CN110218160A - A kind of quinine acid derivative and the preparation method and application thereof - Google Patents
A kind of quinine acid derivative and the preparation method and application thereof Download PDFInfo
- Publication number
- CN110218160A CN110218160A CN201910532392.9A CN201910532392A CN110218160A CN 110218160 A CN110218160 A CN 110218160A CN 201910532392 A CN201910532392 A CN 201910532392A CN 110218160 A CN110218160 A CN 110218160A
- Authority
- CN
- China
- Prior art keywords
- methyl
- quinine
- amide
- reaction
- benzyloxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 title claims abstract description 231
- 235000001258 Cinchona calisaya Nutrition 0.000 title claims abstract description 182
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 title claims abstract description 182
- 229960000948 quinine Drugs 0.000 title claims abstract description 182
- 238000002360 preparation method Methods 0.000 title claims abstract description 71
- 239000002253 acid Substances 0.000 title claims abstract description 55
- -1 (mono-methyl) phosphono Chemical group 0.000 claims abstract description 119
- 125000002252 acyl group Chemical group 0.000 claims abstract description 45
- 241000700605 Viruses Species 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 13
- 208000002606 Paramyxoviridae Infections Diseases 0.000 claims abstract description 10
- 229940079593 drug Drugs 0.000 claims abstract description 9
- 241000712461 unidentified influenza virus Species 0.000 claims abstract description 5
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims abstract description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 261
- 238000006243 chemical reaction Methods 0.000 claims description 201
- 239000002585 base Substances 0.000 claims description 96
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 95
- 239000002904 solvent Substances 0.000 claims description 84
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 82
- ABADUMLIAZCWJD-UHFFFAOYSA-N 1,3-dioxole Chemical compound C1OC=CO1 ABADUMLIAZCWJD-UHFFFAOYSA-N 0.000 claims description 73
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 67
- 239000003153 chemical reaction reagent Substances 0.000 claims description 57
- 230000015572 biosynthetic process Effects 0.000 claims description 42
- 238000003786 synthesis reaction Methods 0.000 claims description 42
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 34
- 239000003921 oil Substances 0.000 claims description 34
- SATCULPHIDQDRE-UHFFFAOYSA-N piperonal Chemical compound O=CC1=CC=C2OCOC2=C1 SATCULPHIDQDRE-UHFFFAOYSA-N 0.000 claims description 34
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 32
- 239000005977 Ethylene Substances 0.000 claims description 32
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 32
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 30
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 30
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 29
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 28
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 26
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- 241000725643 Respiratory syncytial virus Species 0.000 claims description 23
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 23
- XXLFLUJXWKXUGS-UHFFFAOYSA-N quininic acid Natural products N1=CC=C(C(O)=O)C2=CC(OC)=CC=C21 XXLFLUJXWKXUGS-UHFFFAOYSA-N 0.000 claims description 23
- 239000012312 sodium hydride Substances 0.000 claims description 23
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
- 239000003795 chemical substances by application Substances 0.000 claims description 19
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 18
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 17
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 15
- 150000001408 amides Chemical class 0.000 claims description 14
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 claims description 14
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 14
- 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 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 13
- 239000012752 auxiliary agent Substances 0.000 claims description 13
- NIQCNGHVCWTJSM-UHFFFAOYSA-N Dimethyl phthalate Chemical compound COC(=O)C1=CC=CC=C1C(=O)OC NIQCNGHVCWTJSM-UHFFFAOYSA-N 0.000 claims description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 12
- 125000005905 mesyloxy group Chemical group 0.000 claims description 12
- 239000012046 mixed solvent Substances 0.000 claims description 12
- 239000002994 raw material Substances 0.000 claims description 11
- 230000004044 response Effects 0.000 claims description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 150000001412 amines Chemical class 0.000 claims description 9
- 239000003443 antiviral agent Substances 0.000 claims description 9
- 238000013459 approach Methods 0.000 claims description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- 239000000047 product Substances 0.000 claims description 8
- 238000004090 dissolution Methods 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
- 239000007858 starting material Substances 0.000 claims description 7
- 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 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- FBSAITBEAPNWJG-UHFFFAOYSA-N dimethyl phthalate Natural products CC(=O)OC1=CC=CC=C1OC(C)=O FBSAITBEAPNWJG-UHFFFAOYSA-N 0.000 claims description 6
- 229960001826 dimethylphthalate Drugs 0.000 claims description 6
- 229960003019 loprazolam Drugs 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 6
- 229920002554 vinyl polymer Polymers 0.000 claims description 6
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 claims description 5
- 241000790917 Dioxys <bee> Species 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- VONWDASPFIQPDY-UHFFFAOYSA-N dimethyl methylphosphonate Chemical compound COP(C)(=O)OC VONWDASPFIQPDY-UHFFFAOYSA-N 0.000 claims description 5
- 235000010299 hexamethylene tetramine Nutrition 0.000 claims description 5
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 claims description 5
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical group CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 claims description 5
- 229960004011 methenamine Drugs 0.000 claims description 5
- 150000003053 piperidines Chemical class 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 5
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 claims description 5
- 229910015844 BCl3 Inorganic materials 0.000 claims description 4
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 4
- 238000010511 deprotection reaction Methods 0.000 claims description 4
- 239000002552 dosage form Substances 0.000 claims description 4
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 claims description 4
- 239000007791 liquid phase Substances 0.000 claims description 4
- 229910000103 lithium hydride Inorganic materials 0.000 claims description 4
- CEAJFNBWKBTRQE-UHFFFAOYSA-N methanamine;methanol Chemical compound NC.OC CEAJFNBWKBTRQE-UHFFFAOYSA-N 0.000 claims description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 4
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 claims description 4
- 239000002808 molecular sieve Substances 0.000 claims description 4
- 230000003287 optical effect Effects 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- CMHHITPYCHHOGT-UHFFFAOYSA-N tributylborane Chemical compound CCCCB(CCCC)CCCC CMHHITPYCHHOGT-UHFFFAOYSA-N 0.000 claims description 4
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical group CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 claims description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical class OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 3
- 238000004440 column chromatography Methods 0.000 claims description 3
- NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical compound ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 claims description 3
- 150000002460 imidazoles Chemical class 0.000 claims description 3
- 150000003852 triazoles Chemical class 0.000 claims description 3
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 2
- CFRCMZCIUFYREH-UHFFFAOYSA-N 1-butylcyclohexane-1-carboxamide Chemical compound CCCCC1(C(N)=O)CCCCC1 CFRCMZCIUFYREH-UHFFFAOYSA-N 0.000 claims description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 238000010521 absorption reaction Methods 0.000 claims description 2
- 239000000853 adhesive Substances 0.000 claims description 2
- 230000001070 adhesive effect Effects 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 238000007796 conventional method Methods 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims description 2
- 239000002502 liposome Substances 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- 239000000314 lubricant Substances 0.000 claims description 2
- 239000003094 microcapsule Substances 0.000 claims description 2
- 239000002105 nanoparticle Substances 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 235000011164 potassium chloride Nutrition 0.000 claims description 2
- 239000001103 potassium chloride Substances 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 2
- 239000004094 surface-active agent Substances 0.000 claims description 2
- 238000013268 sustained release Methods 0.000 claims description 2
- 239000012730 sustained-release form Substances 0.000 claims description 2
- 239000000080 wetting agent Substances 0.000 claims description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 claims 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 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 1
- 150000003927 aminopyridines Chemical class 0.000 claims 1
- SWLVFNYSXGMGBS-UHFFFAOYSA-N ammonium bromide Chemical compound [NH4+].[Br-] SWLVFNYSXGMGBS-UHFFFAOYSA-N 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 238000002425 crystallisation Methods 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 238000005303 weighing Methods 0.000 claims 1
- 238000011084 recovery Methods 0.000 abstract description 7
- 206010061603 Respiratory syncytial virus infection Diseases 0.000 abstract description 4
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- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 104
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 76
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- 238000003756 stirring Methods 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
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- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 230000000840 anti-viral effect Effects 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 150000004702 methyl esters Chemical class 0.000 description 5
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- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
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- 230000001143 conditioned effect Effects 0.000 description 4
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- 238000005292 vacuum distillation Methods 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
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- TXVWTOBHDDIASC-UHFFFAOYSA-N 1,2-diphenylethene-1,2-diamine Chemical compound C=1C=CC=CC=1C(N)=C(N)C1=CC=CC=C1 TXVWTOBHDDIASC-UHFFFAOYSA-N 0.000 description 1
- UFCLZKMFXSILNL-BKUKFAEQSA-N 3,4-di-O-caffeoylquinic acid Natural products O[C@H]1C[C@](O)(C[C@H](OC(=O)C=Cc2ccc(O)c(O)c2)[C@@H]1OC(=O)C=Cc3ccc(O)c(O)c3)C(=O)O UFCLZKMFXSILNL-BKUKFAEQSA-N 0.000 description 1
- KRZBCHWVBQOTNZ-WXAIXHMISA-N 3,5-di-O-caffeoylquinic acid Natural products O[C@@H]1[C@H](C[C@](O)(C[C@@H]1OC(=O)C=Cc2ccc(O)c(O)c2)C(=O)O)OC(=O)C=Cc3ccc(O)c(O)c3 KRZBCHWVBQOTNZ-WXAIXHMISA-N 0.000 description 1
- 125000004032 5'-inosinyl group Chemical group 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 229910015845 BBr3 Inorganic materials 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical class CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 208000035220 Dyserythropoietic Congenital Anemia Diseases 0.000 description 1
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- 206010024971 Lower respiratory tract infections Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 208000006399 Premature Obstetric Labor Diseases 0.000 description 1
- 206010036600 Premature labour Diseases 0.000 description 1
- 229940124679 RSV vaccine Drugs 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
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- 150000007513 acids Chemical class 0.000 description 1
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- 239000002221 antipyretic Substances 0.000 description 1
- 238000003287 bathing Methods 0.000 description 1
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Substances BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
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- 239000000872 buffer Substances 0.000 description 1
- SXGBREZGMJVYRL-UHFFFAOYSA-N butan-1-amine;hydrobromide Chemical compound [Br-].CCCC[NH3+] SXGBREZGMJVYRL-UHFFFAOYSA-N 0.000 description 1
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- 238000013461 design Methods 0.000 description 1
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- 125000006202 diisopropylaminoethyl group Chemical group [H]C([H])([H])C([H])(N(C([H])([H])C([H])([H])*)C([H])(C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
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- 238000010438 heat treatment Methods 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
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- 238000011534 incubation Methods 0.000 description 1
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- 210000003734 kidney Anatomy 0.000 description 1
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- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical compound CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 description 1
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- 238000012986 modification Methods 0.000 description 1
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- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 208000026440 premature labor Diseases 0.000 description 1
- 208000028529 primary immunodeficiency disease Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- HHVIBTZHLRERCL-UHFFFAOYSA-N sulfonyldimethane Chemical group CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
- C07C311/23—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms
- C07C311/27—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/44—Amides thereof
- C07F9/4461—Amides thereof the amide moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4473—Amides thereof the amide moiety containing a substituent or a structure which is considered as characteristic of cycloaliphatic amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Pulmonology (AREA)
- Biochemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of quinine acid derivative and the preparation method and application thereof, which has the structure as shown in general formula I, wherein R1、R2、R3For OH or AcNH；R1=OH, R2=R3=AcNH or R2=OH, R1=R3=AcNH or R3=OH, R1=R2=AcNH；* R configuration or S configuration are indicated；Ac indicates coffee acyl CAc or its derivative coffee sulfonyl SAc, coffee (mono-methyl) phosphono PAc.Quinine acid derivative of the invention has the advantages that preparation condition is mild, easy to operate and safe, product purity is high, total recovery is higher, obtained quinine acid derivative can be used for preparing treatment virus infective medicament, especially be used to prepare treatment influenza virus, parainfluenza virus and respiratory syncytial virus infection drug.
Description
Technical field
The invention belongs to viral infection resisting drug field, in particular to a kind of quinine acid derivative and preparation method thereof with answer
With.
Background technique
It is well known that respiratory virus infection is one of the communicable disease for seriously endangering human health, wherein influenza is sick
Poison, parainfluenza virus and Respiratory Syncytial Virus(RSV) (RSV) are the main pathogens of respiratory virus infection.RSV is to be only second to first
Type influenza virus the second largest respiratory tract infection virus, Susceptible population is mainly infant, can cause infant's acute tracheitis,
The severes lower respiratory tract infection such as bronchitis, pneumonia.According to statistics, about 95% children infected RSV before 2 years old, and 100%
Children infected before adult RSV (Piedimonte, G., et al.Pediatrics in Review 2014,35:
519-530).The whole world needs the infant of hospitalization up to 3,000,000 because of rsv infection every year, and causes hundreds of thousands of them dead.Human body
Lifetime immunity can not be obtained after infection RSV, therefore RSV is also the weight for causing the elderly and hypoimmunity crowd's respiratory disease
Want pathogen.
Currently, the small-molecule drug of the RSV vaccine and specific treatment rsv infection that clinically there is no safety good.Li Ba
Wei Lin (ribavirin) is generally acknowledged now to the small molecule broad-spectrum antiviral medicament of RSV tool certain curative effect, and suppression is mainly passed through
The activity of host cell inosinyl phosphate inosine dehydrogenase (IMP dehydrogenase) processed achievees the effect that suppressing virus replication, therefore its
It is higher to the toxicity of host cell.Therefore, medical field is still disputable to the clinical efficacy of Ribavirin at present, such as U.S.'s paediatrics
It can be only recommended to be used to treat the spectrometry in high-risk infants being hospitalized.Except small-molecule drug, palivizumab (palivizumab, RSV-F
The neutralizing antibody of albumen) it can be clinically used for the high-risk childrens of the rsv infections such as premature labor, broncho-pulmonary dysplasia, but pa benefit pearl is single
Anti- there are service life drawbacks such as long, costly, not yet can clinically promote the use of (Vogel, A.M., et al.Journal
of Paediatrics and Child Health 2002,38:550-554).Therefore, the specificity of exploitation efficiently, less toxic is anti-
RSV small-molecule drug has important clinical meaning.
Elephants-foot (Elephantopus scaber) is composite family Elephantopus plant, is mainly distributed on China south China and west
Southern area, has effects that heat-clearing, cool blood, dampness removing.Modern pharmacological studies have shown that elephants-foot is with antiviral, antibacterial, antitumor
And the effects of antipyretic.Chinese invention patent CN102219687B discloses the bis- caffeoyl quinine of 3,4-O- extracted from elephants-foot
Acid, 3,5-O- dicaffeoylquinic acid, 4,5-O- dicaffeoylquinic acid and its methyl esters have anti-RSV virus, Parainfluenza Type
With the effect of influenza A virus.Studies have shown that these two caffeoyls class compound structures are unstable, it is easy in blood by water
Solution, half-life short directly affect the application of these natural products clinically.According to medicine core similarity principle and bioelectronics
Deng row's principle, structure optimization is carried out to these natural origin antiviral compounds, is to obtain to have the quick of clinical landscapes primer
Approach.
Summary of the invention
The primary purpose of the present invention is that the shortcomings that overcoming the prior art and deficiency, provide a kind of quinine acid derivative.
Another object of the present invention is to provide the preparation methods of above-mentioned quinine acid derivative.
Another object of the present invention is to provide the applications of above-mentioned quinine acid derivative.
The purpose of the invention is achieved by the following technical solution: a kind of quinine acid derivative, has and ties as shown in general formula I
Structure:
In general formula I, R1、R2、R3For OH or AcNH；Wherein, R1=OH, R2=R3=AcNH or R2=OH, R1=R3=
AcNH or R3=OH, R1=R2=AcNH；* R configuration or S configuration are indicated.
