CN106905154A - A kind of method of synthesis of natural product salviandic acid A methyl esters - Google Patents
A kind of method of synthesis of natural product salviandic acid A methyl esters Download PDFInfo
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- CN106905154A CN106905154A CN201710059688.4A CN201710059688A CN106905154A CN 106905154 A CN106905154 A CN 106905154A CN 201710059688 A CN201710059688 A CN 201710059688A CN 106905154 A CN106905154 A CN 106905154A
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- 239000002253 acid Substances 0.000 title claims abstract description 42
- 150000004702 methyl esters Chemical class 0.000 title claims abstract description 30
- 229930014626 natural product Natural products 0.000 title claims abstract description 8
- 230000015572 biosynthetic process Effects 0.000 title claims description 71
- 238000003786 synthesis reaction Methods 0.000 title claims description 64
- 238000000034 method Methods 0.000 title claims description 13
- 230000004224 protection Effects 0.000 claims abstract description 40
- 150000002148 esters Chemical group 0.000 claims abstract description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 8
- -1 t-Butyldimethylsilyl protection group Chemical group 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 132
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 113
- 238000006243 chemical reaction Methods 0.000 claims description 98
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 90
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 81
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 80
- 239000000243 solution Substances 0.000 claims description 71
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 46
- 239000002904 solvent Substances 0.000 claims description 46
- 239000011780 sodium chloride Substances 0.000 claims description 45
- 238000005406 washing Methods 0.000 claims description 45
- 238000001914 filtration Methods 0.000 claims description 43
- 239000012074 organic phase Substances 0.000 claims description 43
- 230000006837 decompression Effects 0.000 claims description 41
- 229910052757 nitrogen Inorganic materials 0.000 claims description 40
- 238000000605 extraction Methods 0.000 claims description 37
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 31
- 238000001035 drying Methods 0.000 claims description 30
- 238000003756 stirring Methods 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- 239000007787 solid Substances 0.000 claims description 21
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 20
- 238000010898 silica gel chromatography Methods 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 15
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 15
- 238000000926 separation method Methods 0.000 claims description 15
- 239000007864 aqueous solution Substances 0.000 claims description 13
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 12
- QAIPRVGONGVQAS-DUXPYHPUSA-N trans-caffeic acid Chemical compound OC(=O)\C=C\C1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-DUXPYHPUSA-N 0.000 claims description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 11
- 239000000741 silica gel Substances 0.000 claims description 11
- 229910002027 silica gel Inorganic materials 0.000 claims description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- 238000011097 chromatography purification Methods 0.000 claims description 10
- 239000012634 fragment Substances 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- 238000007445 Chromatographic isolation Methods 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 150000001299 aldehydes Chemical class 0.000 claims description 9
- 239000013078 crystal Substances 0.000 claims description 9
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 7
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- ACEAELOMUCBPJP-UHFFFAOYSA-N (E)-3,4,5-trihydroxycinnamic acid Natural products OC(=O)C=CC1=CC(O)=C(O)C(O)=C1 ACEAELOMUCBPJP-UHFFFAOYSA-N 0.000 claims description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-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
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 6
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 6
- 229940074360 caffeic acid Drugs 0.000 claims description 6
- 235000004883 caffeic acid Nutrition 0.000 claims description 6
- QAIPRVGONGVQAS-UHFFFAOYSA-N cis-caffeic acid Natural products OC(=O)C=CC1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-UHFFFAOYSA-N 0.000 claims description 6
- 150000002460 imidazoles Chemical class 0.000 claims description 6
- CUXQLKLUPGTTKL-UHFFFAOYSA-M microcosmic salt Chemical compound [NH4+].[Na+].OP([O-])([O-])=O CUXQLKLUPGTTKL-UHFFFAOYSA-M 0.000 claims description 6
- 238000012544 monitoring process Methods 0.000 claims description 6
- 239000003921 oil Substances 0.000 claims description 6
- JJVNINGBHGBWJH-UHFFFAOYSA-N ortho-vanillin Chemical compound COC1=CC=CC(C=O)=C1O JJVNINGBHGBWJH-UHFFFAOYSA-N 0.000 claims description 6
- 239000000047 product Substances 0.000 claims description 6
- 239000011435 rock Substances 0.000 claims description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 6
- YWWDBCBWQNCYNR-UHFFFAOYSA-N trimethylphosphine Chemical compound CP(C)C YWWDBCBWQNCYNR-UHFFFAOYSA-N 0.000 claims description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
- 239000012043 crude product Substances 0.000 claims description 5
- 239000012071 phase Substances 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 5
- 235000011152 sodium sulphate Nutrition 0.000 claims description 5
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 5
- 238000007039 two-step reaction Methods 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000006130 Horner-Wadsworth-Emmons olefination reaction Methods 0.000 claims description 4
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 4
- 230000008859 change Effects 0.000 claims description 4
- 239000007795 chemical reaction product Substances 0.000 claims description 4
- 229940125782 compound 2 Drugs 0.000 claims description 4
- 239000000284 extract Substances 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 229910052698 phosphorus Inorganic materials 0.000 claims description 4
- 239000011574 phosphorus Substances 0.000 claims description 4
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims description 3
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 3
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 claims description 3
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims description 3
- 241000972773 Aulopiformes Species 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 229940126657 Compound 17 Drugs 0.000 claims description 3
- 241000736199 Paeonia Species 0.000 claims description 3
- 235000006484 Paeonia officinalis Nutrition 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 239000005864 Sulphur Substances 0.000 claims description 3
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 3
- 235000019270 ammonium chloride Nutrition 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 3
- 239000012230 colorless oil Substances 0.000 claims description 3
- 229940125773 compound 10 Drugs 0.000 claims description 3
- 229940125797 compound 12 Drugs 0.000 claims description 3
- 229940126543 compound 14 Drugs 0.000 claims description 3
- 229940126214 compound 3 Drugs 0.000 claims description 3
- 230000032050 esterification Effects 0.000 claims description 3
- 238000005886 esterification reaction Methods 0.000 claims description 3
- 150000002240 furans Chemical class 0.000 claims description 3
- 150000002527 isonitriles Chemical class 0.000 claims description 3
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 3
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical class CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- 238000006386 neutralization reaction Methods 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 150000003222 pyridines Chemical class 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- 230000000171 quenching effect Effects 0.000 claims description 3
- 235000019515 salmon Nutrition 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 229910052710 silicon Inorganic materials 0.000 claims description 3
- 239000010703 silicon Substances 0.000 claims description 3
- 235000010265 sodium sulphite Nutrition 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 3
- NTJBWZHVSJNKAD-UHFFFAOYSA-N triethylazanium;fluoride Chemical compound [F-].CC[NH+](CC)CC NTJBWZHVSJNKAD-UHFFFAOYSA-N 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 238000005598 Sharpless reaction Methods 0.000 claims description 2
