CN108456240B - Isosteviol derivative and preparation and application thereof - Google Patents
Isosteviol derivative and preparation and application thereof Download PDFInfo
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- CN108456240B CN108456240B CN201810106694.5A CN201810106694A CN108456240B CN 108456240 B CN108456240 B CN 108456240B CN 201810106694 A CN201810106694 A CN 201810106694A CN 108456240 B CN108456240 B CN 108456240B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 82
- KFVUFODCZDRVSS-XGBBNYNSSA-N iso-steviol Chemical class C([C@]12C[C@@](C(C2)=O)(CC[C@H]11)C)C[C@H]2[C@@]1(C)CCC[C@@]2(C)C(O)=O KFVUFODCZDRVSS-XGBBNYNSSA-N 0.000 title claims abstract description 25
- 150000001875 compounds Chemical class 0.000 claims abstract description 214
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 171
- 238000006243 chemical reaction Methods 0.000 claims description 107
- 238000001704 evaporation Methods 0.000 claims description 76
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 76
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 75
- 238000005406 washing Methods 0.000 claims description 75
- 238000004440 column chromatography Methods 0.000 claims description 70
- 238000005303 weighing Methods 0.000 claims description 67
- 238000001914 filtration Methods 0.000 claims description 66
- 238000001035 drying Methods 0.000 claims description 63
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 62
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 59
- 238000012544 monitoring process Methods 0.000 claims description 45
- 239000000203 mixture Substances 0.000 claims description 43
- 238000003756 stirring Methods 0.000 claims description 34
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 28
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 238000010791 quenching Methods 0.000 claims description 16
- 230000000171 quenching effect Effects 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 11
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 230000000259 anti-tumor effect Effects 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 8
- UEDUENGHJMELGK-HYDKPPNVSA-N Stevioside Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O UEDUENGHJMELGK-HYDKPPNVSA-N 0.000 claims description 7
- 229940125782 compound 2 Drugs 0.000 claims description 7
- OHHNJQXIOPOJSC-UHFFFAOYSA-N stevioside Natural products CC1(CCCC2(C)C3(C)CCC4(CC3(CCC12C)CC4=C)OC5OC(CO)C(O)C(O)C5OC6OC(CO)C(O)C(O)C6O)C(=O)OC7OC(CO)C(O)C(O)C7O OHHNJQXIOPOJSC-UHFFFAOYSA-N 0.000 claims description 7
- 229940013618 stevioside Drugs 0.000 claims description 7
- 235000019202 steviosides Nutrition 0.000 claims description 7
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 5
- 238000002390 rotary evaporation Methods 0.000 claims description 5
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 claims description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- 229940125898 compound 5 Drugs 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 4
- 230000007935 neutral effect Effects 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- XNRNJIIJLOFJEK-UHFFFAOYSA-N sodium;1-oxidopyridine-2-thione Chemical compound [Na+].[O-]N1C=CC=CC1=S XNRNJIIJLOFJEK-UHFFFAOYSA-N 0.000 claims description 3
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- MUVJLUQRPOPLEQ-UHFFFAOYSA-M di(ethylidene)azanium;iodide Chemical compound [I-].CC=[N+]=CC MUVJLUQRPOPLEQ-UHFFFAOYSA-M 0.000 claims description 2
- VVDUZZGYBOWDSQ-UHFFFAOYSA-M eschenmoser's salt Chemical compound [I-].C[N+](C)=C VVDUZZGYBOWDSQ-UHFFFAOYSA-M 0.000 claims description 2
- SMZORVKKJCIPCG-UHFFFAOYSA-N iodo(trimethyl)-$l^{4}-sulfane Chemical compound CS(C)(C)I SMZORVKKJCIPCG-UHFFFAOYSA-N 0.000 claims description 2
- 239000010410 layer Substances 0.000 claims description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 2
- 235000019341 magnesium sulphate Nutrition 0.000 claims description 2
- 239000012044 organic layer Substances 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 238000000967 suction filtration Methods 0.000 claims description 2
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 claims 2
- 239000002246 antineoplastic agent Substances 0.000 claims 1
- 238000010025 steaming Methods 0.000 claims 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 abstract description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 5
- 150000001412 amines Chemical group 0.000 abstract description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract description 4
- FIHJKUPKCHIPAT-AHIGJZGOSA-N artesunate Chemical group C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@@H](OC(=O)CCC(O)=O)[C@@H]4C FIHJKUPKCHIPAT-AHIGJZGOSA-N 0.000 abstract description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 abstract description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 abstract description 3
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 abstract description 2
- RREANTFLPGEWEN-MBLPBCRHSA-N 7-[4-[[(3z)-3-[4-amino-5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidin-2-yl]imino-5-fluoro-2-oxoindol-1-yl]methyl]piperazin-1-yl]-1-cyclopropyl-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(\N=C/3C4=CC(F)=CC=C4N(CN4CCN(CC4)C=4C(=CC=5C(=O)C(C(O)=O)=CN(C=5C=4)C4CC4)F)C\3=O)=NC=2)N)=C1 RREANTFLPGEWEN-MBLPBCRHSA-N 0.000 abstract description 2
- 125000000217 alkyl group Chemical group 0.000 abstract description 2
