CN117756635A - Ester compound and preparation method and application thereof, and preparation method of (E, E, Z) -2,4, 6-methyltrienoic acid methyl ester - Google Patents
Ester compound and preparation method and application thereof, and preparation method of (E, E, Z) -2,4, 6-methyltrienoic acid methyl ester Download PDFInfo
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- CN117756635A CN117756635A CN202311761414.1A CN202311761414A CN117756635A CN 117756635 A CN117756635 A CN 117756635A CN 202311761414 A CN202311761414 A CN 202311761414A CN 117756635 A CN117756635 A CN 117756635A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 49
- 239000002253 acid Substances 0.000 title claims abstract description 44
- 150000004702 methyl esters Chemical class 0.000 title claims abstract description 23
- -1 Ester compound Chemical class 0.000 title claims abstract description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 96
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims abstract description 60
- 238000002156 mixing Methods 0.000 claims abstract description 48
- 239000003960 organic solvent Substances 0.000 claims abstract description 48
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims abstract description 39
- 238000006722 reduction reaction Methods 0.000 claims abstract description 33
- 238000005886 esterification reaction Methods 0.000 claims abstract description 18
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000005703 Trimethylamine hydrochloride Substances 0.000 claims abstract description 14
- SZYJELPVAFJOGJ-UHFFFAOYSA-N trimethylamine hydrochloride Chemical compound Cl.CN(C)C SZYJELPVAFJOGJ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000011230 binding agent Substances 0.000 claims abstract description 13
- 235000009518 sodium iodide Nutrition 0.000 claims abstract description 13
- 239000011701 zinc Substances 0.000 claims abstract description 11
- 229910052725 zinc Inorganic materials 0.000 claims abstract description 11
- 239000000243 solution Substances 0.000 claims description 61
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 57
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 45
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 40
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 30
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims description 28
- 229940126214 compound 3 Drugs 0.000 claims description 27
- 229940125898 compound 5 Drugs 0.000 claims description 27
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 24
- 239000003054 catalyst Substances 0.000 claims description 22
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 21
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 21
- 239000003223 protective agent Substances 0.000 claims description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 18
- 238000010511 deprotection reaction Methods 0.000 claims description 17
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- 229940125782 compound 2 Drugs 0.000 claims description 16
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 16
- 125000003172 aldehyde group Chemical group 0.000 claims description 15
- 238000005859 coupling reaction Methods 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 230000002378 acidificating effect Effects 0.000 claims description 13
- 239000000126 substance Substances 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- 238000010992 reflux Methods 0.000 claims description 12
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 10
- 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 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- GUJOJGAPFQRJSV-UHFFFAOYSA-N dialuminum;dioxosilane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[O-2].[Al+3].[Al+3].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O GUJOJGAPFQRJSV-UHFFFAOYSA-N 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 6
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- 235000019253 formic acid Nutrition 0.000 claims description 6
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 6
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 229910052901 montmorillonite Inorganic materials 0.000 claims description 5
- HPOKESDSMZRZLC-UHFFFAOYSA-N propan-2-one;hydrochloride Chemical compound Cl.CC(C)=O HPOKESDSMZRZLC-UHFFFAOYSA-N 0.000 claims description 5
- 239000001632 sodium acetate Substances 0.000 claims description 5
- 235000017281 sodium acetate Nutrition 0.000 claims description 5
- JRGFBFKQCOJSNX-UHFFFAOYSA-N 4-methylbenzenesulfonic acid;propan-2-one Chemical compound CC(C)=O.CC1=CC=C(S(O)(=O)=O)C=C1 JRGFBFKQCOJSNX-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- LBZIXWRZFXPLJU-UHFFFAOYSA-N propan-2-one;sulfuric acid Chemical compound CC(C)=O.OS(O)(=O)=O LBZIXWRZFXPLJU-UHFFFAOYSA-N 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical compound [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 claims description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 claims description 2
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 2
- 150000002894 organic compounds Chemical class 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 218
- 235000019439 ethyl acetate Nutrition 0.000 description 77
- 238000000605 extraction Methods 0.000 description 75
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 60
- 239000012074 organic phase Substances 0.000 description 55
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 42
- 229910052938 sodium sulfate Inorganic materials 0.000 description 42
- 235000011152 sodium sulphate Nutrition 0.000 description 42
- 239000003480 eluent Substances 0.000 description 33
- 238000005406 washing Methods 0.000 description 33
- 239000012044 organic layer Substances 0.000 description 32
- 238000003756 stirring Methods 0.000 description 31
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 24
- 238000001035 drying Methods 0.000 description 24
- 238000003818 flash chromatography Methods 0.000 description 24
- 239000000047 product Substances 0.000 description 24
- 239000000741 silica gel Substances 0.000 description 24
- 229910002027 silica gel Inorganic materials 0.000 description 24
- 239000007787 solid Substances 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 238000010898 silica gel chromatography Methods 0.000 description 18
- 239000011259 mixed solution Substances 0.000 description 17
- 239000011780 sodium chloride Substances 0.000 description 15
- 238000001914 filtration Methods 0.000 description 14
- 238000001704 evaporation Methods 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 239000003208 petroleum Substances 0.000 description 9
- 229940125904 compound 1 Drugs 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 150000001299 aldehydes Chemical class 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 238000010791 quenching Methods 0.000 description 6
- 238000006386 neutralization reaction Methods 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 4
- DWDCGCDVZXVWDW-GEZXTYQDSA-N (4z,6e)-7-bromohepta-4,6-dienal Chemical compound Br\C=C\C=C/CCC=O DWDCGCDVZXVWDW-GEZXTYQDSA-N 0.000 description 4
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 4
- 150000001241 acetals Chemical class 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 230000032050 esterification Effects 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- DLNQRJFVXCCDKL-WJTNUVGISA-N formyl 2E,4E,6Z-decatrienoate Chemical compound CCC\C=C/C=C/C=C/C(=O)OC DLNQRJFVXCCDKL-WJTNUVGISA-N 0.000 description 4
- 239000007791 liquid phase Substances 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
- 241001014341 Acrosternum hilare Species 0.000 description 3
- 229940125907 SJ995973 Drugs 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- XZMHJYWMCRQSSI-UHFFFAOYSA-N n-[5-[2-(3-acetylanilino)-1,3-thiazol-4-yl]-4-methyl-1,3-thiazol-2-yl]benzamide Chemical compound CC(=O)C1=CC=CC(NC=2SC=C(N=2)C2=C(N=C(NC(=O)C=3C=CC=CC=3)S2)C)=C1 XZMHJYWMCRQSSI-UHFFFAOYSA-N 0.000 description 3
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- DVVATNQISMINCX-DEQVHDEQSA-N (2Z,4E)-octa-2,4-dienal Chemical compound CCC\C=C\C=C/C=O DVVATNQISMINCX-DEQVHDEQSA-N 0.000 description 2
- 101150003085 Pdcl gene Proteins 0.000 description 2
- WDJHALXBUFZDSR-UHFFFAOYSA-M acetoacetate Chemical compound CC(=O)CC([O-])=O WDJHALXBUFZDSR-UHFFFAOYSA-M 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 238000006772 olefination reaction Methods 0.000 description 2
- 239000003016 pheromone Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- NZLCAHVLJPDRBL-ZIQCHISCSA-N (2z,4e)-octa-2,4-diene Chemical compound CCC\C=C\C=C/C NZLCAHVLJPDRBL-ZIQCHISCSA-N 0.000 description 1
- DLNQRJFVXCCDKL-YPWIGCSLSA-N 2,4,6-Decatrienoic acid-Me ester Natural products CCCC=C/C=C/C=C/C(=O)OC DLNQRJFVXCCDKL-YPWIGCSLSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 238000006130 Horner-Wadsworth-Emmons olefination reaction Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 240000000111 Saccharum officinarum Species 0.000 description 1
- 235000007201 Saccharum officinarum Nutrition 0.000 description 1
- 239000000877 Sex Attractant Substances 0.000 description 1
- 241000607479 Yersinia pestis Species 0.000 description 1
- CQAYJDMWUGRKOJ-UHFFFAOYSA-N acetyloxy-oxido-oxophosphanium Chemical compound CC(=O)O[P+]([O-])=O CQAYJDMWUGRKOJ-UHFFFAOYSA-N 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 150000001993 dienes Chemical class 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000011981 lindlar catalyst Substances 0.000 description 1
- 239000002420 orchard Substances 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
Classifications
-
- 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
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of organic compounds, and particularly relates to an ester compound, a preparation method and application thereof, and a preparation method of (E, E, Z) -2,4, 6-methyl decyltrienoate. The invention provides (E, E, Z) -2,4, 6-decaneThe preparation method of the methyl trienoate comprises the following steps: mixing the compound 6, p-toluenesulfonyl chloride, an acid binding agent, trimethylamine hydrochloride and a third organic solvent for esterification reaction to obtain a compound 7; mixing the compound 7, sodium iodide, zinc and a fourth organic solvent for a first reduction reaction to obtain the (E, E, Z) -2,4, 6-methyltrienoic acid methyl ester; compound 7 is
Description
Technical Field
The invention belongs to the technical field of organic compounds, and particularly relates to an ester compound, a preparation method and application thereof, and a preparation method of (E, E, Z) -2,4, 6-methyl decyltrienoate.
Background
The (E, E, Z) -2,4, 6-decatrienoic acid methyl ester is separated from the body of the male brown wing green stink bug, has aggregation effect on the same male brown wing green stink bug and female brown wing green stink bug in an orchard, can be used as aggregation pheromone of adults, and is convenient for pest management.
