CN116082386A - 一种含酯基脂质的合成方法 - Google Patents
一种含酯基脂质的合成方法 Download PDFInfo
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- CN116082386A CN116082386A CN202211593316.7A CN202211593316A CN116082386A CN 116082386 A CN116082386 A CN 116082386A CN 202211593316 A CN202211593316 A CN 202211593316A CN 116082386 A CN116082386 A CN 116082386A
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- cycloalkyl
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- lipid
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- 150000002632 lipids Chemical class 0.000 title claims abstract description 57
- 125000004185 ester group Chemical group 0.000 title claims abstract description 46
- 238000001308 synthesis method Methods 0.000 title abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 21
- CRUSUKQDRLFRHO-UHFFFAOYSA-N chloromethanesulfonyl fluoride Chemical compound FS(=O)(=O)CCl CRUSUKQDRLFRHO-UHFFFAOYSA-N 0.000 claims abstract description 17
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 15
- 239000003054 catalyst Substances 0.000 claims abstract description 15
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 8
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 7
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 6
- 238000002156 mixing Methods 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 29
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 20
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 16
- 239000002202 Polyethylene glycol Substances 0.000 claims description 14
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
- 229920001223 polyethylene glycol Polymers 0.000 claims description 14
- 238000004821 distillation Methods 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 10
- 125000000304 alkynyl group Chemical group 0.000 claims description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 4
- 239000004215 Carbon black (E152) Substances 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 229930195733 hydrocarbon Natural products 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 238000010189 synthetic method Methods 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 2
- 239000000920 calcium hydroxide Substances 0.000 claims description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 2
- 235000011116 calcium hydroxide Nutrition 0.000 claims description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 2