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 3
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims 3
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims 2
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 claims 1
- YGZSVWMBUCGDCV-UHFFFAOYSA-N chloro(methyl)silane Chemical compound C[SiH2]Cl YGZSVWMBUCGDCV-UHFFFAOYSA-N 0.000 claims 1
- 235000019441 ethanol Nutrition 0.000 claims 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 claims 1
- 238000013461 design Methods 0.000 abstract description 7
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 abstract description 5
- 238000007086 side reaction Methods 0.000 abstract description 4
- 238000010189 synthetic method Methods 0.000 abstract description 4
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 abstract description 2
- 238000005834 sharpless asymmetric dihydroxylation reaction Methods 0.000 abstract description 2
- KCWYOFZQRFCIIE-UHFFFAOYSA-N ethylsilane Chemical compound CC[SiH3] KCWYOFZQRFCIIE-UHFFFAOYSA-N 0.000 abstract 1
- 0 *C1C(*)=CC(CP)=CC1 Chemical compound *C1C(*)=CC(CP)=CC1 0.000 description 8
- 239000000126 substance Substances 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000013329 compounding Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- 206010019668 Hepatic fibrosis Diseases 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- FKDWIMIRRGGDDE-UHFFFAOYSA-N [N].CCN(CC)CC Chemical compound [N].CCN(CC)CC FKDWIMIRRGGDDE-UHFFFAOYSA-N 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000000702 anti-platelet effect Effects 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 150000001721 carbon Chemical class 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- QABCGOSYZHCPGN-UHFFFAOYSA-N chloro(dimethyl)silicon Chemical compound C[Si](C)Cl QABCGOSYZHCPGN-UHFFFAOYSA-N 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 231100000753 hepatic injury Toxicity 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 150000003949 imides Chemical class 0.000 description 2
- QCCWVNLOJADEAV-UHFFFAOYSA-N n,n-dimethyl-1h-pyrrol-3-amine Chemical class CN(C)C=1C=CNC=1 QCCWVNLOJADEAV-UHFFFAOYSA-N 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- GTNUHQSDXQLISO-UHFFFAOYSA-N Bc(c(C=C)c1OC(C)=O)ccc1OC Chemical compound Bc(c(C=C)c1OC(C)=O)ccc1OC GTNUHQSDXQLISO-UHFFFAOYSA-N 0.000 description 1
- KOJNAYXBXYXANE-UHFFFAOYSA-N Cc(ccc(Br)c1C=C)c1O Chemical compound Cc(ccc(Br)c1C=C)c1O KOJNAYXBXYXANE-UHFFFAOYSA-N 0.000 description 1
- 240000007164 Salvia officinalis Species 0.000 description 1
- YMGFTDKNIWPMGF-QHCPKHFHSA-N Salvianolic acid A Natural products OC(=O)[C@H](Cc1ccc(O)c(O)c1)OC(=O)C=Cc2ccc(O)c(O)c2C=Cc3ccc(O)c(O)c3 YMGFTDKNIWPMGF-QHCPKHFHSA-N 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- XLXGCFTYXICXJF-UHFFFAOYSA-N ethylsilicon Chemical compound CC[Si] XLXGCFTYXICXJF-UHFFFAOYSA-N 0.000 description 1
- OUUQCZGPVNCOIJ-UHFFFAOYSA-N hydroperoxyl Chemical compound O[O] OUUQCZGPVNCOIJ-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 235000005412 red sage Nutrition 0.000 description 1
- 235000002020 sage Nutrition 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the new synthetic method to natural products salviandic acid A methyl esters; synthetic route design is unique, novel; Key Strategy and step are using the t-Butyldimethylsilyl protection group being easily removed as the protection group of phenolic hydroxyl group to avoid side reaction; reduce the hydroxyl chiral centre for building C 8' with ethylsilane again using Sharpless asymmetric dihydroxylation reactions; the α of C7 9 in salviandic acid A methyl esters, β beta-unsaturated esters structures are built using Horner Wadsworth Emmons reactions.Synthetic route designed by the present invention is realized to the artificial first fully synthetic of salviandic acid A methyl esters, and route is a kind of synthetic method of convergence type, and required raw material is cheap and easy to get, and product yield is higher, easy to operate, and stability is high, reproducible.
Description
Technical field
The invention belongs to chemical field.Being related to a class has antioxidation, antithrombus formation, anti-platelet activity, anti-
Diabetes, protection acute hepatic injury, anti-hepatic fibrosis and prevention of tumor, the natural product for suppressing the effects such as tumour cell growth
The new synthetic method of thing salviandic acid A methyl esters.Its Key Strategy and step are using the t-Butyldimethylsilyl being easily removed
Protection group, to avoid side reaction, ethyl silicon is used using Sharpless asymmetric dihydroxylation reactions again as the protection group of phenolic hydroxyl group
Alkane reduction builds the hydroxyl chiral centre of C-8', and salviandic acid A first is built using Horner-Wadsworth-Emmons reactions
The alpha, beta-unsaturated esters structure of C7-9 in ester.
Technical background
Natural products salviandic acid A methyl esters (such as Fig. 1) be by Chen Zhengxiong et al. the eighties in 20th century, it is water-soluble in various reds sage root
When property composition carries out system research, ten are separated to from the water soluble ingredient in the red sage root with the technology of various chromatographic purifications
Several pressure differential selfs, including salviandic acid A methyl esters.Pharmacological activity research afterwards shows that salviandic acid A methyl esters has
Have significant anti-oxidant, antithrombus formation, anti-platelet activity, anti-diabetic, protection acute hepatic injury, anti-hepatic fibrosis and
Prevention of tumor etc. is acted on.Its good pharmacological activity and bioactivity, have attracted numerous chemical synthesis men, biomedical family and medicine
The great interest of neo-confucian.
Synthesis for salviandic acid A and salviandic acid A methyl esters is reported there is presently no its reason is probably due to exposed phenol
Hydroxyl easily causes many side reactions.Therefore, the present invention selects the fert-butyidimethylsilyl of easily removing for the protection group of phenolic hydroxyl group
Silicon-based protecting group, filters out suitable removal methods, finally successfully prepares salviandic acid A methyl esters.
The content of the invention
The synthetic method of the salviandic acid A methyl esters that the present invention is provided aims at the artificial synthesized of salviandic acid A methyl esters, therefore sets
Meter with 4- methyl catechols cheap and easy to get, o-vanillin, caffeic acid etc. is base stock, using convergence type synthesis strategy reality
It is existing.It is as shown in Figure 2 against compounding design：The synthesis final step design of end-product salviandic acid A methyl esters 1 is removed by compound 2
Hydroxyl Deprotection is obtained, and the compounding design of the alpha, beta-unsaturated esters structure of the C7-9 in the middle of 2 is passed through by fragment 3 and fragment 4
Horner-Wadsworth-Emmons is synthesized and obtains.The wherein synthesis of fragment 3 is protected by 4- methyl catechols through perhydroxyl radical
Shield, bromo, Wittig reactions etc. are obtained, and the synthesis of fragment 4 is through Sharpless bishydroxies, and triethyl silicane reduction, esterification is anti-
Should wait prepared, the fragment 3 and fragment 4 that will finally prepare are reacted through Horner-Wadsworth-Emmons, the process such as Deprotection
Obtain salviandic acid A methyl esters.
Technical solution of the present invention is as follows：
A kind of method of synthesis of natural product salviandic acid A methyl esters, salviandic acid A methyl esters is type I compound：By the compound of formula II
Type I compound is obtained after the condition of triethylamine hydrofluoride removes t-Butyldimethylsilyl protection group；
The compound of formula II is obtained：The compound of formula III, IV compound
The alpha, beta-unsaturated esters structure for reacting structure C7-9 by Horner-Wadsworth-Emmons obtains the chemical combination of formula II
Thing；
The compound of formula III is obtained：Formula V, VI compound
Reacted by Wittig and build C7 " -8 " unsaturated carbon chains obtain the compound of formula III；
The compound of formula IV is obtained：Including formula VII, VIII compound
The compound of formula IV is obtained by esterification；
The compound of formula VII is obtained：The compound of formula Ⅸ
After the condition of Sharplesss dihydroxylateds carries out bishydroxy to C7'-8', then in trifluoroacetic acid and three second
The single hydroxyl chiral centre of C8' is built under conditions of base silane, the compound of formula VII is obtained.