The current synthesis method of (E, E, Z) -2,4, 6-methyl decyltrienoate mainly comprises two methods, wherein one method is based on Wittig type olefination and alkyne hydrogenation strategies, 2-hexynoic aldehyde is sequentially treated by one 4C ylide or two 2C ylides to obtain methyl (E, E) -2, 4-decen-6-methyl nonynoate, and then Lindlar catalyst is utilized for partial hydrogenation to obtain the (E, E, Z) -2,4, 6-methyl decyltrienoate. Another synthesis method is that fumaral bis (dimethyl acetal) is partially hydrolyzed into (E) -4, 4-dimethoxy-2-butyraldehyde, and then reacts with proper ylide to obtain (Z, E) -2, 4-octadien dimethyl acetal, and the (Z, E) -2, 4-octadienal is obtained by deprotection under mild condition; the conversion of (Z, E) -2, 4-octadienal to methyl (E, E, Z) -2,4, 6-decatrienate was carried out by Horner-Wadsworth-Emmons trans-olefination of trimethyl phosphoacetate with potassium carbonate in water. The current synthesis method comprises the following steps: raw materials are not easy to obtain, the reaction conditions are harsh, the yield is lower, and the effect is reduced.
Disclosure of Invention
In view of the above, the present invention provides an ester compound, a preparation method and application thereof, and a preparation method of (E, E, Z) -2,4, 6-methyltrienoic acid methyl ester, wherein the preparation method provided by the present invention can prepare (E, E, Z) -2,4, 6-methyltrienoic acid methyl ester with high yield, and is convenient for mass production.
In order to solve the technical problems, the invention provides an ester compound, which has a structure shown in a formula 1:
the invention also provides a preparation method of the ester compound in the technical scheme, which comprises the following steps:
mixing the compound 2, a protective agent, a first catalyst and a first organic solvent, and performing an aldehyde group protection reaction to obtain a compound 3;
mixing the compound 3, methyl acrylate, an alkaline substance, a second catalyst and a second organic solvent, and performing Heck coupling reaction to obtain a compound 4;
mixing the compound 4 with an acidic solvent for deprotection reaction to obtain a compound 5;
wherein R is 1 Is that(CH 3 O) 2 CH-or (CH) 3 COO) 2 CH-。
Preferably, the protective agent comprises ethylene glycol, trimethyl orthoformate, triethyl orthoformate, acetic anhydride and propionic anhydride;
the first catalyst comprises phosphoric acid, p-toluenesulfonic acid, sulfuric acid or methanesulfonic acid;
The first organic solvent comprises dichloromethane, chloroform, dichloroethane, benzene, toluene or methanol;
the molar ratio of the compound 2 to the protective agent is 1:1.2-2;
the temperature of the aldehyde group protection reaction is 20-120 ℃ and the time is 4-16 h.
Preferably, the basic substance comprises triethylamine, diisopropylethylamine, sodium acetate, sodium carbonate, potassium carbonate or calcium carbonate;
the second catalyst comprises palladium acetate, palladium chloride and palladium trifluoroacetate;
the second organic solvent comprises N, N-dimethylformamide, tetrahydrofuran, acetonitrile, N-dimethylacetamide or hexamethylphosphoric triamide;
the molar ratio of the compound 3 to the methyl acrylate is 2:2.5-3.5;
the temperature of the Heck coupling reaction is 25-100 ℃ and the time is 5-26 h.
Preferably, the acidic solvent comprises aqueous formic acid, aqueous acetic acid, acetone p-toluenesulfonate, acetone hydrochloride, acetone sulfate or a mixture of montmorillonite and methylene chloride;
the volume ratio of the substance amount of the compound 4 to the acid solvent is 0.24 mol:550-650 mL;
the temperature of the deprotection reaction is 25-100 ℃ and the time is 1-8 h.
The invention also provides an application of the ester compound in the technical scheme or the ester compound prepared by the preparation method in the technical scheme in preparing the compound 6;
The invention also provides an ester derivative, which has a structure shown as a compound 4 or a compound 6:
the invention also provides a preparation method of the (E, E, Z) -2,4, 6-methyl decatrienoate, which comprises the following steps:
mixing a compound 6, p-toluenesulfonyl chloride, an acid binding agent, trimethylamine hydrochloride and a third organic solvent for esterification reaction, wherein the compound 7;
mixing the compound 7, sodium iodide, zinc and a fourth organic solvent for a first reduction reaction to obtain the (E, E, Z) -2,4, 6-methyltrienoic acid methyl ester;
compound 7 is
Preferably, the acid binding agent comprises triethylamine, pyridine or trimethylamine;
the third organic solvent comprises acetonitrile, dichloromethane, benzene or toluene; the fourth organic solvent comprises ethylene glycol dimethyl ether, tetrahydrofuran or methyltetrahydrofuran;
the mol ratio of the compound 6 to the p-toluenesulfonyl chloride is 1.6:1.8-2.2;
the mass ratio of the compound 7 to the zinc is 1:1-15;
the temperature of the esterification reaction is 0-5 ℃ and the time is 1.8-2.2 h;
the first reduction reaction is carried out under the reflux condition, and the time of the first reduction reaction is 9-11 h.
Preferably, the preparation method of the compound 6 comprises the following steps:
Mixing the compound 2, a protective agent, a first catalyst and a first organic solvent, and performing an aldehyde group protection reaction to obtain a compound 3;
mixing the compound 3, methyl acrylate, an alkaline substance, a second catalyst and a second organic solvent, and performing Heck coupling reaction to obtain a compound 4;
mixing the compound 4 with an acidic solvent for deprotection reaction to obtain a compound 5;
and mixing the compound 5, a reducing agent and a fifth organic solvent, and performing a second reduction reaction to obtain the compound 6.
The invention provides a preparation method of (E, E, Z) -2,4, 6-methyl decatrienoate, which comprises the following steps: mixing the compound 6, p-toluenesulfonyl chloride, an acid binding agent, trimethylamine hydrochloride and a third organic solvent for esterification reaction to obtain a compound 7; mixing the compound 7, sodium iodide, zinc and a fourth organic solvent for a first reduction reaction to obtain the (E, E, Z) -2,4, 6-methyltrienoic acid methyl ester; compound 7 isThe preparation method provided by the invention can prepare the (E, E, Z) -2,4, 6-methyl decyltrienoate with higher purity and yield, and is simple and easy to operate and easy for industrial production.
Detailed Description
The invention provides an ester compound, which has a structure shown in a formula 1:
the invention also provides a preparation method of the ester compound in the technical scheme, which comprises the following steps:
mixing the compound 2, a protective agent, a first catalyst and a first organic solvent, and performing an aldehyde group protection reaction to obtain a compound 3;
mixing the compound 3, methyl acrylate, an alkaline substance, a second catalyst and a second organic solvent, and performing Heck coupling reaction to obtain a compound 4;
mixing the compound 4 with an acidic solvent for deprotection reaction to obtain a compound 3;
wherein R is 1 Is that(CH 3 O) 2 CH-or (CH) 3 COO) 2 CH-。
The invention mixes the compound 2, the protective agent, the first catalyst and the first organic solvent to carry out aldehyde group protection reaction to obtain the compound 3. In the present invention, the compound 2 is preferably prepared with reference to "Facile Synthesis of (Z, E) -9, 11-hexadecadial, the Major Sex Pheromone Component ofthe Sugarcane BorerDiatraea Saccharalis: an Efficient Strategy for Synthesis of (Z, E) -Dienic Pheromones" (Y.Tao, X.Yang, Y.Jin, Q.Wang, synth.Commun.43. (2013). 415-424) or "EfficientPreparation ofFunctionalized (E, Z) Dienes Using Acetylene as the Building Block" (Z.Wang, X.Lu, A.Lei, Z.Zhang, J.Org.Chem.63. (1998). 3806-3807). In the present invention, the protective agent preferably includes ethylene glycol, trimethyl orthoformate or acetic anhydride, more preferably ethylene glycol. In the present invention, the first catalyst preferably includes phosphoric acid, p-toluenesulfonic acid, sulfuric acid or methanesulfonic acid, more preferably phosphoric acid. In the present invention, the first organic solvent preferably includes methylene chloride, chloroform, dichloroethane, benzene, toluene or methanol, more preferably methylene chloride. In the present invention, the molar ratio of the compound 2 to the protecting agent is preferably 1:1.2 to 2, more preferably 1:2. In the present invention, the ratio of the mass of the compound 2 to the volume of the first organic solvent is preferably 95g:450 to 550mL, more preferably 95g:500mL.
In the present invention, the temperature of the aldehyde group-protecting reaction is preferably 20 to 120 ℃, more preferably 40 to 110 ℃; the time for the aldehyde group-protecting reaction is preferably 4 to 16 hours, more preferably 11 to 14 hours.
In the present invention, the aldehyde group-protecting reaction is preferably accompanied by reflux, and the present invention removes water generated during the aldehyde group-protecting reaction by reflux. The present invention has no special requirement for the reflux, as long as the water produced by the reaction can be removed.
In the present invention, the aldehyde group-protecting reaction preferably further comprises: washing the aldehyde group protection reaction system by using water, and mixing with sodium sulfate for drying; concentrating the dried product, and performing silica gel chromatography to obtain the compound 3. The invention has no special requirement on the dosage of the sodium sulfate, and only needs to remove water in the product. The method has no special requirement on the concentration mode, and can be carried out by adopting a mode conventional in the field. In the present invention, the eluent for silica gel chromatography is preferably a mixture of Petroleum Ether (PE) and ethyl acetate (EtOAc) in a volume ratio of 20:1.