- 239000000539 dimer Substances 0.000 abstract description 2
- 125000001033 ether group Chemical group 0.000 abstract description 2
- 125000002541 furyl group Chemical group 0.000 abstract description 2
- 125000001041 indolyl group Chemical group 0.000 abstract description 2
- 125000004437 phosphorous atom Chemical group 0.000 abstract description 2
- 239000002243 precursor Substances 0.000 abstract description 2
- 125000004076 pyridyl group Chemical group 0.000 abstract description 2
- 125000000168 pyrrolyl group Chemical group 0.000 abstract description 2
- 125000001424 substituent group Chemical group 0.000 abstract description 2
- 150000007975 iminium salts Chemical class 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 96
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 82
- 238000005160 1H NMR spectroscopy Methods 0.000 description 64
- 229910000027 potassium carbonate Inorganic materials 0.000 description 41
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 22
- 229940125758 compound 15 Drugs 0.000 description 22
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical class C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 19
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 16
- KFVUFODCZDRVSS-UHFFFAOYSA-N isosteviol Natural products C1C(=O)C(C)(CCC23)CC21CCC1C3(C)CCCC1(C)C(O)=O KFVUFODCZDRVSS-UHFFFAOYSA-N 0.000 description 15
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 13
- 229940126142 compound 16 Drugs 0.000 description 13
- -1 aglycon steviol ent-kaurane diterpenoid compound Chemical class 0.000 description 12
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 10
- 230000000843 anti-fungal effect Effects 0.000 description 9
- 239000011363 dried mixture Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 8
- 238000000746 purification Methods 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000011156 evaluation Methods 0.000 description 6
- 229930014626 natural product Natural products 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 3
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 150000002596 lactones Chemical class 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- 229930002348 tetracyclic diterpenoid Natural products 0.000 description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical group CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
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- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- AGIUPQUTLBAVDK-UHFFFAOYSA-N tert-butyl n-(3-aminopropyl)-n-[4-[(2-methylpropan-2-yl)oxycarbonylamino]butyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCCN(CCCN)C(=O)OC(C)(C)C AGIUPQUTLBAVDK-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000002389 tetracyclic diterpenoid group Chemical group 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-N trans-cinnamic acid Chemical compound OC(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-N 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
- C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
- C07J73/003—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by oxygen as hetero atom
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- C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/82—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with 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
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- C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C69/757—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
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- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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Abstract
The invention discloses isosteviol derivatives and preparation and application thereof, wherein the isosteviol derivatives comprise a compound shown as a formula I and a compound shown as a formula II;
wherein the content of the first and second substances,
represents a single bond or a double bond; r1And R2Each independently selected from: hydrogen atom, methylene group and substituent being C1‑C10Aminoalkyl groups, precursor structures capable of replacing carbonyl or methylene groupsStructures such as Mannich bases, iminium salts, and the like;
wherein R is3Selected from OR4OCOCHCHR5、OR4R6、NR4、OR4X⊕(Y)3Z⊙；R4Selecting alkyl, ether chain and amine chain; r5Selected from trifluoromethyl, phenyl, benzyl, pyridyl, furyl, pyrrolyl, indolyl, aminoethyl; r6Selected from the group consisting of H atom, artesunate group, benzyl group, parent nucleus of formula II to form a dimer; x is selected from a P atom or a N atom; selected from methyl, ethyl, isopropyl, butyl, phenyl; z is selected from F, Cl, Br and I.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a series of isosteviol derivatives with novel structures, a preparation method thereof and application of the compounds in the aspects of tumor resistance and fungus resistance.
Background
There are many abundant natural products in nature, and such natural products have the characteristics of wide variety, large quantity, various structures, obvious chiral characteristics, low price and easy availability, etc. How to make high-value use of the potential huge treasures is a topic with great research significance and development and application value.
