或多个碳原子可任选被氧、氮或硫原子代替。
Ra的实例包括例如以下基团:
-CH2-CH2-CH2-CH2-CH2-CH2-,
-CH2-CH=CH-CH2-CH2-CH2-,
-CH2-CH2-CH2-CH2-CH=CH-,
-CH2-C≡C-CH2-CH2-CH2-,
-CH2-CH2-CH2-CH2-CH(CH3)-CH2-,
-CH2-CH2-CH2-CH2-O-CH2-,
-CH2-CH=CH-CH2-O-CH2-,
-CH2-C≡C-CH2-O-CH2-,
-CH2-CH2-CH2-CH2-CH2-CH2-CH2-,
-CH2-CH=CH-CH2-CH2-CH2-CH2-,
-CH2-CH2-CH2-CH2-CH2-CH=CH-,
-CH2-C≡C-CH2-CH2-CH2-CH2-,
-CH2-CH2-CH2-CH2-CH2-CH(CH3)-CH2-,
-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-,
-CH2-CH=CH-CH2-CH2-CH2-CH2-CH2-,
-CH2-CH2-CH2-CH2-CH2-CH2-CH=CH-,
-CH2-C≡C-CH2-CH2-CH2-CH2-CH2-,
-CH2-CH2-CH2-CH2-CH2-CH2-CH(CH3)-CH2-。
优选的Rb为氢原子或被卤素原子(例如氟)取代的含有1-10个碳原子(更优选1-8个碳原子)的烃。
在说明书和权利要求中,术语"羟基的保护基团"是指引入以保护羟基免于氧化的官能团。在本发明中,保护基团可为任何基团,只要其可这样起作用。保护基团的实例可包括甲基、甲氧基甲基、乙基、1-乙氧基乙基、苄基、取代的苄基、烯丙基、四吡喃基、叔丁基二甲基甲硅烷基、三乙基甲硅烷基、三异丙基甲硅烷基、二苯基甲基甲硅烷基、甲酰基、乙酰基、取代的乙酰基、苯甲酰基、取代的苯甲酰基、甲氧基羰基、苄氧基羰基、叔丁基氧基羰基(t-buthloxylcarbonyl)和烯丙氧基羰基。
可用于本发明的氮杂金刚烷-N-烃氧基衍生物的实例包括但不限于2-氮杂金刚烷-N-烃氧基(AZADO)和1-甲基-2-氮杂金刚烷-N-烃氧基(1-Me-AZADO)。氮杂金刚烷-N-烃氧基衍生物还包括这样的化学物质:通过在反应系统中使用辅助氧化剂,其产生与由2-氮杂金刚烷-N-烃氧基(AZADO)、1-甲基-2-氮杂金刚烷-N-烃氧基(1-Me-AZADO)等得到的活性氧化物类相同的化学物类。其实例包括但不限于2-羟基-2-氮杂金刚烷(AZADOL [Nissan Chemical Industries,Ltd.的注册商标])、2-羟基-1-甲基-2-氮杂金刚烷(1-Me-AZADOL)等。
对于每1摩尔待氧化的起始化合物或式(II)的化合物,用于反应的氮杂金刚烷-N-烃氧基衍生物的量可为约0.0005-1.0摩尔,优选约0.001-0.1摩尔。
用于本发明的辅助氧化剂为以下物质:(i) 可将氮杂金刚烷-N-烃氧基衍生物转化为其活性氧化物类;(ii) 可将当a氧化时产生的还原形式的氮杂金刚烷衍生物(例如,2-羟基-2-氮杂金刚烷)转化为活性氧化物类,如以下流程所示。辅助氧化剂的实例可包括次卤酸例如次氯酸或其盐、含卤酸例如亚溴酸或其盐、具有多价碘的化合物例如碘代苯乙酸盐、过氧化物例如3-氯-过苯甲酸、N-卤素取代的琥珀酰亚胺例如N-氯代琥珀酰亚胺。
催化循环和辅助氧化剂(例如,次氯酸钠)的作用
对于每1摩尔当量的待氧化的羟基,在反应中辅助氧化剂的量可为1.0-3摩尔当量,优选1.1-2摩尔当量,更优选1.1-1.5摩尔当量。
反应可在有机溶剂、水性溶剂、它们的混合物或由有机溶剂和水性溶剂组成的两相溶剂体系中进行。
用于本发明的有机溶剂的实例可为芳族烃溶剂例如甲苯、脂族烃溶剂例如己烷、含卤素的溶剂例如二氯甲烷、酮例如丙酮、酯例如乙酸乙酯。