In the invention, when the protective agent is trimethyl orthoformate and the solvent is methanol, the invention preferably utilizes sodium carbonate to quench aldehyde group protection reaction and simultaneously evaporates and removes the methanol, and the system after removing the methanol is extracted by ethyl acetate to obtain an organic layer; washing the organic layer with water, mixing with sodium sulfate, and drying; concentrating the dried product, and performing silica gel chromatography to obtain the compound 3. In the present invention, the number of times of the extraction is preferably 2 to 4 times, more preferably 3 times; the amount of ethyl acetate to be used per extraction is preferably 280 to 320mL, more preferably 300mL. The organic phases obtained by multiple extractions are preferably combined to obtain the final organic layer. The invention has no special requirement on the dosage of the sodium sulfate, and only needs to remove water in the product. The method has no special requirement on the concentration mode, and can be carried out by adopting a mode conventional in the field. In the present invention, the eluent for silica gel chromatography is preferably a mixture of Petroleum Ether (PE) and ethyl acetate (EtOAc) in a volume ratio of 20:1.
In the present invention, when the protecting agent is acetic anhydride, acetic anhydride acts as a solvent while acting as a protecting agent. In the invention, when the protective agent is acetic anhydride, the invention preferably utilizes saturated sodium carbonate aqueous solution to quench aldehyde group protection reaction and then carries out ethyl acetate extraction to obtain an organic layer; washing the organic layer with water, mixing with sodium sulfate, and drying; concentrating the dried product, and performing silica gel chromatography to obtain the compound 3. In the present invention, the number of times of the extraction is preferably 2 to 4 times, more preferably 3 times; the amount of ethyl acetate to be used per extraction is preferably 280 to 320mL, more preferably 300mL. The organic phases obtained by multiple extractions are preferably combined to obtain the final organic layer. The invention has no special requirement on the dosage of the sodium sulfate, and only needs to remove water in the product. The method has no special requirement on the concentration mode, and can be carried out by adopting a mode conventional in the field. In the present invention, the eluent for silica gel chromatography is preferably a mixture of Petroleum Ether (PE) and ethyl acetate (EtOAc) in a volume ratio of 20:1.
In the present invention, the compound 3 is preferably a pale yellow oil.
In the present invention, when R 1 Is thatCompound 3->Is denoted as 3a when R 1 Is (CH) 3 O) 2 CH-time compound 3 is +.>Denoted as 3b, when R 1 Is (CH) 3 COO) 2 CH-time compound 3 is +.>And is designated 3c.
After the compound 3 is obtained, the compound 3, methyl acrylate, alkaline substances, a second catalyst and a second organic solvent are mixed, and Heck coupling reaction is carried out to obtain a compound 4. In the present invention, the basic substance preferably includes triethylamine, diisopropylethylamine, sodium acetate, sodium carbonate, potassium carbonate or calcium carbonate, more preferably triethylamine. In the present invention, the second catalyst preferably comprises palladium acetate, palladium chloride, palladium trifluoroacetate, more preferably palladium acetate (Pd (OAc) 2 ). In the present invention, the second organic solvent preferably includes N, N-dimethylformamide, tetrahydrofuran, acetonitrile, N-dimethylacetamide or hexamethylphosphoric triamide, more preferably N, N-Dimethylformamide (DMF). In the present invention, the molar ratio of the compound 3 to methyl acrylate is preferably 2:2.5 to 3.5, more preferably 2:3 to 3.3. In the present invention, the molar ratio of the compound 3 to the second catalyst is preferably 100:4.5 to 5.5, more preferably 100:5 to 5.3. In the present invention, the mass of the compound and the second organic The volume ratio of the solvent is preferably 93.2 g/250 to 350mL, more preferably 93.2 g/300 mL.
In the present invention, the temperature of the Heck coupling reaction is preferably 25 to 100 ℃, more preferably 30 to 80 ℃; the Heck coupling reaction time is preferably 5 to 26 hours, more preferably 10 to 24 hours.
In the present invention, the Heck coupling reaction preferably further comprises:
cooling the system after Heck coupling reaction, and mixing with hydrochloric acid solution to adjust the pH value;
mixing the pH value-adjusted system with ethyl acetate for extraction to obtain an organic phase;
and (3) washing the organic phase with water, mixing with sodium sulfate, drying, concentrating the dried product, and performing silica gel chromatography to obtain the compound 4.
In the present invention, the temperature after the temperature reduction is preferably 20 to 35 ℃, more preferably 25 to 30 ℃. The invention has no special requirement on the cooling mode. In the present invention, the mass concentration of the hydrochloric acid solution is preferably 4.5 to 5.5%, more preferably 5%. In the present invention, the pH of the pH-adjusted system is preferably 4.8 to 5.2, more preferably 5. The invention has no special requirement on the dosage of the hydrochloric acid solution, as long as the required pH value can be achieved.
In the present invention, the number of times of the extraction is preferably 3 to 5 times, more preferably 4 times; the amount of ethyl acetate to be used per extraction is preferably 280 to 320mL, more preferably 300mL. The organic phases obtained by multiple extractions are preferably combined to obtain the final organic phase.
The invention has no special requirement on the dosage of the sodium sulfate, and only needs to remove water in the product. The invention can remove soluble impurities in the organic phase through water washing. The method has no special requirement on the concentration mode, and can be carried out by adopting a mode conventional in the field. In the present invention, the eluent for silica gel chromatography is preferably a mixture of Petroleum Ether (PE) and ethyl acetate (EtOAc) in a volume ratio of 20:3.
In the present invention, the compound 4 is preferably a pale yellow solid.
In the present inventionIn the clear, when R 1 Is thatCompound 4->Is marked as 4a when R 1 Is (CH) 3 O) 2 CH-time compound 4 is +.>Is denoted as 4b when R 1 Is (CH) 3 COO) 2 CH-time Compound 4 isAnd is designated as 4c.
After the compound 4 is obtained, the compound 4 and an acidic solvent are mixed for deprotection reaction to obtain a compound 5. In the present invention, the acidic solvent preferably includes an aqueous formic acid solution, an aqueous acetic acid solution, an acetone p-toluenesulfonate solution, an acetone hydrochloride solution, an acetone sulfate solution or a mixture of montmorillonite and methylene chloride, more preferably an aqueous formic acid solution. In the present invention, the mass concentration of the acidic solvent is preferably 46 to 53%, more preferably 50% when the acidic solvent is an aqueous formic acid solution, an aqueous acetic acid solution, an acetone p-toluenesulfonate solution, an acetone hydrochloride solution or an acetone sulfate solution. In the present invention, the montmorillonite is preferably montmorillonite K-10; the mass ratio of montmorillonite to dichloromethane is preferably 13-14 g/1L, more preferably 13.5 g/1L. In the present invention, the volume ratio of the substance amount of the compound 4 to the acidic solvent is preferably 0.24mol:550 to 650mL, more preferably 0.24mol:580 to 600mL. In the present invention, the temperature of the deprotection reaction is preferably 25 to 100 ℃, more preferably 50 to 80 ℃; the time for the deprotection reaction is preferably 1 to 8 hours, more preferably 2 to 4 hours. In the present invention, the deprotection reaction is preferably accompanied by stirring; the invention has no special requirement on stirring, so long as the stirring can fully react.
In the present invention, when the protecting agent is ethylene glycol or trimethyl orthoformate, the deprotection reaction preferably further comprises:
mixing the deprotected system with sodium carbonate to perform neutralization reaction;
mixing the neutralization reaction system with ethyl acetate for extraction to obtain an organic phase;
washing and washing the organic phase with sodium carbonate solution, mixing with sodium sulfate, and drying;
concentrating the dried product, and performing silica gel chromatography to obtain the compound 5.
The invention uses sodium carbonate to neutralize the acid in the deprotection reaction system, and has no special requirement on the dosage of the sodium carbonate, so long as the pH value of the system can reach neutrality.
In the present invention, the number of times of the extraction is preferably 2 to 4 times, more preferably 3 times; the amount of ethyl acetate to be used per extraction is preferably 280 to 320mL, more preferably 300mL. The organic phases obtained by multiple extractions are preferably combined to obtain the final organic phase.
In the present invention, the sodium carbonate solution for washing sodium carbonate solution is preferably a saturated sodium carbonate solution. The invention has no special requirement on the dosage of the sodium sulfate, and only needs to remove water in the product. The method has no special requirement on the concentration mode, and can be carried out by adopting a mode conventional in the field. In the present invention, the eluent for silica gel chromatography is preferably a mixture of Petroleum Ether (PE) and ethyl acetate (EtOAc) in a volume ratio of 5:1.
In the present invention, when the protecting agent is acetic anhydride, the deprotection reaction preferably further comprises:
filtering the system after the deprotection reaction to obtain a liquid phase;
washing the liquid phase by saturated sodium carbonate aqueous solution, washing by water, mixing with sodium sulfate and drying;
concentrating the dried product, and performing silica gel chromatography to obtain the compound 5.
The invention has no special requirement on the filtration, and can be realized by adopting a conventional mode in the field.
The method is not particularly limited to the washing of the saturated sodium carbonate aqueous solution and the washing of water, and the method is carried out in a conventional mode in the field. The invention has no special requirement on the dosage of the sodium sulfate, and only needs to remove water in the product.
The method has no special requirement on the concentration mode, and can be carried out by adopting a mode conventional in the field. In the present invention, the eluent for silica gel chromatography is preferably a mixture of Petroleum Ether (PE) and ethyl acetate (EtOAc) in a volume ratio of 5:1.
In the present invention, the compound 5 is preferably a pale yellow solid.