The stevioside is a natural sweetener extracted from the leaves of stevia rebaudiana Bertoni, is widely used and low in price, and has the effect of reducing blood pressure of spontaneous hypertensive rats and anesthetized dogs; can also promote insulin release of patients with type II diabetes, thereby reducing blood sugar, and stevioside also has effects of resisting myocardial ischemia, resisting bacteria and resisting inflammation. The glucoside bond of stevioside is hydrolyzed to obtain the aglycon steviol ent-kaurane diterpenoid compound, and the steviol is subjected to Wagner-Meerwein rearrangement to obtain the tetracyclic diterpenoid compound isosteviol with a Bayesian skeleton. Diterpenoid compounds have been widely noticed due to their unique pharmacological actions, such as antifungal activity, cardiovascular activity, cytotoxic action, etc., among which paclitaxel, salvia miltiorrhiza, oridonin, etc. have become the drugs on the market. Tetracyclic diterpenoids are cyclic diterpenoid natural products which are initially synthesized from geranylgeranyl pyrophosphate through an acid-catalyzed pathway, mainly comprise kaurane diterpenoids, bayeane diterpenoids and the like, and many molecules of the tetracyclic diterpenoid natural products have proved to have wide physiological activities, but the activities of most molecules are weaker.
Disclosure of Invention
In order to solve the defects of the prior art, the invention aims to provide a series of isosteviol derivatives, a preparation method thereof and application of the compounds in antifungal and antitumor aspects. The method is characterized in that cheap and easily-obtained stevioside is used as a starting raw material, isosteviol is obtained through chemical derivation, the Bayesian basic skeleton of the isosteviol is utilized for structural modification and reconstruction, and through continuous structural optimization and improvement, the biological activity of the isosteviol is improved, the toxic and side effects are reduced, the pharmaceutical property of the isosteviol is enhanced, and the method has great significance for finding novel micromolecule drugs. Meanwhile, the waste is turned into wealth, the utilization value and the production added value of a large number of natural products are improved, the production cost is reduced, and the effective utilization of natural resources is enhanced.
In order to achieve the purpose, the technical scheme of the invention is as follows:
in a first aspect of the invention, there is provided a compound of formula I or a pharmaceutically acceptable salt thereof;
wherein the content of the first and second substances,
represents a single bond or a double bond; r1And R2Each independently selected from: hydrogen atom, methylene group and substituent being C1-C10Amine alkyl, precursor structures capable of replacing a carbonyl or methylene group, such as Mannich bases, imine salts, and the like.
Preferably, said R is1And R2Each independently selected from: hydrogen atom, methylene, dimethylamino-ethyl, tetrahydropyrrolyl-1-ethyl, piperidyl-1-ethyl.
Preferably, the pharmaceutically acceptable salt of the compound of formula I is: a salt of a compound of formula I with an inorganic or organic acid.
The inorganic acid is preferably: hydrochloric, sulfuric, or hydrobromic acid;
the organic acid is preferably: methanesulfonic acid, toluenesulfonic acid or trifluoroacetic acid.
Preferably, the compound represented by the formula I or a pharmaceutically acceptable salt thereof is selected from the following compounds:
in a second aspect of the present invention, there is provided a process for the preparation of a compound of formula I as described above, or a pharmaceutically acceptable salt thereof, comprising the steps of:
the method comprises the steps of sequentially carrying out acyl halogenation on isosteviol, reacting with sodium pyrithione to obtain pyridine sulfide, oxidizing into sulfoxide, carrying out heat elimination to modify methyl and carboxyl on an A ring in the isosteviol into a double-bond methylene, protecting a carbonyl on a D ring, oxidizing the double-bond methylene on the A ring into the carbonyl, and sequentially introducing CS at the α th site of the A ring carbonyl2Methyl etherification, sulfur ylide reaction to introduce unsaturated lactone into A ring, thereby obtaining the compound shown as I-1.
Preferably, the compound shown as I-1 introduces a N-containing group on unsaturated lactone of an A ring through a Mannich reaction so as to obtain the compound shown as I-2.
Further preferably, the compound represented by I-2 eliminates an N-containing group introduced on the unsaturated lactone of the A ring and then introduces a double-bond methylene group, thereby obtaining the compound represented by I-3.
Still more preferably, the compound represented by I-3 is obtained by introducing an N-containing group to the D ring through a Mannich reaction to obtain the compound represented by I-4.
More preferably, the compound shown as I-4 introduces a double-bond methylene group after introducing an N-containing group to a D ring and eliminating the N-containing group, thereby obtaining the compound shown as I-5.
In a third aspect of the invention, there is provided a compound of formula II or a pharmaceutically acceptable salt thereof;
wherein the content of the first and second substances,
a.R3selected from OR4OCOCHCHR5、OR4R6、NR4、
(Y)3Z⊙；
b.R4Is selected from C1-C10The hydrocarbon group, an ether chain containing 1 to 5 oxygen atoms in the middle, an amine chain containing 1 to 5 nitrogen atoms or alkyl substituents in the middle, and an amine chain containing a nitrogen atom ring such as piperazine, imidazole, triazole and the like; r5Selected from trifluoromethyl, phenyl, benzyl, substituted phenyl, substituted benzyl (different atoms (e.g. F, Cl, Br, I, NO)2、CF3Etc.), a substituted pyridyl group, a substituted furyl group, a substituted pyrrolyl group, a substituted indolyl group, a substituted aminoethyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, phenyl, etc.); r6Selected from H atom, artesunate group, benzyl;
c.X is selected from P atom or N atom; y is selected from methyl, ethyl, isopropyl, butyl, phenyl or phenyl containing heteroatom substitution;
d.Z is selected from F, Cl, Br, I.