水性溶剂可含有pH调节剂例如碳酸氢钠,pH缓冲剂例如磷酸二氢钾和磷酸二氢钠。
根据本发明,可向反应中加入卤化物盐(例如溴化钠、溴化钾、四丁基溴化铵和四丁基氯化铵)以促进反应。
不限制待加入的卤化物盐的量,并且对于每1摩尔当量的待氧化的羟基可为约0.05-0.5摩尔当量。与此相反,当使用TEMPO (四甲基哌啶-1-烃氧基)代替氮杂金刚烷-N-烃氧基衍生物时,对于每1摩尔当量的待氧化的羟基,需要1.0-2.0摩尔当量的TEMPO。
根据本发明,反应可在-10至50℃(优选约0至20℃)温度下进行。
借助以下实施例来更详细地说明本发明。这些实施例不应用作本发明的任何限制。
实施例1
将0.210g (0.37mmol)醇化合物(1)溶解于1.5ml甲苯中,向其中加入AZADO (2mg/ml在0.3ml,0.0037mmol甲苯中)。将混合物在冰浴中冷却至0℃。向其中加入2.19ml(0.74mmol)的3%碳酸氢钠水溶液和4.4mg (0.037mmol)溴化钾。随后,向反应中逐滴加入0.47ml (0.89mmol)的约1.9M次氯酸钠水溶液,将混合物搅拌2小时。反应混合物随后加入饱和硫代硫酸钠水溶液,混合物用乙酸乙酯萃取三次。萃取物用稀盐酸、饱和碳酸氢钠水溶液、随后盐水洗涤,经无水硫酸镁干燥,过滤,减压浓缩。残余物用硅胶快速层析法(柱:BW-300SP 60g,乙酸乙酯-己烷1:2)纯化,以得到无色油状化合物(2)。产量0.2006g (96.2%)。
1H-NMR (400MHz,在CDCl3中,TMS=0ppm) δ:0.92(3H,t,J=7.1Hz),1.20-2.38(27H,m),2.35(2H,t,J=7.5Hz),2.68-3.05(3H,m),3.47-3.55(1H,m),3.78-3.91(1.5H,m),4.15(0.5H,q,J=7.4Hz),4.58-4.59(0.5H,m),4.67-4.69(0.5H,m),5.11(2H,s),7.29-7.39(5H,m)。
实施例2
将0.210g (0.37mmol)醇化合物(1)溶解于1.5ml甲苯中,向其中加入1-Me-AZADO (2mg/ml在0.3ml,0.0037mmol甲苯中)。将混合物在冰浴中冷却至0℃。向其中加入2.19ml(0.74mmol)的3%碳酸氢钠水溶液和4.4mg (0.037mmol)溴化钾。随后,向反应中逐滴加入0.47ml (0.89mmol)的约1.9M次氯酸钠水溶液,将混合物搅拌20小时。采用与实施例1类似的方式处理和纯化反应混合物,以得到无色油状的化合物(2)。产量0.2036g (97.6%)。
1H-NMR (400MHz,在CDCl3中,TMS=0ppm) δ:0.92(3H,t,J=7.2Hz),1.20-2.38 (27H,m),2.35(2H,t,J=7.5Hz),2.68-3.05(3H,m),3.47-3.54(1H,m),3.78-3.91(1.5H,m),4.15(0.5H,q,J=7.4Hz),4.58-4.59(0.5H,m),4.67-4.69(0.5H,m),5.11(2H,s),7.30-7.39(5H,m)
实施例3
将0.200g (0.34mmol)醇化合物(3)溶解于1.4ml甲苯中,向其中加入AZADO (2mg/ml在0.25ml,0.0034mmol甲苯中)。将混合物在冰浴中冷却至0℃。向其中加入2.04ml(0.69mmol)的3%碳酸氢钠水溶液和4.1mg (0.034mmol)溴化钾。随后,向反应中逐滴加入0.43ml (0.82mmol)的约1.9M次氯酸钠水溶液,将混合物搅拌6小时。采用与实施例1类似的方式处理和纯化反应混合物,以得到无色油状的7-[(1R,2R,3R)-2-((6S)-4,4-二氟-6-甲基-3-氧代辛基)-5-氧代-3-(四氢-2H-吡喃-2-基氧基)环戊基]庚酸苄酯(4)。产量0.1919g (96.6%)。