- 235000011056 potassium acetate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000002585 base Substances 0.000 abstract description 7
- 239000003513 alkali Substances 0.000 abstract description 3
- 230000007062 hydrolysis Effects 0.000 abstract description 2
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 2
- 239000002502 liposome Substances 0.000 abstract description 2
- 230000007704 transition Effects 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 39
- 239000012265 solid product Substances 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 238000012512 characterization method Methods 0.000 description 7
- 238000005886 esterification reaction Methods 0.000 description 7
- 238000001228 spectrum Methods 0.000 description 7
- 230000032050 esterification Effects 0.000 description 6
- 150000001298 alcohols Chemical class 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 235000021355 Stearic acid Nutrition 0.000 description 3
- 150000001735 carboxylic acids Chemical class 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000008117 stearic acid Substances 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 2
- XGCDHPDIERKJPT-UHFFFAOYSA-N [F].[S] Chemical group [F].[S] XGCDHPDIERKJPT-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- SVOSGILHJQWIHT-UHFFFAOYSA-N bromomethanesulfonyl fluoride Chemical compound BrCS(=O)(=O)F SVOSGILHJQWIHT-UHFFFAOYSA-N 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 150000001733 carboxylic acid esters Chemical class 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- JMOLZNNXZPAGBH-UHFFFAOYSA-N hexyldecanoic acid Chemical compound CCCCCCCCC(C(O)=O)CCCCCC JMOLZNNXZPAGBH-UHFFFAOYSA-N 0.000 description 2
- 229950004531 hexyldecanoic acid Drugs 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 150000003014 phosphoric acid esters Chemical class 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- TUNFSRHWOTWDNC-UHFFFAOYSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 239000005935 Sulfuryl fluoride Substances 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
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- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 description 1
- 230000009471 action Effects 0.000 description 1
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- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