The following compounds of formula II:
wherein R in II-17Is trifluoromethyl, R in II-27Is composed of
R in II-37Is composed of
R in II-47Is composed of
R in II-57Is composed of
R in II-67Is composed of
R in II-77Is composed of
R in II-87Is composed of
R in II-97Is composed of
R in II-107Is composed of
R in II-117Is composed of
N in II-15 is 2, n in II-16 is 3, n in II-17 is 4, n in II-18 is 5, n in II-19 is 6, n in II-20 is 8, n in II-21 is 9, n in II-24 is 1, n in II-25 is 2, n in II-26 is 6, n in II-27 is 8, n in II-29 is 1, n in II-30 is 3, n in II-31 is 9, m in II-32 is 1, n is 1, m in II-33 is 1, n is 2, m in II-34 is 1, n is 8, m in II-35 is 3, n is 8, m in II-36 is 9, n is 2, m in II-37 is 9, n is 8, n in II-38 is 1, and n in II-39 is 2.
Wherein the content of the first and second substances,
represents the position of substitution of the group.
In a fourth aspect of the present invention, there is provided a process for preparing a compound represented by the above formula II or a pharmaceutically acceptable salt thereof, comprising the steps of:
the isosteviol is subjected to Aldol-Cannizzaro reaction, carboxyl benzyl protection, primary hydroxyl sulfonylation, secondary hydroxyl PCC oxidation, debenzylation and sulfonyl elimination sequentially to obtain an intermediate 15;
the intermediate 15 uses the A-ring carboxyl and 1, 4-dibromobutane as a connecting chain, and introduces different unsaturated ester groups through substitution reaction to obtain the compounds of the formulas II-1 to II-12. R7Are respectively trifluoromethyl,
The intermediate 15 utilizes the ring carboxyl of A, introduces alkynyl through substitution reaction, and then obtains the compound of formula II-13 through Click reaction.
The intermediate 15 is esterified and coupled by saturated carbon chains with different lengths to obtain the dimer compound shown in the formula II-14-II-21. n is 2-6, 8,9.
And carrying out amidation coupling on the intermediate 15 through ethylenediamine to obtain the compound shown in the formula II-22.
And amidating the intermediate 15, inoculating an amine chain protected by Boc, and removing Boc protection to obtain the compound shown in the formula II-23.
The intermediate 15 is introduced with triphenylphosphine salts with different saturated carbon chain lengths through esterification reaction to obtain compounds of formulas II-24-II-27, wherein n is 1,2,6 and 8.
The intermediate 15 is introduced into a methylpiperazine ring by taking 1, 2-dibromoethane as a connecting chain to obtain the compound shown in the formula II-28.
The intermediate 15 is connected to piperazine ring through different carbon chain length to obtain compounds of formula II-29-II-31. Preferably, the compounds of the formulas II-29 to II-31 are subjected to substitution reaction to introduce triphenylphosphine salts with different carbon chain lengths on the basis of piperazine to obtain the compounds of the formulas II-32 to II-37.
The intermediate 15 is introduced into bromo-PEG chain through esterification reaction, and further introduced into triphenylphosphine salt through substitution reaction, thus obtaining compounds of formulas II-38-II-39.
In a fifth aspect of the present invention, there is provided an application of the above compound or a pharmaceutically acceptable salt thereof in preparing an anti-tumor and/or antifungal medicament.
The invention has the beneficial effects that:
(1) the stevioside is a bulk natural product which is cheap and easy to obtain, the isosteviol which is a hydrolysate of the stevioside is used as a basic mother nucleus, and modification and reconstruction are carried out by virtue of a Bayesian diterpene basic skeleton, so that various compounds with brand new structures can be rapidly prepared on a large scale, the preparation cost is low, and the method is an important way for discovering and innovating small-molecule medicaments.
(2) The invention also firstly reforms the A ring of isosteviol to synthesize a series of compound entities with extremely novel structures.
(3) According to the invention, various structural units with high biological activity are introduced into an isosteviol mother nucleus, including α -methylene cyclopentanone, α -unsaturated ketone, unsaturated ester and the like, and targeted groups are introduced, including basic groups containing nitrogen and the like are introduced to target lysosomes, triphenylphosphine salt, ammonium salt to target mitochondria and the like, so that the activity of the isosteviol mother nucleus is greatly improved, the toxic and side effects are reduced, and a plurality of potential small-molecule drugs with good antitumor and/or antifungal activity are obtained.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments according to the present application. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
In order to make the technical solutions of the present application more clearly understood by those skilled in the art, the technical solutions of the present application will be described below in conjunction with specific embodiments and details.