By obtaining V compound with o-vanillin as raw material.
By obtaining the compound of formula VI with 4- methyl catechols as raw material.
By obtaining the compound of formula Ⅸ with caffeic acid as raw material.
Described method, step is specially：
A. synthesize microcosmic salt 7 first, can be synthesized through two steps by initial feed 4 and obtained：
(1) synthesis of the compound of formula 9
At 0 DEG C, compound 4- methyl catechols (5.0g, 40.28mmol) of formula 8 is dissolved in DMF
(DMF) in, under nitrogen protection, imidazoles (13.7g, 201.39mmol) and tert-butyl chloro-silicane (TBSCl) are added
(18.2g, 120.83mmol), then rises to normal temperature, is stirred overnight；Point plate monitoring reaction afterwards, is quenched to being fully completed with frozen water
Go out reaction, then extract (3 × 150mL) with dichloromethane, merge organic phase, plus the washing of saturation NaCl solution, anhydrous sodium sulfate
Dry, filtering after decompression steams solvent, the compound 14.20g of formula 9 is obtained through chromatogram post separation：
(2) synthesis of the compound of formula 7
Compound 9 (14.2g, 40.27mmol) is dissolved in carbon tetrachloride (80mL), and nitrogen protection is lower to add N- bromos fourth two
Acid imide (NBS) (7.88g, 44.29mmol) and the isonitrile of azo two (0.979g, 6.04mmol), after flowing back 1 hour, point plate prison
Reaction is surveyed to being fully completed, water quenching on the rocks is gone out reaction, then extracts (3 × 100mL) with dichloromethane, merges organic phase, plus satisfy
With NaCl solution washing, anhydrous sodium sulfate drying, filtering is depressurized after steaming solvent, plus the dissolving of 80mL acetonitriles, adds triphenyl
Phosphine (15.84g, 60.41mmol), after flowing back 45 minutes, solvent under reduced pressure is concentrated, then adds toluene washing, and the chemical combination of formula 7 is obtained after filtering
Thing is white powder (15.95g)；
B. next synthesize fragment aldehyde 5, can be synthesized through five steps by initial feed 6 and obtained；
(3) synthesis of the compound of formula 10
At 0 DEG C, by o-vanillin 6 (10.01g, 65.72mmol) and the 4- dimethylamino pyrroles of catalytic amount under nitrogen protection
Pyridine (0.80g, 7.89mmol) is dissolved in diisopropyl ethyl amine (32.86mL), adds acetic anhydride (8.07mL, 85.44mmol),
Then normal temperature is risen to, is stirred overnight, point plate is monitored to reaction and is fully completed；Plus the HCl solution 100mL of 2N, then add methylene chloride
(3 × 100mL) is extracted, and merges organic phase, plus the washing of saturation NaCl solution, anhydrous sodium sulfate drying, and filtering, decompression steams molten
Agent；Recrystallized with absolute ethyl alcohol, obtained the compound of formula 10 for yellow crystals 10.85g；
(4) synthesis of the compound of formula 11
At 0 DEG C, KBr (21.47g, 180.48mmol) is dissolved in water 133mL, be slowly added to bromine (3.73mL,
72.64mmol), compound 10 (10.85g, 55.88mmol), the salmon pink water of formation are added in the backward peony aqueous solution
Solution is stirred overnight at normal temperatures, and point plate is monitored to reaction and is fully completed；Filtering, ethyl acetate washing, then uses ethyl acetate
Recrystallized with n-hexane, obtained the compound of formula 11 for yellow crystals 11.44g；
(5) synthesis of the compound of formula 12
Compound 11 (11.44g, 41.89mmol) is dissolved in methanol aqueous solution (84mL), adds NaHCO3(4.93g,
58.64mmol), the yellow turbid solution of formation in stirring at normal temperature 2 hours, monitor to reaction and be fully completed by point plate, with hydrochloric acid acid
Change, add methylene chloride (3 × 80mL) extraction, merge organic phase, plus the washing of saturation NaCl solution, anhydrous sodium sulfate drying, filter,
Decompression steams solvent；Recrystallized with ethyl acetate and n-hexane, obtained the compound of formula 12 for yellow crystals 8.23g；(6) formula 13
The synthesis of compound
At 0 DEG C, under nitrogen protection, compound 12 (8.23g, 35.62mmol) is dissolved in dry dichloromethane (120mL)
In, Boron tribromide (13.47mL, 142.48mmol) is dissolved in also dry dichloromethane (60mL), then this mixed liquor is delayed
Slow to add to reaction solution, temperature rises to normal temperature, stirs 2 hours, and point plate is monitored to reaction and is fully completed；Plus saturation NaHCO3
Solution terminating reaction, then (3 × 100mL) extraction that adds methylene chloride, merge organic phase, plus the washing of saturation NaCl solution, anhydrous sulphur
Sour sodium is dried, and filtering, decompression steams solvent；It is yellow solid that the compound of formula 13 is obtained after crude on silica gel column chromatography for separation
7.34g；
(7) synthesis of the compound of formula 5
At 0 DEG C, compound 13 (7.34g, 33.82mmol) is dissolved in dry DMF (307mL), nitrogen
Triethylamine (16.50mL, 118.37mmol), DMAP (0.826g, 6.76mmol) and tertiary fourth are added under gas shielded
Base dimethylchlorosilane (TBSCl) (15.29g, 101.46mmol), temperature rises to normal temperature, is stirred overnight, and point plate is monitored to reaction
It is fully completed；Added water terminating reaction, then (3 × 80mL) extraction that adds methylene chloride, and merges organic phase, plus saturation NaCl solution is washed
Wash, anhydrous sodium sulfate drying, filter, decompression steams solvent；It is Huang that the compound of formula 5 can be obtained after crude on silica gel column chromatography for separation
Color oil product 13.86g；
C. next, the synthesis of aldehyde 3 can be synthesized by following two-step reaction and be obtained：
(8) synthesis of the compound of formula 14
At -78 DEG C, microcosmic salt 7 (19.47g, 28.06mmol) is dissolved in dry tetrahydrofuran (100mL), nitrogen is protected
Shield is lower to add n-BuLi (25.81mmol), after stirring 30 minutes, aldehyde 5 (5.0g, 11.22mmol) is dissolved in into 40mL dry
In tetrahydrofuran, then by this mixed liquor being slowly added into reaction bulb at -78 DEG C, and stir 2 hours at such a temperature, point
Plate is monitored to reaction reaction completely and terminated；Plus saturated ammonium chloride terminating reaction, then add ethyl acetate (3 × 80mL) extraction, merge
Organic phase, plus the washing of saturation NaCl solution, anhydrous sodium sulfate drying, filtering, decompression steam solvent；Crude on silica gel column chromatography
The compound as colourless oil product 6.56g of formula 14 is obtained after separation；
(9) synthesis of the compound of formula 3
At -78 DEG C, compound 14 (6.56g, 8.41mmol) is dissolved in dry tetrahydrofuran (40mL), nitrogen is protected
Shield is lower to add n-BuLi (16.82mmol), after stirring 30 minutes, by DMF (6.48mL, 84.08mmol)
Dry tetrahydrofuran (10mL) is dissolved in, this mixed liquor is slowly added into reaction bulb at -78 DEG C, 3 are stirred at this temperature
Hour, point plate is monitored to reaction and is fully completed, plus saturated ammonium chloride terminating reaction, then adds ethyl acetate (3 × 50mL) extraction, is closed
And organic phase, plus the washing of saturation NaCl solution, anhydrous sodium sulfate drying, filtering, depressurize and steam solvent；Crude on silica gel post layer