The Ac indicates coffee acyl CAc or its derivative coffee sulfonyl SAc, coffee (mono-methyl) phosphono
PAc, structure are as follows:
The quinine acid derivative is preferably compound CL-01~CL-24, and the structure of compound CL-01~CL-24 is such as
Shown in lower:
The preparation method of above-mentioned quinine acid derivative, includes the following steps:
The synthesis of (1a) benzene a pair of horses going side by side [d] [1,3] dioxolen (piperonyl cyclonene):
Using catechol as starting material, it is dissolved in n,N-Dimethylformamide, adds reagent a and sodium bicarbonate,
Reaction obtains parallel [d] [1, the 3] dioxolen of benzene；
The synthesis of (1b) 3,4- dioxymethylene benzaldehyde (piperonal):
Parallel [d] [1, the 3] dioxolen of benzene obtained in step (1a) is added dissolved in the isopropanol of catalyst, examination is added
Agent b, reaction, obtains 3,4-methylenedioxy benzaldehyde；
The synthesis of (1c) (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid:
3,4-methylenedioxy benzaldehyde and reagent c that step (1b) obtains are dissolved in alkali, reacts, obtains (E) -3- (benzene
Parallel [d] [1,3] dioxolen -5- base) acrylic acid；
The synthesis of (1c ') (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- sulfonic acid:
3,4- dioxymethylene benzaldehyde and Loprazolam acid anhydride that step (1b) obtains are dissolved in dry tetrahydrofuran
(THF), sodium hydride is added, reaction obtains (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- sulfonic acid；
The synthesis of (1c ") (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) vinyl phosphonic dimethyl phthalate:
3,4- dioxymethylene benzaldehyde and dimethyl methyl phosphonate that step (1b) obtains are dissolved in dry tetrahydro furan
It mutters, sodium hydride is added, reaction obtains (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) vinyl phosphonic dimethyl phthalate；
The synthesis of (1d ") (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- phosphonic acids mono-methyl:
(E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) vinyl phosphonic dimethyl phthalate that step (1c ") is obtained is molten
In dry tetrahydrofuran, reagent d " is added, obtains (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- phosphonic acids
Mono-methyl；
The synthesis of (2a) quininic acid methyl esters:
Using quininic acid as raw material, it is dissolved in methanol, thionyl chloride is added after balance, reacts, obtains quininic acid methyl esters；
The synthesis of (2b) N- methyl quinuclidine amide:
The quininic acid methyl esters that step (2a) obtains is dissolved in methanol, methylamine methanol solution is added, reaction obtains N- methyl Kui
Peaceful amide；
The synthesis of (2c) N- methyl -3,4- acetonylidene dioxy quinine amide:
The N- methyl quinuclidine amide that step (2b) obtains is dissolved in protection reagent, p-methyl benzenesulfonic acid and deicer is added, instead
It answers, removes deicer, obtain N- methyl -3,4- acetonylidene dioxy quinine amide；
The synthesis of (2d) N- methyl -3,4- acetonylidene dioxy -1,5- benzyloxy quinine amide:
N- methyl -3,4- acetonylidene dioxy quinine amide that step (2c) obtains is dissolved in and steams tetrahydrofuran again, is added four
Sodium hydride is added after balance in butylammonium bromide, reacts, and cylite is added dropwise, and reaction obtains N- methyl -3,4- acetonylidene dioxy -1,
5- benzyloxy quinine amide；
(2e) N- methyl-1, the synthesis of 5- benzyloxy quinine amide:
N- methyl -3,4- acetonylidene dioxy -1,5- benzyloxy quinine the amide that step (2d) obtains is dissolved in dichloromethane
Alkane, trifluoroacetic acid and water are added dropwise after balance, and reaction obtains N- methyl-1,5- benzyloxy quinine amide；
The synthesis of two mesyloxy -1,5- benzyloxy quinine amide of (2f) N- methyl -3,4-:
The N- methyl-1 that step (2e) is obtained, 5- benzyloxy quinine amide is dissolved in steams methylene chloride again, addition 4- (N,
N- dimethyl) aminopyridine, triethylamine is added, reagent f is added dropwise again after balance, reacts, obtains bis- methylsulfonyl oxygen of N- methyl -3,4-
Base -1,5- benzyloxy quinine amide；
The synthesis of (2g) N- methyl -3,4- diazido -1,5- benzyloxy quinine amide:
Two mesyloxy -1,5- benzyloxy quinine the amide of N- methyl -3,4- that step (2f) obtains is dissolved in N, N-
The mixed solvent of dimethylformamide (DMF) and hexamethylphosphoramide (HMPA), is added sodium azide, and reaction obtains N- first
Base -3- nitrine -4- mesyloxy -1,5- benzyloxy quinine amide；
Obtained N- methyl -3- nitrine -4- mesyloxy -1,5- benzyloxy quinine amide is dissolved in N, N- dimethyl
The mixed solvent of formamide (DMF) and hexamethylphosphoramide (HMPA), is added sodium azide, and reaction obtains N- methyl -3,4-
Diazido -1,5- benzyloxy quinine amide；
(2h) N- methyl -3,4- diaminostilbene, the synthesis of 5- benzyloxy quinine amide:
N- methyl -3,4- diazido -1,5- benzyloxy quinine the amide that step (2g) obtains is dissolved in first alcohol and water
Mixed solvent, be added triphenylphosphine, reaction, obtain containing N- methyl -3,4- diaminostilbene, 5- benzyloxy quinine amide
Residue；
The synthesis of (2c ') N- methyl -3,5- two (tertiary butyl dimethyl Si base) quinine amide:
The N- methyl quinuclidine amide that step (2b) obtains is dissolved in dry tetrahydrofuran, imidazoles is added and using drying
Tert-butyl chloro-silicane (TBSCl) solution of n,N-Dimethylformamide (DMF) dissolution, reaction obtain N- methyl -3,5-
Two (tertiary butyl dimethyl Si base) quinine amides；
The synthesis of (2d ') N- methyl -3,5- two (tertiary butyl dimethyl Si base) -1,4- benzyloxy quinine amide:
N- methyl -3,5- two (tertiary butyl dimethyl Si base) quinine amide that step (2c ') is obtained is according to step
(2d) is synthesized using identical reagent/auxiliary agent/solvent, is obtained N- methyl -3,5- bis- (tertiary butyl dimethyl Si base) -
1,4- benzyloxy quinine amide；
(2e ') N- methyl-1, the synthesis of 4- benzyloxy quinine amide:
N- methyl -3,5- two (tertiary butyl dimethyl Si base) -1,4- benzyloxy quinine acyl that step (2d ') is obtained
Amine is dissolved in methylene chloride, and trifluoroacetic acid is added dropwise after balance, and reaction obtains N- methyl-1,4- benzyloxy quinine amide；
The synthesis of two mesyloxy -1,4- benzyloxy quinine amide of (2f ') N- methyl -3,5-:
The N- methyl-1 that step (2e ') is obtained, 4- benzyloxy quinine amide is according to step (2f), using identical examination
Agent/auxiliary agent/solvent is synthesized, and bis- mesyloxies of N- methyl -3,5--Isosorbide-5-Nitrae-benzyloxy quinine amide is obtained；
The synthesis of (2g ') N- methyl -3,5- diazido -1,4- benzyloxy quinine amide:
Two mesyloxy -1,4- benzyloxy quinine the amide of N- methyl -3,5- that step (2f ') is obtained is according to step
(2g) is synthesized using identical reagent/auxiliary agent/solvent, obtains N- methyl -3,5- diazido-Isosorbide-5-Nitrae-benzyloxy Kui
Peaceful amide；
(2h ') N- methyl -3,5- diaminostilbene, the synthesis of 4- benzyloxy quinine amide:
N- methyl -3,5- diazido -1,4- benzyloxy quinine the amide that step (2g ') is obtained is according to step
(2h) is synthesized using identical reagent/auxiliary agent/solvent, is obtained containing N- methyl -3,5- diaminostilbene, 4- benzyloxy
The residue of quinine amide；
(E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid that step (1c) obtains is dissolved in and steams N again by (3a),
Dinethylformamide, is added condensing agent and 1- hydroxy benzenes a pair of horses going side by side triazole (HOBt), and n,N-diisopropylethylamine is added in reaction
(DIPEA), contain N- methyl -3,4- diaminostilbene for what step (2h) obtained, the residue of 5- benzyloxy quinine amide is molten
It is added dropwise after n,N-Dimethylformamide into reaction system, reacts, obtain containing-two coffee acyl -3 N- methyl-N ', N ',
4- diaminostilbene, the residue of 5- dihydroxy butylcyclohexane -1- formamide；
(3b) contains-two coffee acyl -3,4- diaminostilbene of N- methyl-N ', N ', 5- dihydroxy for what step (3a) obtained
The residue of hexamethylene -1- formamide is dissolved in steams methylene chloride again, and deprotection agent is added dropwise after balance, and reaction, stirring is anti-at room temperature
It answers, obtains-two coffee acyl -3,4- diaminostilbene of N- methyl-N ', N ', 5- dihydroxy butylcyclohexane -1- formamide CL-01~CL-
04。
Reagent a described in step (1a) is formaldehyde, CH2Cl2、CH2Br2And CH2I2One of；Preferably CH2I2。
The dosage of reagent a described in step (1a) is 1.0~1.5:1.0 by the molar ratio of itself and the catechol
Proportion；It is preferably 1.2:1.0 proportion by the molar ratio of itself and the 3,4- dioxymethylene benzaldehyde.
The temperature of reaction described in step (1a) is 70~100 DEG C；Preferably 80 DEG C.
The time of reaction described in step (1a) is 5~20h；Preferably 12h.
A pair of horses going side by side [d] [1, the 3] dioxolen of benzene described in step (1b) is to be added dropwise under the conditions of 55 DEG C dissolved with catalyst
In isopropanol, drip within 0.5 hour.
Catalyst described in step (1b) is one of phosphorus oxychloride, nitric acid and acetic anhydride；Preferably acetic anhydride.
Reagent b described in step (1b) is one of N,N-dimethylformamide, glyoxalic acid and methenamine；It is preferred that
For methenamine.
The dosage of reagent b described in step (1b) is by the molar ratio of itself and parallel [d] [1,3] dioxolen of the benzene
400~700:1.0 proportion；It is preferably 660:1.0 proportion by the molar ratio of itself and parallel [d] [1,3] dioxolen of the benzene.
The temperature of reaction described in step (1b) is 80~120 DEG C；Preferably 110 DEG C.
The time of reaction described in step (1b) is 0.5~3h；Preferably 1h.
Reagent c described in step (1c) is one of acetic anhydride and malonic acid；Preferably malonic acid.
Alkali described in step (1c) is the sodium salt or sylvite, piperidines/pyridine, sodium hydride, diisopropylaminoethyl of respective acids
One of lithium (LDA) and potassium tert-butoxide；Preferably piperidines/pyridine.
The dosage of reagent c described in step (1c) is by the molar ratio of itself and the 3,4- dioxymethylene benzaldehyde
1.0~6.0:1.0 proportion；It is preferably 2:1 proportion by the molar ratio of itself and the 3,4- dioxymethylene benzaldehyde.
The dosage of 3,4- dioxymethylene benzaldehyde described in step (1c '), Loprazolam acid anhydride and sodium hydride is according to rubbing
You match than 1.0:1.0~2.0:1.5~3.0 and calculate；It preferably matches and calculates according to molar ratio 1.0:1.5:1.5.
The dosage of 3,4- dioxymethylene benzaldehyde, dimethyl methyl phosphonate and sodium hydride described in step (1c ") is pressed
It matches and calculates according to molar ratio 1.0:1.0~2.0:1.5~3.0；It preferably matches and calculates according to molar ratio 1.0:1.5:1.5.
Reaction described in step (1c), (1c ') and (1c ") is to be heated to reflux 4~1h at 90~130 DEG C of oil bath；
Preferably 2h is heated to reflux at 115 DEG C of oil bath.
Reagent d described in step (1d ") " it is one of lithium hydroxide, lithium carbonate and tri butyl boron lithium hydride；It is preferred that
For tri butyl boron lithium hydride.
Addition reagent d described in step (1d ") " it is to be added dropwise under nitrogen protection.
The dosage of quininic acid described in step (2a) by the molar ratio of itself and the thionyl chloride be 1.0:1.0~
2.0 proportions calculate；It is preferably that 1.0:1.35 proportion calculates by the molar ratio of itself and thionyl chloride.
Reaction described in step (2a) reacts 15~40min under the conditions of being -20~-10 DEG C, then moves to room temperature and continues instead
Answer 8~20h；React 30min under the conditions of preferably -15 DEG C, then room temperature the reaction was continued 12h.
Methanol described in step (2a) and (2b) is dry methanol.
The dosage of methylamine methanol solution described in step (2b) is excessive.
The time of reaction described in step (2b) is 5~20h；Preferably 12h.
Protection reagent described in step (2c) is one of formaldehyde, acetone, benzaldehyde；Preferably acetone.
Deicer described in step (2c) isAt least one of molecular sieve and anhydrous magnesium sulfate；PreferablyPoint
Son sieve and anhydrous magnesium sulfate.
The dosage of N- methyl quinuclidine amide described in step (2c) is 5 by the molar ratio of itself and the p-methyl benzenesulfonic acid
~10:1 proportion calculates；It is preferably that 8.5:1 proportion calculates by the molar ratio of itself and p-methyl benzenesulfonic acid.
Reaction described in step (2c) is 5~20h of back flow reaction under the conditions of 45~70 DEG C；Preferably 58 DEG C of conditions are next time
Stream reaction 12h.
Tetrabutylammonium bromide described in step (2d), sodium hydride, cylite and N- methyl -3,4- acetonylidene dioxy quinine
Amide is matched according to molar ratio 1:100~130:25~40:10~15 and is calculated；Preferably match according to molar ratio 1:120:36:12
Than calculating.
Sodium hydride described in step (2d) is added in three times.
In step (2d), the reaction after sodium hydride is added reacts 5~30min under the conditions of being -15~0 DEG C；Preferably -5 DEG C
Under the conditions of react 10min；Reaction after cylite is added dropwise reacts 20~50min under the conditions of being -15~0 DEG C, then is stirred at room temperature anti-
Answer 20~50min；30min is reacted under the conditions of preferably -5 DEG C, then reaction 30min is stirred at room temperature.
The dosage of trifluoroacetic acid described in step (2e) is 1:1 calculating by the volume ratio of itself and water.
Reaction described in step (2e) reacts 2~5h under the conditions of being -10~10 DEG C；3h is reacted under the conditions of preferably 0 DEG C.
Addition triethylamine described in step (2f) is that triethylamine is added under condition of ice bath.
Reagent f described in step (2f) is one of mesyl chloride and paratoluensulfonyl chloride.
The dosage of reagent f described in step (2f) presses itself and the N- methyl-1,5- benzyloxy quinine amide
Molar ratio is that 1~5:1 proportion calculates；Preferably press itself and the N- methyl-1, the molar ratio of 5- benzyloxy quinine amide
It matches and calculates for 3:1.
Reaction described in step (2f) is 20~50min to be reacted under condition of ice bath, then 5~20h of reaction is stirred at room temperature；It is excellent
It is selected as reacting 30min under condition of ice bath, then reaction 12h is stirred at room temperature.
The dosage of N,N-dimethylformamide described in step (2g) is by the volume ratio of itself and hexamethylphosphoramide
3:1 is calculated.
In step (2g), the dosage for the sodium azide being added for the first time presses itself and bis- methylsulfonyl of N- methyl -3,4-
Oxy-1, the molar ratio of 5- benzyloxy quinine amide are that 1~5:1 proportion calculates；Itself and methyl -3 N- are preferably pressed,
The molar ratio of bis- mesyloxy -1,5- benzyloxy quinine amide of 4- is that 3:1 proportion calculates；Second of sodium azide being added
Dosage by the molar ratio of itself and the N- methyl -3- nitrine -4- mesyloxy -1,5- benzyloxy quinine amide be 2
~8:1 proportion calculates；Preferably press itself and the N- methyl -3- nitrine -4- mesyloxy -1,5- benzyloxy quinine acyl
The molar ratio of amine is that 5:1 proportion calculates.
In step (2g), first set reaction is 5~20h of reaction under the conditions of 50~100 DEG C of oil baths；Preferably 70 DEG C of oil bath items
12h is reacted under part；Second secondary response is 10~30h of reaction under the conditions of 100~150 DEG C of oil baths；Under the conditions of preferably 125 DEG C of oil baths
Reaction is for 24 hours.
The dosage of methanol described in step (2h) is 5:1 proportion by the volume ratio of itself and water.
The dosage of triphenylphosphine described in step (2h) presses itself and the N- methyl -3,4- diazido -1,5- two
The molar ratio of benzyloxy quinine amide is that 0.5~2:1 proportion calculates；Preferably press itself and two nitrine of N- methyl -3,4-
The molar ratio of base -1,5- benzyloxy quinine amide is that 1.5:1 proportion calculates.
Reaction described in step (2h) is 3~10h of back flow reaction under the conditions of 50~80 DEG C of oil baths；Preferably 68 DEG C of oil baths
Under the conditions of back flow reaction 5h.
The dosage of tert-butyl chloro-silicane described in step (2c ') presses itself and the N- methyl quinuclidine amide
Molar ratio is that 1~4:1 proportion calculates；It is preferably based on 2.4:1 proportion by the molar ratio of itself and the N- methyl quinuclidine amide
It calculates.
The time being stirred to react described in step (2c ') is 1~5h；Preferably 1.5h.
The dosage of trifluoroacetic acid described in step (2e ') preferably presses every 1mL trifluoroacetic acid proportion methyl -3 1mmol N-,
5- bis- (tertiary butyl dimethyl Si base) -1,4- benzyloxy quinine amide calculates.
Be stirred to react described in step (2e ') be 60~100 DEG C under the conditions of be stirred to react 1~5h；Preferably 80 DEG C of items
2h is stirred to react under part.
The product that step (2h) and (2h ') are obtained may have 4 optical isomers, separated or be directly entered to product
It is separated again after the reaction of next step；It is preferred that being separated again after being directly entered the reaction of next step.
Condensing agent described in step (3a) is N, N'- diisopropylcarbodiimide (DIC), 1- (3- dimethylamino third
Base) one of -3- ethyl-carbodiimide hydrochloride (EDCI) and ethyl chloroformate；Preferably 1- (3- dimethylamino-propyl)-
3- ethyl-carbodiimide hydrochloride.
The dosage of condensing agent described in step (3a) is by itself and described (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -
5- yl) acrylic acid molar ratio be 0.5~2:1 proportion calculate；Preferably press itself and (E) -3- (benzene a pair of horses going side by side [d] [1,3] two
Oxygen amylene -5- base) acrylic acid molar ratio be 1.2:1 proportion calculate.
In step (3a), the time of first set reaction is 20~50min, and the time of the second secondary response is 5~20h；It is preferred that
The time of first set reaction is 30min, and the time of the second secondary response is 12h.
It further include by described tetra- kinds of optical isomers of CL-01~CL-04 in step (3b) using column chromatography, efficient liquid phase
One of method and recrystallization method or at least two the step of isolating and purifying.
Deprotecting regent described in step (3b) is BCl3And BBr3One of；Preferably BCl3。
The dosage of deprotection agent described in step (3b) contains-two caffeoyl of N- methyl-N ', N ' with described by it
Base -3,4- diaminostilbene, the molar ratio of the residue of 5- dihydroxy butylcyclohexane -1- formamide are that 1~5:1 proportion calculates；It is preferred that
To contain-two coffee acyl -3,4- diaminostilbene of N- methyl-N ', N ', 5- dihydroxy butylcyclohexane -1- formyl with described by it
The molar ratio of the residue of amine is that 2.5:1 proportion calculates.
Reaction described in step (3b) reacts 15~45min under the conditions of being 0~-20 DEG C, then it is stirred to react 1 at room temperature~
5h；30min is reacted under the conditions of preferably -10 DEG C, then is stirred to react 2h at room temperature.
- two coffee acyl -3,5- diaminostilbene of N- methyl-N ', N ', 4- dihydroxy butylcyclohexane -1- formamide (CL-05~
CL-08 preparation process) is carried out by step (3a) and (3b), N- methyl -3,4- that wherein starting material is obtained by step (2h)
Diaminostilbene, 5- benzyloxy quinine amide are changed to the N- methyl -3,5- diaminostilbene that step (2h ') obtains, bis- benzyloxy of 4-
Base quinine amide, other reagents, auxiliary agent are identical with solvent type.
- two coffee sulfonyl -3,4- diaminostilbene of N- methyl-N ', N ', 5- dihydroxy butylcyclohexane -1- formamide (CL-09
~CL-12) preparation process by step (3a) and (3b) carry out, (E) -3- (benzene that wherein starting material is obtained by step (1c)
Parallel [d] [1,3] dioxolen -5- base) acrylic acid is changed to (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxy penta that step (1c ') obtains
Alkene -5- base) ethylene -1- sulfonic acid, other reagents, auxiliary agent are identical with solvent type.
- two coffee sulfonyl -3,5- diaminostilbene of N- methyl-N ', N ', 4- dihydroxy butylcyclohexane -1- formamide (CL-13
~CL-16) preparation process by step (3a) and (3b) carry out, (E) -3- (benzene that wherein starting material is obtained by step (1c)
Parallel [d] [1,3] dioxolen -5- base) acrylic acid is changed to (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxy penta that step (1c ') obtains
Alkene -5- base) ethylene -1- sulfonic acid, N- methyl -3,4- diaminostilbene that step (2h) obtains, the replacement of 5- benzyloxy quinine amide
For N- methyl -3,5- diaminostilbene that step (2h ') obtains, 4- benzyloxy quinine amide, other reagents, auxiliary agent and solvent kind
Class is identical.
N- methyl-N ', N '-two coffee phosphine (mono-methyl) acyl group -3,4- diaminostilbene, 5- dihydroxy butylcyclohexane -1- formyl
The preparation process of amine (CL-17~CL-20) is carried out by step (3a) and (3b), and wherein starting material is obtained by step (1c)
(E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid be changed to (E) -2- that step (1d ") obtains (benzene a pair of horses going side by side [d] [1,
3] dioxolen -5- base) ethylene -1- phosphonic acids mono-methyl, other reagents, auxiliary agent are identical with solvent type.
N- methyl-N ', N '-two coffee phosphine (mono-methyl) acyl group -3,5- diaminostilbene, 4- dihydroxy butylcyclohexane -1- formyl
The preparation of amine (CL-21~CL-24) is carried out by step (3a) and (3b), (E) -3- that wherein starting material is obtained by step (1c)
(benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid is changed to (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxy that step (1d ") obtains
Amylene -5- base) ethylene -1- phosphonic acids mono-methyl, N- methyl -3,4- diaminostilbene that step (2h) obtains, 5- benzyloxy quinine
Amide is changed to N- methyl -3,5- diaminostilbene that step (2h ') obtains, 4- benzyloxy quinine amide, other reagents, auxiliary agent
It is identical with solvent type.
Institute in (E) -3- described in step (1c) (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid, step (1c ')
(E) -2- (benzene described in (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- sulfonic acid and step (1d ") stated
Parallel [d] [1,3] dioxolen -5- base) vinyl phosphonic acid mono-methyl synthetic route as shown in approach 1:
N- methyl -3,4- diaminostilbene described in step (2h), 5- benzyloxy hexamethylene -1- formamide and step
N- methyl -3,5- diaminostilbene described in (2h '), synthetic route such as 2 He of approach of 4- benzyloxy hexamethylene -1- formamide
Shown in approach 3:
Institute in (E) -3- described in step (1c) (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid, step (1c ')
(E) -2- (benzene described in (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- sulfonic acid and step (1d ") stated
Parallel [d] [1,3] dioxolen -5- base) vinyl phosphonic acid mono-methyl respectively with N- methyl -3,4- diamino described in step (2h)
N- methyl -3,5- diaminostilbene, bis- benzyloxy of 4- described in base -1,5- benzyloxy-hexamethylene -1- formamide, step (2h ')
Benzyl is sloughed after the condensation of butylcyclohexane -1- formamide, obtains the route of quinine acid derivative as shown in approach 4:
Application of the above-mentioned quinine acid derivative in preparation antiviral drugs.