Example 1: preparation of Compound 5
(1) Step 1: preparation of Compound 2
Stevia sugar (4.0g) was weighed into a round bottom flask and 10% H was added2SO4Dissolving, heating and stirring for reaction. After the reaction is finished, the system is cooled to room temperature, filtered and washed by water to obtain a white solid compound 2.1H NMR(400MHz,CDCl3)δ2.63(dd,J＝18.6,2.4Hz,1H),2.15(d,J＝13.3Hz,1H),1.90–1.53(m,9H),1.49(dd,J＝13.6,2.9Hz,1H),1.45–1.32(m,3H),1.24(s,3H),1.22–1.11(m,3H),1.07–1.00(m,1H),0.97(s,3H),0.95–0.85(m,1H),0.77(s,3H).
(2) Step 2: preparation of Compound 5
Weighing Compound 2(200mg) in a round bottom flask, adding anhydrous dichloromethane (5mL) to dissolve, N2Oxalyl chloride (60. mu.L) and anhydrous DMF (1. mu.L) were added under ice-bath protection, followed by reaction at room temperature. After the reaction was completed, the reaction mixture was evaporated to dryness under reduced pressure to obtain yellow solid 3. And adding 3mL of anhydrous toluene for dissolving, adding sodium pyrithione (110mg) and DMAP (7.6mg) at room temperature, cooling to room temperature after the reaction is finished, carrying out suction filtration, and evaporating the filtrate under reduced pressure to dryness to obtain a brown yellow oily liquid 4. Adding 1.5mL of anhydrous dichloromethane, N2Under protection, m-CPBA (108mg) was added, and after 1 hour of reaction, the mixture was allowed to stand at room temperature, and toluene (4mL) was added to the mixture to conduct the reaction overnight. After the reaction is finished, water is added, a water layer is extracted by dichloromethane, organic layers are combined, dried by magnesium sulfate, filtered, decompressed and evaporated to remove the solvent, and the white solid 5 is obtained after column chromatography purification.1HNMR(400MHz,CDCl3)δ4.72(s,1H),4.45(s,1H),2.70(dd,J＝18.6,3.8Hz,1H),2.32–2.23(m,1H),1.98(td,J＝13.0,5.9Hz,1H),1.83(d,J＝18.7Hz,1H),1.79–1.71(m,3H),1.62–1.54(m,5H),1.50–1.31(m,5H),1.29–1.17(m,2H),1.06(td,J＝12.9,4.9Hz,1H),0.99(s,3H),0.69(s,3H).
Example 2: preparation of Compound I-1
(1) Step 1: preparation of Compound 6
Weighing a compound 5(136mg) in a round-bottom flask, adding cyclohexane (5mL) for dissolving, adding ethylene glycol (0.5mL) and camphorsulfonic acid (2mg), carrying out water diversion and reflux in a water separator, adding ethyl acetate after complete reaction, sequentially washing with water, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, filtering, carrying out reduced pressure rotary evaporation, and carrying out column chromatography purification to obtain a compound 6.1H NMR(400MHz,CDCl3)δ4.69(s,1H),4.42(s,1H),3.92–3.79(m,4H),2.33–2.21(m,2H),2.02–1.91(m,1H),1.78–1.71(m,2H),1.62–1.53(m,7H),1.48–1.19(m,5H),1.13(dd,J＝12.5,4.5Hz,1H),1.07–1.01(m,2H),0.85(s,3H),0.71(s,3H).
(2) Step 2: preparation of Compound 7
Weighing the compound 6(550mg) in a three-neck flask, adding anhydrous dichloromethane (30mL) and anhydrous methanol (30mL) to dissolve the compound, introducing ozone at-78 ℃, stopping ozone when the solution turns blue, introducing nitrogen to empty the ozone, slowly adding dimethyl sulfide (2.5mL), and slowly raising the temperature to room temperature for reaction overnight. And (3) monitoring the reaction progress by using a point plate, after the reaction is finished, evaporating to dryness under reduced pressure, and purifying by using column chromatography to obtain a compound 7.1H NMR(400MHz,CDCl3)δ3.97–3.72(m,4H),2.33–2.25(m,2H),2.22(dd,J＝14.4,2.8Hz,1H),2.10(d,J＝8.7Hz,1H),1.98–1.80(m,3H),1.78–1.71(m,1H),1.70–1.45(m,6H),1.41–1.15(m,5H),1.03(dd,J＝11.4,2.7Hz,1H),0.84(s,3H),0.75(s,3H).