1H-NMR (400MHz,在CDCl3中,TMS=0ppm) δ:0.88(3H,t,J=7.4Hz),0.97(3H,d,J=6.5Hz),1.20-2.38(26H,m),2.35(2H,t,J=7.5Hz),2.68-3.05(3H,m),3.47-3.54(1H,m),3.78-3.91(1.5H,m),4.15(0.5H,q,J=7.4Hz),4.58-4.59(0.5H,m),4.67-4.69(0.5H,m),5.11 (2H,s),7.30-7.39(5H,m)
实施例4
将0.200g (0.34mmol)醇化合物(3)溶解于1.4ml甲苯中,向其中加入1-Me-AZADO (2mg/ml在0.25ml,0.0034mmol甲苯中)。将混合物在冰浴中冷却至0℃。向其中加入2.04ml(0.69mmol)的3%碳酸氢钠水溶液和4.1mg (0.034mmol)溴化钾。随后,向反应中逐滴加入0.43ml (0.82mmol)的约1.9M次氯酸钠水溶液,将混合物搅拌15小时。采用与实施例1类似的方式处理和纯化反应混合物,以得到无色油状的7-[(1R,2R,3R)-2-((6S)-4,4-二氟-6-甲基-3-氧代辛基)-5-氧代-3-(四氢-2H-吡喃-2-基氧基)环戊基]庚酸苄酯(4)。产量0.1973g (99.3%)。
1H-NMR (400MHz,在CDCl3中,TMS=0ppm) δ:0.88(3H,t,J=7.4Hz),0.97(3H,d,J=6.1Hz),1.20-2.38(26H,m),2.35(2H,t,J=7.5Hz),2.68-3.05(3H,m),3.47-3.54(1H,m),3.78-3.91(1.5H,m),4.15(0.5H,q,J=7.4Hz),4.58-4.59(0.5H,m),4.67-4.69(0.5H,m),5.11(2H,s),7.29-7.39 (5H,m)
醇化合物(3)的合成
向((5S)-3,3-二氟-5-甲基-2-氧代庚基)膦酸二甲酯(A) (74.7g,274mmol)在叔丁基甲基醚(1120ml)中的溶液中加入一水合氢氧化锂(11.5g,273mmol),将混合物在室温下搅拌1小时。向其中加入7-[(1R,2R,3R,5S)-5-乙酰氧基-2-甲酰基-3-(2-四氢吡喃基-氧基)环戊基]庚酸甲酯(B) (64.02g,160.6mmol)在叔丁基甲基醚(278ml)和水(21.7ml)中的溶液,将混合溶液加热回流约31小时(内温:约53℃)。冷却至室温后,将水(351ml)加入到溶液中,搅拌混合物,静置,随后分离为两层。水层用乙酸乙酯(234ml)萃取两次。将有机层组合,用饱和氯化钠水溶液(351ml)洗涤两次,经无水硫酸镁(55g)干燥。减压浓缩后,残余物通过硅胶柱层析法(Fuji Silysia BW-300:2110g;乙酸乙酯:己烷=1:4至1:2)纯化。含有杂质的馏分通过硅胶柱层析法(Fuji Silysia BW-300:850g;乙酸乙酯:己烷=1:4至1:2)再次纯化,以得到浅黄色油状的7-[(1R,2R,3R,5S)-5-乙酰氧基-2-((E)-(6S)-4,4-二氟-6-甲基-3-氧代-1-辛烯基)-3-(2-四氢吡喃基氧基)环戊基]庚酸甲酯(C) (75.03g;137.8mmol;收率:85.8%)。
1H-NMR (200 MHz,CDCl3):δ (ppm):0.88 (3H,t,J =7.3Hz),0.97 (3H,t,J=6.4Hz),2.07 (3H,s),2.15-1.03 (23H,m),2.28 (2H,t,J=7.5Hz),2.87-2.36 (2H,m),3.50-3.31 (1H,m),3.66 (3H,s),3.88-3.60 (1H,m),4.19-3.93 (1H,m),4.61-4.46 (1H,m),5.19-5.09 (1H,m),6.63 (0.5H,d,J=15.6Hz),6.68 (0.5H,d,J=15.6Hz),7.05 (0.5H,dd,J=15.6,7.0Hz),7.10 (0.5H,dd,J=15.6,6.5Hz)。