Analysis obtains the compound 5.21g of formula 3 after separating；
D. next, the synthesis of chiral phosphorus acid esters 4 can be synthesized by the following steps and be obtained：
(10) synthesis of the compound of formula 16
Under nitrogen protection, caffeic acid 15 (2.0g, 11.10mmol) is dissolved in 140mL methyl alcohol, is subsequently adding the concentrated sulfuric acid
4mL, is heated to 70 DEG C, and back flow reaction 1 hour, point plate is monitored to reaction and is fully completed；Room temperature is subsequently cooled to, saturated carbon is added
Sour hydrogen sodium water solution neutralization reaction, then (3 × 50mL) extraction that adds methylene chloride, merge organic phase, plus the washing of saturation NaCl solution,
Anhydrous sodium sulfate drying, filtering, decompression steams solvent, obtains the compound of crude product formula 16 for gray solid 2.15g；
(11) synthesis of the compound of formula 17
At 0 DEG C, under nitrogen protection, the compound of formula 16 (2.15g, 11.07mmol) is dissolved in the dry N of 60mL, N-
In dimethylformamide (DMF), imidazoles (5.28g, 77.51mmol) and tert-butyl chloro-silicane (TBSCl) are added
(5.0g, 33.22mmol), after temperature rises to normal temperature, is then reacted 6 hours at such a temperature, and point plate is monitored to reaction and tied completely
Beam；Add water and reaction is quenched, then add ethyl acetate (3 × 60mL) extraction, merge organic phase, plus the washing of saturation NaCl solution, it is anhydrous
Sodium sulphate is dried, and filtering, decompression steams solvent；The compound of formula 17 is obtained after crude on silica gel column chromatographic isolation and purification for white is solid
Body 4.74g；
(12) synthesis of the compound of formula 18
Under nitrogen protection, AD-mix- α (15.25g, 15.19mmol) and methylsulfonamides (20mmol) are dissolved in 80mL
In the tert-butyl alcohol, it is stirred vigorously, until two phase liquid all becomes transparent clear state；Then the mixture is transferred to 0 DEG C, will be changed
Compound 17 (4.74g, 10.85mmol) is dissolved in the tert-butyl alcohol of 40mL, is slowly added into above-mentioned clear solution, and temperature rises to
Normal temperature, stirring reaction 28 hours at this temperature, point plate is monitored to being fully completed；Afterwards, the mixed solution is transferred to 0 again
DEG C, sodium sulfite (5g) is added, after temperature rises to normal temperature, stirring 1 hour is further continued for, then add ethyl acetate (3 × 60mL) extraction,
Merge organic phase, plus the potassium hydroxide aqueous solution of 2N is washed, and is washed with saturation NaCl solution again afterwards, anhydrous sodium sulfate drying,
Filtering, decompression steams solvent；It is white solid that compound 18 is obtained after the crude on silica gel column chromatographic isolation and purification of gained
4.46g；
(13) synthesis of the compound of formula 19
At 0 DEG C, under nitrogen protection, the compound of formula 18 (4.46g, 9.77mmol) is dissolved in the dry dichloromethanes of 40mL
In alkane, triethyl silicane (48.83mmol) and trifluoroacetic acid (97.7mmol), stirring reaction 10 hours at 0 DEG C, point plate prison are added
Survey to reaction and be fully completed；Plus saturated sodium bicarbonate aqueous solution is quenched reaction, then add ethyl acetate (3 × 50mL) extraction, merge
Organic phase, plus the washing of saturation NaCl solution, anhydrous sodium sulfate drying, filtering, decompression steam solvent；Crude on silica gel column chromatography
It is 3.44g that colorless oil compound 19 is obtained after isolating and purifying；
(14) synthesis of the compound of formula 4
At 0 DEG C, under nitrogen protection, by the compound of formula 19 (3.44g, 7.81mmol) and trimethyl-phosphine acyl acetic acid
(12.49mmol) is dissolved in the dry dichloromethane of 40mL, add dicyclohexylcarbodiimide (DCC) (12.49mmol) and
DMAP (DMAP) (0.19g, 1.56mmol), is stirred 1 hour under normal temperature, and point plate is monitored to reaction and is fully completed；
The solution that adds water is quenched reaction, then (3 × 20mL) extraction that adds methylene chloride, and merges organic phase, plus the washing of saturation NaCl solution, anhydrous
Sodium sulphate is dried, and filtering, decompression steams solvent；White semi-solid compound is obtained after crude on silica gel column chromatographic isolation and purification
4 is 4.15g；
E. the synthesis of the compound of (15) formula 2
At -78 DEG C, under nitrogen protection, compound 4 (415mg, 0.703mmol) is dissolved in the dry tetrahydrochysene furans of 5mL
Mutter in solution, add n-BuLi (0.29mmol), stir 30 minutes at this temperature；Then by compound 3 (427mg,
0.59mmol) it is dissolved in the dry tetrahydrofurans of 2mL, is added dropwise in -78 DEG C of low-temperature mixed things, 2 is stirred at this temperature
Hour, point plate is monitored to reaction and is fully completed；Plus saturated aqueous ammonium chloride is quenched reaction, then add ethyl acetate (3 × 15mL)
Extraction, merges organic phase, plus the washing of saturation NaCl solution, and anhydrous sodium sulfate drying, filtering, decompression steams solvent；Crude product is passed through
It is yellow solid 0.56g that the compound of formula 2 is obtained after silica gel column chromatography separating purification；
(16) synthesis of salviandic acid A methyl esters 1
At 0 DEG C, compound 2 (500mg, 0.42mmol) is dissolved in the dry pyridines of 4mL, nitrogen protection is lower to add three
Ethamine hydrofluoride (5.02mmol), temperature is increased to normal temperature, stirs 0.5 hour, and point plate is monitored to reaction and is fully completed；It is on the rocks
Water terminating reaction, then (3 × 20mL) extraction that adds methylene chloride, merge organic phase, plus the washing of saturation NaCl solution, anhydrous sodium sulfate
Dry, filtering, decompression steams solvent；It is yellow solid 0.19g that end-product 1 is obtained after crude on silica gel column chromatography for separation.
Innovative point of the invention is as follows：One is that salviandic acid A methyl esters not yet has artificial synthesized report, this hair in the world at present
The bright synthetic route being related to provides a process route for artificial synthesized salviandic acid A methyl esters first；Two are directed to salviandic acid A
The characteristics of phenolic hydroxyl group of methyl esters easily causes very big difficult in follow-up removing, fert-butyidimethylsilyl of the present invention from easily removing
Silicon-based protecting group, and suitable removal methods are filtered out in the later stage, salviandic acid A methyl esters is finally successfully prepared, this is also salviandic acid A
The exposed phenolic hydroxyl group of series compound it is artificial synthesized there is provided extraordinary reference.Three be whole synthetic route design it is only
Special novel, its course of reaction raw material is easy to get, mild condition, and speed is fast, and side reaction is less, easy to operate, stability and repeatability
It is good.