The virus is influenza virus, parainfluenza virus or Respiratory Syncytial Virus(RSV) (RSV).
A kind of antiviral drugs includes above-mentioned quinine acid derivative.
The antiviral drugs can also contain a kind of or at least two pharmaceutically acceptable carrier or auxiliary materials.
The auxiliary material be preferably sustained release agent, excipient, filler, adhesive, wetting agent, disintegrating agent, sorbefacient,
Absorption carrier, surfactant or lubricant etc..
The carrier is at least one of micro-capsule, microballoon, nanoparticle and liposome.
Various dosage forms can be further made in the antiviral drugs, and the drug of various dosage forms can be according to pharmaceutical field
Conventional method be prepared.
The present invention has the following advantages and effects with respect to the prior art:
(1) present invention is according to medicine core similarity principle and bioisostere principle, with natural two coffee
Acyl quininic acid and its methyl esters are primer, and design synthesis has the quinine acid derivative of antivirus action.It is real using plaque subtrahend
The Anti-viral activity in vitro for detecting serial quininic acid derivative is tested, and assesses serial quinine acid derivative respectively using MMT method
Cytotoxicity.The result shows that the designed quinine acid derivative synthesized of the present invention all has strong anti respiratory syncytial virus
(RSV) and parainfluenza 3 type viral (PIV3) activity, and cytotoxicity is low, the selectivity index of anti-RSV and PIV3 (SI value,
SI=CC50/IC50) be higher than positive control drug Ribavirin, natural primer 3,4-O, O- dicaffeoylquinic acid methyl esters and 3,
5-O, O- dicaffeoylquinic acid methyl esters, wherein acted on CL-23 anti-RSV and PIV3 best.In addition, it has also been found that being
Column quinine acid derivative also has certain anti-influenza A virus activity, the SI value and Ribavirin of anti-influenza A virus
Quite.
(2) quinine acid derivative stability with higher of the invention, the stability in fetal calf serum is than 3,4-
O, O- dicaffeoylquinic acid methyl esters and 3,5-O, O- dicaffeoylquinic acid methyl esters are high.
(3) the preparation method reaction condition of quinine acid derivative of the invention is mild, and automation easy to accomplish is easy to operate
Safety, industrialized production easy to accomplish.
Specific embodiment
Below with reference to embodiment, the present invention is described in further detail, it will be appreciated by those skilled in the art that
Following embodiments and embodiment are merely to illustrate the present invention, and are not construed as limiting the scope of the invention.Specific item is not specified
Part person carries out according to conventional conditions or manufacturer's recommended conditions.Reagents or instruments used without specified manufacturer, being can
With the conventional products obtained by commercially available purchase.
1-two coffee acyl-3,4- diaminostilbene of N- methyl-N ', N ' of embodiment, 5- dihydroxy butylcyclohexane-1- formamide
It the preparation of (CL-01~CL-04) and isolates and purifies
(1) preparation of (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid
The preparation of (1a) benzene a pair of horses going side by side [d] [1,3] dioxolen (piperonyl cyclonene)
It weighs catechol (110.1mg, 1.0mmol) to be placed in 50mL round-bottomed flask, n,N-Dimethylformamide is added
15mL, stirring dissolve catechol, add diiodomethane (321.4mg, 1.2mmol) and sodium bicarbonate (210.0mg,
2.5mmol), 12h is reacted in 80 DEG C of heating.After completion of the reaction, product is poured slowly into ice water while stirring, ethyl acetate extraction
3 times, organic layer is dry with anhydrous sodium sulfate, and vacuum rotary steam removes ethyl acetate, silica gel column chromatography (Beijing Xin Weier glass apparatus
Co., Ltd) (petroleum ether: ethyl acetate=10:1, V:V) is isolated and purified, faint yellow solid 75.8mg is obtained, yield is
62.1%.1H NMR(300MHz,CDCl3)δ:6.83-6.79(m,4H),5.90(s,2H)；13C NMR(300MHz,CDCl3)δ:
147.5,121.7,108.7,100.7。
The preparation of (1b) 3,4- dioxymethylene benzaldehyde (piperonal)
75.0g catalyst acetic acid acid anhydride is added in 200mL there-necked flask, is added with stirring isopropanol 10mL, heats to 55
DEG C, parallel [d] [1,3] dioxolen (5.0g, 40.9mmol) of benzene that step (1a) obtains is slowly added dropwise, drips off within 0.5 hour, is added
Methenamine (3.8g, 27.0mmol), charging finishes, and is warming up to 110 DEG C, keeps the temperature 1 hour, samples liquid phase analysis, cools to 60
~70 DEG C, water 700mL is added, stirs 3 hours, ethyl acetate is added and extracts twice, merges organic phase, saturated common salt washing is added
It washs, separates organic phase, anhydrous sodium sulfate 5g is added and is dried, filters, ethyl acetate, extraction raffinate oil pump is concentrated in filtrate at 40 DEG C
Vacuum distillation is to get piperonal 3.58g, yield 58.2%, purity 96%.1H NMR(300MHz,CDCl3)δ:9.82(s,1H),
7.43(d,1H),7.34(s,1H),6.95(d,1H),6.08(s,2H)；13C NMR(75MHz,CDCl3)δ:190.3,153.1,
148.7,130.9,128.7,108.3,106.9,102.1。
The preparation of (1c) (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid
In 250mL round-bottomed flask, piperonal (12g, 79.9mmol) that step (1b) is obtained, malonic acid (16.6g,
159.9mmol) with reaction solution is obtained after 7.2mL piperidines and 140mL pyridinium dissolution, reaction solution is moved to 115 DEG C of oil bath and is heated back
Stream about 2 hours.Reaction process is monitored to piperonal with thin-layer chromatography TLC and is completely disappeared, and shows fully reacting.Reaction solution is cooled to
After room temperature, reaction solution is slowly poured into 200mL hydrochloric acid solution (2mol/L) under ice bath, there are a large amount of yellowish-white solids to analyse
Out.Through filter obtain faint yellow solid filter cake, after faint yellow solid filter cake wash with 400mL water dispersion, then through suction filtration obtain
Yellowish-white solid filter cake, and repeating above operation to filter cake pH value is neutrality.It is recrystallized with hot water, collects yellowish-white solid
It dries under filter cake to infrared lamp to constant weight, obtains yellowish-white solid 11.9g, yield 77.1%.1H NMR(300MHz,CDCl3)
δ:12.05(s,1H),7.45(d,1H),7.12(s,1H),7.06(d,1H),6.95(d,1H),6.27(d,1H),6.07(s,
2H)；13C NMR(75MHz,CDCl3)δ:171.5,151.1,148.6,144.9,127.6,122.7,116.5,108.3,
106.9,102.1。
(2) N- methyl -3,4- diaminostilbene, the preparation of 5- benzyloxy hexamethylene -1- formamide
The preparation of (2a) quininic acid methyl esters
Quininic acid (1.92g, 10mmol) is weighed in dry 100mL round-bottomed flask, is dissolved with suitable dry methanol,
Flask is placed in cryogenic thermostat stirring reactive bath, keep -15 DEG C of conditional equilibrium 15min, then measure thionyl chloride (0.98mL,
It 13.5mmol) is slowly dropped in reaction system, after reacting 30min, reaction solution is moved into room temperature, the reaction was continued 12h.Wait react
It finishes, 3mL water is slowly added under condition of ice bath, and extracted with ethyl acetate EtOAc (4 × 100mL), after merging organic phase
It is washed with saturated salt solution (100mL × 2), organic phase anhydrous Na2SO4It dries, filters, vacuum revolving removes solvent, TLC exhibition
Opening agent condition is CHCl3:CH3OH=3:1 (V:V) separates (CHCl through silica gel column chromatography3:CH3OH=3:1, V:V), collect RfValue
For 0.39 fraction, revolving removes solvent, obtains pale yellow oily liquid 1.88g, yield 91.3%.1H NMR(300MHz,D2O)
δ:3.96(m,1H,H-3),3.85(m,1H,H-5),3.56(s,3H,H-8),3.36(m,1H,H-4),1.69-1.96(m,4H,
H-2,6)；13C NMR(75MHz,D2O)δ:175.6,75.4,74.2,69.4,66.2,48.8,39.7,36.4；ESI-MS(m/
z):207.2[M+H]+,229.3[M+Na]+。
The preparation of (2b) N- methyl quinuclidine amide
Quininic acid methyl esters (1.85g, 9mmol) that step (2a) obtains is weighed in dry 100mL round-bottomed flask, with suitable
The drying methanol of amount dissolves, and excessive methylamine methanol solution is added into reaction system at room temperature, and in room temperature condition
Lower reaction 12h.To end of reaction, vacuum revolving removes solvent, and TLC solvent condition is CHCl3:CH3OH=3:1 (V:V), warp
Silica gel column chromatography separates (CHCl3:CH3OH=3:1, V:V), collect RfValue is 0.31 fraction, and revolving removes solvent, obtains white
Solid 1.82g, yield 98.7%.1H NMR(300MHz,CD3OD)δ:7.62(s,1H),4.13(m,1H,H-3),3.99(m,
1H, H-5), 3.40 (dd, J=3.0,3.0Hz, 1H, H-4), 2.75 (s, 3H, H-8), 1.84-2.03 (m, 4H, H-2,6)；13C
NMR(75MHz,CD3OD)δ:178.1,78.1,77.1,72.3,68.3,42.6,39.0,26.4；ESI-MS(m/z):206.2
[M+H]+,228.3[M+Na]+。
The preparation of (2c) N- methyl -3,4- acetonylidene dioxy quinine amide
N- methyl quinuclidine amide (1.74g, 8.5mmol) that step (2b) obtains is weighed in dry 100mL round-bottomed flask
In, it is dissolved, and p-methyl benzenesulfonic acid (172mg, 1.0mmol) is added, is then added suitable with suitable dry acetoneMolecule
Sieve and anhydrous magnesium sulfate are as deicer, and flow back 12h under conditions of 58 DEG C.To end of reaction, it is filtered to removeMolecular sieve and
Anhydrous magnesium sulfate is added suitable saturated salt solution dilute reaction solution, and uses CH2Cl2(4 × 100mL) is extracted, and is associated with
Machine Xiang Houyong saturated salt solution (100mL × 2) washing, organic phase anhydrous Na2SO4It drying, filtering, vacuum revolving removes solvent,
TLC solvent condition is CHCl3:CH3OH=15:1 (V:V), separates through silica gel column chromatography, collects RfThe fraction that value is 0.65, rotation
Solvent is evaporated off, obtains yellow oily liquid 1.53g, yield 73.5%.1H NMR(300MHz,CD3OD)δ:7.61(s,1H),
4.50 (m, 1H, H-3), 3.99 (m, 1H, H-5), 3.88 (dd, J=6.0,6.0Hz, 1H, H-4), 2.76 (d, J=6.0Hz
3H,H-8),1.90-2.33(m,4H,H-2,6),1.44(s,3H,H-4′),1.29(s,3H,H-5′)；ESI-MS(m/z):
246.1[M+H]+,268.3[M+Na]+。
The preparation of (2d) N- methyl -3,4- acetonylidene dioxy -1,5- benzyloxy quinine amide
N- methyl -3,4- acetonylidene dioxy quinine amide (1.47g, 6mmol) that step (2c) obtains is weighed in dry
In 100mL round-bottomed flask, dissolved with suitable heavy steaming tetrahydrofuran, and tetrabutylammonium bromide (161mg, 0.5mmol) is added, so
The reaction solution in flask is placed under conditions of low-temp reaction bathes -5 DEG C afterwards and balances 5min.Ready to balance finishes, and points 3 times to reaction solution
In be slowly added to sodium hydride (1.44g, 60mmol), keep -5 DEG C of conditioned response 10min.Then measure cylite (2.13mL,
It 18mmol) is slowly dropped in reaction system, after keeping -5 DEG C of cryogenic conditions 30min, then moves to room temperature, continue to stir 5h.To
The methanol quenching reaction of 5mL is slowly added dropwise under condition of ice bath, then moves in separatory funnel reaction solution, adds for end of reaction
Enter suitable saturated salt solution dilute reaction solution, extracted with methylene chloride (DCM, 4 × 100mL), is used after merging organic phase
Saturated salt solution (2 × 100mL) washing, organic phase anhydrous Na2SO4It dries, filters, vacuum revolving removes solvent, through silicagel column
Chromatography (EtOAc:PE=1:50, V:V) is EtOAc:PE=1:25 (V:V) in TLC solvent condition, collects RfValue is
0.40 fraction, revolving remove solvent, obtain colourless oil liquid 2.08g, yield 81.7%.1H NMR(300MHz,CDCl3)δ:
7.63(s,1H),7.25-7.36(m,10H,H-Ph,Ph′),4.61(m,4H,-CH2-Ph,-CH2-Ph′),4.16(m,2H,H-
3,5),3.97(m,1H,H-4),3.17(s,3H,H-8),2.42-2.58(m,4H,H-2,6),1.48(s,3H,H-4′),1.40
(s,3H,H-5′)；13C NMR(75MHz,CDCl3)δ:172.0,138.7,137.8,137.4,128.8,128.5,128.4
(2C),128.3,128.1(2C),127.8,127.7,108.9,81.5,80.0,75.1,73.8,72.1,66.6,35.6,
35.4,32.7,28.3,25.9。
(2e) N- methyl-1, the preparation of 5- benzyloxy quinine amide
Weigh N- methyl -3,4- acetonylidene dioxy -1,5- benzyloxy quinine amide that step (2d) obtains (1.91g,
It 4.5mmol) in dry 100mL round-bottomed flask, is dissolved with methylene chloride (20mL), and flask is placed in low-temp reaction bath 0
5min is balanced under conditions of DEG C, is then slowly dropped into 5mL trifluoroacetic acid and water (TFA:H to reaction system2O=1:1, V:V)
Mixed solvent reacts 3h under conditions of 0 DEG C.To end of reaction, reaction solution is poured into saturated ammonium chloride solution, is then shifted
To separatory funnel, suitable saturated salt solution dilute reaction solution is added, is extracted with DCM (4 × 100mL), organic phase is merged
It is washed afterwards with saturated salt solution (2 × 100mL), organic phase anhydrous Na2SO4It dries, filters, vacuum revolving removes solvent, through silicon
Plastic column chromatography separates (CHCl3:CH3OH=80:1, V:V), it is CHCl in TLC solvent condition3:CH3OH=40:1 (V:V) is received
Collect RfThe fraction that value is 0.50, revolving remove solvent, obtain colourless oil liquid 1.52g, yield 87.5%.1H NMR
(300MHz,CDCl3)δ:7.64(s,1H),7.24-7.30(m,10H,H-Ph,Ph′),4.51(m,4H,-CH2-Ph,-CH2-
Ph′),4.08(m,1H,H-3),3.68(m,1H,H-5),3.55(m,1H,H-4),3.02(s,3H,H-8),1.88-2.66(m,
4H,H-2,6)；13C NMR(75MHz,CDCl3)δ:170.3,138.3,137.0,136.4,128.7,128.6,128.5(2C),
128.2,128.0(2C),127.8,127.6,84.1,74.9,74.4,71.9,70.4,67.0,36.0,35.2,34.3。
The preparation of two mesyloxy -1,5- benzyloxy quinine amide of (2f) N- methyl -3,4-
The N- methyl-1 that step (2e) obtains is weighed, 5- benzyloxy quinine amide (1.35mg, 3.5mmol) is in dry
In 100mL round-bottomed flask, dissolved with suitable heavy steaming methylene chloride, and be added 4- (N, N- dimethyl) aminopyridine (37mg,
0.3mmol), then flask is placed under condition of ice bath, is added acid binding agent triethylamine 1.45mL (10.5mmol), balance 5min.
Ready to balance finishes, and is slowly added dropwise into reaction solution mesyl chloride 0.82mL (10.5mmol), and condition of ice bath is kept to react 30min
Afterwards, room temperature is then moved to, continues to stir 12h.To end of reaction, 5mL pure water quenching reaction is slowly added dropwise in condition of ice bath, then
Reaction solution is moved in separatory funnel, suitable saturated salt solution dilute reaction solution is added, is extracted with DCM (4 × 100mL)
It takes, is washed after merging organic phase with saturated salt solution (2 × 100mL), organic phase anhydrous Na2SO4It dries, filters, vacuum revolving
Solvent is removed, residue separates (EtOAc:PE=1:4, V:V) through silica gel column chromatography, is EtOAc:PE in TLC solvent condition
=1:2 (V:V) collects RfThe fraction that value is 0.32, revolving remove solvent, obtain white powder 1.47g, yield 77.6%.1H
NMR(300MHz,CDCl3)δ:7.63(s,1H),7.26-7.37(m,10H,H-Ph,Ph′),5.52(m,1H,H-4),4.99
(m,1H,H-5),4.67(m,4H,-CH2-Ph,-CH2-Ph′),4.35(m,1H,H-3),3.22(s,3H,-SO2CH3),3.20
(s,3H,-SO2CH3),2.80(s,3H,H-8),2.32-2.84(m,4H,H-2,6)；13C NMR(75MHz,CDCl3)δ:
172.8,139.0,138.8,138.7,129.4,129.2(2),129.1,128.8,128.7,128.6,128.4,128.2,
81.9,79.5,77.9,74.2,72.6,66.7,38.5,38.2(2),35.5,35.0。
The preparation of (2g) N- methyl -3,4- diazido -1,5- benzyloxy quinine amide
Weigh the two mesyloxy -1,5- benzyloxy quinine amide of N- methyl -3,4- that step (2f) obtains
(812.4mg, 1.5mmol) in dry 50mL round-bottomed flask, with appropriate n,N-Dimethylformamide (DMF) and hempa
The mixed solvent (DMF:HMPA=3:1, V:V) of acyl triamine (HMPA) dissolves, and sodium azide (293mg, 4.5mmol) is added,
12h is reacted under the conditions of 70 DEG C of oil bath.To end of reaction, 5mL pure water quenching reaction is slowly added dropwise under condition of ice bath, so
Reaction solution is moved in separatory funnel afterwards, suitable saturated salt solution dilute reaction solution is added, is extracted with DCM (3 × 50mL)
It takes, is washed after merging organic phase with saturated salt solution (2 × 100mL), organic phase anhydrous Na2SO4It dries, filters, vacuum revolving
Low boiling point solvent is removed, residue separates (EtOAc:PE=1:4, V:V) through silica gel column chromatography, is in TLC solvent condition
EtOAc:PE=1:2 (V:V) collects RfThe fraction that value is 0.29, revolving remove solvent, obtain yellow oil 617.1mg, yield
It is 84.2%.This is N- methyl -3- nitrine -4- mesyloxy -1,5- benzyloxy quinine amide.