The invention also provides an application of the ester compound in the technical scheme or the ester compound prepared by the preparation method in the technical scheme in preparing the compound 6;
The invention also provides an ester derivative, which has a structure shown as a compound 4 or a compound 6:
the invention also provides a preparation method of the (E, E, Z) -2,4, 6-methyl decatrienoate, which comprises the following steps:
mixing a compound 6, p-toluenesulfonyl chloride, an acid binding agent, trimethylamine hydrochloride and a third organic solvent for esterification reaction, wherein the compound 7;
mixing the compound 7, sodium iodide, zinc and a fourth organic solvent for a first reduction reaction to obtain the (E, E, Z) -2,4, 6-methyltrienoic acid methyl ester;
compound 7 is
According to the invention, the compound 6, the p-toluenesulfonyl chloride, the acid binding agent, the trimethylamine hydrochloride and the third organic solvent are mixed for esterification reaction, and the compound 7 is prepared. In the present invention, the mixing preferably includes the steps of:
dissolving p-toluenesulfonyl chloride in part of the third organic solvent to obtain a p-toluenesulfonyl chloride solution;
dissolving a compound 6, an acid binding agent and trimethylamine hydrochloride in the rest third organic solvent to obtain a mixed solution;
and adding the p-toluenesulfonyl chloride solution into the mixed solution.
The invention dissolves the tosyl chloride in part of the third organic solvent to obtain the tosyl chloride solution. In the present invention, the third organic solvent preferably includes acetonitrile, dichloromethane, benzene or toluene, more preferably acetonitrile. In the present invention, the molar concentration of the p-toluenesulfonyl chloride solution is preferably 1 to 1.5mmol/mL, more preferably 1.25 to 1.5mmol/mL.
The invention dissolves the compound 6, acid binding agent and trimethylamine hydrochloride in the residual third organic solvent to obtain the mixed solution. In the present invention, the preparation method of the compound 6 preferably comprises the steps of
Mixing the compound 2, a protective agent, a first catalyst and a first organic solvent, and performing an aldehyde group protection reaction to obtain a compound 3;
mixing the compound 3, methyl acrylate, an alkaline substance, a second catalyst and a second organic solvent, and performing Heck coupling reaction to obtain a compound 4;
mixing the compound 4 with an acidic solvent for deprotection reaction to obtain a compound 5;
and mixing the compound 5, a reducing agent and a fifth organic solvent, and performing a second reduction reaction to obtain the compound 6.
In the present invention, the methods for preparing compound 3, compound 4 and compound 5 are preferably consistent with the above-described technical schemes, and the detailed description thereof will not be repeated.
In the present invention, the reducing agent preferably includes sodium borohydride or potassium borohydride, more preferably sodium borohydride. In the present invention, the fifth organic solvent preferably includes methanol or ethanol, more preferably methanol. In the present invention, the molar ratio of the compound 5 to the reducing agent is preferably 0.2:0.1 to 0.14, more preferably 0.2:0.12. In the present invention, the ratio of the mass of the compound 5 to the volume of the fifth organic solvent is preferably 38.8 g:380-420 mL, more preferably 38.8g:400mL. In the present invention, the temperature of the second reduction reaction is preferably 0 to 3 ℃, more preferably 0 ℃; the time of the second reduction reaction is preferably 2 to 4 hours, more preferably 3 hours. In the present invention, the second reduction reaction is preferably accompanied by stirring, and the present invention is not particularly limited as long as the reaction is complete. The second reduction reaction is preferably quenched with a 5% strength by mass hydrochloric acid solution.
In the present invention, the second reduction reaction preferably further comprises: evaporating the second reduction reaction system, mixing with ethyl acetate, and extracting to obtain an organic phase; washing the organic phase with water and washing with sodium chloride solution sequentially, mixing the washed system with sodium sulfate, drying, concentrating the dried product, and performing silica gel chromatography to obtain the compound 6. The present invention has no special requirement for evaporation, as long as the solvent can be removed. In the present invention, the number of times of the extraction is preferably 3 to 5 times, more preferably 4 times; the amount of ethyl acetate to be used per extraction is preferably 180 to 220mL, more preferably 200mL. The organic phases obtained by multiple extractions are preferably combined to obtain the final organic phase. The invention has no special requirement on the dosage of the sodium sulfate, and only needs to remove water in the product. The method has no special requirement on the concentration mode, and can be carried out by adopting a mode conventional in the field. In the present invention, the eluent for silica gel chromatography is preferably a mixture of Petroleum Ether (PE) and ethyl acetate (EtOAc) in a volume ratio of 2:1.
In the present invention, the compound 6 is preferably a white solid.
In the present invention, the acid-binding agent preferably includes triethylamine, pyridine or trimethylamine, more preferably triethylamine. The invention uses acid binding agent to neutralize acid generated in the esterification reaction process. In the present invention, the trimethylamine hydrochloride acts as a catalyst. In the present invention, the molar concentration of the compound 6 in the mixed solution is preferably 0.8 to 1.2mmol/mL, more preferably 1mmol/mL; the molar concentration of the acid-binding agent in the mixed solution is preferably 1.3-1.7 mmol/mL, more preferably 1.5mmol/mL; the molar concentration of trimethylamine hydrochloride in the mixed solution is preferably 0.08-0.12 mmol/mL, more preferably 0.1mmol/mL;
after the p-toluenesulfonyl chloride solution and the mixed solution are obtained, the p-toluenesulfonyl chloride solution is added into the mixed solution. In the present invention, the molar ratio of the compound 6 to the p-toluenesulfonyl chloride is preferably 1.6:1.8 to 2.2, more preferably 1.6:2. In the present invention, the addition of the p-toluenesulfonyl chloride solution to the mixed solution is preferably accompanied by stirring; the stirring is not particularly limited as long as it can be uniformly mixed.
In the present invention, the temperature of the esterification reaction is preferably 0 to 5 ℃, more preferably 1 to 4 ℃; the time of the esterification reaction is preferably 1.8 to 2.2 hours, more preferably 2 hours. In the present invention, the esterification reaction is preferably accompanied by stirring; the stirring is not particularly limited in the present invention.
In the present invention, the esterification reaction preferably further comprises: evaporating the esterification reaction system to remove the solvent; mixing the solvent-removed system with water, and extracting with ethyl acetate to obtain an organic phase; washing the organic phase with water and washing with sodium chloride solution sequentially, mixing the washed system with sodium sulfate, drying, concentrating the dried product, and performing silica gel chromatography to obtain the compound 7. The present invention has no special requirement for evaporation, as long as the solvent can be removed. In the present invention, the number of times of the extraction is preferably 3 to 5 times, more preferably 4 times; the amount of ethyl acetate to be used per extraction is preferably 180 to 220mL, more preferably 200mL. The organic phases obtained by multiple extractions are preferably combined to obtain the final organic phase. The invention has no special requirement on the dosage of the sodium sulfate, and only needs to remove water in the product. The method has no special requirement on the concentration mode, and can be carried out by adopting a mode conventional in the field. In the present invention, the eluent for silica gel chromatography is preferably a mixture of Petroleum Ether (PE) and ethyl acetate (EtOAc) in a volume ratio of 20:1.
In the present invention, the compound 7 is preferably a white solid.
After the compound 7 is obtained, the compound 7, sodium iodide, zinc and a fourth organic solvent are mixed for a first reduction reaction to obtain the (E, E, Z) -2,4, 6-methyl decatrienoate. In the present invention, the fourth organic solvent preferably includes ethylene glycol dimethyl ether, tetrahydrofuran, methyltetrahydrofuran, more preferably ethylene glycol dimethyl ether. In the invention, the sodium iodide has the function of an auxiliary agent. In the present invention, the zinc is preferably zinc powder. The particle size of the zinc powder is not particularly limited, and the zinc powder is obtained by adopting a conventional commercial product. In the present invention, the zinc functions as a reducing agent. In the present invention, the molar ratio of the compound 7 to zinc is preferably 1:1 to 15, more preferably 1:5 to 10; the molar ratio of the compound 7 to sodium iodide is preferably 1:1 to 10, more preferably 1:2 to 5.
In the present invention, the first reduction reaction is performed under reflux conditions; the time of the first reduction reaction is preferably 9 to 11 hours, more preferably 10 hours. In the present invention, the first reduction reaction is preferably accompanied by stirring, and the present invention is not particularly limited as long as the reaction is complete.
In the present invention, the first reduction reaction preferably further includes: filtering the system after the first reduction reaction to obtain a liquid phase; mixing the liquid phase with water, and extracting by using ethyl acetate to obtain an organic phase; washing the organic phase with water and washing with sodium chloride solution sequentially, mixing the washed system with sodium sulfate, drying, concentrating the dried product, and performing silica gel chromatography to obtain the (E, E, Z) -2,4, 6-methyltrienoic acid methyl ester. The invention has no special requirement on the filtration, and can be realized by adopting a conventional mode in the field. The invention removes unreacted sodium iodide and zinc in the system by filtration. In the present invention, the number of times of the extraction is preferably 3 to 5 times, more preferably 4 times; the amount of ethyl acetate to be used per extraction is preferably 180 to 220mL, more preferably 200mL. The organic phases obtained by multiple extractions are preferably combined to obtain the final organic phase. The invention has no special requirement on the dosage of the sodium sulfate, and only needs to remove water in the product. The method has no special requirement on the concentration mode, and can be carried out by adopting a mode conventional in the field. In the present invention, the eluent for silica gel chromatography is preferably a mixture of Petroleum Ether (PE) and ethyl acetate (EtOAc) in a volume ratio of 45:1.
In the present invention, the (E, E, Z) -2,4, 6-decyltrienoic acid methyl ester has the structural formulaThe (E, E, Z) -2,4, 6-decatrienoic acid methyl ester is colorless oily matter.