(3) And step 3: preparation of Compound 8
Weighing compound 7(653mg) in a double-neck flask, adding anhydrous THF (15mL) for dissolution, dropwise adding LiHMDS (3.2mL) under nitrogen protection, reacting for 1h, and adding CS2(630. mu.L) was allowed to cool to room temperature, and methyl iodide was added to the reaction solution to react overnight. And (3) after the reaction is completely monitored by a point plate, adding water for quenching, extracting by ethyl acetate, washing by saturated sodium chloride, drying by anhydrous sodium sulfate, filtering, carrying out reduced pressure rotary evaporation, and carrying out column chromatography purification to obtain the compound 8.1H NMR(400MHz,CDCl3)δ3.99–3.78(m,4H),3.24(ddd,J＝16.4,5.8,2.3Hz,1H),2.53(ddd,J＝16.6,12.6,6.2Hz,1H),2.33(s,6H),2.22(dd,J＝14.4,2.6Hz,1H),2.17–2.10(m,1H),1.97(ddd,J＝13.1,6.1,2.1Hz,1H),1.85–1.72(m,2H),1.67–1.52(m,6H),1.48–1.39(m,1H),1.34(d,J＝10.4Hz,1H),1.27–1.19(m,2H),1.03(dd,J＝11.4,2.5Hz,1H),0.86(s,3H),0.82(s,3H).
(4) And 4, step 4: preparation of Compound 9
Weighing trimethyl sulfur iodide (46.5mg) in a double-mouth bottle, adding anhydrous THF (1mL) -dropwise adding n-butyl lithium (96 mu L) at 20 ℃, continuing to react for 2h, then dropwise adding an anhydrous THF solution of a compound 8(20mg), continuing to react for 1h, and monitoring the completion of the reaction by a dot-and-plate methodAdding water, extracting with ethyl acetate, washing with water, drying with anhydrous sodium sulfate, and evaporating to dryness under reduced pressure to obtain compound 9.1H NMR(600MHz,CDCl3)δ7.13(d,J＝1.8Hz,1H),3.92–3.80(m,4H),2.58(dd,J＝17.5,6.6Hz,1H),2.45(ddd,J＝17.5,12.3,6.2Hz,1H),2.35(dd,J＝14.4,2.8Hz,1H),2.30(s,3H),2.20–2.14(m,1H),1.94(dd,J＝13.1,6.8Hz,1H),1.80–1.75(m,1H),1.74–1.69(m,2H),1.64–1.60(m,3H),1.56–1.51(m,2H),1.39–1.33(m,1H),1.24–1.13(m,3H),1.09(dd,J＝11.4,2.7Hz,1H),0.86(s,3H),0.70(s,3H).
(5) And 5: preparation of Compound I-1
Compound 9 with 0.5M addition of H2SO4/CH3And (3) reacting the obtained product with an OH solution (3mL) for 4 hours, adding water and ethyl acetate for extraction after the reaction is completed, washing the obtained product with water, washing the obtained product with saturated saline solution, filtering the obtained product, carrying out reduced pressure rotary evaporation, and carrying out column chromatography purification to obtain the compound I-1.1H NMR(400MHz,CDCl3)δ4.82–4.56(m,2H),2.77(dd,J＝18.6,3.8Hz,1H),2.40–2.29(m,2H),2.26–2.13(m,1H),1.96(dd,J＝13.3,6.5Hz,1H),1.89(d,J＝18.7Hz,1H),1.82(ddd,J＝13.3,6.8,2.7Hz,1H),1.73–1.58(m,6H),1.56–1.20(m,6H),1.01(s,3H),0.76(s,3H).
Example 3: preparation of Compound I-2
Weighing the compound I-1(68mg) into a double-mouth bottle, adding anhydrous THF (2mL) for dissolving, dropwise adding bis (trimethylsilyl) aminolithium under the protection of nitrogen, adding (N, N-dimethylmethylene) ammonium iodide (123mg), and continuing to react for 1 h. And (3) monitoring the reaction completion by a dot plate, adding water for quenching, adding dichloromethane for extraction, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, decompressing and evaporating to dryness, and purifying by column chromatography to obtain the compound I-2.1H NMR(400MHz,CDCl3)δ4.95(d,J＝7.1Hz,1H),2.84(dd,J＝13.9,1.1Hz,1H),2.78(dd,J＝18.7,3.6Hz,1H),2.37(s,6H),2.34–2.26(m,2H),2.24–2.17(m,2H),1.97–1.79(m,3H),1.78–1.61(m,5H),1.56–1.47(m,2H),1.45–1.36(m,2H),1.36–1.28(m,2H),1.01(s,3H),0.75(s,3H).