向7-[(1R,2R,3R,5S)-5-乙酰氧基-2-((E)-(6S)-4,4-二氟-6-甲基-3-氧代-1-辛烯基)-3-(2-四氢吡喃基氧基)环戊基]庚酸甲酯(C) (76.78g,141.0mmol)在乙酸乙酯(357ml)中的溶液中加入5%-钯/碳(7.30g),将溶液在室温和环境压力下氢化。将反应混合物过滤,将滤液减压浓缩,以得到无色油状的7-[(1R,2R,3R,5S)-5-乙酰氧基-2-((6S)-4,4-二氟-6-甲基-3-氧代辛基)-3-(2-四氢吡喃基氧基)环戊基]庚酸甲酯(D) (72.69g;133.0mmol;收率:94.3%)。
将7-[(1R,2R,3R,5S)-5-乙酰氧基-2-((6S)-4,4-二氟-6-甲基-3-氧代辛基)-3-(2-四氢吡喃基氧基)环戊基]庚酸甲酯(D) (72.56g,132.7mmol)在甲醇(290ml)中的溶液冷却至约-20℃,向其中加入硼氢化钠(5.00g,132.2mmol)。搅拌约35分钟后,逐滴加入乙酸(7.5ml,131mmol),将反应混合物减压浓缩。对残余物补充水(326ml),用乙酸乙酯(226ml)萃取三次。将有机层组合,用3%氯化钠水溶液(323ml)和饱和氯化钠水溶液(323ml)洗涤,经无水硫酸镁干燥(40.6g)。将溶液减压浓缩,以得到无色油状的7-[(1R,2R,3R,5S)-5-乙酰氧基-2-((6S)-4,4-二氟-6-甲基-3-羟基辛基)-3-(2-四氢吡喃基氧基)环戊基]庚酸甲酯(E) (73.01g;定量收率)。
将7-[(1R,2R,3R,5S)-5-乙酰氧基-2-((6S)-4,4-二氟-6-甲基-3-羟基辛基)-3-(2-四氢吡喃基氧基)环戊基]庚酸甲酯(E) (132.5mmol)在乙醇(213ml)中的溶液在冰上冷却,向其中逐滴加入24%氢氧化钠水溶液(135ml,1029mmol)。于室温下搅拌约3.5小时后,将反应混合物减压浓缩。将残余物与水(281ml)和叔丁基甲基醚(141ml)混合,并在冰上冷却。在逐滴加入6M-盐酸以调节至pH 3-4后,溶液用乙酸乙酯(281ml)萃取三次。将有机层组合,顺次用水(281ml)洗涤两次和饱和氯化钠水溶液(338ml)洗涤。经无水硫酸镁(50g)干燥后,将溶液减压浓缩,以得到白色固体状的粗品7-[(1R,2R,3R,5S)-2-((6S)-4,4-二氟-6-甲基-3-羟基辛基)-5-羟基-3-(2-四氢吡喃基氧基)环戊基]庚酸(F)。不经纯化,将全部量用于接下来的步骤。
向乙腈(319ml)中的粗品7-[(1R,2R,3R,5S)-2-((6S)-4,4-二氟-6-甲基-3-羟基辛基)-5-羟基-3-(2-四氢吡喃基氧基)环戊基]庚酸(F)中加入二异丙基乙基胺(68.9ml,368mmol)和苄基溴(46.7ml,366mmol),将混合物在室温下搅拌约13.5小时。将反应混合物减压浓缩,向残余物中加入乙酸乙酯(369ml)和水(283ml),搅拌混合物,静置,随后分离为两层。水层用乙酸乙酯(226ml)萃取两次。将有机层组合,用1M-盐酸(339ml)、饱和碳酸氢钠水溶液(339ml)和饱和氯化钠水溶液(339ml)洗涤。经无水硫酸镁(50g)干燥后,将溶液减压浓缩。浓缩残余物通过硅胶柱层析法(Fuji Silysia BW-300:2400g;乙酸乙酯:己烷=1:2)纯化,以得到无色油状的7-[(1R,2R,3R,5S)-2-((6S)-4,4-二氟-3-羟基-6-甲基辛基)-5-羟基-3-(四氢-2H-吡喃-2-基氧基)环戊基]庚酸苄酯(3) (76.16g;130.7mmol;收率:98.7%)。