In the present invention, the equation for preparing methyl (E, E, Z) -2,4, 6-decatrienoate is shown in formula a:
the technical solutions provided by the present invention are described in detail below in conjunction with examples for further illustrating the present invention, but they should not be construed as limiting the scope of the present invention.
Example 1
Preparation of compound 3a ((Z, E) -6-bromo-3, 5-hexadienyl) -1, 3-dioxolane:
(Z, E) -7-bromo-4, 6-heptadienal (Compound 2) (95 g,0.5 mol), ethylene glycol (62 g,1 mol), a phosphoric acid solution having a mass concentration of 85% and methylene chloride (500 mL) were mixed and then subjected to an aldehyde group protection reaction (accompanied by reflux) for 12 hours; the organic layer was washed with water, mixed with sodium sulfate, dried, then concentrated, and the concentrated product was purified by silica gel flash chromatography (eluent PE/etoac=20:1) to give acetal 3a (111 g) as a pale yellow oil;
1 H NMR(400MHz,CDCl 3 )δ:7.03(ddd,J＝13.3,1.6,1.2Hz,1H),6.47(dd,J＝13.3,1.3Hz,1H),5.96(ddd,J＝11.6,11.1,1.3Hz,1H),5.52(dtd,J＝11.1,7.5,1.2Hz,1H),4.79(t,J＝4Hz,1H),3.90(t,J＝6.2Hz,2H),3.78(t,J＝6.3Hz,2H),2.28-2.23(m,2H),1.69-1.63(m,2H).
13 C NMR(101MHz,CDCl 3 )δ:132.9,131.5,126.4,109.2,104.6,65.3(2C),32.0,23.0.
preparation of the compound 4a (E, E, Z) -9- (1, 3-dioxolan-2-yl) -2,4, 6-nonyltrienoic acid methyl ester:
compound 3a (93.2 g,0.4 mol), triethylamine (81 g,0.8 mol), pd (OAc) 2 (4.5 g,20 mmol), methyl acrylate (51.2 g,0.6 mol) and N, N-dimethylformamide (300 mL) were mixed and subjected to Heck coupling reaction at 70℃for 24 hours, the reaction mixture was cooled to a value of 30℃and then was mixed with a 5% strength by mass hydrochloric acid solution to neutralize to pH 5, extraction was performed 4 times with ethyl acetate, and 300mL of ethyl acetate was used for each extraction; combining the organic layers of each extraction to obtain an organic phase; the organic phase is washed with water, dried over sodium sulfate and then concentrated; flash chromatography on silica gel (eluent PE/etoac=20:3) afforded compound 4a (71.4 g) as a pale yellow solid;
1 H NMR(400MHz,CDCl 3 )δ:7.27(dd,J＝15.3,11.2Hz,1H),6.51(dd,J＝14.8,10.7Hz,1H),6.25-6.10(m,2H),5.99-5.89(m,1H),5.85(d,J＝15.3Hz,1H),4.86(t,J＝4.6Hz,1H),3.97-3.81(m,4H),3.72(s,3H),2.27(dd,J＝15.1,7.4Hz,2H),1.81-1.72(m,2H).
13 C NMR(101MHz,CDCl 3 )δ:167.7,145.1,141.1,139.3,130.3,128.2,119.9,103.9,65.0(2C),51.6,33.2,27.5.
HRMS(ESI,m/z):[M+H] + ,Calcd for[C 13 H 19 O 4 ] + :239.1278,found:239.1278.
Preparation of the Compound 5 (E, E, Z) -10-oxo-2, 4, 6-decyltrienoic acid methyl ester
Compound 4a (57.2 g,0.24 mol) and a 50% strength by mass formic acid solution (600 mL) were mixed and deprotected at 60 ℃ for 4h with stirring; after neutralization of the reaction mixture with solid sodium carbonate, extraction with ethyl acetate was 3 times, 300mL of ethyl acetate was used for each extraction; combining the organic layers of each extraction to obtain an organic phase; washing the organic phase with saturated sodium carbonate solution and water in turn, drying with sodium sulfate, and concentrating; purification by flash chromatography on silica gel (eluent PE/etoac=5:1) afforded compound 5 (45.2 g) as a pale yellow solid;
1 H NMR(400MHz,CDCl 3 )δ:9.79(t,J＝1.6Hz,1H),7.29(dd,J＝15.3,11.2Hz,1H),6.51(dd,J＝14.9,10.7Hz,1H),6.29-6.13(m,2H),5.96-5.81(m,2H),3.74(s,3H),2.70-2.38(m,4H).
13 C NMR(101MHz,CDCl 3 )δ:201.35,167.64,144.79,140.50,137.25,131.02,128.87,120.32,51.60,42.93,25.41.
HRMS(ESI,m/z):[M+H] + ,Calcd for[C 11 H 15 O 3 ] + :195.1016,found:195.1016.
preparation of the Compound methyl 6 (E, E, Z) -10-hydroxy-2, 4, 6-decyltrienoic acid
Compound 5 (38.8 g,0.2 mol), sodium borohydride (4.54 g,120 mmol) and methanol (400 mL) were mixed and then subjected to reduction reaction (with stirring) at 0 ℃ for 3 hours; quenching the reduction reaction with 5% hydrochloric acid, and then evaporating methanol; then extracted 4 times with ethyl acetate, 200mL ethyl acetate for each extraction; combining the organic layers of each extraction to obtain an organic phase; washing the organic phase with water and sodium chloride water in sequence, drying with sodium sulfate, and concentrating; purification by flash chromatography on silica gel (eluent PE/etoac=2:1) afforded compound 6 (33.7 g) as a white solid;
1 H NMR(400MHz,CDCl 3 )δ:7.28(dd,J＝15.3,11.3Hz,1H),6.51(dd,J＝14.9,10.7Hz,1H),6.25-6.11(m,2H),5.98-5.87(m,1H),5.85(d,J＝15.3Hz,1H),3.72(s,3H),3.64(t,J＝6.4Hz,2H),2.23(dt,J＝7.4,7.2Hz,2H),1.73-1.61(m,2H).
13 C NMR(101MHz,CDCl 3 )δ:167.80,145.11,141.15,139.62,130.41,128.18,119.85,62.26,51.61,31.92,29.36.
HRMS(ESI,m/z):[M+H] + ,Calcd for[C 11 H 17 O 3 ] + :197.1172,found:197.1165.
Preparation of Compound 1 (E, E, Z) -2,4, 6-decyltrienoic acid methyl ester
P-toluenesulfonyl chloride (38.2 g,200 mmol) was dissolved in acetonitrile (160 mL) to give a p-toluenesulfonyl chloride solution;
compound 6 (160 mmol), triethylamine (24.2 g,240 mmol), trimethylamine hydrochloride (1530 mg,16mmol,10 mol%) were dissolved in acetonitrile (160 mL) to obtain a mixed solution;
adding (stirring) the p-toluenesulfonyl chloride solution into the mixed solution at 0 ℃ to perform esterification (stirring) for 2 hours; after evaporation of acetonitrile, water was added and extraction was performed 4 times with ethyl acetate, 200mL of ethyl acetate was used for each extraction; combining the organic layers of each extraction to obtain an organic phase; washing with water and sodium chloride solution in turn, drying with sodium sulfate, and concentrating; flash chromatography on silica gel (eluent PE/etoac=20:1) afforded compound 7 as a white solid;
compound 7 (47.6 g,136 mmol), sodium iodide (120 g,0.8 mol), zn powder (104.6 g,1.6 mol) and ethylene glycol dimethyl ether (320 mL) were mixed and then reduced under reflux with stirring for 10 hours; filtering the reaction system, pouring the filtrate obtained by filtering into water, extracting with ethyl acetate for 4 times, wherein 200mL of ethyl acetate is used for each extraction; combining the organic layers of each extraction to obtain an organic phase; washing with water and sodium chloride solution in turn, drying with sodium sulfate, and concentrating; flash chromatography on silica gel (eluent PE/EtOAc=45:1) afforded compound 1 (19.6 g) as a colorless oil.
1 H NMR(400MHz,CDCl 3 )δ:7.31(dd,J＝15.3,11.3Hz,1H,H-3),6.53(dd,J＝14.9,10.7Hz,1H,H-5),6.27-6.07(m,2H,H-4,H-6),5.94(dt,J＝10.7,7.3Hz,1H,H-7),5.84(d,J＝15.3Hz,1H,H-2),3.74(s,3H),2.12(q,J＝7.3Hz,2H),1.50-1.39(m,2H),0.92(t,J＝7.4Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ:167.8,145.2,141.5,140.7,130.1,127.8,119.6,51.6,35.2,22.3,13.8.
Example 2
Preparation of compound 3a ((Z, E) -6-bromo-3, 5-hexadienyl) -1, 3-dioxolane:
the (Z, E) -7-bromo-4, 6-heptadienal (Compound 2) (95 g,0.5 mol), ethylene glycol (56 g,0.9 mol), p-toluenesulfonic acid (1.72 g,10 mmol) and benzene (500 mL) were mixed and then the aldehyde group-protecting reaction (with reflux) was carried out for 16h; the organic layer was washed with water, mixed with sodium sulfate, dried, then concentrated, and the concentrated product was purified by silica gel flash chromatography (eluent PE/etoac=20:1) to give acetal 3a (110 g) as a pale yellow oil;
1 H NMR(400MHz,CDCl 3 )δ:7.03(ddd,J＝13.3,1.6,1.2Hz,1H),6.47(dd,J＝13.3,1.3Hz,1H),5.96(ddd,J＝11.6,11.1,1.3Hz,1H),5.52(dtd,J＝11.1,7.5,1.2Hz,1H),4.79(t,J＝4Hz,1H),3.90(t,J＝6.2Hz,2H),3.78(t,J＝6.3Hz,2H),2.28-2.23(m,2H),1.69-1.63(m,2H).