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- 239000007822 coupling agent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
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- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
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- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol Substances OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 150000002327 glycerophospholipids Chemical class 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- ACCCMOQWYVYDOT-UHFFFAOYSA-N hexane-1,1-diol Chemical compound CCCCCC(O)O ACCCMOQWYVYDOT-UHFFFAOYSA-N 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 108700021021 mRNA Vaccine Proteins 0.000 description 1
- 229940126582 mRNA vaccine Drugs 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- QVXGAQDVHLRLJW-UHFFFAOYSA-N methoxymethane;propane-1,2,3-triol Chemical compound COC.OCC(O)CO QVXGAQDVHLRLJW-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000006709 oxidative esterification reaction Methods 0.000 description 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 238000001338 self-assembly Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- OBTWBSRJZRCYQV-UHFFFAOYSA-N sulfuryl difluoride Chemical compound FS(F)(=O)=O OBTWBSRJZRCYQV-UHFFFAOYSA-N 0.000 description 1
- -1 t-butyldimethylsilyl group Chemical group 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010490 three component reaction Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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Classifications
-
- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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Abstract
本发明属于有机合成技术领域,公开了一种含酯基脂质的合成方法。该合成方法包括以下步骤:将羧酸、醇、碱催化剂、氯甲基磺酰氟混合,反应,制得含酯基脂质。本发明的合成方法将羧酸、醇、碱催化剂、氯甲基磺酰氟混合,反应,制得所述含酯基脂质,条件温和,低于绝大多数脂质体的相变温度与水解温度,并且产物产率显著提高,例如不低于82%,更适用于脂质的合成。
Description
技术领域
本发明属于有机合成技术领域,特别涉及一种含酯基脂质的合成方法。
背景技术
脂质纳米颗粒(Lipid nano particles,简称LNPs)递送系统是常见的mRNA疫苗或药物递送系统。LNPs一般由可离子化或阳离子脂质、膦脂、胆固醇和聚乙二醇化的脂质组成。结构上均为具有自组装性能的两亲性分子,LNPs各成分结构确定,重现性好,利于质量监管。同时因其具有较长的体内循环时间、良好的生物相容性等优点而受到广泛关注。
由于天然脂质通常为混合物,品质不稳定且安全性难以保证,目前的LNPs递送系统均使用合成脂质构建。但合成脂质的步骤复杂、提纯困难,往往难以大规模生产。