Weigh N- methyl -3- nitrine -4- mesyloxy -1,5- benzyloxy quinine amide (586.3mg, 1.2mmol)
In dry 50mL round-bottomed flask, dissolved with the mixed solvent (DMF:HMPA=3:1, V:V) of appropriate DMF and HMPA, and add
Enter sodium azide (390mg, 6mmol), is reacted for 24 hours under the conditions of 125 DEG C of oil bath.It is slow in condition of ice bath to end of reaction
5mL pure water quenching reaction is added dropwise, then reaction solution is moved in separatory funnel, suitable saturated salt solution diluting reaction is added
Liquid is extracted with DCM (3 × 50mL), is washed after merging organic phase with saturated salt solution (2 × 100mL), and organic phase is with anhydrous
Na2SO4Dry, filter, vacuum revolving remove low boiling point solvent, residue through silica gel column chromatography separate (EtOAc:PE=1:4, V:
V), it is EtOAc:PE=1:2 (V:V) in TLC solvent condition, collects RfThe fraction that value is 0.36, revolving remove solvent, obtain depth
Yellow oil 399.8mg, yield 76.5%.This is N- methyl -3,4- diazido -1,5- benzyloxy quinine amide.1H NMR(300MHz,CDCl3)δ:7.64(s,1H),7.28-7.33(m,10H,H-Ph,Ph′),5.46(m,1H,H-4),5.13
(m,1H,H-5),4.68(m,4H,-CH2-Ph,-CH2-Ph′),4.35(m,1H,H-3),2.86(s,3H,H-8),2.32-1.91
(m,4H,H-2,6)；13C NMR(75MHz,CDCl3)δ:173.1,138.9,138.7,138.6,129.3,129.1(2),
129.0,128.8,128.7,128.6,128.4,128.2,81.9,79.5,77.9,74.2,72.6,66.7,38.5,35.5,
35.0。
(2h) N- methyl -3,4- diaminostilbene, the preparation of 5- benzyloxy quinine amide
Weigh N- methyl -3,4- diazido -1,5- benzyloxy quinine amide that step (2g) obtains (370.2mg,
0.85mmol) in dry 50mL round-bottomed flask, with the mixed solvent (MeOH:H of proper amount of methanol and water2O=5:1, V:V) it is molten
Solution, and triphenylphosphine (336mg, 1.28mmol) is added, it flows back under the conditions of 68 DEG C of oil bath, reacts 5h.Wait react
Finish, suitable distilled water dilute reaction solution is added, reaction solution is then adjusted to faintly acid with the hydrochloric acid solution of 0.1M, then use DCM
(2 × 50mL) is extracted, and organic phase is discarded, and retains water phase.Water phase is adjusted to alkalescent with the sodium hydroxide solution of 0.1M, uses
DCM (3 × 50mL) is extracted, and is washed after merging organic phase with saturated salt solution (2 × 100mL), organic phase anhydrous Na2SO4
It dries, filters, vacuum revolving removes solvent, obtains residue.Due in product structure there are two free amine groups, stability compared with
Difference, and be not easy to separate, therefore residue is directly used in and is reacted in next step.
(3)-two coffee acyl -3,4- diaminostilbene of N- methyl-N ', N ', 5- dihydroxy butylcyclohexane -1- formamide (CL-01
~CL-04) preparation and isolate and purify
(3a) weighs (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid that step (1c) obtains
(384.3mg, 2.0mmol) is dissolved in dry 50mL round-bottomed flask with suitable heavy steaming DMF, and is respectively added slowly to
EDCI (460mg, 2.4mmol) and 1- hydroxy benzenes a pair of horses going side by side triazole (HOBt, 324mg, 2.4mmol), react 30min under room temperature.
It is subsequently added into n,N-diisopropylethylamine (DIPEA, 0.42mL, 2.4mmol), and step (2h) is reacted into gained residue (about
It 0.8mmol) with dry DMF dissolution, is then slowly dropped in reaction system, the reaction was continued at room temperature 12h.To anti-
It should finish, 5mL pure water quenching reaction is slowly added dropwise under condition of ice bath, then moves to reaction solution in separatory funnel, be added
Suitable saturated salt solution dilute reaction solution is extracted with DCM (3 × 50mL), uses saturated salt solution (2 after merging organic phase
× 100mL) washing, organic phase anhydrous Na2SO4It dries, filters, vacuum revolving removes solvent, and gained residue is directly entered down
The reaction of one step.
Step (3a) is reacted gained residue (about 0.6mmol) and is placed in dry 100mL round-bottomed flask by (3b), with suitable
The methylene chloride of steaming again (DCM) dissolution of amount, and under conditions of flask is placed in -10 DEG C, balance 5min.Ready to balance finishes, to anti-
The DCM solution for answering the concentration that boron chloride (1.5mL, 1.5mmol) is slowly added dropwise in liquid to be 1M, keeps -10 DEG C of conditioned response
After 30min, room temperature is then moved to, continues to stir 2h.To end of reaction, 3mL methanol quenching reaction is slowly added dropwise under condition of ice bath,
Then reaction solution is moved in separatory funnel, suitable saturated salt solution dilute reaction solution is added, carried out with DCM (3 × 50mL)
Extraction is washed after merging organic phase with saturated salt solution (2 × 100mL), organic phase anhydrous Na2SO4It dries, filters, vacuum rotation
Solvent is evaporated off, residue is isolated and purified with RP-HPLC, and the eluant, eluent condition of RP-HPLC purifying is MeOH:H2O:HCO2H=
33:77:0.5 (V:V:V), RT=26.2~22.3min obtain light green solid 451.5mg, total recovery 85.6%.
- two coffee acyl -3,4- diaminostilbene of (1S, 3S, 4S, 5R)-N- methyl-N ', N ', 5- dihydroxy butylcyclohexane -1-
Formamide (CL-01): collecting retention time RT=26.2min fraction, and vacuum revolving removes solvent, and residue freeze-drying obtains
Light green solid 270.9mg, yield 51.4%.1H NMR(300MHz,CD3OD)δ:9.52(s,4H),8.32(s,2H),7.51
(d, J=16.0Hz, 1H), 7.48 (s, 1H), 7.32 (d, J=16.0Hz, 1H), 7.11 (s, 2H), 6.89 (d, J=2.5Hz,
1H), 6.87 (d, J=2.5Hz, 1H), 6.63 (d, J=2.5Hz, 2H), 6.78 (dd, J=8.0,2.5Hz, 2H), 6.19 (d, J
=16.0Hz, 1H), 6.11 (d, J=16.0Hz, 1H), 5.37 (br, 1H), 4.62 (br, 1H), 4.21 (dd, J=7.5,
3.0Hz, 1H), 4.16 (m, 2H), 2.83 (d, J=3.2Hz, 3H), 2.19-2.11 (m, 2H), 1.92-1.86 (m, 2H)；13C
NMR(75MHz,CD3OD)δ:173.9,169.4,168.9,148.9(2C),146.8(2C),142.8,142.8,131.0
(2C),128.5(2C),122.4(2C),118.8(2C),118.5(2C),116.6(2C),115.3(2C),80.5,73.5,
56.7,51.9,40.5,35.5,26.8。
- two coffee acyl -3,4- diaminostilbene of (1S, 3S, 4R, 5R)-N- methyl-N ', N ', 5- dihydroxy butylcyclohexane -1-
Formamide (CL-02): collecting retention time RT=24.4min fraction, and vacuum revolving removes solvent, and residue freeze-drying obtains
Light green solid 67.7mg, yield 12.8%.1H NMR(300MHz,CD3OD)δ:9.51(s,4H),8.33(s,2H),7.50
(d, J=16.0Hz, 1H), 7.49 (s, 1H), 7.33 (d, J=16.0Hz, 1H), 7.12 (s, 2H), 6.90 (d, J=2.5Hz,
1H), 6.88 (d, J=2.5Hz, 1H), 6.64 (d, J=2.5Hz, 2H), 6.79 (dd, J=8.0,2.5Hz, 2H), 6.18 (d, J
=16.0Hz, 1H), 6.12 (d, J=16.0Hz, 1H), 5.36 (br, 1H), 4.61 (br, 1H), 4.22 (dd, J=7.5,
3.0Hz, 1H), 4.17 (m, 2H), 2.85 (d, J=3.2Hz, 3H), 2.18-2.10 (m, 2H), 1.93-1.87 (m, 2H)；13C
NMR(75MHz,CD3OD)δ:174.0,169.5,169.0,148.8(2C),146.9(2C),142.7,142.5,131.1
(2C),128.6(2C),122.5(2C),118.7(2C),118.6(2C),116.7(2C),115.4(2C),80.6,73.6,
56.6,51.8,40.6,35.4,26.7。
- two coffee acyl -3,4- diaminostilbene of (1S, 3R, 4S, 5R)-N- methyl-N ', N ', 5- dihydroxy butylcyclohexane -1-
Formamide (CL-03): collecting retention time RT=23.6min fraction, and vacuum revolving removes solvent, and residue freeze-drying obtains
Light green solid 90.3mg, yield 17.1%.1H NMR(300MHz,CD3OD)δ:9.53(s,4H),8.34(s,2H),7.52
(d, J=16.0Hz, 1H), 7.47 (s, 1H), 7.34 (d, J=16.0Hz, 1H), 7.13 (s, 2H), 6.91 (d, J=2.5Hz,
1H), 6.89 (d, J=2.5Hz, 1H), 6.65 (d, J=2.5Hz, 2H), 6.81 (dd, J=8.0,2.5Hz, 2H), 6.19 (d, J
=16.0Hz, 1H), 6.13 (d, J=16.0Hz, 1H), 5.38 (br, 1H), 4.63 (br, 1H), 4.23 (dd, J=7.5,
3.0Hz, 1H), 4.18 (m, 2H), 2.86 (d, J=3.2Hz, 3H), 2.21-2.14 (m, 2H), 1.95-1.86 (m, 2H)；13C
NMR(75MHz,CD3OD)δ:175.2,169.6,169.3,148.7(2C),147.1(2C),142.6,142.4,131.2
(2C),128.4(2C),122.3(2C),118.6(2C),118.5(2C),116.6(2C),115.5(2C),80.7,73.8,
56.7,51.9,40.7,35.6,26.8。
- two coffee acyl -3,4- diaminostilbene of (1S, 3R, 4R, 5R)-N- methyl-N ', N ', 5- dihydroxy butylcyclohexane -1-
Formamide (CL-04): collecting retention time RT=22.3min fraction, and vacuum revolving removes solvent, and residue freeze-drying obtains
Light green solid 22.6mg, yield 4.3%.1H NMR(300MHz,CD3OD)δ:9.52(s,4H),8.33(s,2H),7.53(d,
J=16.0Hz, 1H), 7.48 (s, 1H), 7.35 (d, J=16.0Hz, 1H), 7.14 (s, 2H), 6.92 (d, J=2.5Hz, 1H),
6.90 (d, J=2.5Hz, 1H), 6.64 (d, J=2.5Hz, 2H), 6.82 (dd, J=8.0,2.5Hz, 2H), 6.18 (d, J=
16.0Hz, 1H), 6.14 (d, J=16.0Hz, 1H), 5.37 (br, 1H), 4.62 (br, 1H), 4.24 (dd, J=7.5,3.0Hz,
1H), 4.19 (m, 2H), 2.87 (d, J=3.2Hz, 3H), 2.20-2.13 (m, 2H), 1.94-1.87 (m, 2H)；13C NMR
(75MHz,CD3OD)δ:175.3,169.5,169.4,148.6(2C),147.2(2C),142.5,142.3,131.4(2C),
128.5(2C),122.5(2C),118.7(2C),118.5(2C),116.7(2C),115.6(2C),80.6,73.6,56.6,
51.8,40.6,35.7,26.9。
2-two coffee acyl-3,5- diaminostilbene of N- methyl-N ', N ' of embodiment, 4- dihydroxy butylcyclohexane-1- formamide
It the preparation of (CL-05~CL-08) and isolates and purifies
(1) preparation of (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid, according to the step in embodiment 1
(1) it carries out.
(2) N- methyl -3,5- diaminostilbene, the preparation of 4- benzyloxy hexamethylene -1- formamide
The preparation of (2a) quininic acid methyl esters is carried out according to (2a) in 1 step of embodiment (2).
The preparation of (2b) N- methyl quinuclidine amide is carried out according to (2b) in 1 step of embodiment (2).
The preparation of (2c ') N- methyl -3,5- two (tertiary butyl dimethyl Si base) quinine amide
N- methyl quinuclidine amide (1.74g, 8.5mmol) that step (2b) obtains is weighed in dry 100mL round-bottomed flask
In, it is dissolved with suitable dry THF, imidazoles (3.50mg, 51.0mmol) then is added into reaction flask, be finally added dropwise and be dissolved in
Tert-butyl chloro-silicane (TBSCl) (2.33g, 20.5mmol) solution in the dry DMF of 15mL, it is small to stir 1.5 at room temperature
When.To the end of reacting, 150mL methylene chloride is added, and washed 3 times with water (3 × 100mL), removes DMF, finally collect organic phase,
The dry water removal of anhydrous magnesium sulfate, filtering, vacuum revolving remove solvent, separate through silica gel column chromatography, be in TLC solvent condition
CHCl3:CH3OH=15:1 (V:V) collects RfThe fraction that value is 0.69, revolving remove solvent, obtain yellow oily liquid 3.27g,
Yield is 88.6%.1H NMR(300MHz,CD3OD)δ:7.52(s,1H),5.91(br,1H),4.62(br,1H),4.50(m,
1H), 3.99 (m, 1H), 3.88 (dd, J=6.0,6.0Hz, 1H), 2.76 (d, J=6.0Hz, 3H), 2.12 (m, 2H), 1.93
(m,2H),0.97(s,18H),0.23(s,12H)；ESI-MS(m/z):434.5[M+H]+,457.2[M+Na]+。
The preparation of (2d ') N- methyl -3,5- two (tertiary butyl dimethyl Si base) -1,4- benzyloxy quinine amide
Weigh N- methyl -3,5- bis- (tertiary butyl dimethyl Si base) quinine amide that step (2c ') obtains (2.6g,
6.0mmol) in dry 100mL round-bottomed flask, dissolved with suitable heavy steaming tetrahydrofuran, and tetrabutylammonium bromide is added
Then flask is placed under conditions of low-temp reaction bathes -5 DEG C and balances 5min by (161mg, 0.5mmol).Ready to balance finishes, and divides 3 times
It is slowly added into reaction solution sodium hydride (1.44g, 60mmol), keeps -5 DEG C of conditioned response 10min.Then cylite is measured
(2.13mL, 18mmol) is slowly dropped in reaction system, after keeping -5 DEG C of cryogenic conditions 30min, is then moved to room temperature, is continued to stir
Mix 5h.To end of reaction, the methanol quenching reaction of 5mL is slowly added dropwise under condition of ice bath, reaction solution is then moved into liquid separation leakage
In bucket, suitable saturated salt solution dilute reaction solution is added, is extracted with DCM (4 × 100mL), with full after merging organic phase
It is washed with saline solution (2 × 100mL), organic phase anhydrous Na2SO4It dries, filters, vacuum revolving removes solvent, through silica gel column layer
Analysis separation (EtOAc:PE=1:50, V:V) is EtOAc:PE=1:25 (V:V) in TLC solvent condition, collects RfValue is
0.40 fraction, revolving remove solvent, obtain colourless oil liquid 2.08g, yield 81.7%.1H NMR(300MHz,CDCl3)δ:
7.61(s,1H),7.35-7.24(m,10H,H-Ph,Ph′),4.63(br,1H),4.58(m,4H,-CH2-Ph,-CH2-Ph′),
4.17 (m, 2H), 3.96 (m, 1H), 2.77 (d, J=6.0Hz, 3H), 2.12 (m, 2H), 1.91 (m, 2H), 0.98 (s, 18H),
0.24(s,12H)；13C NMR(75MHz,CDCl3)δ:173.7,138.5,137.9,128.8,128.6,128.4(2),
128.3,128.1(2),127.8,127.7(2),96.7,75.2,74.1(2),68.8,68.6,38.6,38.4,30.9(2),
28.3,25.9(6),-2.0(4)。
(2e ') N- methyl-1, the preparation of 4- benzyloxy quinine amide
Weigh N- methyl -3,5- two (tertiary butyl dimethyl Si base) -1,4- benzyloxy quinine that step (2d ') obtains
Amide (1.91g, 4.5mmol) is dissolved in dry 100mL round-bottomed flask with methylene chloride (20mL), and flask is placed in
Low-temp reaction balances 5min under conditions of bathing 0 DEG C, is then slowly dropped into 4.5mL trifluoroacetic acid to reaction system, is warming up to 80 DEG C,
It is stirred to react 2 hours.To end of reaction, saturated sodium bicarbonate solution is added into reaction solution and removes trifluoroacetic acid, and uses dichloro
Methane extracts 3 times (3 × 50ml), merges organic phase, and the dry water removal of anhydrous magnesium sulfate is added, filters, vacuum distillation.Residue warp
Silica gel column chromatography separates (CHCl3:CH3OH=80:1, V:V), it is CHCl in TLC solvent condition3:CH3OH=40:1 (V:V),
Collect RfThe fraction that value is 0.46, revolving remove solvent, obtain colourless oil liquid 1.26g, yield 72.6%.1H NMR
(300MHz,CDCl3)δ:7.63(s,1H),7.31-7.23(m,10H,H-Ph,Ph′),4.52(m,4H,-CH2-Ph,-CH2-
Ph '), 4.07 (m, 1H), 3.69 (m, 1H), 3.56 (m, 1H), 2.82 (d, J=6.0Hz, 3H), 2.12 (m, 2H), 1.91 (m,
2H)；13C NMR(75MHz,CDCl3)δ:170.3,138.3,137.0,136.4,128.7,128.6,128.5(2C),128.2,
128.0(2C),127.8,127.6,84.1,74.9,74.4,71.9,70.4,67.0,36.0,35.2,34.3。
The preparation of two mesyloxy -1,4- benzyloxy quinine amide of (2f ') N- methyl -3,5-
The N- methyl-1 that step (2e ') obtains is weighed, 4- benzyloxy quinine amide (1.35mg, 3.5mmol) is in drying
100mL round-bottomed flask in, dissolved with suitable heavy steaming methylene chloride, and be added 4- (N, N- dimethyl) aminopyridine (37mg,
0.3mmol), then flask is placed under condition of ice bath, is added acid binding agent triethylamine 1.45mL (10.5mmol), balance 5min.
Ready to balance is finished, and is slowly added dropwise into reaction solution mesyl chloride 0.82mL (10.5mmol), after keeping condition of ice bath reaction 30min,
Room temperature is then moved to, continues to stir 12h.To end of reaction, 5mL pure water quenching reaction is slowly added dropwise in condition of ice bath, then will
Reaction solution moves in separatory funnel, and suitable saturated salt solution dilute reaction solution is added, and is extracted with DCM (4 × 100mL),
It is washed after merging organic phase with saturated salt solution (2 × 100mL), organic phase anhydrous Na2SO4It dries, filters, vacuum revolving is removed
Solvent is removed, residue separates (EtOAc:PE=1:4, V:V) through silica gel column chromatography, is EtOAc:PE=in TLC solvent condition
1:2 (V:V) collects RfThe fraction that value is 0.36, revolving remove solvent, obtain white powder 1.56g, yield 82.5%.1H NMR
(300MHz,CDCl3)δ:7.62(s,1H),7.34-7.23(m,10H,H-Ph,Ph′),5.48(m,1H),4.96(m,1H),
4.75(m,4H,-CH2-Ph,-CH2-Ph′),4.35(m,1H),3.23(s,3H,-SO2CH3),3.21(s,3H,-SO2CH3),
2.82 (d, J=6.0Hz, 3H), 2.12 (m, 2H), 1.91 (m, 2H)；13C NMR(75MHz,CDCl3)δ:173.2,139.1,
138.9,138.6,129.5,129.3(2),129.2,128.9,128.7,128.5,128.4,128.2,81.9,79.5,
77.9,74.2,72.6,66.7,38.5,38.2(2),35.3,34.8。
The preparation of (2g ') N- methyl -3,5- diazido -1,4- benzyloxy quinine amide
Weigh the two mesyloxy -1,4- benzyloxy quinine amide of N- methyl -3,5- that step (2f ') obtains
(812.4mg, 1.5mmol) in dry 50mL round-bottomed flask, with the mixed solvent (DMF:HMPA=of appropriate DMF and HMPA
3:1, V:V) dissolution, and sodium azide (293mg, 4.5mmol) is added, 12h is reacted under the conditions of 70 DEG C of oil bath.Wait react
Finish, 5mL pure water quenching reaction is slowly added dropwise under condition of ice bath, then moves to reaction solution in separatory funnel, is added appropriate
Saturated salt solution dilute reaction solution, extracted with DCM (3 × 50mL), merge organic phase after with saturated salt solution (2 ×
It 100mL) washs, organic phase anhydrous Na2SO4It dries, filters, vacuum revolving removes low boiling point solvent, and residue is through silica gel column layer
Analysis separation (EtOAc:PE=1:4, V:V) is EtOAc:PE=1:2 (V:V) in TLC solvent condition, collects RfValue is 0.29
Fraction, revolving remove solvent, obtain yellow oil 617.1mg, yield 84.2%.This is N- methyl -3- nitrine -5- methylsulphur
Acyloxy -1,4- benzyloxy quinine amide.