13 C NMR(101MHz,CDCl 3 )δ:132.9,131.5,126.4,109.2,104.6,65.3(2C),32.0,23.0.
preparation of the compound 4a (E, E, Z) -9- (1, 3-dioxolan-2-yl) -2,4, 6-nonyltrienoic acid methyl ester:
compound 3a (93.2 g,0.4 mol), sodium acetate (65.6 g,0.8 mol), pdCl 2 (3.55 g,20 mmol), methyl acrylate (51.2 g,0.6 mol) and acetonitrile (300 mL) were mixed and Heck-coupled at 80℃for 10 hours, the reaction mixture was cooled to 30℃and then mixed with a 5% strength by mass hydrochloric acid solution to neutralize to pH 5, acetonitrile was distilled off, extraction was performed 4 times with ethyl acetate, and 300mL of ethyl acetate was used for each extraction; combining the organic layers of each extraction to obtain an organic phase; the organic phase is washed with water, dried over sodium sulfate and then concentrated; flash chromatography on silica gel (eluent PE/etoac=20:3) afforded compound 4a (64.8 g) as a pale yellow solid;
1 H NMR(400MHz,CDCl 3 )δ:7.27(dd,J＝15.3,11.2Hz,1H),6.51(dd,J＝14.8,10.7Hz,1H),6.25-6.10(m,2H),5.99-5.89(m,1H),5.85(d,J＝15.3Hz,1H),4.86(t,J＝4.6Hz,1H),3.97-3.81(m,4H),3.72(s,3H),2.27(dd,J＝15.1,7.4Hz,2H),1.81-1.72(m,2H).
13 C NMR(101MHz,CDCl 3 )δ:167.7,145.1,141.1,139.3,130.3,128.2,119.9,103.9,65.0(2C),51.6,33.2,27.5.
HRMS(ESI,m/z):[M+H] + ,Calcd for[C 13 H 19 O 4 ] + :239.1278,found:239.1278.
Preparation of the Compound 5 (E, E, Z) -10-oxo-2, 4, 6-decyltrienoic acid methyl ester
Compound 4a (57.2 g,0.24 mol) and 5% strength by mass acetone hydrochloride solution (600 mL) were mixed and deprotected at 40 ℃ for 4h with stirring; after neutralization of the reaction mixture with solid sodium carbonate, acetone was distilled off, extracted 3 times with ethyl acetate, 300mL of ethyl acetate being used for each extraction; combining the organic layers of each extraction to obtain an organic phase; washing the organic phase with saturated sodium carbonate solution and water in turn, drying with sodium sulfate, and concentrating; purification by flash chromatography on silica gel (eluent PE/etoac=5:1) afforded compound 5 (43.3 g) as a pale yellow solid;
1 H NMR(400MHz,CDCl 3 )δ:9.79(t,J＝1.6Hz,1H),7.29(dd,J＝15.3,11.2Hz,1H),6.51(dd,J＝14.9,10.7Hz,1H),6.29-6.13(m,2H),5.96-5.81(m,2H),3.74(s,3H),2.70-2.38(m,4H).
13 C NMR(101MHz,CDCl 3 )δ:201.35,167.64,144.79,140.50,137.25,131.02,128.87,120.32,51.60,42.93,25.41.
HRMS(ESI,m/z):[M+H] + ,Calcd for[C 11 H 15 O 3 ] + :195.1016,found:195.1016.
preparation of the Compound methyl 6 (E, E, Z) -10-hydroxy-2, 4, 6-decyltrienoic acid
Compound 5 (38.8 g,0.2 mol), potassium borohydride (6.48 g,120 mmol) and ethanol (400 mL) were mixed and subjected to reduction reaction (with stirring) at 0 ℃ for 3 hours; quenching the reduction reaction with 5% hydrochloric acid, and then evaporating ethanol; then extracted 4 times with ethyl acetate, 200mL ethyl acetate for each extraction; combining the organic layers of each extraction to obtain an organic phase; washing the organic phase with water and sodium chloride water in sequence, drying with sodium sulfate, and concentrating; purification by flash chromatography on silica gel (eluent PE/etoac=2:1) afforded compound 6 (31.8 g) as a white solid;
1 H NMR(400MHz,CDCl 3 )δ:7.28(dd,J＝15.3,11.3Hz,1H),6.51(dd,J＝14.9,10.7Hz,1H),6.25-6.11(m,2H),5.98-5.87(m,1H),5.85(d,J＝15.3Hz,1H),3.72(s,3H),3.64(t,J＝6.4Hz,2H),2.23(dt,J＝7.4,7.2Hz,2H),1.73-1.61(m,2H).
13 C NMR(101MHz,CDCl 3 )δ:167.80,145.11,141.15,139.62,130.41,128.18,119.85,62.26,51.61,31.92,29.36.
HRMS(ESI,m/z):[M+H] + ,Calcd for[C 11 H 17 O 3 ] + :197.1172,found:197.1165.
Preparation of Compound 1 (E, E, Z) -2,4, 6-decyltrienoic acid methyl ester
P-toluenesulfonyl chloride (38.2 g,200 mmol) was dissolved in dichloromethane (200 mL) to give a p-toluenesulfonyl chloride solution;
compound 6 (160 mmol), triethylamine (24.2 g,240 mmol), trimethylamine hydrochloride (1530 mg,16mmol,10 mol%) were dissolved in dichloromethane (200 mL) to obtain a mixed solution;
adding (stirring) the p-toluenesulfonyl chloride solution into the mixed solution at 0 ℃ to perform esterification (stirring) for 2 hours; after evaporation of acetonitrile, water was added and extraction was performed 4 times with ethyl acetate, 200mL of ethyl acetate was used for each extraction; combining the organic layers of each extraction to obtain an organic phase; washing with water and sodium chloride solution in turn, drying with sodium sulfate, and concentrating; flash chromatography on silica gel (eluent PE/etoac=20:1) afforded compound 7 as a white solid;
compound 7 (46 g,131 mmol), sodium iodide (120 g,0.8 mol), zn powder (104.6 g,1.6 mol) and ethylene glycol dimethyl ether (320 mL) were mixed and then reduced under reflux with stirring for 10 hours; filtering the reaction system, pouring the filtrate obtained by filtering into water, extracting with ethyl acetate for 4 times, wherein 200mL of ethyl acetate is used for each extraction; combining the organic layers of each extraction to obtain an organic phase; washing with water and sodium chloride solution in turn, drying with sodium sulfate, and concentrating; flash chromatography on silica gel (eluent PE/EtOAc=45:1) afforded compound 1 (17.9 g) as a colorless oil.
1 H NMR(400MHz,CDCl 3 )δ:7.31(dd,J＝15.3,11.3Hz,1H,H-3),6.53(dd,J＝14.9,10.7Hz,1H,H-5),6.27-6.07(m,2H,H-4,H-6),5.94(dt,J＝10.7,7.3Hz,1H,H-7),5.84(d,J＝15.3Hz,1H,H-2),3.74(s,3H),2.12(q,J＝7.3Hz,2H),1.50-1.39(m,2H),0.92(t,J＝7.4Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ:167.8,145.2,141.5,140.7,130.1,127.8,119.6,51.6,35.2,22.3,13.8.
Example 3
Preparation of compound 3b (E, Z) -1-bromo-7, 7-dimethoxy-1, 3-heptadiene:
(Z, E) -7-bromo-4, 6-heptadienal (Compound 2) (95 g,0.5 mol), trimethyl orthoformate (159 g,1.5 mol), concentrated sulfuric acid (1 mL) were dissolved in methanol (500 mL), and the aldehyde group was allowed to undergo a protection reaction (with stirring) at 30℃for 5 hours, quenched by addition of sodium carbonate, and distilled off; extraction with ethyl acetate was 3 times, 300mL of ethyl acetate was used for each extraction; combining the organic layers of each extraction to obtain an organic phase; the organic layer was washed with water, mixed with sodium sulfate, dried, then concentrated, and the concentrated product purified by silica gel flash chromatography (eluent PE/etoac=20:1) to afford acetal 3b (112 g, 95%) as a pale yellow oil;
1 HNMR(400MHz,CDCl 3 )δ:7.02(ddd,J＝13.3,11.6,1.2Hz,1H),6.45(dd,J＝13.3,1.3Hz,1H),5.98(ddd,J＝11.6,11.1,1.3Hz,1H),5.55(dtd,J＝11.1,7.5,1.2Hz,1H),4.28(t,J＝5.7Hz,1H),3.24(s,6H),2.28-2.23(m,2H),1.69-1.63(m,2H)；
13 C NMR(100MHz,CDCl 3 )δ:132.9,131.5,126.4,109.2,103.7,52.8,32.0,23.0.
preparation of compound 4b (E, Z) -10, 10-dimethoxy-2, 4, 6-decyltrienoic acid methyl ester:
compound 3b (94 g,0.4 mol), sodium carbonate (84.8 g,0.8 mol), pdCl 2 (3.55 g,20 mmol), methyl acrylate (51.2 g,0.6 mol) and N, N-dimethylacetamide (400 mL) were mixed and subjected to Heck coupling reaction at 80℃for 8 hours, the reaction mixture was cooled to 30℃and then mixed with a 5% strength by mass hydrochloric acid solution to neutralize to pH 5, extraction was performed 4 times with ethyl acetate, and 300mL of ethyl acetate was used for each extraction; combining the organic layers of each extraction to obtain an organic phase; the organic phase is washed with water, dried over sodium sulfate and then concentrated; flash chromatography on silica gel (eluent PE/etoac=20:3) afforded compound 4b (69.2 g, 72%) as a pale yellow solid;
1 H NMR(400MHz,CDCl 3 )δ:7.27(dd,J＝15.3,11.2Hz,1H),6.51(dd,J＝14.8,10.7Hz,1H),6.25-6.10(m,2H),5.99-5.89(m,1H),5.85(d,J＝15.3Hz,1H),4.38(t,J＝4.6Hz,1H),3.72(s,3H),3.37(s,6H),2.27(dd,J＝15.1,7.4Hz,2H),1.81-1.72(m,2H).