1H-NMR (200 MHz,CDCl3):δ (ppm):0.88(3H,t,J=7.5Hz),0.98(3H,d,J=6.2Hz),1.21-2.47(30.5H,m),2.35(2H,t,J=7.5Hz),2.81(0.5H,d,J=6.4Hz),3.46-4.14(5H,m),4.61-4.66(1H,m),5.11 (2H,s),7.30-7.39(5H,m)。
实施例5
将0.233g (0.49mmol)醇化合物(5)溶解于1.6ml甲苯中,向其中加入在甲苯中的AZADO(2mg/ml在0.35ml,0.0049mmol甲苯中)。将混合物在冰浴中冷却至0℃。向其中加入中性磷酸盐缓冲溶液(2.0ml)、5.8mg (0.049mmol)溴化钾。随后,向反应中逐滴加入0.62ml (1.17mmol)的约1.9M次氯酸钠水溶液,将混合物于0℃下搅拌1小时。采用与实施例1类似的方式处理和纯化反应混合物,以得到无色油状的化合物(6)。产量0.2009g (90.3%)。
1H-NMR (400MHz,在CDCl3中,TMS=0ppm) δ:0.93(3H,t,J=7.2Hz),1.22-2.38(28H,m),2.34(2H,t,J=7.6Hz),2.69-3.05(3H,m),3.48-3.56(1H,m),3.79-3.92(1.5H,m),4.15(0.5H,q,J=7.3Hz),4.59-4.60(0.5H,m),4.68-4.70(0.5H,m)。
实施例6
将0.200g (0.50mmol)醇化合物(7)溶解于1.4ml二氯甲烷中,向混合物中加入甲苯中的AZADO(2mg/ml在0.2ml,0.0049mmol甲苯中),和随后加入[双(乙酰氧基)碘代]苯(BAIB) 0.1769g (0.560mmol)。将混合物在室温下搅拌5小时。采用与实施例1类似的方式处理和纯化反应混合物,以得到无色油状的化合物(8)。产量0.1900g (95.5%)。
1H-NMR (400MHz,在CDCl3中,TMS=0ppm) δ:1.19-2.18(18H,m),2.07(3H,s),2.29(2H,t,J=7.5Hz),2.32-2.43(1H,m),2.81-3.01(1H,m),3.41-3.50(1H,m),3.66(3H,s),3.76-3.83(1H,m),4.36-4.46(1H,m),4.54-4.60(1H,m),5.11-5.17(1H,m),9.78(1H,dd,J=3.1,20.9Hz)
对比实施例1 (Swern氧化)
在干冰/甲醇浴中冷却在二氯甲烷(634ml)中的56.9ml (652mmol)草酰氯。向其中逐滴加入二甲基亚砜(DMSO) 92.5ml (1303 mmol),将混合物搅拌30分钟。向混合物中逐滴加入在二氯甲烷(198ml)中的7-[(1R,2R,3R,5S)-2-(4,4-二氟-3-羟基辛基)-5-羟基-3-(2-四氢吡喃基氧基)环戊基]庚酸苄酯(1) (74.21g,130.5mmol),将混合物搅拌1.5小时。随后,在搅拌下向反应混合物中逐滴加入三乙胺273ml(1959mmol),将反应混合物温热至0℃。随后向反应中加入饱和氯化铵水溶液(594ml)。将反应混合物搅拌,随后静置和分离。水相用二氯甲烷萃取两次。组合的有机相用0.1N盐酸(594ml)、水(594ml)、饱和碳酸氢钠水溶液(594ml)和随后用饱和氯化钠水溶液(594ml)连续洗涤。混合物经无水硫酸镁(48mg)干燥,减压浓缩。将残余物溶解于适量的乙酸乙酯/己烷(1:10)混合溶剂中,滤除不溶性物质。将滤液蒸发,用硅胶柱层析法(BW-300 Fuji Silysia Chemical Ltd,2260g,乙酸乙酯-己烷1:4)纯化,以得到7-[(1R,2R,3R)-2-(4,4-二氟-3-氧基辛基)-5-氧基-3-(2-四氢吡喃基氧基)环戊基]庚酸苄酯(2)。产量69.22g,122.6mmol,95.3%。