Figure of description
The chemical constitution of Fig. 1 salviandic acid A methyl esters
The inverse compounding design of Fig. 2 salviandic acid A methyl esters
The synthetic route of fragment 3 in Fig. 3 salviandic acid A methyl esters
The synthetic route of Fig. 4 salviandic acid A methyl esters
Specific embodiment
Synthetic route involved by the design is as shown in Figure 3, Figure 4.
In order that the present invention becomes more apparent, with reference to embodiments, the present invention will be described in further detail.Should
Work as understanding, specific embodiment described herein is only used to explain the present invention, is not intended to limit the present invention.
Embodiment 1
1st, synthesize microcosmic salt 7 first, can be synthesized through two steps by initial feed 4 and obtained.
(1) synthesis of the compound of formula 9
At 0 DEG C, 4- methyl catechols 8 (5.0g, 40.28mmol) are dissolved in DMF (DMF), nitrogen
Under gas shielded, add imidazoles (13.7g, 201.39mmol) and tert-butyl chloro-silicane (TBSCl) (18.2g,
120.83mmol), normal temperature is then risen to, is stirred overnight.Point plate monitoring reaction afterwards, reaction is quenched with frozen water to being fully completed,
Then (3 × 150mL) is extracted with dichloromethane, merges organic phase, plus the washing of saturation NaCl solution, anhydrous sodium sulfate drying, mistake
Filter, after decompression steams solvent, the compound 14.20g of formula 9, yield 99% is obtained through chromatogram post separation.
(2) synthesis of the compound of formula 7
Compound 9 (14.2g, 40.27mmol) is dissolved in carbon tetrachloride (80mL), and nitrogen protection is lower to add N- bromos fourth two
Acid imide (NBS) (7.88g, 44.29mmol) and the isonitrile of azo two (0.979g, 6.04mmol), after flowing back 1 hour, point plate prison
Reaction is surveyed to being fully completed, water quenching on the rocks is gone out reaction, then extracts (3 × 100mL) with dichloromethane, merges organic phase, plus satisfy
With NaCl solution washing, anhydrous sodium sulfate drying, filtering is depressurized after steaming solvent, plus the dissolving of 80mL acetonitriles, adds triphenyl
Phosphine (15.84g, 60.41mmol), after flowing back 45 minutes, solvent under reduced pressure is concentrated, then adds toluene washing, and the chemical combination of formula 7 is obtained after filtering
Thing is white powder (15.95g), two-step reaction gross production rate 70%.
2nd, next synthesize fragment aldehyde 5, can be synthesized through five steps by initial feed 6 and obtained.
(3) synthesis of the compound of formula 10
At 0 DEG C, by o-vanillin 6 (10.01g, 65.72mmol) and the 4- dimethylamino pyrroles of catalytic amount under nitrogen protection
Pyridine (0.80g, 7.89mmol) is dissolved in diisopropyl ethyl amine (32.86mL), adds acetic anhydride (8.07mL, 85.44mmol),
Then normal temperature is risen to, is stirred overnight, point plate is monitored to reaction and is fully completed.Plus the HCl solution 100mL of 2N, then add methylene chloride
(3 × 100mL) is extracted, and merges organic phase, plus the washing of saturation NaCl solution, anhydrous sodium sulfate drying, and filtering, decompression steams molten
Agent.Recrystallized with absolute ethyl alcohol, obtained the compound of formula 10 for yellow crystals 10.85g, yield 85%.
(4) synthesis of the compound of formula 11
At 0 DEG C, KBr (21.47g, 180.48mmol) is dissolved in water 133mL, be slowly added to bromine (3.73mL,
72.64mmol), compound 10 (10.85g, 55.88mmol), the salmon pink water of formation are added in the backward peony aqueous solution
Solution is stirred overnight at normal temperatures, and point plate is monitored to reaction and is fully completed.Filtering, ethyl acetate washing, then uses ethyl acetate
Recrystallized with n-hexane, obtained the compound of formula 11 for yellow crystals 11.44g, yield 75%.
(5) synthesis of the compound of formula 12
Compound 11 (11.44g, 41.89mmol) is dissolved in methanol aqueous solution (84mL), adds NaHCO3(4.93g,
58.64mmol), the yellow turbid solution of formation in stirring at normal temperature 2 hours, monitor to reaction and be fully completed by point plate, with hydrochloric acid acid
Change, add methylene chloride (3 × 80mL) extraction, merge organic phase, plus the washing of saturation NaCl solution, anhydrous sodium sulfate drying, filter,
Decompression steams solvent.Recrystallized with ethyl acetate and n-hexane, obtained the compound of formula 12 for yellow crystals 8.23g, yield
85%.
(6) synthesis of the compound of formula 13
At 0 DEG C, under nitrogen protection, compound 12 (8.23g, 35.62mmol) is dissolved in dry dichloromethane (120mL)
In, Boron tribromide (13.47mL, 142.48mmol) is dissolved in also dry dichloromethane (60mL), then this mixed liquor is delayed
Slow to add to reaction solution, temperature rises to normal temperature, stirs 2 hours, and point plate is monitored to reaction and is fully completed.Plus saturation NaHCO3
Solution terminating reaction, then (3 × 100mL) extraction that adds methylene chloride, merge organic phase, plus the washing of saturation NaCl solution, anhydrous sulphur
Sour sodium is dried, and filtering, decompression steams solvent.It is yellow solid that the compound of formula 13 is obtained after crude on silica gel column chromatography for separation
7.34g, yield 95%.
(7) synthesis of the compound of formula 5
At 0 DEG C, compound 13 (7.34g, 33.82mmol) is dissolved in dry DMF (307mL), nitrogen
Triethylamine (16.50mL, 118.37mmol), DMAP (0.826g, 6.76mmol) and tertiary fourth are added under gas shielded
Base dimethylchlorosilane (TBSCl) (15.29g, 101.46mmol), temperature rises to normal temperature, is stirred overnight, and point plate is monitored to reaction
It is fully completed.Added water terminating reaction, then (3 × 80mL) extraction that adds methylene chloride, and merges organic phase, plus saturation NaCl solution is washed
Wash, anhydrous sodium sulfate drying, filter, decompression steams solvent.It is Huang that the compound of formula 5 can be obtained after crude on silica gel column chromatography for separation
Color oil product 13.86g, yield 92%.
3rd, next, the synthesis of aldehyde 3 can be synthesized by following two-step reaction and be obtained：
(8) synthesis of the compound of formula 14
At -78 DEG C, microcosmic salt 7 (19.47g, 28.06mmol) is dissolved in dry tetrahydrofuran (100mL), nitrogen is protected
Shield is lower to add n-BuLi (25.81mmol), after stirring 30 minutes, aldehyde 5 (5.0g, 11.22mmol) is dissolved in into 40mL dry
In tetrahydrofuran, then by this mixed liquor being slowly added into reaction bulb at -78 DEG C, and stir 2 hours at such a temperature, point
Plate is monitored to reaction reaction completely and terminated.Plus saturated ammonium chloride terminating reaction, then add ethyl acetate (3 × 80mL) extraction, merge
Organic phase, plus the washing of saturation NaCl solution, anhydrous sodium sulfate drying, filtering, decompression steam solvent.Crude on silica gel column chromatography
The compound as colourless oil product 6.56g of formula 14, yield 75% are obtained after separation.