酯基是构建合成脂质最重要的一种母核。目前羧酸酯的构建方法非常广泛,例如,钯催化的芳基卤化物、一氧化碳和醇的三组分反应提供了一种在高温和高一氧化碳压力下直接酯化的方法(参见文献:Angew.Chem.Int.Ed.2009,48,4114;Org.Lett.2012,14,284;Angew.Chem.Int.Ed.2012,124,12710)。醛与醇的氧化酯化也是一种使用化学计量比氧化剂的替代方法,但其中相应的醛需要通过醇的选择性氧化来合成(参见文献:Nat.Chem.2010,2,61;Org.Lett.2003,5,1031;Chem.Eur.J.2010,16,8012;Science 2006,311,362)。在过渡金属催化剂的存在下,醇直接转化为酯被认为是一种更方便和直接的方法,但通常需要昂贵的金属催化剂,如金、钌、铑、铱和钯(参见文献:Angew.Chem.Int.Ed.2009,48,4206;Green Chem.2009,11,1366;J.Am.Chem.Soc.2005,127,10840;Chem.Commun.2008,624;J.Am.Chem.Soc.2009,131,3146;Angew.Chem.Int.Ed.2009,48,559;Tetrahedron Lett.2006,47,9199;J.Org.Chem.2011,76,2937)。因此,尽管各种各样的酯化反应日益发展成熟,但活性酸衍生物与醇的反应仍然是羧酸酯类衍生物的合成中最主要的反应。然而,传统的直接脱水缩合往往受平衡限制,反应不能进行完全,需要高温蒸去产生的酯,因此难以用于合成高沸点的脂质。为了克服这些缺点,现有技术中记载了许多经典的偶联剂,如碳酰二亚胺、膦、脲、铵盐等,以在温和的条件下原位活化羧酸,然而,现有的这些方法大多数都存在成本高、原子经济性差和纯化过程繁琐等问题(参见文献:J.Am.Chem.Soc.1955,77,1067–1068;J.Am.Chem.Soc.1969,91,5669–5671;J.Org.Chem.2001,66,5245–5247)。因此,仍然迫切需要开发更经济、更简便的方法来构建含酯基的脂质。
现有技术记载了硫酰氟介导的羧酸与醇脱水偶联制备酯的简便方法,然而该方法成本较高,且所用试剂为气体,应用于合成脂质产率不稳定。
因此,亟需提供一种新的含酯基脂质的合成方法,该合成方法不仅可在低温下进行,而且经济高效,产物产率高。
发明内容
本发明旨在至少解决上述现有技术中存在的技术问题之一。为此,本发明提出一种含酯基脂质的合成方法。所述合成方法的反应条件温和、经济高效、产物易纯化、产率高。所述合成方法用于解决目前合成方法的缺点与不足,高效经济地合成多种含酯基脂质。
本发明的发明构思为:本发明制得的产物是一类含酯基脂质,是通过简单的硫氟交换活化羧基,在辅助碱的作用下,脱去一分子磺酸进行酯化得到的。本发明基于硫氟交换点击化学创新性地开发了一种羧酸/醇直接酯化方法,该方法反应条件温和、操作简单、安全环保、经济高效、易于纯化,产率高(产率不低于82%),可以应用于一系列含酯基脂质的合成,满足实验室大量制备和工业生产放大的条件。
本发明提供一种含酯基脂质的合成方法。
具体的,一种含酯基脂质的合成方法,包括以下步骤:
将羧酸、醇、碱催化剂、氯甲基磺酰氟混合,反应,制得所述含酯基脂质。
即上述合成方法以羧酸、醇为原料,在碱催化剂存在的条件下,以氯甲基磺酰氟原位活化羧酸反应生成含酯基脂质。
进一步优选的,所述聚乙二醇、聚乙二醇单甲醚的重均分子量为200-50000。
进一步优选的,所述取代的C1-C25烷基、C2-C25烯基、C2-C25炔基、C3-C25环烷基的取代基为C1-C10烃基、C1-C10环烷基、甲氧基或氟中的至少一种。
进一步优选的,所述取代的聚乙二醇、聚乙二醇单甲醚的取代基为保护或未保护的羧基、巯基、羟基、氨基、C1-C6烷基。所述保护为预先连接上保护基团。
优选的,所述C1-C25烷基、C2-C25烯基、C2-C25炔基、C3-C25环烷基中包含或不包含其他官能团,其他官能团包括醚键、酯基、羰基、羟基、羧基、磷酸酯中的至少一种。
进一步优选的,所述聚乙二醇、聚乙二醇单甲醚的重均分子量为200-50000。
进一步优选的,所述取代的C1-C25烷基、C2-C25烯基、C2-C25炔基、C3-C25环烷基的取代基为C1-C10烃基、C3-C10环烷基、甲氧基、氟、取代或未取代的磷酸酯。
进一步优选的,所述取代的聚乙二醇、聚乙二醇单甲醚的取代基为保护或未保护的羧基、巯基、羟基、氨基、C1-C6烷基。所述保护为预先连接上保护基团。保护基团为酰基类、醚类、苄基类、缩醛类、缩酮类、硅醚类、氧羰基类、三苯甲基、磺酸类基团,或与上述保护基团作用相同,用于提高反应选择性并且能够通过化学手段脱去且不对分子其它结构造成影响的基团。
进一步优选的,所述C1-C25烷基、C2-C25烯基、C2-C25炔基、C3-C25环烷基中包含或不包含其他官能团,官能团包括醚键、酯基、羰基、羟基、羧基、磷酸酯。
优选的,所述碱催化剂选自碳酸氢钾、碳酸钠、碳酸钾、氢氧化钠、氢氧化钾、氢氧化钙、醋酸钾、N,N-二异丙基乙胺、三乙胺、碳酸氢钠、DBU、磷酸钾、碳酸铯中的至少一种;优选碳酸钠。
中的至少一种,其中,TBS表示叔丁基二甲基硅基。
上述合成方法的合成路径如下所示:
优选的,所述反应的温度为0-80℃;进一步优选的,所述反应的温度为10-25℃。
优选的,所述反应的时间为1-48小时,优选5-16小时。根据反应的原料种类不同,反应时间有所不同。
优选的,所述羧酸、醇、氯甲基磺酰氟、碱催化剂的摩尔比为1:(0.1-35):(0.1-11):(0.05-12);进一步优选的,所述羧酸、醇、氯甲基磺酰氟、碱催化剂的摩尔比为1:(0.2-30):(0.2-10):(0.1-10);更优选的,所述所述羧酸、醇、氯甲基磺酰氟、碱催化剂的摩尔比为1:(1-2):1:1.2。若酯化基团大于等于2个,则对应的醇/酸的摩尔比相应增加。
优选的,所述反应是在溶剂条件下进行,即将各原料加入到溶剂中进行反应。