对比测试实施例
检验在实施例1和对比实施例1中得到的产物中的杂质。通过Swern氧化产生酮化合物(2)的14-甲硫基和14-氯代类似物。测定那些杂质的量。结果示于下表1:
ND:未检测
如以上结果所示,Swern氧化引入产生14-甲硫基和14-氯代化合物。那些杂质难以通过硅胶柱层析法除去,并且可降低终产物的纯度。与此相反,通过AZADO氧化不产生那些杂质。也就是,可得到具有高纯度的产物。
Claims (8)
1. 一种用于制造式(I)表示的脂肪酸衍生物的方法:
条件是X1、Y1和Z1中的至少一个为;
A为-CH3、-CH2OH、-COCH2OH、-COOH或它们的官能衍生物;
B为单键、-CH2-、-CH2-CH2-、-CH=CH-或-C≡C-、-CH2-CH2-CH2-、-CH=CH-CH2-、-CH2-CH=CH-、-C≡C-CH2-或-CH2-C≡C-;
Ra为二价饱和或不饱和的低级-中等脂族烃基,其未被取代或被卤素原子、低级烷基、低级烷氧基、氧代、芳基或杂环基团取代,条件是所述脂族烃基的一个或多个碳原子可任选被氧、氮或硫原子代替;和
Rb为氢原子;饱和或不饱和的低级-中等脂族烃基,其未被取代或被以下取代:卤素、氧代、羟基、低级烷氧基、低级烷酰基氧基、环(低级)烷基、环(低级)烷氧基、芳基、芳氧基、杂环或杂环氧基;环(低级)烷基;环(低级)烷氧基;芳基;芳氧基;杂环;或杂环氧基,
所述方法包括在氮杂金刚烷-N-烃氧基衍生物存在下,使式(II)的化合物与辅助氧化剂反应的步骤:
A、B、Ra和Rb与以上相同。
2. 权利要求1的方法,其中A为-COOH或它们的官能衍生物。
3. 权利要求1的方法,其中所述氮杂金刚烷-N-烃氧基衍生物为2-氮杂金刚烷-N-烃氧基。
4. 权利要求1的方法,其中所述氮杂金刚烷-N-烃氧基衍生物为1-甲基-2-氮杂金刚烷-N-烃氧基。
5. 权利要求1的方法,其中所述氮杂金刚烷-N-烃氧基衍生物为2-羟基-2-氮杂金刚烷。
6. 权利要求1的方法,其中所述氮杂金刚烷-N-烃氧基衍生物为2-羟基-1-甲基-2-氮杂金刚烷。
7. 7-[(1R,2R,3R,5S)-2-((6S)-4,4-二氟-3-羟基-6-甲基辛基)-5-羟基-3-(四氢-2H-吡喃-2-基氧基)环戊基]庚酸苄酯。
8. 7-[(1R,2R,3R)-2-((6S)-4,4-二氟-6-甲基-3-氧代辛基)-5-氧代-3-(四氢-2H-吡喃-2-基氧基)环戊基]庚酸苄酯。
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060036108A1 (en) * | 2004-08-02 | 2006-02-16 | R-Tech Ueno, Ltd. | Method for manufacturing prostaglandin analogue |
EP1775296A1 (en) * | 2004-06-25 | 2007-04-18 | Tohoku University | Alcohol oxidation catalyst and method of synthesizing the same |
US20070185206A1 (en) * | 2006-02-07 | 2007-08-09 | R-Tech Ueno, Ltd. | Method for preparing 15-keto-prostaglandin E derivative |