Weigh N- methyl -3- nitrine -5- mesyloxy-Isosorbide-5-Nitrae-benzyloxy quinine amide (586.3mg, 1.2mmol)
In dry 50mL round-bottomed flask, dissolved with the mixed solvent (DMF:HMPA=3:1, V:V) of appropriate DMF and HMPA, and add
Enter sodium azide (390mg, 6mmol), is reacted for 24 hours under the conditions of 125 DEG C of oil bath.It is slow in condition of ice bath to end of reaction
5mL pure water quenching reaction is added dropwise, then reaction solution is moved in separatory funnel, suitable saturated salt solution diluting reaction is added
Liquid is extracted with DCM (3 × 50mL), is washed after merging organic phase with saturated salt solution (2 × 100mL), and organic phase is with anhydrous
Na2SO4Dry, filter, vacuum revolving remove low boiling point solvent, residue through silica gel column chromatography separate (EtOAc:PE=1:4, V:
V), it is EtOAc:PE=1:2 (V:V) in TLC solvent condition, collects RfThe fraction that value is 0.38, revolving remove solvent, obtain depth
Yellow oil 427.0mg, yield 81.7%.This is N- methyl -3,5- diazido -1,4- benzyloxy quinine amide.1H NMR(300MHz,CDCl3)δ:7.62(s,1H),7.32-7.24(m,10H,H-Ph,Ph′),5.43(m,1H),5.12(m,
1H),4.76(m,4H,-CH2-Ph,-CH2- Ph '), 4.37 (m, 1H), 2.83 (d, J=6.0Hz, 3H), 2.13 (m, 2H), 1.92
(m,2H)；13C NMR(75MHz,CDCl3)δ:173.2,138.8,138.6,138.5,129.2,129.1(2),129.0,
128.7,128.6,128.5,128.4,128.2,81.9,79.5,77.9,74.2,72.6,66.7,38.6,35.4,35.1。
(2h ') N- methyl -3,5- diaminostilbene, the preparation of 4- benzyloxy quinine amide
Weigh N- methyl -3,5- diazido-Isosorbide-5-Nitrae-benzyloxy quinine amide that step (2g ') obtains (370.2mg,
0.85mmol) in dry 50mL round-bottomed flask, with the mixed solvent (MeOH:H of proper amount of methanol and water2O=5:1, V:V) it is molten
Solution, and triphenylphosphine (336mg, 1.28mmol) is added, it flows back under the conditions of 68 DEG C of oil bath, reacts 5h.Wait react
Finish, suitable distilled water dilute reaction solution is added, reaction solution is then adjusted to faintly acid with the hydrochloric acid solution of 0.1M, then use DCM
(2 × 50mL) is extracted, and organic phase is discarded, and retains water phase.Water phase is adjusted to alkalescent with the sodium hydroxide solution of 0.1M, uses
DCM (3 × 50mL) is extracted, and is washed after merging organic phase with saturated salt solution (2 × 100mL), organic phase anhydrous Na2SO4
It dries, filters, vacuum revolving removes solvent, obtains residue.Due in product structure there are two free amine groups, stability compared with
Difference, and be not easy to separate, therefore residue is directly used in and is reacted in next step.
(3)-two coffee acyl -3,5- diaminostilbene of N- methyl-N ', N ', 4- dihydroxy butylcyclohexane -1- formamide (CL-05
~CL-08) preparation and isolate and purify
(3a) weigh (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid that step (1) obtains (384.3mg,
2.0mmol) in dry 50mL round-bottomed flask, dissolved with suitable heavy steaming DMF, and be respectively added slowly to EDCI (460mg,
2.4mmol) with HOBt (324mg, 2.4mmol), 30min is reacted under room temperature.Be subsequently added into DIPEA (0.42mL,
2.4mmol), and step (2h) is reacted the dry DMF of gained residue (about 0.8mmol) to dissolve, is then slowly dropped to
In reaction system, the reaction was continued at room temperature 12h.To end of reaction, the pure water quenching of 5mL is slowly added dropwise under condition of ice bath
Go out reaction, then reaction solution moved in separatory funnel, suitable saturated salt solution dilute reaction solution is added, with DCM (3 ×
It 50mL) is extracted, is washed after merging organic phase with saturated salt solution (2 × 100mL), organic phase anhydrous Na2SO4It is dry, mistake
Filter, vacuum revolving remove solvent, and residue is directly entered the reaction of next step.
Step (3a) is reacted gained residue (about 0.6mmol) and is placed in dry 100mL round-bottomed flask by (3b), with suitable
The methylene chloride of steaming again (DCM) dissolution of amount, and under conditions of flask is placed in -10 DEG C, balance 5min.Ready to balance finishes, to anti-
The DCM solution for answering the concentration that boron chloride (1.5mL, 1.5mmol) is slowly added dropwise in liquid to be 1M, keeps -10 DEG C of conditioned response
After 30min, room temperature is then moved to, continues to stir 2h.To end of reaction, 3mL methanol quenching reaction is slowly added dropwise under condition of ice bath,
Then reaction solution is moved in separatory funnel, suitable saturated salt solution dilute reaction solution is added, carried out with DCM (3 × 50mL)
Extraction is washed after merging organic phase with saturated salt solution (2 × 100mL), organic phase anhydrous Na2SO4It dries, filters, vacuum rotation
Solvent is evaporated off, residue is isolated and purified with RP-HPLC, and the eluant, eluent condition of RP-HPLC purifying is MeOH:H2O:HCO2H=
33:77:0.5 (V:V:V), RT=27.6~23.4min obtain light green solid 364.6mg, total recovery 86.4%.
- two coffee acyl -3,5- diaminostilbene of (1S, 3S, 4r, 5R)-N- methyl-N ', N ', 4- dihydroxy butylcyclohexane -1-
Formamide (CL-05): collecting retention time RT=27.6min fraction, and vacuum revolving removes solvent, and residue freeze-drying obtains
Light green solid 47.4mg, yield 11.2%.1H NMR(300MHz,CD3OD)δ:9.51(s,4H),8.31(s,2H),7.57
(d, J=16.0Hz, 1H), 7.51 (d, J=16.0Hz, 1H), 7.46 (s, 1H), 7.12 (s, 2H), 6.78 (dd, J=8.0,
2.5Hz, 2H), 6.73 (d, J=2.5Hz, 2H), 6.39 (d, J=2.5Hz, 1H), 6.21 (d, J=2.5Hz, 1H), 6.19 (d,
J=16.0Hz, 1H), 6.11 (d, J=16.0Hz, 1H), 5.37 (br, 1H), 4.62 (br, 1H), 4.21 (dd, J=7.5,
3.0Hz, 1H), 4.16 (m, 2H), 2.83 (d, J=3.2Hz, 3H), 2.19-2.11 (m, 2H), 1.92-1.86 (m, 2H)；13C
NMR(75MHz,CD3OD)δ:175.6,169.5,168.7,148.6(2C),146.7(2C),142.8,142.5,131.1
(2C),128.4(2C),122.3(2C),118.7(2C),118.4(2C),116.5(2C),115.2(2C),80.4,73.3,
56.6,51.8,40.7,35.6,26.7。
- two coffee acyl -3,5- diaminostilbene of (1S, 3R, 4S, 5R)-N- methyl-N ', N ', 4- dihydroxy butylcyclohexane -1-
Formamide (CL-06): collecting retention time RT=26.24min fraction, and vacuum revolving removes solvent, and residue freeze-drying obtains
Light green solid 21.9mg, yield 5.2%.1H NMR(300MHz,CD3OD)δ:9.52(s,4H),8.32(s,2H),7.58(d,
J=16.0Hz, 1H), 7.52 (d, J=16.0Hz, 1H), 7.47 (s, 1H), 7.13 (s, 2H), 6.77 (dd, J=8.0,
2.5Hz, 2H), 6.74 (d, J=2.5Hz, 2H), 6.38 (d, J=2.5Hz, 1H), 6.22 (d, J=2.5Hz, 1H), 6.19 (d,
J=16.0Hz, 1H), 6.11 (d, J=16.0Hz, 1H), 5.37 (br, 1H), 4.62 (br, 1H), 4.21 (dd, J=7.5,
3.0Hz, 1H), 4.16 (m, 2H), 2.83 (d, J=3.2Hz, 3H), 2.19-2.11 (m, 2H), 1.92-1.86 (m, 2H)；13C
NMR(75MHz,CD3OD)δ:175.0,169.6,169.2,148.7(2C),146.8(2C),142.8,142.6,131.2
(2C),128.7(2C),122.5(2C),118.7(2C),118.6(2C),116.7(2C),115.4(2C),80.6,73.6,
56.6,51.8,40.6,35.5,26.8。
- two coffee acyl -3,4- diaminostilbene of (1R, 3S, 4R, 5S)-N- methyl-N ', N ', 5- dihydroxy butylcyclohexane -1-
Formamide (CL-07): collecting retention time RT=25.8min fraction, and vacuum revolving removes solvent, and residue freeze-drying obtains
Light green solid 309.9mg, yield 58.8%.1H NMR(300MHz,CD3OD)δ:9.54(s,4H),8.33(s,2H),7.56
(d, J=16.0Hz, 1H), 7.53 (d, J=16.0Hz, 1H), 7.48 (s, 1H), 7.13 (s, 2H), 6.77 (dd, J=8.0,
2.5Hz, 2H), 6.74 (d, J=2.5Hz, 2H), 6.38 (d, J=2.5Hz, 1H), 6.22 (d, J=2.5Hz, 1H), 6.19 (d,
J=16.0Hz, 1H), 6.11 (d, J=16.0Hz, 1H), 5.37 (br, 1H), 4.62 (br, 1H), 4.21 (dd, J=7.5,
3.0Hz, 1H), 4.16 (m, 2H), 2.83 (d, J=3.2Hz, 3H), 2.20-2.12 (m, 2H), 1.93-1.87 (m, 2H)；13C
NMR(75MHz,CD3OD)δ:175.1,169.7,169.2,148.6(2C),147.1(2C),142.6,142.4,131.2
(2C),128.4(2C),122.3(2C),118.6(2C),118.5(2C),116.6(2C),115.5(2C),80.7,73.8,
56.7,51.9,40.8,35.7,26.9。
- two coffee acyl -3,5- diaminostilbene of (1r, 3R, 4S, 5S)-N- methyl-N ', N ', 4- dihydroxy butylcyclohexane -1-
Formamide (CL-08): collecting retention time RT=24.9min fraction, and vacuum revolving removes solvent, and residue freeze-drying obtains
Light green solid 47.4mg, yield 11.2%.1H NMR(300MHz,CD3OD)δ:9.53(s,4H),8.35(s,2H),7.54
(d, J=16.0Hz, 1H), 7.47 (s, 1H), 7.36 (d, J=16.0Hz, 1H), 7.14 (s, 2H), 6.92 (d, J=2.5Hz,
1H), 6.90 (d, J=2.5Hz, 1H), 6.64 (d, J=2.5Hz, 2H), 6.82 (dd, J=8.0,2.5Hz, 2H), 6.18 (d, J
=16.0Hz, 1H), 6.14 (d, J=16.0Hz, 1H), 5.37 (br, 1H), 4.62 (br, 1H), 4.24 (dd, J=7.5,
3.0Hz, 1H), 4.19 (m, 2H), 2.87 (d, J=3.2Hz, 3H), 2.21-2.14 (m, 2H), 1.93-1.89 (m, 2H)；13C
NMR(75MHz,CD3OD)δ:175.3,169.5,169.4,148.6(2C),147.2(2C),142.5,142.3,131.4
(2C),128.5(2C),122.5(2C),118.7(2C),118.5(2C),116.7(2C),115.6(2C),80.6,73.6,
56.6,51.8,40.6,35.7,26.9。
3-two coffee sulfonyl-3,4- diaminostilbene of N- methyl-N ', N ' of embodiment, 5- dihydroxy butylcyclohexane-1- formyl
It the preparation of amine (CL-09~CL-12) and isolates and purifies
The preparation of (1a-b) (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- sulfonic acid, according to embodiment 1
(1a) and (1b) in step (1) obtains piperonal.
The preparation of (1c ') (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- sulfonic acid
In 250mL round-bottomed flask, piperonal (12g, 79.9mmol) and Loprazolam acid anhydride that step (1a-b) is obtained
(20.9g, 120mmol) is dissolved with 150mL dry THF, and NaH (2.9g, 120mmol) is added portionwise, after reaction solution moved into oil
115 DEG C of bath is heated to reflux about 2 hours.Reaction process is monitored to piperonal with TLC and is completely disappeared, and shows fully reacting.Reaction solution
After being cooled to room temperature, reaction solution is slowly poured into 200mL hydrochloric acid solution (2mol/L) under ice bath, there are a large amount of yellowish whites solid
Body is precipitated.Obtain faint yellow solid filter cake through filtering, after faint yellow solid filter cake is washed with 400mL water dispersion, then through filtering
Yellowish-white solid filter cake is obtained, and repeating above operation to filter cake pH value is neutrality.It is recrystallized with hot water, collects yellowish white
It dries under solid filter cake to infrared lamp to constant weight, obtains yellowish-white solid 13.2g, yield 72.2%.1H NMR(300MHz,
CDCl3) δ: 7.81 (d, J=16.0Hz, 1H), 7.31 (d, J=6.0Hz, 1H), 7.24 (s, 1H), 7.08 (d, J=16.0Hz,
1H), 6.95 (d, J=6.0Hz, 1H), 6.07 (s, 2H)；13C NMR(75MHz,CDCl3)δ:149.1,148.2,134.6,
128.3,124.6,113.5,108.3,101.6。
(2) N- methyl -3,4- diaminostilbene, the preparation of 5- benzyloxy hexamethylene -1- formamide, according to 1 step of embodiment
Suddenly (2) obtain.
(3)-two coffee sulfonyl -3,4- diaminostilbene of N- methyl-N ', N ', 5- dihydroxy butylcyclohexane -1- formamide (CL-
09~CL-12) preparation and isolate and purify
It is carried out by 1 step of embodiment (3), wherein raw material (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid
It is changed to (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- sulfonic acid.
Residue is isolated and purified with RP-HPLC, and the eluant, eluent condition of RP-HPLC purifying is MeOH:H2O:HCO2H=33:
80:0.5 (V:V:V), RT=25.3~21.5min obtain light green solid 365.5mg, total recovery 76.2%.
- two coffee sulfonyl -3,4- diaminostilbene of (1S, 3S, 4S, 5R)-N- methyl-N ', N ', 5- dihydroxy butylcyclohexane -
1- formamide (CL-09): collecting retention time RT=25.3min fraction, and vacuum revolving removes solvent, and residue is freeze-dried,
Obtain light green solid 219.3mg, yield 45.7%.1H NMR(300MHz,CD3OD) δ: 9.54 (s, 4H), 7.56 (d, J=
16.0Hz, 2H), 7.48 (s, 1H), 7.31 (d, J=16.0Hz, 2H), 7.06 (s, 2H), 7.05 (s, 2H), 6.89 (d, J=
2.5Hz, 1H), 6.87 (d, J=2.5Hz, 1H), 6.63 (d, J=2.5Hz, 2H), 6.78 (dd, J=8.0,2.5Hz, 2H),
5.37 (br, 1H), 4.62 (br, 1H), 4.21 (dd, J=7.5,3.0Hz, 1H), 4.16 (m, 2H), 2.83 (d, J=3.2Hz,
3H),2.19-2.11(m,2H),1.92-1.86(m,2H)；13C NMR(75MHz,CD3OD)δ:173.7,148.9(2),146.8
(2),142.8,142.8,134.5(2C),128.5(2C),124.4(2C),118.8(2C),118.5(2C),116.6(2C),
115.3(2C),80.5,73.5,56.7,51.9,40.5,35.5,26.8。
- two coffee sulfonyl -3,4- diaminostilbene of (1S, 3S, 4R, 5R)-N- methyl-N ', N ', 5- dihydroxy butylcyclohexane -
1- formamide (CL-10): collecting retention time RT=24.6min fraction, and vacuum revolving removes solvent, and residue is freeze-dried,
Obtain light green solid 54.7mg, yield 11.4%.1H NMR(300MHz,CD3OD) δ: 9.54 (s, 4H), 7.56 (d, J=
16.0Hz, 2H), 7.48 (s, 1H), 7.31 (d, J=16.0Hz, 2H), 7.06 (s, 2H), 7.05 (s, 2H), 6.89 (d, J=
2.5Hz, 1H), 6.87 (d, J=2.5Hz, 1H), 6.63 (d, J=2.5Hz, 2H), 6.78 (dd, J=8.0,2.5Hz, 2H),
5.37 (br, 1H), 4.62 (br, 1H), 4.21 (dd, J=7.5,3.0Hz, 1H), 4.16 (m, 2H), 2.83 (d, J=3.2Hz,
3H),2.19-2.11(m,2H),1.92-1.86(m,2H)；13C NMR(75MHz,CD3OD)δ:173.7,148.9(2),146.8
(2),142.8,142.8,134.5(2C),128.5(2C),124.4(2C),118.8(2C),118.5(2C),116.6(2C),
115.3(2C),80.5,73.6,56.6,51.8,40.4,35.6,26.7。
- two coffee sulfonyl -3,4- diaminostilbene of (1S, 3R, 4S, 5R)-N- methyl-N ', N ', 5- dihydroxy butylcyclohexane -
1- formamide (CL-11): collecting retention time RT=23.4min fraction, and vacuum revolving removes solvent, and residue is freeze-dried,
Obtain light green solid 73.1mg, yield 15.2%.1H NMR(300MHz,CD3OD) δ: 9.55 (s, 4H), 7.55 (d, J=
16.0Hz, 2H), 7.49 (s, 1H), 7.32 (d, J=16.0Hz, 2H), 7.07 (s, 2H), 7.04 (s, 2H), 6.88 (d, J=
2.5Hz, 1H), 6.86 (d, J=2.5Hz, 1H), 6.64 (d, J=2.5Hz, 2H), 6.76 (dd, J=8.0,2.5Hz, 2H),
5.38 (br, 1H), 4.63 (br, 1H), 4.21 (dd, J=7.5,3.0Hz, 1H), 4.16 (m, 2H), 2.84 (d, J=3.2Hz,
3H),2.20-2.12(m,2H),1.93-1.87(m,2H)；13C NMR(75MHz,CD3OD)δ:173.8,148.8(2),146.9
(2),142.9,142.7,134.6(2C),128.5(2C),124.4(2C),118.8(2C),118.5(2C),116.6(2C),
115.3(2C),80.5,73.6,56.7,51.9,40.5,35.8,26.9。
- two coffee sulfonyl -3,4- diaminostilbene of (1S, 3R, 4R, 5R)-N- methyl-N ', N ', 5- dihydroxy butylcyclohexane -
1- formamide (CL-12): collecting retention time RT=21.5min fraction, and vacuum revolving removes solvent, and residue is freeze-dried,
Obtain light green solid 18.3mg, yield 3.8%.1H NMR(300MHz,CD3OD) δ: 9.53 (s, 4H), 7.52 (d, J=
16.0Hz, 2H), 7.47 (s, 1H), 7.33 (d, J=16.0Hz, 2H), 7.08 (s, 2H), 7.05 (s, 2H), 6.88 (d, J=
2.5Hz, 1H), 6.86 (d, J=2.5Hz, 1H), 6.64 (d, J=2.5Hz, 2H), 6.76 (dd, J=8.0,2.5Hz, 2H),
5.38 (br, 1H), 4.63 (br, 1H), 4.21 (dd, J=7.5,3.0Hz, 1H), 4.16 (m, 2H), 2.84 (d, J=3.2Hz,
3H),2.20-2.12(m,2H),1.93-1.87(m,2H)；13C NMR(75MHz,CD3OD)δ:173.8,148.8(2),146.9
(2),142.9,142.7,134.6(2C),128.5(2C),124.4(2C),118.8(2C),118.5(2C),116.6(2C),
115.3(2C),80.5,73.7,56.6,51.8,40.6,35.7,26.8。
4-two coffee sulfonyl-3,5- diaminostilbene of N- methyl-N ', N ' of embodiment, 4- dihydroxy butylcyclohexane-1- formyl
It the preparation of amine (CL-13~CL-16) and isolates and purifies
(1) preparation of (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- sulfonic acid, according to 3 step of embodiment
(1) method obtains.