优选的,所述溶剂选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1,4-二氧六环、苯、甲苯、乙腈、丙酮、乙酸乙酯、氯苯、四氢呋喃、四氢吡咯、二氯甲烷、二氯乙烷、硝基甲烷、N-甲基吡咯烷酮、氯仿、中的至少一种;优选二氯乙烷。
优选的,所述反应结束后,过滤,取滤液,蒸馏回收溶剂,取蒸馏所剩固体,重结晶得到纯度高的产物(含酯基脂质)。
优选的,所述重结晶所用的溶剂为水、DMF、氯苯、二甲苯、甲苯、乙腈、乙醇、THF、氯仿、乙酸乙酯、冰醋酸、四氯化碳、苯、环己烷、丁酮、丙酮、石油醚、乙醚、DMSO、六甲基磷酰胺、N-甲基吡咯烷酮、1,4-二氧六环、乙二醇单甲醚中的至少一种;优选甲苯。
相对于现有技术,本发明的有益效果如下:
与传统的直接酯化方法相比,本发明所述合成方法将羧酸、醇、碱催化剂、氯甲基磺酰氟混合,反应,制得所述含酯基脂质,条件温和,低于绝大多数脂质体的相变温度与水解温度,并且产率显著提高,例如不低于82%,更适用于脂质的合成。与传统的偶联试剂催化酯化方法相比,本发明所述合成方法更加经济高效、易于纯化,产率高,所用氯甲基磺酰氟催化剂可使用二氯甲烷轻松合成,并且反应液通过简单的过滤、重结晶即可得到高纯度产物,所用溶剂均可回收套用,所用重结晶母液均可循环利用。而与传统的酰氯法、酸酐法酯化方法相比,本发明所述合成方法操作简单、安全环保、经济高效、易于纯化,无须经过单独的羧酸预活化步骤即可一步得到产物,并且避免生成脂质不耐受的氯化氢气体,更适用于脂质的合成。
具体实施方式
为了让本领域技术人员更加清楚明白本发明所述技术方案,现列举以下实施例进行说明。需要指出的是,以下实施例对本发明要求的保护范围不构成限制作用。
以下实施例中所用的原料、试剂或装置如无特殊说明,均可从常规商业途径得到,或者可以通过现有已知方法得到。
实施例1
上述含酯基脂质的合成方法,包括以下步骤:
在25℃下,向500mL圆底烧瓶中依次加入碳酸钠(120.0mmol)、二氯甲烷(200mL)、十八酸(200.0mmol)、(TBS表示叔丁基二甲基硅基,100.0mmol)和氯甲基磺酰氟(100mmol),随后反应8h,反应结束后减压抽滤,使用二氯甲烷润洗滤饼两次,收集滤液并使用减压蒸馏回收二氯甲烷,取蒸馏所剩固体(即蒸馏残余物),加入甲苯结晶得到固体产物,收集固体产物并在真空中干燥至恒重得产物66.51g,产物的纯度为99.8%(质量分数),产物的产率为90%,产物为白色固体。
本实施例制得的产物含酯基脂质的核磁共振氢谱表征结果为:1HNMR(500MHz,CDCl3)δ(ppm)5.01(d,J=2.0Hz,1H),4.28(dd,J1=4.5Hz,J2=12.0Hz,1H),4.10(dd,J1=4.0Hz,J2=12.0Hz,1H),3.66-3.65(m,2H),2.26-2.62(m,4H),1.58-1.53(m,4H),1.24-1.20(m,56H),0.84-0.80(m,15H),0.01-0.00(m,6H)。
实施例2
上述含酯基脂质的合成方法,包括以下步骤:
在25℃下,向250mL圆底烧瓶中依次加入碳酸钠(12.0mmol)、二氯乙烷(50mL)、N,N-二甲基-4-氨基丁酸(10.0mmol)、上述反应方程式所示的醇(10.0mmol)和氯甲基磺酰氟(10.0mmol),随后反应5h,反应结束后减压抽滤,使用二氯乙烷润洗滤饼两次,收集滤液并使用减压蒸馏回收二氯乙烷,取蒸馏所剩固体,加入丙酮结晶得到固体产物,收集固体产物并在真空中干燥至恒重得产物6.16g,产物的纯度为97%(质量分数),产物的产率为91%。
本实施例制得的产物含酯基脂质的核磁共振氢谱表征结果为:1HNMR(500MHz,CDCl3)δ(ppm)5.46-5.23(m,8H),4.93-4.77(m,1H),2.83-2.66(m,4H),2.37-2.22(m,4H),2.20(s,6H),2.10-1.96(m,9H),1.85-1.69(m,2H),1.49(d,J=5.4,4H),1.39-1.15(m,39H),0.95-0.75(m,6H)。
实施例3
含酯基脂质的制备,涉及的反应方程式(方程式中只记录目标产物)如下所示:
上述含酯基脂质的合成方法,包括以下步骤:
在25℃下,向250mL圆底烧瓶中依次加入碳酸钠(12.0mmol)、二氯乙烷(50mL)、十八酸(20.0mmol)、磷酸甘油酯(10.0mmol)和氯甲基磺酰氟(10.0mmol),随后反应12h,反应结束后减压抽滤,使用二氯乙烷润洗滤饼两次,收集滤液并使用减压蒸馏回收二氯乙烷,取蒸馏所剩固体,加入丙酮结晶得到固体产物,收集固体产物并在真空中干燥至恒重得产物6.31g,产物的纯度为99.5%(质量分数),产物的产率为90%。
本实施例制得的产物含酯基脂质的核磁共振氢谱表征结果为:1HNMR(500MHz,CDCl3)δ(ppm)7.3(s,2H),5.28-5.25(m,1H),4.29-4.24(m,4H),2.25(t,J=7.0Hz,4H),1.43-1.39(m,4H),1.30-1.24(m,56H),0.85(t,6H)。
实施例4
上述含酯基脂质的合成方法,包括以下步骤:
在0℃下,向500mL圆底烧瓶中依次加入碳酸钠(120.0mmol)、二氯乙烷(200mL)、2-己基癸酸(100.0mmol)、己二醇(200.0mmol)和氯甲基磺酰氟(100mmol),随后在10℃下反应16h,反应结束后水洗并用二氯甲烷萃取,合并有机层,旋干得产物28.43g,产物的纯度为99%(质量分数),产物的产率为82%,产物为淡黄色液体。