Example 4: preparation of Compound I-3
Compound I-2(23mg) was weighed into a round-bottomed flask, and dissolved in anhydrous dichloromethane (0.5mL) and anhydrous ether (1.5mL),dropwise adding methyl iodide (100 mu L), stirring at room temperature, after the reaction is finished, evaporating the solvent, adding anhydrous dichloromethane (2mL) and alumina (100mg), reacting at room temperature, monitoring the reaction by a dot plate, evaporating the solvent, and performing neutral alumina column chromatography to obtain a compound I-3.1H NMR(400MHz,CDCl3)δ5.15(d,J＝2.5Hz,1H),5.03(d,J＝2.6Hz,1H),2.77(dd,J＝18.6,3.8Hz,1H),2.51–2.37(m,2H),2.35–2.23(m,1H),2.18(dd,J＝12.2,2.9Hz,1H),1.99(dd,J＝13.4,6.6Hz,1H),1.90(d,J＝18.7Hz,1H),1.87–1.81(m,1H),1.78–1.61(m,5H),1.51(dd,J＝11.7,3.8Hz,1H),1.47–1.38(m,2H),1.34(dd,J＝12.7,4.6Hz,1H),1.30–1.26(m,1H),1.01(s,3H),0.78(s,3H).
Example 5: preparation of Compound I-4
Weighing a compound I-3(40mg) into a round-bottom flask, adding anhydrous THF (2mL) for dissolving, dropwise adding LiHMDS (200 mu L) under the protection of nitrogen, continuing to react for 1h, adding (N, N-dimethyl) methylene ammonium iodide (74mg), reacting at room temperature for 2h, adding water for quenching after the reaction is finished, extracting by dichloromethane, washing by saturated saline, drying by anhydrous sodium sulfate, filtering, decompressing, evaporating to dryness, and purifying by column chromatography to obtain a compound I-4.1H NMR(400MHz,CDCl3)δ5.15(s,1H),5.05(s,1H),2.64–2.46(m,3H),2.40(dd,J＝19.4,6.8Hz,1H),2.23(s,6H),2.08(d,J＝11.7Hz,2H),2.00–1.90(m,2H),1.86–1.72(m,2H),1.62(d,J＝9.6Hz,1H),1.45–1.32(m,5H),1.28–1.18(m,3H),0.96(s,3H),0.79(s,3H).
Example 6: preparation of Compound I-5
Weighing a compound I-4(20mg) into a round-bottom flask, adding anhydrous dichloromethane (0.5mL) and anhydrous ether (1.5mL) to dissolve the compound I-4, dropwise adding methyl iodide (82 mu L), stirring at room temperature to complete the reaction, evaporating the solvent, adding anhydrous dichloromethane (2mL) and alumina (100mg), reacting at room temperature, monitoring the reaction by a dot-plate, evaporating the solvent, and performing neutral alumina column chromatography to obtain a compound I-5.1H NMR(400MHz,CDCl3)δ6.15(s,1H),5.43(s,1H),5.18(d,J＝2.7Hz,1H),5.05(d,J＝2.7Hz,1H),2.54(dd,J＝12.6,3.5Hz,1H),2.41(dd,J＝19.5,6.5Hz,1H),2.33–2.19(M,2H),2.10–2.03(m,1H),2.02–1.91(m,2H),1.89–1.78(m,2H),1.74(dd,J＝13.8,4.6Hz,1H),1.59–1.56(m,1H),1.52–1.47(m,2H),1.34–1.29(m,3H),1.06(s,3H),0.75(s,3H).
Example 7: preparation of Compound II-1
(1) Step 1: preparation of Compound 10
Compound 2(10g) was weighed, dissolved in ethanol (50mL), and added dropwise with NaOH solution (2g) and HCHO solution (6.6mL) at room temperature, followed by reaction for 5 hours. And (3) monitoring the reaction progress by a point plate, adding water after the reaction is finished, extracting with ethyl acetate, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, filtering, evaporating to dryness, and purifying by column chromatography to obtain the compound 10.1H NMR(400MHz,MeOD)δ3.81(dd,J＝10.6,5.2Hz,1H),3.54(d,J＝4.7Hz,1H),3.46(dd,J＝10.5,8.7Hz,1H),3.32(s,2H),2.09(d,J＝13.2Hz,1H),2.00(ddd,J＝8.3,5.2,3.3Hz,1H),1.94–1.80(m,2H),1.80–1.61(m,5H),1.59–1.51(m,1H),1.42–1.32(m,2H),1.15(s,3H),1.14–1.06(m,2H),1.05–0.92(m,3H),0.88(s,3H),0.86(s,3H).