(2) N- methyl -3,5- diaminostilbene, the preparation of 4- benzyloxy hexamethylene -1- formamide, according to 2 step of embodiment
Suddenly the method for (2) obtains.
(3)-two coffee sulfonyl -3,5- diaminostilbene of N- methyl-N ', N ', 4- dihydroxy butylcyclohexane -1- formamide (CL-
13~CL-16) preparation and isolate and purify by 2 step of embodiment (3) method progress, wherein raw material (E) -3- (benzene a pair of horses going side by side [d]
[1,3] dioxolen -5- base) acrylic acid is changed to (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) that step (1) obtains
Ethylene -1- sulfonic acid.
Residue is isolated and purified with RP-HPLC, and the eluant, eluent condition of RP-HPLC purifying is MeOH:H2O:HCO2H=33:
80:0.5 (V:V:V), RT=26.9~22.3min obtain light green solid 390.0mg, total recovery 81.3%.
- two coffee acyl -3,5- diaminostilbene of (1S, 3S, 4r, 5R)-N- methyl-N ', N ', 4- dihydroxy butylcyclohexane -1-
Formamide (CL-13): collecting retention time RT=26.9min fraction, and vacuum revolving removes solvent, and residue freeze-drying obtains
Light green solid 50.7mg, yield 10.7%.1H NMR(300MHz,CD3OD) δ: 9.55 (s, 4H), 7.55 (d, J=16.0Hz,
2H), 7.49 (s, 1H), 7.32 (d, J=16.0Hz, 2H), 7.07 (s, 2H), 7.04 (s, 2H), 6.88 (d, J=2.5Hz,
1H), 6.86 (d, J=2.5Hz, 1H), 6.64 (d, J=2.5Hz, 2H), 6.76 (dd, J=8.0,2.5Hz, 2H), 5.38 (br,
1H), 4.63 (br, 1H), 4.21 (dd, J=7.5,3.0Hz, 1H), 4.16 (m, 2H), 2.84 (d, J=3.2Hz, 3H), 2.20-
2.12(m,2H),1.93-1.87(m,2H)；13C NMR(75MHz,CD3OD)δ:173.8,148.8(2),146.9(2),
142.9,142.7,134.6(2C),128.5(2C),124.4(2C),118.8(2C),118.5(2C),116.6(2C),115.3
(2C),80.5,73.6,56.7,51.9,40.5,35.8,26.9。
- two coffee acyl -3,5- diaminostilbene of (1S, 3R, 4S, 5R)-N- methyl-N ', N ', 4- dihydroxy butylcyclohexane -1-
Formamide (CL-14): collecting retention time RT=25.3min fraction, and vacuum revolving removes solvent, and residue freeze-drying obtains
Light green solid 23.4mg, yield 4.9%.1H NMR(300MHz,CD3OD) δ: 9.54 (s, 4H), 7.56 (d, J=16.0Hz,
2H), 7.48 (s, 1H), 7.31 (d, J=16.0Hz, 2H), 7.06 (s, 2H), 7.05 (s, 2H), 6.89 (d, J=2.5Hz,
1H), 6.87 (d, J=2.5Hz, 1H), 6.63 (d, J=2.5Hz, 2H), 6.78 (dd, J=8.0,2.5Hz, 2H), 5.37 (br,
1H), 4.62 (br, 1H), 4.21 (dd, J=7.5,3.0Hz, 1H), 4.16 (m, 2H), 2.83 (d, J=3.2Hz, 3H), 2.19-
2.11(m,2H),1.92-1.86(m,2H)；13C NMR(75MHz,CD3OD)δ:173.7,148.9(2),146.8(2),
142.8,142.8,134.5(2C),128.5(2C),124.4(2C),118.8(2C),118.5(2C),116.6(2C),115.3
(2C),80.5,73.6,56.6,51.8,40.4,35.6,26.7。
- two coffee acyl -3,4- diaminostilbene of (1R, 3S, 4R, 5S)-N- methyl-N ', N ', 5- dihydroxy butylcyclohexane -1-
Formamide (CL-15): collecting retention time RT=24.1min fraction, and vacuum revolving removes solvent, and residue freeze-drying obtains
Light green solid 265.2mg, yield 55.3%.1H NMR(300MHz,CD3OD) δ: 9.53 (s, 4H), 7.52 (d, J=
16.0Hz, 2H), 7.47 (s, 1H), 7.33 (d, J=16.0Hz, 2H), 7.08 (s, 2H), 7.05 (s, 2H), 6.88 (d, J=
2.5Hz, 1H), 6.86 (d, J=2.5Hz, 1H), 6.64 (d, J=2.5Hz, 2H), 6.76 (dd, J=8.0,2.5Hz, 2H),
5.38 (br, 1H), 4.63 (br, 1H), 4.21 (dd, J=7.5,3.0Hz, 1H), 4.16 (m, 2H), 2.84 (d, J=3.2Hz,
3H),2.20-2.12(m,2H),1.93-1.87(m,2H)；13C NMR(75MHz,CD3OD)δ:173.8,148.8(2),146.9
(2),142.9,142.7,134.6(2C),128.5(2C),124.4(2C),118.8(2C),118.5(2C),116.6(2C),
115.3(2C),80.5,73.7,56.6,51.8,40.6,35.7,26.8。
- two coffee acyl -3,5- diaminostilbene of (1r, 3R, 4S, 5S)-N- methyl-N ', N ', 4- dihydroxy butylcyclohexane -1-
Formamide (CL-16): collecting retention time RT=22.3min fraction, and vacuum revolving removes solvent, and residue freeze-drying obtains
Light green solid 50.7mg, yield 10.6%.1H NMR(300MHz,CD3OD) δ: 9.54 (s, 4H), 7.56 (d, J=16.0Hz,
2H), 7.48 (s, 1H), 7.31 (d, J=16.0Hz, 2H), 7.06 (s, 2H), 7.05 (s, 2H), 6.89 (d, J=2.5Hz,
1H), 6.87 (d, J=2.5Hz, 1H), 6.63 (d, J=2.5Hz, 2H), 6.78 (dd, J=8.0,2.5Hz, 2H), 5.37 (br,
1H), 4.62 (br, 1H), 4.21 (dd, J=7.5,3.0Hz, 1H), 4.16 (m, 2H), 2.83 (d, J=3.2Hz, 3H), 2.19-
2.11(m,2H),1.92-1.86(m,2H)；13C NMR(75MHz,CD3OD)δ:173.7,148.9(2),146.8(2),
142.8,142.8,134.5(2C),128.5(2C),124.4(2C),118.8(2C),118.5(2C),116.6(2C),115.3
(2C),80.5,73.5,56.7,51.9,40.5,35.5,26.8。
Embodiment 5 N- methyl-N ', N '-two coffee phosphine (mono-methyl) acyl group -3,4- diaminostilbene, 5- dihydroxy hexamethylene
It the preparation of alkane -1- formamide (CL-17~CL-20) and isolates and purifies
The preparation of (1a-b) (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- phosphonic acids mono-methyl, according to reality
(1a) and (1b) method applied in 1 step of example (1) obtains piperonal.
The preparation of (1c ") (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- dimethyl phosphonate
In 250mL round-bottomed flask, piperonal (12g, 79.9mmol) and methylphosphonic acid two that step (1a-b) is obtained
Methyl esters (14.9g, 120mmol) with 150mL dry THF dissolve, NaH (2.9g, 120mmol) is added portionwise, after reaction solution is moved
It is heated to reflux about 2 hours to 115 DEG C of oil bath.Reaction process is monitored to piperonal with TLC and is completely disappeared, and shows fully reacting.Instead
After answering liquid to be cooled to room temperature, reaction solution is slowly poured into 200mL hydrochloric acid solution (2mol/L) under ice bath, ethyl acetate extraction
3 times, organic layer is dry with anhydrous sodium sulfate, and vacuum rotary steam removes ethyl acetate, silica gel column chromatography separating purification (petroleum ether: second
Acetoacetic ester=10:1, V:V), obtain light yellow viscous liquid 14.1g, yield 68.5%.1H NMR(300MHz,CDCl3)δ:7.32
(d, J=6.0Hz, 1H), 7.23 (s, 1H), 6.95 (d, J=6.0Hz, 1H), 6.91 (d, J=17.0Hz, 1H), 5.63 (d, J
=17.0Hz, 1H), 6.06 (s, 2H), 4.23 (s, 6H)；13C NMR(75MHz,CDCl3)δ:150.1,147.9,147.8,
128.5,123.5,111.5,111.2,109.2,101.2,61.9(2)；31P NMR(162MHz,CDCl3)δP:20.0。
The preparation of (1d ") (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- phosphonic acids mono-methyl
In 100mL round-bottomed flask, (E) -2- that step (1c ") is obtained (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base)
Ethylene -1- dimethyl phosphonate (1.28g, 5mmol) 30mL dry THF dissolves, and under nitrogen protection, is added dropwise 1.0M's in room temperature
3 solution (6.0mL, 6.0mmol) of LiBH (s-Bu), TLC tracking is until hydrolysis is complete.Then, by reaction solution under ice bath
It is slowly poured into 50mL hydrochloric acid solution (2mol/L), there are a large amount of yellowish-white solids to be precipitated.It is filtered and obtains faint yellow solid filter
Cake, after faint yellow solid filter cake is washed with 100mL water dispersion, then obtain yellowish-white solid filter cake through filtering, and repeat with
Upper operation to filter cake pH value is neutrality.It is recrystallized with hot water, collects and dried under yellowish-white solid filter cake to infrared lamp to constant weight,
Obtain yellowish-white solid 1.13g, yield 93.2%.1H NMR(300MHz,CDCl3) δ: 7.34 (d, J=6.0Hz, 1H),
7.235 (s, 1H), 6.96 (d, J=6.0Hz, 1H), 6.92 (d, J=17.0Hz, 1H), 5.64 (d, J=17.0Hz, 1H),
6.07(s,2H),4.25(s,3H)；13C NMR(75MHz,CDCl3)δ:150.2,147.8,147.7,128.6,123.4,
111.6,111.3,109.3,101.2,61.8；31P NMR(162MHz,CDCl3)δP:34.8。
(2) N- methyl -3,4- diaminostilbene, the preparation of 5- benzyloxy hexamethylene -1- formamide, according to 1 step of embodiment
Suddenly (2) method obtains.
(3) N- methyl-N ', N '-two coffee phosphine (mono-methyl) acyl group -3,4- diaminostilbene, 5- dihydroxy butylcyclohexane -1- first
It the preparation of amide (CL-17~CL-20) and isolates and purifies
It is carried out by 1 step of embodiment (3), wherein raw material (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid
It is changed to (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- phosphonic acids mono-methyl that step (1d ") obtains.
Residue is isolated and purified with RP-HPLC, and the eluant, eluent condition of RP-HPLC purifying is MeOH:H2O:HCO2H=40:
80:0.5 (V:V:V), RT=28.5~24.2min obtain light green solid 259.4mg, total recovery 68.9%.
(1S, 3S, 4S, 5R)-N- methyl-N ', N '-two coffee phosphine (mono-methyl) acyl group -3,4- diaminostilbene, 5- dihydroxy
Hexamethylene -1- formamide (CL-17): collecting retention time RT=28.5min fraction, and vacuum revolving removes solvent, and residue is cold
It is lyophilized dry, obtains light green solid 155.6mg, yield 41.3%.1H NMR(300MHz,CD3OD)δ:9.53(s,4H),7.55(d,
J=16.0Hz, 2H), 7.47 (s, 1H), 7.32 (d, J=16.0Hz, 2H), 7.05 (s, 2H), 7.03 (s, 2H), 6.87 (d, J
=2.5Hz, 1H), 6.85 (d, J=2.5Hz, 1H), 6.63 (d, J=2.5Hz, 2H), 6.78 (dd, J=8.0,2.5Hz, 2H),
5.36 (br, 1H), 4.63 (br, 1H), 4.22 (dd, J=7.5,3.0Hz, 1H), 4.16 (m, 2H), 3.92 (s, 6H), 2.83
(d, J=3.2Hz, 3H), 2.19-2.13 (m, 2H), 1.92-1.87 (m, 2H)；13C NMR(75MHz,CD3OD)δ:173.6,
148.8(2),146.7(2),142.6,142.5,134.4(2C),128.5(2C),124.4(2C),118.8(2C),118.5
(2C),116.6(2C),115.3(2C),80.5,73.5,56.7,54.6(2),51.9,40.5,35.5,26.8；31P NMR
(162MHz,CDCl3)δP:25.8。
(1S, 3S, 4R, 5R)-N- methyl-N ', N '-two coffee phosphine (mono-methyl) acyl group -3,4- diaminostilbene, 5- dihydroxy
Hexamethylene -1- formamide (CL-18): collecting retention time RT=27.2min fraction, and vacuum revolving removes solvent, and residue is cold
It is lyophilized dry, obtains light green solid 38.9mg, yield 10.3%.1H NMR(300MHz,CD3OD)δ:9.52(s,4H),7.54(d,J
=16.0Hz, 2H), 7.48 (s, 1H), 7.34 (d, J=16.0Hz, 2H), 7.06 (s, 2H), 7.04 (s, 2H), 6.89 (d, J=
2.5Hz, 1H), 6.86 (d, J=2.5Hz, 1H), 6.63 (d, J=2.5Hz, 2H), 6.78 (dd, J=8.0,2.5Hz, 2H),
5.36 (br, 1H), 4.63 (br, 1H), 4.22 (dd, J=7.5,3.0Hz, 1H), 4.16 (m, 2H), 3.92 (s, 6H), 2.83
(d, J=3.2Hz, 3H), 2.19-2.13 (m, 2H), 1.92-1.87 (m, 2H)；13C NMR(75MHz,CD3OD)δ:173.7,
148.7(2),146.6(2),142.6,142.5,134.4(2C),128.5(2C),124.4(2C),118.8(2C),118.5
(2C),116.6(2C),115.3(2C),80.5,73.5,56.7,54.6(2),51.9,40.5,35.5,26.8；31P NMR
(162MHz,CDCl3)δP:25.9。
(1S, 3R, 4S, 5R)-N- methyl-N ', N '-two coffee phosphine (mono-methyl) acyl group -3,4- diaminostilbene, 5- dihydroxy
Hexamethylene -1- formamide (CL-19): collecting retention time RT=26.3min fraction, and vacuum revolving removes solvent, and residue is cold
It is lyophilized dry, obtains light green solid 51.9mg, yield 13.8%.1H NMR(300MHz,CD3OD)δ:9.54(s,4H),7.53(d,J
=16.0Hz, 2H), 7.49 (s, 1H), 7.35 (d, J=16.0Hz, 2H), 7.06 (s, 2H), 7.04 (s, 2H), 6.89 (d, J=
2.5Hz, 1H), 6.86 (d, J=2.5Hz, 1H), 6.63 (d, J=2.5Hz, 2H), 6.78 (dd, J=8.0,2.5Hz, 2H),
5.36 (br, 1H), 4.63 (br, 1H), 4.22 (dd, J=7.5,3.0Hz, 1H), 4.16 (m, 2H), 3.92 (s, 6H), 2.83
(d, J=3.2Hz, 3H), 2.19-2.13 (m, 2H), 1.93-1.89 (m, 2H)；13C NMR(75MHz,CD3OD)δ:173.8,
148.8(2),146.7(2),142.6,142.4,134.4(2C),128.5(2C),124.4(2C),118.8(2C),118.5
(2C),116.6(2C),115.3(2C),80.5,73.5,56.7,54.6(2),51.9,40.5,35.5,26.8；31P NMR
(162MHz,CDCl3)δP:25.7。
(1S, 3R, 4R, 5R)-N- methyl-N ', N '-two coffee phosphine (mono-methyl) acyl group -3,4- diaminostilbene, 5- dihydroxy
Hexamethylene -1- formamide (CL-20): collecting retention time RT=24.2min fraction, and vacuum revolving removes solvent, and residue is cold
It is lyophilized dry, obtains light green solid 13.0mg, yield 3.4%.1H NMR(300MHz,CD3OD)δ:9.52(s,4H),7.51(d,J
=16.0Hz, 2H), 7.47 (s, 1H), 7.34 (d, J=16.0Hz, 2H), 7.05 (s, 2H), 7.03 (s, 2H), 6.87 (d, J=
2.5Hz, 1H), 6.86 (d, J=2.5Hz, 1H), 6.63 (d, J=2.5Hz, 2H), 6.78 (dd, J=8.0,2.5Hz, 2H),
5.36 (br, 1H), 4.63 (br, 1H), 4.22 (dd, J=7.5,3.0Hz, 1H), 4.16 (m, 2H), 3.92 (s, 6H), 2.83
(d, J=3.2Hz, 3H), 2.19-2.13 (m, 2H), 1.93-1.89 (m, 2H)；13C NMR(75MHz,CD3OD)δ:173.9,
148.7(2),146.7(2),142.6,142.4,134.4(2C),128.5(2C),124.4(2C),118.8(2C),118.5
(2C),116.6(2C),115.3(2C),80.5,73.5,56.7,54.6(2),51.9,40.5,35.4,26.7；31P NMR
(162MHz,CDCl3)δP:25.8。
Embodiment 6 N- methyl-N ', N '-two coffee phosphine (mono-methyl) acyl group -3,5- diaminostilbene, 4- dihydroxy hexamethylene
It the preparation of alkane -1- formamide (CL-21~CL-24) and isolates and purifies
(1) preparation of (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- phosphonic acids mono-methyl, according to implementation
Example 5 step (1) method obtains.
(2) N- methyl -3,5- diaminostilbene, the preparation of 4- benzyloxy hexamethylene -1- formamide, according to 2 step of embodiment
Suddenly (2) method obtains.
(3) N- methyl-N ', N '-two coffee phosphine (mono-methyl) acyl group -3,5- diaminostilbene, 4- dihydroxy butylcyclohexane -1- first
It the preparation of amide (CL-21~CL-24) and isolates and purifies
It is carried out by embodiment 2 step (3) method, wherein raw material (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) third
Olefin(e) acid is changed to (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- phosphonic acids mono-methyl that step (1) obtains.
Residue is isolated and purified with RP-HPLC, and the eluant, eluent condition of RP-HPLC purifying is MeOH:H2O:HCO2H=40:
80:0.5 (V:V:V), RT=27.6~23.4min obtain light green solid 273.3mg, total recovery 72.6%.