本实施例制得的产物含酯基脂质的核磁共振氢谱表征结果为:1HNMR(500MHz,CDCl3)δ(ppm)4.07(t,J=7.0Hz,2H),3.65(t,J=6.0Hz,2H),2.35-2.30(m,1H),1.72-1.57(m,10H),1.32-1.26(m,24H),0.86(t,J=7.0Hz,6H)。
实施例5
上述含酯基脂质的合成方法,包括以下步骤:
在25℃下,向250mL圆底烧瓶中依次加入碳酸钠(12.0mmol)、二氯乙烷(50mL)、十四酸(20.0mmol)、聚乙二醇单甲醚-甘油(重均分子量为2000,10.0mmol)和氯甲基磺酰氟(10.0mmol),随后反应16h,反应结束后减压抽滤,使用二氯乙烷润洗滤饼两次,收集滤液并使用减压蒸馏回收二氯乙烷,取蒸馏所剩固体,加入甲苯结晶得到固体产物,收集固体产物并在真空中干燥至恒重得产物23.53g,产物的纯度为95%(质量分数),产物的产率为88%。
本实施例制得的产物含酯基脂质的核磁共振氢谱表征结果为:1HNMR(500MHz,CDCl3)δ(ppm)4.21(t,J=5.0Hz,1H),3.78-3.47(m,87H),2.29(t,J=7.5Hz,4H),1.63-1.57(m,4H),1.40-1.22(m,40H),0.86(t,J=7Hz,6H)。
实施例6
上述含酯基脂质的合成方法,包括以下步骤:
在25℃下,向250mL圆底烧瓶中依次加入碳酸钠(26.0mmol)、二氯乙烷(75mL)、2-己基癸酸(20.0mmol)、上述反应方程式所示的醇(10.0mmol)和氯甲基磺酰氟(20.0mmol),随后反应12h,反应结束后减压抽滤,使用二氯乙烷润洗滤饼两次,收集滤液并使用减压蒸馏回收二氯乙烷,取蒸馏所剩固体,加入甲苯结晶得到固体产物,收集固体产物并在真空中干燥至恒重得产物7.57g,产物的纯度为99%(质量分数),产物的产率为85%。
本实施例制得的产物含酯基脂质脱TBS基团后的核磁共振氢谱表征结果为:1HNMR(500MHz,CDCl3)δ(ppm)4.07(t,J=6.5Hz,4H),3.68(t,J=5.5Hz,2H),2.90(t,J=7.5Hz,2H),2.85-2.82(m,4H),2.35-2.29(m,2H),1.89-1.83(m,2H),1.72-1.57(m,14H),1.47-1.37(m,12H),1.32-1.26(m,48H),0.86(t,J=7Hz,12H)。
对比例1
在25℃下,向100mL圆底烧瓶中依次加入碳酸钠(12.0mmol)、二氯甲烷(30mL),十八酸(20.0mmol)、TBS-甘油(10.0mmol)和溴甲基磺酰氟(10mmol),随后反应8h,反应结束后减压抽滤,使用二氯甲烷润洗滤饼两次,收集滤液并使用减压蒸馏回收二氯甲烷,取蒸馏所剩固体,加入甲苯结晶得到固体产物,收集固体产物并在真空中干燥至恒重得产物2.01g,产物的纯度为98%(质量分数),产物的产率为25%,产物为白色固体。
本实施例制得的产物含酯基脂质的核磁共振氢谱表征结果为:1HNMR(500MHz,CDCl3)δ(ppm)5.01(d,J=2.0Hz,1H),4.28(dd,J1=4.5Hz,J2=12.0Hz,1H),4.10(dd,J1=4.0Hz,J2=12.0Hz,1H),3.66-3.65(m,2H),2.26-2.62(m,4H),1.58-1.53(m,4H),1.24-1.20(m,56H),0.84-0.80(m,15H),0.01-0.00(m,6H)。
从上述实施例结果可以看出,在本发明的合成条件下制得的含酯基脂质的产率显著高于对比例条件下的含酯基脂质产率。
Claims (10)
1.一种含酯基脂质的合成方法,其特征在于,包括以下步骤:
将羧酸、醇、碱催化剂、氯甲基磺酰氟混合,反应,制得所述含酯基脂质。
3.根据权利要求2所述的合成方法,其特征在于,所述取代的C1-C25烷基、C2-C25烯基、C2-C25炔基、C3-C25环烷基的取代基为C1-C10烃基、C1-C10环烷基、甲氧基或氟中的至少一种。
5.根据权利要求4所述的合成方法,其特征在于,所述取代的C1-C25烷基、C2-C25烯基、C2-C25炔基、C3-C25环烷基的取代基为C1-C10烃基、C3-C10环烷基、甲氧基、氟、取代或未取代的磷酸酯。
6.根据权利要求1所述的合成方法,其特征在于,所述碱催化剂选自碳酸氢钾、碳酸钠、碳酸钾、氢氧化钠、氢氧化钾、氢氧化钙、醋酸钾、N,N-二异丙基乙胺、三乙胺、碳酸氢钠、DBU、磷酸钾、碳酸铯中的至少一种。
7.根据权利要求1-6任一项所述的合成方法,其特征在于,所述反应的温度为0-80℃。
8.根据权利要求7所述的合成方法,其特征在于,所述羧酸、醇、氯甲基磺酰氟、碱催化剂的摩尔比为1:(0.1-35):(0.1-11):(0.05-12)。
9.根据权利要求7所述的合成方法,其特征在于,所述反应是在溶剂条件下进行,所述溶剂选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1,4-二氧六环、苯、甲苯、乙腈、丙酮、乙酸乙酯、氯苯、四氢呋喃、四氢吡咯、二氯甲烷、二氯乙烷、硝基甲烷、N-甲基吡咯烷酮、氯仿、中的至少一种。
10.根据权利要求7所述的合成方法,其特征在于,所述反应结束后,过滤,取滤液,蒸馏回收溶剂,取蒸馏所剩固体,重结晶得到所述含酯基脂质。
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