13 C NMR(101MHz,CDCl 3 )δ:167.7,145.1,141.1,139.3,130.3,128.2,119.9,104.5,53.2(2C),51.7,33.4,27.8.
Preparation of the Compound 5 (E, E, Z) -10-oxo-2, 4, 6-decyltrienoic acid methyl ester
Compound 4b (57.7 g,0.24 mol) and a solution of p-toluenesulfonic acid (2 g,12 mmol) in acetone (480 mL) were mixed and deprotected at 40 ℃ for 5h with stirring; after neutralization of the reaction mixture with solid sodium carbonate, acetone was distilled off, extracted 3 times with ethyl acetate, 300mL of ethyl acetate being used for each extraction; combining the organic layers of each extraction to obtain an organic phase; washing the organic phase with saturated sodium carbonate solution and water in turn, drying with sodium sulfate, and concentrating; purification by flash chromatography on silica gel (eluent PE/etoac=5:1) afforded compound 5 (44.3 g, 95%) as a pale yellow solid;
1 H NMR(400MHz,CDCl 3 )δ:9.79(t,J＝1.6Hz,1H),7.29(dd,J＝15.3,11.2Hz,1H),6.51(dd,J＝14.9,10.7Hz,1H),6.29-6.13(m,2H),5.96-5.81(m,2H),3.74(s,3H),2.70-2.38(m,4H).
13 C NMR(101MHz,CDCl 3 )δ:201.35,167.64,144.79,140.50,137.25,131.02,128.87,120.32,51.60,42.93,25.41.HRMS(ESI,m/z):[M+H] + ,Calcd for[C 11 H 15 O 3 ] + :195.1016,found:195.1016.
preparation of the Compound methyl 6 (E, E, Z) -10-hydroxy-2, 4, 6-decyltrienoic acid
Compound 5 (38.8 g,0.2 mol), potassium borohydride (6.48 g,120 mmol) and 95% ethanol (400 mL) were mixed and subjected to reduction reaction (with stirring) at 0 ℃ for 3 hours; quenching the reduction reaction with 5% hydrochloric acid, and then evaporating ethanol; then extracted 4 times with ethyl acetate, 200mL ethyl acetate for each extraction; combining the organic layers of each extraction to obtain an organic phase; washing the organic phase with water and sodium chloride water in sequence, drying with sodium sulfate, and concentrating; purification by flash chromatography on silica gel (eluent PE/etoac=2:1) afforded compound 6 (33.4 g, 85%) as a white solid;
1 H NMR(400MHz,CDCl 3 )δ:7.28(dd,J＝15.3,11.3Hz,1H),6.51(dd,J＝14.9,10.7Hz,1H),6.25-6.11(m,2H),5.98-5.87(m,1H),5.85(d,J＝15.3Hz,1H),3.72(s,3H),3.64(t,J＝6.4Hz,2H),2.23(dt,J＝7.4,7.2Hz,2H),1.73-1.61(m,2H).
13 C NMR(101MHz,CDCl 3 )δ:167.80,145.11,141.15,139.62,130.41,128.18,119.85,62.26,51.61,31.92,29.36.HRMS(ESI,m/z):[M+H] + ,Calcd for[C 11 H 17 O 3 ] + :197.1172,found:197.1165.
Preparation of Compound 1 (E, E, Z) -2,4, 6-decyltrienoic acid methyl ester
P-toluenesulfonyl chloride (38.2 g,200 mmol) was dissolved in dichloromethane (200 mL) to give a p-toluenesulfonyl chloride solution;
compound 6 (160 mmol), triethylamine (24.2 g,240 mmol), trimethylamine hydrochloride (1530 mg,16mmol,10 mol%) were dissolved in dichloromethane (200 mL) to obtain a mixed solution;
adding (stirring) the p-toluenesulfonyl chloride solution into the mixed solution at 0 ℃ to perform esterification (stirring) for 2 hours; after evaporation of acetonitrile, water was added and extraction was performed 4 times with ethyl acetate, 200mL of ethyl acetate was used for each extraction; combining the organic layers of each extraction to obtain an organic phase; washing with water and sodium chloride solution in turn, drying with sodium sulfate, and concentrating; flash chromatography on silica gel (eluent PE/etoac=20:1) afforded compound 7 as a white solid;
compound 7 (46 g,131 mmol), sodium iodide (120 g,0.8 mol), zn powder (104.6 g,1.6 mol) and ethylene glycol dimethyl ether (320 mL) were mixed and then reduced under reflux with stirring for 10 hours; filtering the reaction system, pouring the filtrate obtained by filtering into water, extracting with ethyl acetate for 4 times, wherein 200mL of ethyl acetate is used for each extraction; combining the organic layers of each extraction to obtain an organic phase; washing with water and sodium chloride solution in turn, drying with sodium sulfate, and concentrating; flash chromatography on silica gel (eluent PE/EtOAc=45:1) afforded compound 1 (17.9 g) as a colorless oil.
1 H NMR(400MHz,CDCl 3 )δ:7.31(dd,J＝15.3,11.3Hz,1H,H-3),6.53(dd,J＝14.9,10.7Hz,1H,H-5),6.27-6.07(m,2H,H-4,H-6),5.94(dt,J＝10.7,7.3Hz,1H,H-7),5.84(d,J＝15.3Hz,1H,H-2),3.74(s,3H),2.12(q,J＝7.3Hz,2H),1.50-1.39(m,2H),0.92(t,J＝7.4Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ:167.8,145.2,141.5,140.7,130.1,127.8,119.6,51.6,35.2,22.3,13.8.
Example 4
Preparation of compound 3c diacetic acid (Z, E) -7-bromo-4, 6-heptadiene-1, 1-diester:
(Z, E) -7-bromo-4, 6-heptadienal (Compound 2) (95 g,0.5 mol), acetic anhydride (153 g,1.5 mol) and concentrated sulfuric acid (1 mL) were mixed, the aldehyde group was protected at 25℃for 5 hours (with stirring), and the reaction was quenched by addition of saturated aqueous sodium carbonate; extraction with ethyl acetate was 3 times, 300mL of ethyl acetate was used for each extraction; combining the organic layers extracted each time to obtain an organic layer; the organic layer was washed with water, mixed with sodium sulfate, dried, then concentrated, and the concentrated product purified by silica gel flash chromatography (eluent PE/etoac=20:1) to afford acetal 3c (134 g, 92%) as a pale yellow oil;
1 H NMR(400MHz,CDCl 3 )δ:7.01(ddd,J＝13.3,11.6,1.2Hz,1H),6.41(dd,J＝13.3,1.3Hz,1H),6.32(t,J＝5.9Hz,1H),5.93(ddd,J＝11.6,11.1,1.3Hz,1H),5.49(dtd,J＝11.1,7.5,1.2Hz,1H),2.40(s,6H),2.28-2.23(m,2H),1.69-1.63(m,2H)；
13 C NMR(100MHz,CDCl 3 )δ:170.1(2C),132.7,131.7,126.8,109.5,101.1,33.2,23.6,21.2(2C).
preparation of compound 4c diacetic acid (Z, E) -10-methoxy-10-oxo-4, 6, 8-decyltriene-1, 1-diester:
compound 3c (94 g,0.4 mol), sodium acetate (65.6 g,0.8 mol), pd (OAc) 2 (4.5 g,20 mmol), methyl acrylate (51.2 g,0.6 mol) and tetrahydrofuran (400 mL) were mixed and Heck-coupled at 80℃for 16h, the reaction mixture was cooled to 30℃and then mixed with 5% strength by mass hydrochloric acid solution to neutralize to pH 5, extraction was performed 4 times with ethyl acetate using 300mL ethyl acetate for each extraction; combining the organic layers of each extraction to obtain an organic phase; the organic phase is washed with water, dried over sodium sulfate and then concentrated; flash chromatography on silica gel (eluent PE/etoac=20:3) gives Pale yellow solid compound 4c (80.6 g, 68%);
1 H NMR(400MHz,CDCl 3 )δ:7.28(dd,J＝15.3,11.2Hz,1H),6.50(dd,J＝14.8,10.7Hz,1H),6.33(t,J＝5.8Hz,1H),6.28-6.11(m,2H),5.99-5.89(m,1H),5.87(d,J＝15.3Hz,1H),3.72(s,3H),2.38(s,6H),2.27(dd,J＝15.1,7.4Hz,2H),1.81-1.72(m,2H).
13 C NMR(101MHz,CDCl 3 )δ:170.2(2C),167.7,145.1,141.1,139.3,130.3,128.2,119.9,101.2,51.7,33.4,27.8,20.9(2C).
preparation of the Compound 5 (E, E, Z) -10-oxo-2, 4, 6-decyltrienoic acid methyl ester
Compound 4c (71 g,0.24 mol) and montmorillonite K-10 (13.5 g,48 mmol) were mixed with dichloromethane (1L) and deprotected at 40 ℃ for 6h (with stirring); after filtration, the organic phase is washed with saturated sodium carbonate solution and water in sequence, dried with sodium sulfate and then concentrated; purification by flash chromatography on silica gel (eluent PE/etoac=5:1) afforded compound 5 (43.8 g, 94%) as a pale yellow solid;
1 H NMR(400MHz,CDCl 3 )δ:9.79(t,J＝1.6Hz,1H),7.29(dd,J＝15.3,11.2Hz,1H),6.51(dd,J＝14.9,10.7Hz,1H),6.29-6.13(m,2H),5.96-5.81(m,2H),3.74(s,3H),2.70-2.38(m,4H).