(1S, 3S, 4r, 5R)-N- methyl-N ', N '-two coffee phosphine (mono-methyl) acyl group -3,5- diaminostilbene, 4- dihydroxy
Hexamethylene -1- formamide (CL-21): collecting retention time RT=27.6min fraction, and vacuum revolving removes solvent, and residue is cold
It is lyophilized dry, obtains light green solid 35.5mg, yield 9.4%.1H NMR(300MHz,CD3OD)δ:9.54(s,4H),7.53(d,J
=16.0Hz, 2H), 7.49 (s, 1H), 7.35 (d, J=16.0Hz, 2H), 7.06 (s, 2H), 7.04 (s, 2H), 6.89 (d, J=
2.5Hz, 1H), 6.86 (d, J=2.5Hz, 1H), 6.63 (d, J=2.5Hz, 2H), 6.78 (dd, J=8.0,2.5Hz, 2H),
5.36 (br, 1H), 4.63 (br, 1H), 4.22 (dd, J=7.5,3.0Hz, 1H), 4.16 (m, 2H), 3.92 (s, 6H), 2.83
(d, J=3.2Hz, 3H), 2.19-2.13 (m, 2H), 1.93-1.89 (m, 2H)；13C NMR(75MHz,CD3OD)δ:173.8,
148.8(2),146.7(2),142.6,142.4,134.4(2C),128.5(2C),124.4(2C),118.8(2C),118.5
(2C),116.6(2C),115.3(2C),80.5,73.5,56.7,54.6(2),51.9,40.5,35.5,26.8；31P NMR
(162MHz,CDCl3)δP:25.7。
(1S, 3R, 4S, 5R)-N- methyl-N ', N '-two coffee phosphine (mono-methyl) acyl group -3,5- diaminostilbene, 4- dihydroxy
Hexamethylene -1- formamide (CL-22): collecting retention time RT=26.4min fraction, and vacuum revolving removes solvent, and residue is cold
It is lyophilized dry, obtains light green solid 16.4mg, yield 4.4%.1H NMR(300MHz,CD3OD)δ:9.52(s,4H),7.51(d,J
=16.0Hz, 2H), 7.47 (s, 1H), 7.34 (d, J=16.0Hz, 2H), 7.05 (s, 2H), 7.03 (s, 2H), 6.87 (d, J=
2.5Hz, 1H), 6.86 (d, J=2.5Hz, 1H), 6.63 (d, J=2.5Hz, 2H), 6.78 (dd, J=8.0,2.5Hz, 2H),
5.36 (br, 1H), 4.63 (br, 1H), 4.22 (dd, J=7.5,3.0Hz, 1H), 4.16 (m, 2H), 3.92 (s, 6H), 2.83
(d, J=3.2Hz, 3H), 2.19-2.13 (m, 2H), 1.93-1.89 (m, 2H)；13C NMR(75MHz,CD3OD)δ:173.9,
148.7(2),146.7(2),142.6,142.4,134.4(2C),128.5(2C),124.4(2C),118.8(2C),118.5
(2C),116.6(2C),115.3(2C),80.5,73.5,56.7,54.6(2),51.9,40.5,35.4,26.7；31P NMR
(162MHz,CDCl3)δP:25.8。
(1R, 3S, 4R, 5S)-N- methyl-N ', N '-two coffee phosphine (mono-methyl) acyl group -3,4- diaminostilbene, 5- dihydroxy
Hexamethylene -1- formamide (CL-23): collecting retention time RT=25.3min fraction, and vacuum revolving removes solvent, and residue is cold
It is lyophilized dry, obtains light green solid 185.8mg, yield 49.4%.1H NMR(300MHz,CD3OD)δ:9.53(s,4H),7.55(d,
J=16.0Hz, 2H), 7.47 (s, 1H), 7.32 (d, J=16.0Hz, 2H), 7.05 (s, 2H), 7.03 (s, 2H), 6.87 (d, J
=2.5Hz, 1H), 6.85 (d, J=2.5Hz, 1H), 6.63 (d, J=2.5Hz, 2H), 6.78 (dd, J=8.0,2.5Hz, 2H),
5.36 (br, 1H), 4.63 (br, 1H), 4.22 (dd, J=7.5,3.0Hz, 1H), 4.16 (m, 2H), 3.92 (s, 6H), 2.83
(d, J=3.2Hz, 3H), 2.19-2.13 (m, 2H), 1.92-1.87 (m, 2H)；13C NMR(75MHz,CD3OD)δ:173.6,
148.8(2),146.7(2),142.6,142.5,134.4(2C),128.5(2C),124.4(2C),118.8(2C),118.5
(2C),116.6(2C),115.3(2C),80.5,73.5,56.7,54.6(2),51.9,40.5,35.6,26.9；31P NMR
(162MHz,CDCl3)δP:25.8。
(1r, 3R, 4S, 5S)-N- methyl-N ', N '-two coffee phosphine (mono-methyl) acyl group -3,5- diaminostilbene, 4- dihydroxy
Hexamethylene -1- formamide (CL-24): collecting retention time RT=23.4min fraction, and vacuum revolving removes solvent, and residue is cold
It is lyophilized dry, obtains light green solid 35.5mg, yield 9.4%.1H NMR(300MHz,CD3OD)δ:9.52(s,4H),7.51(d,J
=16.0Hz, 2H), 7.47 (s, 1H), 7.34 (d, J=16.0Hz, 2H), 7.05 (s, 2H), 7.03 (s, 2H), 6.87 (d, J=
2.5Hz, 1H), 6.86 (d, J=2.5Hz, 1H), 6.63 (d, J=2.5Hz, 2H), 6.78 (dd, J=8.0,2.5Hz, 2H),
5.36 (br, 1H), 4.63 (br, 1H), 4.22 (dd, J=7.5,3.0Hz, 1H), 4.16 (m, 2H), 3.92 (s, 6H), 2.83
(d, J=3.2Hz, 3H), 2.19-2.13 (m, 2H), 1.93-1.89 (m, 2H)；13C NMR(75MHz,CD3OD)δ:173.9,
148.7(2),146.7(2),142.6,142.4,134.4(2C),128.5(2C),124.4(2C),118.8(2C),118.5
(2C),116.6(2C),115.3(2C),80.5,73.5,56.7,54.6(2),51.9,40.5,35.4,26.7；31P NMR
(162MHz,CDCl3)δP:25.8。
The preventing respiratory viruses Activity determination of 7 quinine acid derivative of embodiment
Virus, host cell material: selecting Respiratory Syncytial Virus(RSV) (RSV), and host cell is laryngeal cancer cell (HEp-2)；
It selects parainfluenza virus III (PIV3), host cell HEp-2；Influenza A virus (FluA, H1N1), host cell are dog kidney
Passage cell (MDCK).Viral RSV, PIV3, H1N1 and cell HEp-2, MDCK are purchased from medicinal institute of viruses, Wuhan University.
Cell growth medium is the MEM culture medium containing the calf serum (FBS) that concentration is percent by volume 10%, cell dimension
Holding liquid is the MEM culture medium containing percent by volume 1%FBS.
Positive control drug be Ribavirin, natural products 3,4-O, O- the dicaffeoylquinic acid methyl esters from elephants-foot and
3,5-O, O- dicaffeoylquinic acid methyl esters.
Tetrazolium salts (MMT) solution is prepared: being configured to 5mg/mL solution with buffer PBS (0.1M, pH7.4).
Sample solution is prepared: quinine acid derivative prepared by Examples 1 to 6 and Ribavirin are used cell maintenance medium
It is made into the sample solution of 200 μ g/mL and 100 μ g/mL respectively.
(1) it uses the cytotoxicity of MMT method detection compound: HEp-2 cell and mdck cell is inoculated in 96 holes respectively
In plate, inoculum density is 1 × 104A/hole, after waiting cell monolayers to grow well, it is molten that addition cell maintenance medium dilutes the sample prepared
Liquid is to series of concentrations (3.1~200 μ g/mL), in 37 DEG C, 5% CO2It is cultivated 3 days in incubator, the MTT that 10 μ L are prepared is added
Solution continues to cultivate 4h.Sample solution is sucked out, 100 μ L dimethyl sulfoxides (DMSO) is added, 96 orifice plates is placed in micro- sky at room temperature
10min is shaken in the plate oscillator of hole, then with the OD value at microplate reader detection 570nm, calculates separately HEp-2 cell and MDCK is thin
Born of the same parents' survival rate；Every group sets 4 balance holes, is repeated 3 times.Calculated result draws curve, finds out half toxic concentration (CC50), detection
It the results are shown in Table 1~3.
(2) antiviral activity is measured to the inhibition level of cytopathic effect by observation sample: by HEp-2 cell and
Mdck cell is cultivated respectively in 96 plate holes, wait cell monolayers grow it is good after, 100 times of halves that addition has been diluted with cell maintenance medium
Infective dose (100TCID50) RSV, PIV3 and FluA H1N1 virus liquid, add with cell maintenance medium dilution prepare sample
Solution is to series of concentrations (0.4~100.0 μ g/mL), in 37 DEG C, 5% CO2It is cultivated 3~4 days in incubator.Daily in inversion
The degree of microscopically observation cytopathic effect (CPE), and record.Indicate no CPE；+ indicate that 0~25% cell has
CPE；2+ indicates that 25~50% cell has CPE；3+ indicates that 50~70% cell has CPE；4+ indicates 75~100% cell
There is CPE.Finally estimate half-inhibitory concentration (IC50).Selectivity index (SI)=CC50/IC50.Experimental result is shown in Table 1~3.
The anti respiratory syncytial virus of 1 quinine acid derivative of table and positive control activity
* note: the host cell of the respiratory tract born of the same parents combination of syndromes malicious (RSV) is HEp-2, CC50For half toxic concentration, IC50For half
Inhibition concentration, SI are selectivity index, SI=CC50/IC50。
Table 1 statistics indicate that, with positive control drug Ribavirin and the native compound from elephants-foot 3,4-O, O- bis-
Caffeoylquinic acids methyl esters and 3,5-O, O- dicaffeoylquinic acid methyl esters are compared, quinine acid derivative (CL-01~CL-24)
Cytotoxicity, preventing respiratory born of the same parents' combination of syndromes cytotoxic activity and selectivity index more preferably than Ribavirin, wherein especially with CL-07, CL-15
It is best with the overall merit of CL-23；Quinine acid derivative is commented than the synthesis of corresponding natural origin dicaffeoylquinic acid methyl esters
Valence wants high.
The anti-parainfluenza virus III of 2 quinine acid derivative of table and positive control activity
* note: the host cell of parainfluenza virus III (PIV3) is HEp-2, CC50For half toxic concentration, IC50For half
Inhibition concentration, SI are selectivity index, SI=CC50/IC50。
Table 2 statistics indicate that, with positive control drug Ribavirin and the native compound from elephants-foot 3,4-O, O- bis-
Caffeoylquinic acids methyl esters and 3,5-O, O- dicaffeoylquinic acid methyl esters are compared, the cell of 3,5- diamino quinine acid derivatives
Toxicity, anti-parainfluenza virus III activity and selectivity index more preferably than Ribavirin, wherein especially with CL-07, CL-14, CL-
15, the overall merit of CL-22, CL-23 and CL-24 are best；Quinine acid derivative is than corresponding two caffeoyl quinine of natural origin
The overall merit of sour methyl esters wants high.
The anti-influenza virus activity of table 3 quinine acid derivative and positive control
* note: the host cell of Influenza virus H1N1 (FluA H1N1) is MDCK, CC50For half toxic concentration,
IC50For half-inhibitory concentration, SI is selectivity index, SI=CC50/IC50。
Table 3 statistics indicate that, with positive control drug Ribavirin and the native compound from elephants-foot 3,4-O, O- bis-
Caffeoylquinic acids methyl esters and 3,5-O, O- dicaffeoylquinic acid methyl esters are compared, the cell of 3,5- diamino quinine acid derivatives
Toxicity, anti-influenza A virus H1N1 activity and selectivity index more preferably than Ribavirin, wherein especially with CL-07, CL-15 and
The overall merit of CL-23 is best；Overall merit of the quinine acid derivative than corresponding natural origin dicaffeoylquinic acid methyl esters
Want high.
Stability of the 8 part quinine acid derivative of embodiment in fetal calf serum
Experimental material: calf serum (FBS) and culture medium DMEM are purchased from GIBCO company.
Experimentation: 1) standard working curve of test sample using high-efficient liquid phase technique is established；2) it configures final concentration of
Sample (the natural products 3,4-O, O- bis- of CL-07, CL-15, CL-23 and elephants-foot prepared by embodiment 2,4 and 6 of 20mM
Caffeoylquinic acids methyl esters and 3,5-O, O- dicaffeoylquinic acid methyl esters) solution, add the tire of 200 μ L sample solution and 1.8mL
For cow's serum in 6 orifice plates, 37 DEG C of incubations in 0.25h, 0.5h, 1h, 2h, 4h, 8h, 12h, take 10 μ L mixing samples respectively for 24 hours,
90 μ L 20% (v/v) Thyronorman's alcoholic solutions are added, oscillation stands 30min after mixing, 10000rpm is centrifuged 5min.Take supernatant
Liquid HPLC analysis.With when the mapping of m- concentration, obtain half-life period of the sample to be tested in fetal calf serum, the results are shown in Table 4.
Stability of the 4 quinine acid derivative of table in fetal calf serum
| Sample | t1/2(h) |
| 3,4-O, O- dicaffeoylquinic acid methyl esters | 0.2 |
| 3,5-O, O- dicaffeoylquinic acid methyl esters | 0.3 |
| CL-07 | 4.8 |
| CL-15 | 5.3 |
| CL-23 | 5.2 |
As seen from Table 4, natural 3,4-O, O- dicaffeoylquinic acid methyl esters and 3,5-O, bis- caffeoyl quinine of O-
The half-life period of sour methyl esters is very short, respectively 0.2h and 0.3h；And the half-life period of quinine acid derivative CL-07, CL-15, CL-23 point
Not Wei 4.8h, 5.3h and 5.2h, have raising by a relatively large margin.
The above embodiment is a preferred embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment
Limitation, other any changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principles of the present invention,
It should be equivalent substitute mode, be included within the scope of the present invention.
Claims (10)
1. a kind of quinine acid derivative, it is characterised in that have the structure as shown in general formula I:
In general formula I, R1、R2、R3For OH or AcNH；Wherein, R1=OH, R2=R3=AcNH or R2=OH, R1=R3=AcNH or
Person R3=OH, R1=R2=AcNH；* R configuration or S configuration are indicated；
The Ac indicates coffee acyl CAc or its derivative coffee sulfonyl SAc, coffee (mono-methyl) phosphono PAc,
Structure is as follows:
2. quinine acid derivative according to claim 1, it is characterised in that: the quinine acid derivative is compound
The structure of CL-01~CL-24, compound CL-01~CL-24 are as follows:
3. the preparation method of the described in any item quinine acid derivatives of claim 1~2, it is characterised in that include the following steps:
The synthesis of (1a) benzene a pair of horses going side by side [d] [1,3] dioxolen:
Using catechol as starting material, it is dissolved in n,N-Dimethylformamide, adds reagent a and sodium bicarbonate, is reacted,
Obtain parallel [d] [1,3] dioxolen of benzene；
The synthesis of (1b) 3,4- dioxymethylene benzaldehyde:
Parallel [d] [1, the 3] dioxolen of benzene obtained in step (1a) is added dissolved in the isopropanol of catalyst, reagent b is added,
Reaction, obtains 3,4-methylenedioxy benzaldehyde；
The synthesis of (1c) (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid:
3,4-methylenedioxy benzaldehyde and reagent c that step (1b) obtains are dissolved in alkali, reacted, (E) -3- (benzene a pair of horses going side by side [d] is obtained
[1,3] dioxolen -5- base) acrylic acid；
The synthesis of (1c ') (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- sulfonic acid:
3,4-methylenedioxy benzaldehyde and Loprazolam acid anhydride that step (1b) obtains are dissolved in dry tetrahydrofuran, hydrogen is added
Change sodium, reaction obtains (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- sulfonic acid；
The synthesis of (1c ") (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) vinyl phosphonic dimethyl phthalate:
3,4-methylenedioxy benzaldehyde and dimethyl methyl phosphonate that step (1b) obtains are dissolved in dry tetrahydrofuran, added
Enter sodium hydride, react, obtains (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) vinyl phosphonic dimethyl phthalate；
The synthesis of (1d ") (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- phosphonic acids mono-methyl:
(E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) vinyl phosphonic dimethyl phthalate that step (1c ") obtains is dissolved in dry
Reagent d " is added in dry tetrahydrofuran, obtains (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- phosphonic acids list first
Ester；
The synthesis of (2a) quininic acid methyl esters:
Using quininic acid as raw material, it is dissolved in methanol, thionyl chloride is added after balance, reacts, obtains quininic acid methyl esters；
The synthesis of (2b) N- methyl quinuclidine amide:
The quininic acid methyl esters that step (2a) obtains is dissolved in methanol, methylamine methanol solution is added, reaction obtains N- methyl quinuclidine acyl
Amine；
The synthesis of (2c) N- methyl -3,4- acetonylidene dioxy quinine amide:
The N- methyl quinuclidine amide that step (2b) obtains is dissolved in protection reagent, p-methyl benzenesulfonic acid and deicer is added, reaction removes
Deicer is removed, N- methyl -3,4- acetonylidene dioxy quinine amide is obtained；
The synthesis of (2d) N- methyl -3,4- acetonylidene dioxy -1,5- benzyloxy quinine amide:
N- methyl -3,4- acetonylidene dioxy quinine amide that step (2c) obtains is dissolved in and steams tetrahydrofuran again, the tetrabutyl is added
Sodium hydride is added after balance in ammonium bromide, reacts, and cylite is added dropwise, and reaction obtains N- methyl -3,4- acetonylidene dioxy -1,5- bis-
Benzyloxy quinine amide；
(2e) N- methyl-1, the synthesis of 5- benzyloxy quinine amide:
N- methyl -3,4- acetonylidene dioxy -1,5- benzyloxy quinine amide that step (2d) obtains is dissolved in methylene chloride, is put down
Trifluoroacetic acid and water are added dropwise after weighing apparatus, reaction obtains N- methyl-1,5- benzyloxy quinine amide；
The synthesis of two mesyloxy -1,5- benzyloxy quinine amide of (2f) N- methyl -3,4-:
The N- methyl-1 that step (2e) is obtained, 5- benzyloxy quinine amide is dissolved in steams methylene chloride again, and 4- (N, N- bis- is added
Methyl) aminopyridine, triethylamine is added, reagent f is added dropwise again after balance, reacts, obtains bis- mesyloxy of N- methyl -3,4- -
1,5- benzyloxy quinine amide；
The synthesis of (2g) N- methyl -3,4- diazido -1,5- benzyloxy quinine amide:
Two mesyloxy -1,5- benzyloxy quinine the amide of N- methyl -3,4- that step (2f) obtains is dissolved in N, N- diformazan
The mixed solvent of base formamide and hexamethylphosphoramide, is added sodium azide, and reaction obtains N- methyl -3- nitrine -4- methylsulphur
Acyloxy -1,5- benzyloxy quinine amide；
Obtained N- methyl -3- nitrine -4- mesyloxy -1,5- benzyloxy quinine amide is dissolved in N, N- dimethyl formyl
The mixed solvent of amine and hexamethylphosphoramide, is added sodium azide, and reaction obtains N- methyl -3,4- diazido -1,5- bis-
Benzyloxy quinine amide；
(2h) N- methyl -3,4- diaminostilbene, the synthesis of 5- benzyloxy quinine amide:
N- methyl -3,4- diazido -1,5- benzyloxy quinine the amide that step (2g) obtains is dissolved in the mixed of first alcohol and water
Bonding solvent, is added triphenylphosphine, and reaction is obtained containing N- methyl -3,4- diaminostilbene, the residual of 5- benzyloxy quinine amide
Object；
The synthesis of (2c ') N- methyl -3,5- two (tertiary butyl dimethyl Si base) quinine amide:
The N- methyl quinuclidine amide that step (2b) obtains is dissolved in dry tetrahydrofuran, imidazoles is added and using dry N, N-
The tert-butyl chloro-silicane solution of dimethylformamide dissolution, reaction obtain bis- (fert-butyidimethylsilyl of N- methyl -3,5-
Siloxy) quinine amide；
The synthesis of (2d ') N- methyl -3,5- two (tertiary butyl dimethyl Si base) -1,4- benzyloxy quinine amide:
(tertiary butyl dimethyl Si base) the quinine amide of N- methyl -3,5- bis- that step (2c ') is obtained is adopted according to step (2d)
It is synthesized with identical reagent/auxiliary agent/solvent, obtains N- methyl -3,5- bis- (tertiary butyl dimethyl Si base)-Isosorbide-5-Nitrae-dibenzyl
Oxygroup quinine amide；
(2e ') N- methyl-1, the synthesis of 4- benzyloxy quinine amide:
N- methyl -3,5- two (tertiary butyl dimethyl Si base) -1,4- benzyloxy quinine amide that step (2d ') is obtained is molten
Trifluoroacetic acid is added dropwise after methylene chloride, balance, reacts, obtains N- methyl-1,4- benzyloxy quinine amide；
The synthesis of two mesyloxy -1,4- benzyloxy quinine amide of (2f ') N- methyl -3,5-:
The N- methyl-1 that step (2e ') is obtained, 4- benzyloxy quinine amide according to step (2f), using identical reagent/
Auxiliary agent/solvent is synthesized, and bis- mesyloxies of N- methyl -3,5--Isosorbide-5-Nitrae-benzyloxy quinine amide is obtained；
The synthesis of (2g ') N- methyl -3,5- diazido -1,4- benzyloxy quinine amide:
Two mesyloxy -1,4- benzyloxy quinine the amide of N- methyl -3,5- that step (2f ') is obtained is according to step
(2g) is synthesized using identical reagent/auxiliary agent/solvent, obtains N- methyl -3,5- diazido-Isosorbide-5-Nitrae-benzyloxy Kui
Peaceful amide；
(2h ') N- methyl -3,5- diaminostilbene, the synthesis of 4- benzyloxy quinine amide:
N- methyl -3,5- diazido-Isosorbide-5-Nitrae-benzyloxy quinine amide that step (2g ') is obtained is adopted according to step (2h)
It is synthesized with identical reagent/auxiliary agent/solvent, obtains N- methyl -3,5- diaminostilbene, 4- benzyloxy quinine amide；