US20080221331A1 (en) * | 2007-03-06 | 2008-09-11 | Nissan Chemical Industries Ltd. | Alcohol oxidation catalyst and its preparation process |
US20090124806A1 (en) * | 2007-11-08 | 2009-05-14 | Nissan Chemical Industries, Ltd. | Process for producing carboxylic acid from primary alcohol |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2150287C (en) * | 1994-06-03 | 2004-08-10 | Ryuji Ueno | Agent for treating hepato-biliary diseases |
CN101379051B (zh) * | 2006-02-07 | 2014-05-28 | 株式会社·R-技术上野 | 用于制备前列腺素衍生物的方法 |
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1775296A1 (en) * | 2004-06-25 | 2007-04-18 | Tohoku University | Alcohol oxidation catalyst and method of synthesizing the same |
US20060036108A1 (en) * | 2004-08-02 | 2006-02-16 | R-Tech Ueno, Ltd. | Method for manufacturing prostaglandin analogue |
US20070185206A1 (en) * | 2006-02-07 | 2007-08-09 | R-Tech Ueno, Ltd. | Method for preparing 15-keto-prostaglandin E derivative |
US20080221331A1 (en) * | 2007-03-06 | 2008-09-11 | Nissan Chemical Industries Ltd. | Alcohol oxidation catalyst and its preparation process |
US20090124806A1 (en) * | 2007-11-08 | 2009-05-14 | Nissan Chemical Industries, Ltd. | Process for producing carboxylic acid from primary alcohol |
Non-Patent Citations (1)
Title |
---|
MASATOSHI SHIBUYA ET AL: "2-Azaadamantane N-Oxyl (AZADO) and 1-Me-AZADO: Highly Efficient Organocatalysts for Oxidation of Alcohols", 《J. AM. CHEM. SOC.》, vol. 128, no. 26, 14 June 2006 (2006-06-14), XP007915500, DOI: doi:10.1021/ja0620336 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114957005A (zh) * | 2022-07-11 | 2022-08-30 | 湖南工程学院 | 一种无金属催化芳族酮c(co)-c氧化断裂制备芳族酯类化合物的方法 |
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