13 C NMR(101MHz,CDCl 3 )δ:201.35,167.64,144.79,140.50,137.25,131.02,128.87,120.32,51.60,42.93,25.41.HRMS(ESI,m/z):[M+H] + ,Calcd for[C 11 H 15 O 3 ] + :195.1016,found:195.1016.
preparation of the Compound methyl 6 (E, E, Z) -10-hydroxy-2, 4, 6-decyltrienoic acid
Compound 5 (38.8 g,0.2 mol), potassium borohydride (6.48 g,120 mmol) and 95% ethanol (400 mL) were mixed and subjected to reduction reaction (with stirring) at 0 ℃ for 3 hours; quenching the reduction reaction with 5% hydrochloric acid, and then evaporating ethanol; then extracted 4 times with ethyl acetate, 200mL ethyl acetate for each extraction; combining the organic layers of each extraction to obtain an organic phase; washing the organic phase with water and sodium chloride water in sequence, drying with sodium sulfate, and concentrating; purification by flash chromatography on silica gel (eluent PE/etoac=2:1) afforded compound 6 (33.4 g, 85%) as a white solid;
1 H NMR(400MHz,CDCl 3 )δ:7.28(dd,J＝15.3,11.3Hz,1H),6.51(dd,J＝14.9,10.7Hz,1H),6.25-6.11(m,2H),5.98-5.87(m,1H),5.85(d,J＝15.3Hz,1H),3.72(s,3H),3.64(t,J＝6.4Hz,2H),2.23(dt,J＝7.4,7.2Hz,2H),1.73-1.61(m,2H).
13 C NMR(101MHz,CDCl 3 )δ:167.80,145.11,141.15,139.62,130.41,128.18,119.85,62.26,51.61,31.92,29.36.HRMS(ESI,m/z):[M+H] + ,Calcd for[C 11 H 17 O 3 ] + :197.1172,found:197.1165.
preparation of Compound 1 (E, E, Z) -2,4, 6-decyltrienoic acid methyl ester
P-toluenesulfonyl chloride (38.2 g,200 mmol) was dissolved in dichloromethane (200 mL) to give a p-toluenesulfonyl chloride solution;
compound 6 (160 mmol), triethylamine (24.2 g,240 mmol), trimethylamine hydrochloride (1530 mg,16mmol,10 mol%) were dissolved in dichloromethane (200 mL) to obtain a mixed solution;
adding (stirring) the p-toluenesulfonyl chloride solution into the mixed solution at 0 ℃ to perform esterification (stirring) for 2 hours; after evaporation of acetonitrile, water was added and extraction was performed 4 times with ethyl acetate, 200mL of ethyl acetate was used for each extraction; combining the organic layers of each extraction to obtain an organic phase; washing with water and sodium chloride solution in turn, drying with sodium sulfate, and concentrating; flash chromatography on silica gel (eluent PE/etoac=20:1) afforded compound 7 as a white solid;
compound 7 (46 g,131 mmol), sodium iodide (120 g,0.8 mol), zn powder (104.6 g,1.6 mol) and ethylene glycol dimethyl ether (320 mL) were mixed and then reduced under reflux with stirring for 10 hours; filtering the reaction system, pouring the filtrate obtained by filtering into water, extracting with ethyl acetate for 4 times, wherein 200mL of ethyl acetate is used for each extraction; combining the organic layers of each extraction to obtain an organic phase; washing with water and sodium chloride solution in turn, drying with sodium sulfate, and concentrating; flash chromatography on silica gel (eluent PE/EtOAc=45:1) afforded compound 1 (17.9 g) as a colorless oil.
1 H NMR(400MHz,CDCl 3 )δ:7.31(dd,J＝15.3,11.3Hz,1H,H-3),6.53(dd,J＝14.9,10.7Hz,1H,H-5),6.27-6.07(m,2H,H-4,H-6),5.94(dt,J＝10.7,7.3Hz,1H,H-7),5.84(d,J＝15.3Hz,1H,H-2),3.74(s,3H),2.12(q,J＝7.3Hz,2H),1.50-1.39(m,2H),0.92(t,J＝7.4Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ:167.8,145.2,141.5,140.7,130.1,127.8,119.6,51.6,35.2,22.3,13.8.
The purity of the intermediates and final products of examples 1 to 4 were measured by gas chromatography and the purity and yield are shown in Table 1.
TABLE 1 purity and yield of intermediates and final products in examples 1-4
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According to the hydrogen mass spectrum detection result and the carbon mass spectrum detection result of the intermediate and the compound, the preparation method provided by the invention can be used for preparing (E, E, Z) -2,4, 6-methyl decatrienoate; as can be seen from the results of Table 1, the (E, E, Z) -2,4, 6-methyltrienoic acid methyl ester prepared by the preparation method of the present invention has higher purity and yield.
Although the foregoing embodiments have been described in some, but not all, embodiments of the invention, it should be understood that other embodiments may be devised in accordance with the present embodiments without departing from the spirit and scope of the invention.
Claims (10)
1. An ester compound having a structure represented by formula 1:
2. the method for preparing the ester compound according to claim 1, comprising the steps of:
mixing the compound 2, a protective agent, a first catalyst and a first organic solvent, and performing an aldehyde group protection reaction to obtain a compound 3;
mixing the compound 3, methyl acrylate, an alkaline substance, a second catalyst and a second organic solvent, and performing Heck coupling reaction to obtain a compound 4;
Mixing the compound 4 with an acidic solvent for deprotection reaction to obtain a compound 5;
wherein R is 1 Is that(CH 3 O) 2 CH-or (CH) 3 COO) 2 CH-。
3. The preparation method according to claim 2, wherein the protective agent comprises ethylene glycol, trimethyl orthoformate, triethyl orthoformate, acetic anhydride and propionic anhydride;
the first catalyst comprises phosphoric acid, p-toluenesulfonic acid, sulfuric acid or methanesulfonic acid;
the first organic solvent comprises dichloromethane, chloroform, dichloroethane, benzene, toluene or methanol;
the molar ratio of the compound 2 to the protective agent is 1:1.2-2;
the temperature of the aldehyde group protection reaction is 20-120 ℃ and the time is 4-16 h.
4. The production method according to claim 2, wherein the basic substance comprises triethylamine, diisopropylethylamine, sodium acetate, sodium carbonate, potassium carbonate, or calcium carbonate;
the second catalyst comprises palladium acetate, palladium chloride and palladium trifluoroacetate;
the second organic solvent comprises N, N-dimethylformamide, tetrahydrofuran, acetonitrile, N-dimethylacetamide or hexamethylphosphoric triamide;
the molar ratio of the compound 3 to the methyl acrylate is 2:2.5-3.5;
the temperature of the Heck coupling reaction is 25-100 ℃ and the time is 5-26 h.
5. The preparation method according to claim 2, wherein the acidic solvent comprises formic acid aqueous solution, acetic acid aqueous solution, p-toluenesulfonic acid acetone solution, hydrochloric acid acetone solution, sulfuric acid acetone solution or a mixture of montmorillonite and methylene chloride;
the volume ratio of the substance amount of the compound 4 to the acid solvent is 0.24 mol:550-650 mL;
the temperature of the deprotection reaction is 25-100 ℃ and the time is 1-8 h.
6. The use of an ester compound as claimed in claim 1 or an ester compound as produced by the production method as claimed in any one of claims 2 to 5 for producing compound 6;
7. an ester derivative having a structure represented by compound 4 or compound 6:
8. a method for preparing (E, E, Z) -2,4, 6-methyl decatrienoate, which comprises the following steps:
mixing a compound 6, p-toluenesulfonyl chloride, an acid binding agent, trimethylamine hydrochloride and a third organic solvent for esterification reaction, wherein the compound 7;
mixing the compound 7, sodium iodide, zinc and a fourth organic solvent for a first reduction reaction to obtain the (E, E, Z) -2,4, 6-methyltrienoic acid methyl ester;
compound 7 is
9. The method of claim 8, wherein the acid binding agent comprises triethylamine, pyridine, or trimethylamine;
The third organic solvent comprises acetonitrile, dichloromethane, benzene or toluene; the fourth organic solvent comprises ethylene glycol dimethyl ether, tetrahydrofuran or methyltetrahydrofuran;
the mol ratio of the compound 6 to the p-toluenesulfonyl chloride is 1.6:1.8-2.2;
the mass ratio of the compound 7 to the zinc is 1:1-15;
the temperature of the esterification reaction is 0-5 ℃ and the time is 1.8-2.2 h;
the first reduction reaction is carried out under the reflux condition, and the time of the first reduction reaction is 9-11 h.
10. The preparation method according to claim 8, wherein the preparation method of the compound 6 comprises the following steps:
mixing the compound 2, a protective agent, a first catalyst and a first organic solvent, and performing an aldehyde group protection reaction to obtain a compound 3;
mixing the compound 3, methyl acrylate, an alkaline substance, a second catalyst and a second organic solvent, and performing Heck coupling reaction to obtain a compound 4;
mixing the compound 4 with an acidic solvent for deprotection reaction to obtain a compound 5;
and mixing the compound 5, a reducing agent and a fifth organic solvent, and performing a second reduction reaction to obtain the compound 6.
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