(E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid that step (1c) obtains is dissolved in and steams N again by (3a), N- bis-
Condensing agent and 1- hydroxy benzenes a pair of horses going side by side triazole is added in methylformamide, and n,N-diisopropylethylamine is added in reaction, and step (2h) is obtained
That arrives contains N- methyl -3,4- diaminostilbene, and the residue of 5- benzyloxy quinine amide is dissolved in dry N, N- dimethyl formyl
It is added dropwise after amine into reaction system, reacts, obtain containing-two coffee acyl -3,4- diaminostilbene of N- methyl-N ', N ', 5- dihydroxy
The residue of butylcyclohexane -1- formamide, and be directly entered and react in next step；
(3b) contains-two coffee acyl -3,4- diaminostilbene of N- methyl-N ', N ', 5- dihydroxy hexamethylene for what step (3a) obtained
The residue of alkane -1- formamide is dissolved in steams methylene chloride again, and deprotecting regent is added dropwise after balance, and reaction obtains N- methyl-N ',
- two coffee acyl -3,4- diaminostilbene of N ', 5- dihydroxy butylcyclohexane -1- formamide CL-01~CL-04；
Reagent a described in step (1a) is formaldehyde, CH2Cl2、CH2Br2And CH2I2One of；
Catalyst described in step (1b) is one of phosphorus oxychloride, nitric acid and acetic anhydride；
Reagent b described in step (1b) is one of N,N-dimethylformamide, glyoxalic acid and methenamine；
Reagent c described in step (1c) is one of acetic anhydride and malonic acid；
Alkali described in step (1c) be respective acids sodium salt or sylvite, piperidines/pyridine, sodium hydride, lithium diisopropylamine and
One of potassium tert-butoxide；
Reagent d described in step (1d ") " it is one of lithium hydroxide, lithium carbonate and tri butyl boron lithium hydride；
Protection reagent described in step (2c) is one of formaldehyde, acetone, benzaldehyde；
Deicer described in step (2c) isAt least one of molecular sieve and anhydrous magnesium sulfate；
Reagent f described in step (2f) is one of mesyl chloride and paratoluensulfonyl chloride；
The product that step (2h) and (2h ') are obtained may have 4 optical isomers, separated or be directly entered to product and is next
It is separated again after the reaction of step；
Condensing agent described in step (3a) is N, N'- diisopropylcarbodiimide, 1- (3- dimethylamino-propyl) -3- ethyl carbon
One of diimmonium salt hydrochlorate and ethyl chloroformate；
Deprotecting regent described in step (3b) is BCl3；
- two coffee acyl -3,5- diaminostilbene of N- methyl-N ', N ', 4- dihydroxy butylcyclohexane -1- formamide (CL-05~CL-
08) preparation is carried out by step (3a) and (3b), N- methyl -3,4- diaminostilbene that wherein raw material is obtained by step (2h), 5-
Benzyloxy quinine amide is changed to the N- methyl -3,5- diaminostilbene that step (2h ') obtains, 4- benzyloxy quinine amide；
- two coffee sulfonyl -3,4- diaminostilbene of N- methyl-N ', N ', 5- dihydroxy butylcyclohexane -1- formamide (CL-09~CL-
12) preparation is carried out by step (3a) and (3b), (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxy that wherein raw material is obtained by step (1c)
Amylene -5- base) acrylic acid is changed to (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- that step (1c ') obtains
Sulfonic acid；
- two coffee sulfonyl -3,5- diaminostilbene of N- methyl-N ', N ', 4- dihydroxy butylcyclohexane -1- formamide (CL-13~CL-
16) preparation is carried out by step (3a) and (3b), (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxy that wherein raw material is obtained by step (1c)
Amylene -5- base) acrylic acid is changed to (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- that step (1c ') obtains
Sulfonic acid, N- methyl -3,4- diaminostilbene that step (2h) obtains, 5- benzyloxy quinine amide are changed to step (2h ') and obtain
N- methyl -3,5- diaminostilbene, 4- benzyloxy quinine amide；
N- methyl-N ', N '-two coffee phosphine (mono-methyl) acyl group -3,4- diaminostilbene, 5- dihydroxy butylcyclohexane -1- formamide
The preparation of (CL-17~CL-20) is carried out by step (3a) and (3b), (E) -3- (benzene a pair of horses going side by side that wherein raw material is obtained by step (1c)
[d] [1,3] dioxolen -5- base) acrylic acid is changed to (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen-that step (1d ") obtains
5- yl) ethylene -1- phosphonic acids mono-methyl；
N- methyl-N ', N '-two coffee phosphine (mono-methyl) acyl group -3,5- diaminostilbene, 4- dihydroxy butylcyclohexane -1- formamide
The preparation of (CL-21~CL-24) is carried out by step (3a) and (3b), (E) -3- (benzene a pair of horses going side by side that wherein raw material is obtained by step (1c)
[d] [1,3] dioxolen -5- base) acrylic acid is changed to (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen-that step (1d ") obtains
5- yl) ethylene -1- phosphonic acids mono-methyl, N- methyl -3,4- diaminostilbene that step (2h) obtains, 5- benzyloxy quinine amide is more
It is changed to the N- methyl -3,5- diaminostilbene that step (2h ') obtains, 4- benzyloxy quinine amide.
4. the preparation method of quinine acid derivative according to claim 3, it is characterised in that:
Reagent a described in step (1a) is CH2I2；
Catalyst described in step (1b) is acetic anhydride；
Reagent b described in step (1b) is methenamine；
Reagent c described in step (1c) is malonic acid；
Alkali described in step (1c) is piperidines/pyridine；
Reagent d described in step (1d ") " it is tri butyl boron lithium hydride；
Protection reagent described in step (2c) is acetone；
Deicer described in step (2c) isMolecular sieve and anhydrous magnesium sulfate；
Condensing agent described in step (3a) is 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride；
Deprotecting regent described in step (3b) is BCl3；
Step (3b) further includes by described tetra- kinds of optical isomers of CL-01~CL-04 using column chromatography, high-efficient liquid phase technique and again
One of crystallisation or at least two the step of isolating and purifying.
5. the preparation method of quinine acid derivative according to claim 3, it is characterised in that:
The temperature of reaction described in step (1a) is 70~100 DEG C；
The time of reaction described in step (1a) is 5~20h；
A pair of horses going side by side [d] [1, the 3] dioxolen of benzene described in step (1b) is added dropwise to the isopropanol dissolved with catalyst under the conditions of 55 DEG C
In, it drips within 0.5 hour；
The temperature of reaction described in step (1b) is 80~120 DEG C；
The time of reaction described in step (1b) is 0.5~3h；
Reaction described in step (1c), (1c ') and (1c ") is to be heated to reflux 4~1h at 90~130 DEG C of oil bath；
Addition reagent d described in step (1d ") " it is to be added dropwise under nitrogen protection；
15~40min, then room temperature the reaction was continued 8~20h are reacted in reaction described in step (2a) under the conditions of being -20~-10 DEG C；
The time of reaction described in step (2b) is 5~20h；
Reaction described in step (2c) is 5~20h of back flow reaction under the conditions of 45~70 DEG C；
Sodium hydride described in step (2d) is added in three times；
In step (2d), the reaction after sodium hydride is added reacts 5~30min under the conditions of being -15~0 DEG C；After cylite is added dropwise
Reaction reacts 20~50min under the conditions of being -15~0 DEG C, then 20~50min of reaction is stirred at room temperature；
Reaction described in step (2e) reacts 2~5h under the conditions of being -10~10 DEG C；
Addition triethylamine described in step (2f) is that triethylamine is added under condition of ice bath.
Reaction after reagent f is added dropwise in step (2f) be 20~50min is reacted under condition of ice bath, then be stirred at room temperature reaction 5~
20h；
In step (2g), first set reaction is 5~20h of reaction under the conditions of 50~100 DEG C of oil baths；Second secondary response is 100~150
10~30h is reacted under the conditions of DEG C oil bath；
Reaction described in step (2h) is 3~10h of back flow reaction under the conditions of 50~80 DEG C of oil baths；
The time being stirred to react described in step (2c ') is 1~5h；
Be stirred to react described in step (2e ') be 80 DEG C under the conditions of be stirred to react 2h；
In step (3a), the time of first set reaction is 20~50min, and the time of the second secondary response is 5~20h；
Reaction described in step (3b) reacts 15~45min under the conditions of being 0~-20 DEG C, then is stirred to react 1~5h at room temperature；
The dosage of reagent a described in step (1a) is that 1.0~1.5:1.0 matches by the molar ratio of itself and the catechol
Than；
The dosage of reagent b described in step (1b) is 400 by the molar ratio of itself and parallel [d] [1,3] dioxolen of the benzene
~700:1.0 proportion；
The dosage of reagent c described in step (1c) by its molar ratio 1.0 with the 3,4- dioxymethylene benzaldehyde~
2.0:1.0 proportion；
The dosage of 3,4- dioxymethylene benzaldehyde described in step (1c '), Loprazolam acid anhydride and sodium hydride is according to molar ratio
The proportion of 1.0:1.0~2.0:1.5~3.0 calculates；
The dosage of 3,4- dioxymethylene benzaldehyde, dimethyl methyl phosphonate and sodium hydride described in step (1c ") is according to rubbing
You match than 1.0:1.0~2.0:1.5~3.0 and calculate；
The dosage of quininic acid described in step (2a) is that the proportion of 1:1~2 calculates by the molar ratio of itself and the thionyl chloride；
The dosage of N- methyl quinuclidine amide described in step (2c) by the molar ratio of itself and the p-methyl benzenesulfonic acid be 5~
10:1 proportion calculates；
Tetrabutylammonium bromide described in step (2d), sodium hydride, cylite and N- methyl -3,4- acetonylidene dioxy quinine amide
It matches and calculates according to molar ratio 1:100~130:25~40:10~15；
The dosage of trifluoroacetic acid described in step (2e) is 1:1 calculating by the volume ratio of itself and water；
The dosage of reagent f described in step (2f) presses itself and the N- methyl-1, mole of 5- benzyloxy quinine amide
It is calculated than being matched for 1~5:1；
In step (2g), the dosage for the sodium azide being added for the first time presses itself and bis- mesyloxy of N- methyl -3,4- -
The molar ratio of 1,5- benzyloxy quinine amide is 1~5:1；The dosage of second of sodium azide being added presses itself and the N-
The molar ratio of methyl -3- nitrine -4- mesyloxy -1,5- benzyloxy quinine amide is that 2~8:1 proportion calculates；
The dosage of N,N-dimethylformamide described in step (2g) by its volume ratio with hexamethylphosphoramide for 3:1 based on
It calculates；
The dosage of methanol described in step (2h) is 5:1 calculating by the volume ratio of itself and water.
The dosage of triphenylphosphine described in step (2h) presses itself and two benzyloxy of N- methyl -3,4- diazido -1,5-
The molar ratio of base quinine amide is that 0.5~2:1 proportion calculates；
The dosage of tert-butyl chloro-silicane described in step (2c ') presses mole of itself and the N- methyl quinuclidine amide
It is calculated than being matched for 1~4:1；
The dosage of trifluoroacetic acid described in step (2e ') matches two (uncle of 1mmol N- methyl -3,5- by every 1mL trifluoroacetic acid
Butyldimethylsilanyloxy) calculating of -1,4- benzyloxy quinine amide；
The dosage of condensing agent described in step (3a) is by itself and described (the E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base)
The molar ratio of acrylic acid is that 0.5~2:1 proportion calculates；
The dosage of deprotection agent described in step (3b) contains-two coffee acyl -3 N- methyl-N ', N ' with described by it,
4- diaminostilbene, the molar ratio of the residue of 5- dihydroxy butylcyclohexane -1- formamide are that 1~5:1 proportion calculates.
6. the preparation method of quinine acid derivative according to claim 5, it is characterised in that:
The temperature of reaction described in step (1a) is 80 DEG C；
The time of reaction described in step (1a) is 12h；
The temperature of reaction described in step (1b) is 110 DEG C；
The time of reaction described in step (1b) is 1h；
Being heated to reflux described in step (1c), (1c ') and (1c ") is to be heated to reflux 2h at 115 DEG C of oil bath；
Reaction described in step (2a) reacts 30min under the conditions of being -15 DEG C, then room temperature the reaction was continued 8~12h；
The time of reaction described in step (2b) is 12h；
Reaction described in step (2c) is back flow reaction 12h under the conditions of 58 DEG C；
In step (2d), the reaction after sodium hydride is added reacts 10min under the conditions of being -5 DEG C；Reaction after cylite is added dropwise is -5
30min is reacted under the conditions of DEG C, then reaction 30min is stirred at room temperature；
Reaction described in step (2e) reacts 3h under the conditions of being 0 DEG C；
Reaction after reagent f is added dropwise in step (2f) is to react 30min under condition of ice bath, then reaction 12h is stirred at room temperature；
In step (2g), first set reaction be 70 DEG C of oil baths under the conditions of react 12h；Under the conditions of second secondary response is 125 DEG C of oil bath
Reaction is for 24 hours；
Reaction described in step (2h) is back flow reaction 5h under the conditions of 68 DEG C of oil baths；
The time being stirred to react described in step (2c ') is 1.5h；
Be stirred to react described in step (2e ') be 80 DEG C under the conditions of be stirred to react 2h；
In step (3a), the time of first set reaction is 30min, and the time of the second secondary response is 12h；
Reaction described in step (3b) reacts 30min under the conditions of being -10 DEG C, then is stirred to react 2h at room temperature；
The dosage of reagent a described in step (1a) is 1.2:1.0 proportion by the molar ratio of itself and the catechol；
The dosage of reagent b described in step (1b) is 660 by the molar ratio of itself and parallel [d] [1,3] dioxolen of the benzene:
1.0 proportion；
The dosage of reagent c described in step (1c) is 2.0 by the molar ratio of itself and the 3,4- dioxymethylene benzaldehyde:
1.0 proportion；
The dosage of 3,4- dioxymethylene benzaldehyde described in step (1c '), Loprazolam acid anhydride and sodium hydride is according to molar ratio
It matches and calculates for 1.0:1.5:1.5；
The dosage of 3,4- dioxymethylene benzaldehyde, dimethyl methyl phosphonate and sodium hydride described in step (1c ") is according to rubbing
You are than being that 1.0:1.5:1.5 proportion calculates；
The dosage of quininic acid described in step (2a) is that 1:1.35 proportion calculates by the molar ratio of itself and the thionyl chloride；
The dosage of N- methyl quinuclidine amide described in step (2c) is 8.5:1 by the molar ratio of itself and the p-methyl benzenesulfonic acid
Proportion calculates；
Tetrabutylammonium bromide described in step (2d), sodium hydride, cylite and N- methyl -3,4- acetonylidene dioxy quinine amide
It matches and calculates according to molar ratio 1:120:36:12；
The dosage of reagent f described in step (2f) presses itself and the N- methyl-1, mole of 5- benzyloxy quinine amide
It is calculated than being matched for 3:1；
In step (2g), the dosage for the sodium azide being added for the first time presses itself and bis- mesyloxy of N- methyl -3,4- -
The molar ratio of 1,5- benzyloxy quinine amide is that 3:1 proportion calculates；The dosage of second of sodium azide being added presses itself and institute
The molar ratio for the N- methyl -3- nitrine -4- mesyloxy -1,5- benzyloxy quinine amide stated is that 5:1 proportion calculates；
The dosage of triphenylphosphine described in step (2h) presses itself and two benzyloxy of N- methyl -3,4- diazido -1,5-
The molar ratio of base quinine amide is that 1.5:1 proportion calculates；
The dosage of tert-butyl chloro-silicane described in step (2c ') presses mole of itself and the N- methyl quinuclidine amide
It is calculated than being matched for 2.4:1；
The dosage of condensing agent described in step (3a) is by itself and described (the E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base)
The molar ratio of acrylic acid is that 1.2:1 proportion calculates；
The dosage of deprotection agent described in step (3b) contains-two coffee acyl -3 N- methyl-N ', N ' with described by it,
4- diaminostilbene, the molar ratio of the residue of 5- dihydroxy butylcyclohexane -1- formamide are that 2.5:1 proportion calculates.
7. the preparation method of quinine acid derivative according to claim 3, it is characterised in that:
Described in (E) -3- described in step (1c) (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid, step (1c ')
(E) (E) -2- (benzene a pair of horses going side by side [d] described in -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- sulfonic acid and step (1d ")
[1,3] dioxolen -5- base) vinyl phosphonic acid mono-methyl synthetic route as shown in approach 1:
N- methyl -3,4- diaminostilbene described in step (2h), 5- benzyloxy hexamethylene -1- formamide and step (2h ')
Described in N- methyl -3,5- diaminostilbene, the synthetic route such as approach 2 and approach 3 of 4- benzyloxy hexamethylene -1- formamide
It is shown:
Described in (E) -3- described in step (1c) (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid, step (1c ')
(E) (E) -2- (benzene a pair of horses going side by side [d] described in -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- sulfonic acid and step (1d ")
[1,3] dioxolen -5- base) vinyl phosphonic acid mono-methyl respectively with N- methyl -3,4- diaminostilbene described in step (2h),
N- methyl -3,5- diaminostilbene, 4- benzyloxy ring described in 5- benzyloxy-hexamethylene -1- formamide, step (2h ')
Benzyl is sloughed after the condensation of hexane -1- formamide, obtains the route of quinine acid derivative as shown in approach 4:
8. application of the described in any item quinine acid derivatives of claim 1~7 in preparation antiviral drugs, feature exist
In: the virus is influenza virus, parainfluenza virus or Respiratory Syncytial Virus(RSV).
9. a kind of antiviral drugs, including the described in any item quinine acid derivatives of claim 1~7.
10. antiviral drugs according to claim 9, it is characterised in that:
The antiviral drugs contains a kind of or at least two pharmaceutically acceptable carrier or auxiliary materials；
The auxiliary material is sustained release agent, excipient, filler, adhesive, wetting agent, disintegrating agent, sorbefacient, absorption load
At least one of body, surfactant and lubricant；
The carrier is at least one of micro-capsule, microballoon, nanoparticle and liposome；
The antiviral drugs is further made various dosage forms, the drugs of various dosage forms according to pharmaceutical field conventional method system
It is standby to obtain.
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Inventor after: Tang Wei Inventor after: Chen Heru Inventor after: Li Yaolan Inventor after: Li Manmei Inventor after: Wu Donghui Inventor after: Rao Shuwen Inventor after: He Yepu Inventor before: Chen Heru Inventor before: Li Yaolan Inventor before: Li Manmei Inventor before: Wu Donghui Inventor before: Tang Wei Inventor before: Rao Shuwen Inventor before: He Yepu |