(9) synthesis of the compound of formula 3
At -78 DEG C, compound 14 (6.56g, 8.41mmol) is dissolved in dry tetrahydrofuran (40mL), nitrogen is protected
Shield is lower to add n-BuLi (16.82mmol), after stirring 30 minutes, by DMF (6.48mL, 84.08mmol)
Dry tetrahydrofuran (10mL) is dissolved in, this mixed liquor is slowly added into reaction bulb at -78 DEG C, 3 are stirred at this temperature
Hour, point plate is monitored to reaction and is fully completed, plus saturated ammonium chloride terminating reaction, then adds ethyl acetate (3 × 50mL) extraction, is closed
And organic phase, plus the washing of saturation NaCl solution, anhydrous sodium sulfate drying, filtering, depressurize and steam solvent.Crude on silica gel post layer
Analysis obtains the compound 5.21g of formula 3, yield 85% after separating.
4th, next, the synthesis of chiral phosphorus acid esters 4 can be synthesized by the following steps and be obtained：
(10) synthesis of the compound of formula 16
Under nitrogen protection, caffeic acid 15 (2.0g, 11.10mmol) is dissolved in 140mL methyl alcohol, is subsequently adding the concentrated sulfuric acid
4mL, is heated to 70 DEG C, and back flow reaction 1 hour, point plate is monitored to reaction and is fully completed.Room temperature is subsequently cooled to, saturated carbon is added
Sour hydrogen sodium water solution neutralization reaction, then (3 × 50mL) extraction that adds methylene chloride, merge organic phase, plus the washing of saturation NaCl solution,
Anhydrous sodium sulfate drying, filtering, decompression steams solvent, obtains the compound of crude product formula 16 for gray solid 2.15g, yield 100%.
(11) synthesis of the compound of formula 17
At 0 DEG C, under nitrogen protection, the compound of formula 16 (2.15g, 11.07mmol) is dissolved in the dry N of 60mL, N-
In dimethylformamide (DMF), imidazoles (5.28g, 77.51mmol) and tert-butyl chloro-silicane (TBSCl) are added
(5.0g, 33.22mmol), after temperature rises to normal temperature, is then reacted 6 hours at such a temperature, and point plate is monitored to reaction and tied completely
Beam.Add water and reaction is quenched, then add ethyl acetate (3 × 60mL) extraction, merge organic phase, plus the washing of saturation NaCl solution, it is anhydrous
Sodium sulphate is dried, and filtering, decompression steams solvent.The compound of formula 17 is obtained after crude on silica gel column chromatographic isolation and purification for white is solid
Body 4.74g, yield 98%.
(12) synthesis of the compound of formula 18
Under nitrogen protection, AD-mix- α (15.25g, 15.19mmol) and methylsulfonamides (20mmol) are dissolved in 80mL
In the tert-butyl alcohol, it is stirred vigorously, until two phase liquid all becomes transparent clear state.Then the mixture is transferred to 0 DEG C, will be changed
Compound 17 (4.74g, 10.85mmol) is dissolved in the tert-butyl alcohol of 40mL, is slowly added into above-mentioned clear solution, and temperature rises to
Normal temperature, stirring reaction 28 hours at this temperature, point plate is monitored to being fully completed.Afterwards, the mixed solution is transferred to 0 again
DEG C, sodium sulfite (5g) is added, after temperature rises to normal temperature, stirring 1 hour is further continued for, then add ethyl acetate (3 × 60mL) extraction,
Merge organic phase, plus the potassium hydroxide aqueous solution of 2N is washed, and is washed with saturation NaCl solution again afterwards, anhydrous sodium sulfate drying,
Filtering, decompression steams solvent.It is white solid that compound 18 is obtained after the crude on silica gel column chromatographic isolation and purification of gained
4.46g, yield 90%, ee values 90%.
(13) synthesis of the compound of formula 19
At 0 DEG C, under nitrogen protection, the compound of formula 18 (4.46g, 9.77mmol) is dissolved in the dry dichloromethanes of 40mL
In alkane, triethyl silicane (48.83mmol) and trifluoroacetic acid (97.7mmol), stirring reaction 10 hours at 0 DEG C, point plate prison are added
Survey to reaction and be fully completed.Plus saturated sodium bicarbonate aqueous solution is quenched reaction, then add ethyl acetate (3 × 50mL) extraction, merge
Organic phase, plus the washing of saturation NaCl solution, anhydrous sodium sulfate drying, filtering, decompression steam solvent.Crude on silica gel column chromatography
It is 3.44g, yield 80% that colorless oil compound 19 is obtained after isolating and purifying.
(14) synthesis of the compound of formula 4
At 0 DEG C, under nitrogen protection, by the compound of formula 19 (3.44g, 7.81mmol) and trimethyl-phosphine acyl acetic acid
(12.49mmol) is dissolved in the dry dichloromethane of 40mL, add dicyclohexylcarbodiimide (DCC) (12.49mmol) and
DMAP (DMAP) (0.19g, 1.56mmol), is stirred 1 hour under normal temperature, and point plate is monitored to reaction and is fully completed.
The solution that adds water is quenched reaction, then (3 × 20mL) extraction that adds methylene chloride, and merges organic phase, plus the washing of saturation NaCl solution, anhydrous
Sodium sulphate is dried, and filtering, decompression steams solvent.White semi-solid compound is obtained after crude on silica gel column chromatographic isolation and purification
4 is 4.15g, yield 90%.
Next it is exactly to synthesize final by following two-step reaction after crucial chiral phosphorus acid esters intermediate 4 is taken
Required natural products Salvianolic Acid A methyl esters (1)：
(15) synthesis of the compound of formula 2
At -78 DEG C, under nitrogen protection, compound 4 (415mg, 0.703mmol) is dissolved in the dry tetrahydrochysene furans of 5mL
Mutter in solution, add n-BuLi (0.29mmol), stir 30 minutes at this temperature.Then by compound 3 (427mg,
0.59mmol) it is dissolved in the dry tetrahydrofurans of 2mL, is added dropwise in -78 DEG C of low-temperature mixed things, 2 is stirred at this temperature
Hour, point plate is monitored to reaction and is fully completed.Plus saturated aqueous ammonium chloride is quenched reaction, then add ethyl acetate (3 × 15mL)
Extraction, merges organic phase, plus the washing of saturation NaCl solution, and anhydrous sodium sulfate drying, filtering, decompression steams solvent.Crude product is passed through
It is yellow solid 0.56g, yield 80% that the compound of formula 2 is obtained after silica gel column chromatography separating purification.
(16) synthesis of salviandic acid A methyl esters 1
At 0 DEG C, compound 2 (500mg, 0.42mmol) is dissolved in the dry pyridines of 4mL, nitrogen protection is lower to add three
Ethamine hydrofluoride (5.02mmol), temperature is increased to normal temperature, stirs 0.5 hour, and point plate is monitored to reaction and is fully completed.It is on the rocks
Water terminating reaction, then (3 × 20mL) extraction that adds methylene chloride, merge organic phase, plus the washing of saturation NaCl solution, anhydrous sodium sulfate
Dry, filtering, decompression steams solvent.It is yellow solid 0.19g, yield that end-product 1 is obtained after crude on silica gel column chromatography for separation
90%.
The foregoing is only presently preferred embodiments of the present invention, be not intended to limit the invention, it is all it is of the invention spirit and
Any modification, equivalent and improvement for being made within principle etc., should be included within the scope of the present invention.
Claims (5)
1. a kind of method of synthesis of natural product salviandic acid A methyl esters, it is characterised in that：Salviandic acid A methyl esters is type I compound：
By the compound of formula II
Type I compound is obtained after the condition of triethylamine hydrofluoride removes t-Butyldimethylsilyl protection group；
The compound of formula II is obtained：The compound of formula III, IV compound
The alpha, beta-unsaturated esters structure for reacting structure C7-9 by Horner-Wadsworth-Emmons obtains the compound of formula II；
The compound of formula III is obtained：Formula V, VI compound
Reacted by Wittig and build C7 " -8 " unsaturated carbon chains obtain the compound of formula III；
The compound of formula IV is obtained：Including formula VII, VIII compound
The compound of formula IV is obtained by esterification；
The compound of formula VII is obtained：The compound of formula Ⅸ
After the condition of Sharplesss dihydroxylateds carries out bishydroxy to C7'-8', then in trifluoroacetic acid and triethyl group silicon
The single hydroxyl chiral centre of C8' is built under conditions of alkane, the compound of formula VII is obtained.
2. method according to claim 1, it is characterised in that step is specially：
A. synthesize microcosmic salt 7 first, can be synthesized through two steps by initial feed 4 and obtained：
(1) synthesis of the compound of formula 9
At 0 DEG C, compound 4- methyl catechols (5.0g, 40.28mmol) of formula 8 is dissolved in DMF (DMF)
In, nitrogen protection under, add imidazoles (13.7g, 201.39mmol) and tert-butyl chloro-silicane (TBSCl) (18.2g,
120.83mmol), normal temperature is then risen to, is stirred overnight；Point plate monitoring reaction afterwards, reaction is quenched with frozen water to being fully completed,
Then (3 × 150mL) is extracted with dichloromethane, merges organic phase, plus the washing of saturation NaCl solution, anhydrous sodium sulfate drying, mistake
Filter, after decompression steams solvent, the compound 14.20g of formula 9 is obtained through chromatogram post separation：
(2) synthesis of the compound of formula 7
Compound 9 (14.2g, 40.27mmol) is dissolved in carbon tetrachloride (80mL), and nitrogen protection is lower to add N- bromos succinyl sub-
Amine (NBS) (7.88g, 44.29mmol) and the isonitrile of azo two (0.979g, 6.04mmol), after flowing back 1 hour, point plate monitoring is anti-
Should be to being fully completed, water quenching on the rocks is gone out reaction, then extracts (3 × 100mL) with dichloromethane, merges organic phase, plus saturation
NaCl solution is washed, anhydrous sodium sulfate drying, filtering, after decompression steams solvent, plus the dissolving of 80mL acetonitriles, add triphenylphosphine
(15.84g, 60.41mmol), after flowing back 45 minutes, solvent under reduced pressure is concentrated, then adds toluene washing, and the compound of formula 7 is obtained after filtering
It is white powder (15.95g)；
B. next synthesize fragment aldehyde 5, can be synthesized through five steps by initial feed 6 and obtained；
(3) synthesis of the compound of formula 10
At 0 DEG C, by o-vanillin 6 (10.01g, 65.72mmol) and the DMAP of catalytic amount under nitrogen protection
(0.80g, 7.89mmol) is dissolved in diisopropyl ethyl amine (32.86mL), adds acetic anhydride (8.07mL, 85.44mmol), so
After rise to normal temperature, be stirred overnight, point plate is monitored to reaction and is fully completed；Plus the HCl solution 100mL of 2N, then add methylene chloride (3
× 100mL) extraction, merge organic phase, plus the washing of saturation NaCl solution, anhydrous sodium sulfate drying, filtering, decompression steams solvent；
Recrystallized with absolute ethyl alcohol, obtained the compound of formula 10 for yellow crystals 10.85g；
(4) synthesis of the compound of formula 11
At 0 DEG C, KBr (21.47g, 180.48mmol) is dissolved in water 133mL, be slowly added to bromine (3.73mL,
72.64mmol), compound 10 (10.85g, 55.88mmol), the salmon pink water of formation are added in the backward peony aqueous solution
Solution is stirred overnight at normal temperatures, and point plate is monitored to reaction and is fully completed；Filtering, ethyl acetate washing, then uses ethyl acetate
Recrystallized with n-hexane, obtained the compound of formula 11 for yellow crystals 11.44g；
(5) synthesis of the compound of formula 12
Compound 11 (11.44g, 41.89mmol) is dissolved in methanol aqueous solution (84mL), adds NaHCO3(4.93g,
58.64mmol), the yellow turbid solution of formation in stirring at normal temperature 2 hours, monitor to reaction and be fully completed by point plate, with hydrochloric acid acid
Change, add methylene chloride (3 × 80mL) extraction, merge organic phase, plus the washing of saturation NaCl solution, anhydrous sodium sulfate drying, filter,
Decompression steams solvent；Recrystallized with ethyl acetate and n-hexane, obtained the compound of formula 12 for yellow crystals 8.23g；
(6) synthesis of the compound of formula 13
At 0 DEG C, under nitrogen protection, compound 12 (8.23g, 35.62mmol) is dissolved in dry dichloromethane (120mL),
Boron tribromide (13.47mL, 142.48mmol) is dissolved in also dry dichloromethane (60mL), then this mixed liquor is slowly added
Enter to reaction solution, temperature rises to normal temperature, stir 2 hours, point plate is monitored to reaction and is fully completed；Plus saturation NaHCO3Solution
Terminating reaction, then (3 × 100mL) extraction that adds methylene chloride, merge organic phase, plus the washing of saturation NaCl solution, anhydrous sodium sulfate
Dry, filtering, decompression steams solvent；It is yellow solid 7.34g that the compound of formula 13 is obtained after crude on silica gel column chromatography for separation；
(7) synthesis of the compound of formula 5
At 0 DEG C, compound 13 (7.34g, 33.82mmol) is dissolved in dry DMF (307mL), and nitrogen is protected
Shield is lower to add triethylamine (16.50mL, 118.37mmol), DMAP (0.826g, 6.76mmol) and the tert-butyl group two
Methylchlorosilane (TBSCl) (15.29g, 101.46mmol), temperature rises to normal temperature, is stirred overnight, and point plate is monitored complete to reaction
Terminate；Add water terminating reaction, then (3 × 80mL) extraction that adds methylene chloride, and merges organic phase, plus the washing of saturation NaCl solution, nothing
Aqueous sodium persulfate is dried, and filtering, decompression steams solvent；The compound of formula 5 can be obtained after crude on silica gel column chromatography for separation for yellow oil
Shape product 13.86g；
C. next, the synthesis of aldehyde 3 can be synthesized by following two-step reaction and be obtained：
(8) synthesis of the compound of formula 14
At -78 DEG C, microcosmic salt 7 (19.47g, 28.06mmol) is dissolved in dry tetrahydrofuran (100mL), under nitrogen protection
N-BuLi (25.81mmol) is added, after stirring 30 minutes, aldehyde 5 (5.0g, 11.22mmol) the dry tetrahydrochysenes of 40mL is dissolved in
In furans, then by this mixed liquor being slowly added into reaction bulb at -78 DEG C, and stir 2 hours at such a temperature, point plate prison
Survey to reaction reaction completely and terminate；Plus saturated ammonium chloride terminating reaction, then add ethyl acetate (3 × 80mL) extraction, merge organic
Phase, plus the washing of saturation NaCl solution, anhydrous sodium sulfate drying, filtering, decompression steam solvent；Crude on silica gel column chromatography for separation
The compound as colourless oil product 6.56g of formula 14 is obtained afterwards；
(9) synthesis of the compound of formula 3
At -78 DEG C, compound 14 (6.56g, 8.41mmol) is dissolved in dry tetrahydrofuran (40mL), under nitrogen protection
N-BuLi (16.82mmol) is added, after stirring 30 minutes, DMF (6.48mL, 84.08mmol) is dissolved in
Dry tetrahydrofuran (10mL), this mixed liquor is slowly added into reaction bulb at -78 DEG C, is stirred 3 hours at this temperature,
Point plate is monitored to reaction and is fully completed, plus saturated ammonium chloride terminating reaction, then adds ethyl acetate (3 × 50mL) extraction, is associated with
Machine phase, plus the washing of saturation NaCl solution, anhydrous sodium sulfate drying, filtering, decompression steam solvent；Crude on silica gel column chromatography point
The compound 5.21g of formula 3 is obtained after；
D. next, the synthesis of chiral phosphorus acid esters 4 can be synthesized by the following steps and be obtained：
(10) synthesis of the compound of formula 16
Under nitrogen protection, caffeic acid 15 (2.0g, 11.10mmol) is dissolved in 140mL methyl alcohol, is subsequently adding concentrated sulfuric acid 4mL, plus
Heat to 70 DEG C, monitor to reaction and be fully completed by back flow reaction 1 hour, point plate；Room temperature is subsequently cooled to, saturated sodium bicarbonate is added
Aqueous solution neutralization reaction, then (3 × 50mL) extraction that adds methylene chloride, merge organic phase, plus the washing of saturation NaCl solution, anhydrous sulphur
Sour sodium is dried, and filtering, decompression steams solvent, obtains the compound of crude product formula 16 for gray solid 2.15g；
(11) synthesis of the compound of formula 17
At 0 DEG C, under nitrogen protection, the compound of formula 16 (2.15g, 11.07mmol) is dissolved in the dry N of 60mL, N- diformazans
In base formamide (DMF), add imidazoles (5.28g, 77.51mmol) and tert-butyl chloro-silicane (TBSCl) (5.0g,
33.22mmol), after temperature rises to normal temperature, then react 6 hours at such a temperature, point plate is monitored to reaction and is fully completed；Add water
Reaction is quenched, then adds ethyl acetate (3 × 60mL) extraction, merge organic phase, plus the washing of saturation NaCl solution, anhydrous sodium sulfate is done
Dry, filtering, decompression steams solvent；It is white solid 4.74g that the compound of formula 17 is obtained after crude on silica gel column chromatographic isolation and purification；
(12) synthesis of the compound of formula 18
Under nitrogen protection, AD-mix- α (15.25g, 15.19mmol) and methylsulfonamides (20mmol) are dissolved in the tertiary fourths of 80mL
In alcohol, it is stirred vigorously, until two phase liquid all becomes transparent clear state；Then the mixture is transferred to 0 DEG C, by compound
17 (4.74g, 10.85mmol) are dissolved in the tert-butyl alcohol of 40mL, are slowly added into above-mentioned clear solution, and temperature rises to often
Temperature, stirring reaction 28 hours at this temperature, point plate is monitored to being fully completed；Afterwards, the mixed solution is transferred to 0 DEG C again,
Sodium sulfite (5g) is added, after temperature rises to normal temperature, stirring 1 hour is further continued for, then adds ethyl acetate (3 × 60mL) extraction, closed
And organic phase, plus the potassium hydroxide aqueous solution of 2N is washed, and is washed with saturation NaCl solution again afterwards, anhydrous sodium sulfate drying, mistake
Filter, decompression steams solvent；It is white solid 4.46g that compound 18 is obtained after the crude on silica gel column chromatographic isolation and purification of gained；
(13) synthesis of the compound of formula 19
At 0 DEG C, under nitrogen protection, the compound of formula 18 (4.46g, 9.77mmol) is dissolved in the dry dichloromethane of 40mL
In, add triethyl silicane (48.83mmol) and trifluoroacetic acid (97.7mmol), stirring reaction 10 hours at 0 DEG C, point plate monitoring
It is fully completed to reaction；Plus saturated sodium bicarbonate aqueous solution is quenched reaction, then add ethyl acetate (3 × 50mL) extraction, be associated with
Machine phase, plus the washing of saturation NaCl solution, anhydrous sodium sulfate drying, filtering, decompression steam solvent；Crude on silica gel column chromatography point
It is 3.44g from colorless oil compound 19 is obtained after purification；
(14) synthesis of the compound of formula 4
At 0 DEG C, under nitrogen protection, by the compound of formula 19 (3.44g, 7.81mmol) and trimethyl-phosphine acyl acetic acid
(12.49mmol) is dissolved in the dry dichloromethane of 40mL, add dicyclohexylcarbodiimide (DCC) (12.49mmol) and
DMAP (DMAP) (0.19g, 1.56mmol), is stirred 1 hour under normal temperature, and point plate is monitored to reaction and is fully completed；
The solution that adds water is quenched reaction, then (3 × 20mL) extraction that adds methylene chloride, and merges organic phase, plus the washing of saturation NaCl solution, anhydrous
Sodium sulphate is dried, and filtering, decompression steams solvent；White semi-solid compound is obtained after crude on silica gel column chromatographic isolation and purification
4 is 4.15g；
E. the synthesis of the compound of (15) formula 2
At -78 DEG C, under nitrogen protection, compound 4 (415mg, 0.703mmol) is dissolved in the dry tetrahydrofurans of 5mL molten
In liquid, n-BuLi (0.29mmol) is added, stirred 30 minutes at this temperature；Then by compound 3 (427mg, 0.59mmol)
It is dissolved in the dry tetrahydrofurans of 2mL, is added dropwise in -78 DEG C of low-temperature mixed things, stir 2 hours at this temperature, puts plate
Monitoring to reaction is fully completed；Plus saturated aqueous ammonium chloride is quenched reaction, then add ethyl acetate (3 × 15mL) extraction, merge
Organic phase, plus the washing of saturation NaCl solution, anhydrous sodium sulfate drying, filtering, decompression steam solvent；Crude on silica gel column chromatography
It is yellow solid 0.56g that the compound of formula 2 is obtained after isolating and purifying；
(16) synthesis of salviandic acid A methyl esters 1
At 0 DEG C, compound 2 (500mg, 0.42mmol) is dissolved in the dry pyridines of 4mL, nitrogen protection is lower to add triethylamine
Hydrofluoride (5.02mmol), temperature is increased to normal temperature, stirs 0.5 hour, and point plate is monitored to reaction and is fully completed；Water end on the rocks
Only react, then (3 × 20mL) extraction that adds methylene chloride, merging organic phase, plus the washing of saturation NaCl solution, anhydrous sodium sulfate is done
Dry, filtering, decompression steams solvent；It is yellow solid 0.19g that end-product 1 is obtained after crude on silica gel column chromatography for separation.
3. method according to claim 1, it is characterised in that by obtaining V compound with o-vanillin as raw material.
4. method according to claim 1, it is characterised in that by obtaining the change of formula VI with 4- methyl catechols as raw material
Compound.
5. method according to claim 1, it is characterised in that by obtaining the compound of formula Ⅸ with caffeic acid as raw material.
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| CN108484593A (en) * | 2018-05-15 | 2018-09-04 | 常州大学 | A kind of synthetic method of fibrauretine |
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| CN108358761A (en) * | 2018-03-13 | 2018-08-03 | 上海交通大学 | A kind of salviandic acid A intermediate and preparation method thereof |
| CN108358761B (en) * | 2018-03-13 | 2020-11-06 | 上海交通大学 | Salvianolic acid A intermediate and preparation method thereof |
| CN108484593A (en) * | 2018-05-15 | 2018-09-04 | 常州大学 | A kind of synthetic method of fibrauretine |
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