(2) Step 2: preparation of Compound 11
Weighing compound 10(4.7g), placing in a 100mL round-bottom flask, adding anhydrous DMF (40mL) for dissolving, sequentially adding potassium carbonate (5.6g), benzyl bromide (3.2mL) and potassium iodide (0.45g), reacting at room temperature, monitoring the reaction progress by using a dot plate, adding water after the reaction is finished, extracting with ethyl acetate, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, filtering, evaporating to dryness, and purifying by using column chromatography to obtain compound 11.1H NMR(400MHz,CDCl3)δ7.42–7.29(m,5H),5.12(d,J＝12.3Hz,1H),5.01(d,J＝12.3Hz,1H),3.83(dd,J＝9.8,4.9Hz,1H),3.61(d,J＝4.7Hz,1H),3.40(t,J＝10.4Hz,1H),2.19(d,J＝13.4Hz,1H),1.96–1.89(m,1H),1.84–1.48(m,10H),1.45–1.38(m,1H),1.35(dd,J＝11.8,2.7Hz,1H),1.18(s,3H),1.09–0.93(m,4H),0.92(s,3H),0.85(td,J＝13.5,4.6Hz,1H),0.68(s,3H).
(3) And step 3: preparation of Compound 12
Weighing compound 11(4.1g), placing in a 100mL round-bottom flask, adding anhydrous pyridine (40mL) for dissolution, under the protection of nitrogen, sequentially adding TsCl (2.1g) and DMAP (1.1g) under ice bath, stirring at room temperature for reaction, monitoring the reaction progress by a point plate, adding ethyl acetate after the reaction is finished, washing with dilute hydrochloric acid, washing with water, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, evaporating to dryness,purifying by column chromatography to obtain compound 12.1H NMR(400MHz,CDCl3)δ7.80(d,J＝8.3Hz,2H),7.39–7.29(m,7H),5.07(s,2H),4.26(dd,J＝9.5,4.9Hz,1H),3.94(t,J＝9.6Hz,1H),3.41(t,J＝4.2Hz,1H),2.44(s,3H),2.22–2.14(m,1H),2.13–2.06(m,1H),1.78–1.64(m,5H),1.59–1.43(m,4H),1.42–1.35(m,1H),1.29(dd,J＝11.9,2.5Hz,1H),1.15(s,3H),1.05–0.99(m,2H),0.98–0.89(m,3H),0.85(s,3H),0.80(dd,J＝13.6,4.5Hz,1H),0.57(s,3H).
(4) And 4, step 4: preparation of Compound 13
Weighing compound 12(0.9g) and placing the compound in a 50mL round-bottom flask, adding anhydrous dichloromethane (20mL) to dissolve the compound, sequentially adding a proper amount of diatomite and PCC (0.5g), reacting at room temperature, monitoring the reaction completion by using a spot plate, filtering out the diatomite, adding water to filtrate for washing, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, evaporating to dryness, and purifying by using column chromatography to obtain compound 13.1H NMR(400MHz,CDCl3)δ7.72(d,J＝8.2Hz,2H),7.40–7.31(m,7H),5.13(d,J＝12.1Hz,1H),5.03(d,J＝12.0Hz,1H),4.15(dd,J＝9.7,4.7Hz,1H),4.07(dd,J＝9.7,2.2Hz,1H),2.45(s,3H),2.38–2.33(m,1H),2.19(d,J＝13.3Hz,1H),1.98–1.90(m,1H),1.88–1.81(m,1H),1.77(dd,J＝11.7,2.5Hz,1H),1.66–1.52(m,5H),1.42–1.32(m,2H),1.24(dd,J＝12.0,2.0Hz,2H),1.20(s,3H),1.16–1.12(m,2H),1.10–1.02(m,1H),0.99(dd,J＝13.5,4.1Hz,1H),0.88(s,3H),0.87–0.81(m,1H),0.47(s,3H).
(5) And 5: preparation of Compound 14
Weighing compound 13(66mg) in a round bottom flask, adding absolute ethyl alcohol (3mL) to dissolve, adding 10% Pd/C, H2And then, reacting at room temperature, performing spot plate monitoring on the reaction, filtering out a solid, evaporating to dryness, and performing column chromatography purification to obtain the compound 14.1H NMR(400MHz,CDCl3)δ7.73(d,J＝8.2Hz,2H),7.35(d,J＝8.2Hz,2H),4.29(dd,J＝9.7,2.4Hz,1H),4.24(dd,J＝9.7,4.7Hz,1H),2.52–2.45(m,1H),2.44(s,3H),2.16(d,J＝13.3Hz,1H),2.03(d,J＝14.2Hz,1H),1.91–1.55(m,7H),1.47–1.36(m,2H),1.33–1.25(m,3H),1.25(s,3H),1.21–1.11(m,3H),1.02(td,J＝13.4,3.8Hz,1H),0.91(s,3H),0.68(s,3H).
(6) Step 6: preparation of Compound 15
Weighing compound 14(50mg), adding anhydrous pyridine (3mL) for dissolving, adding DMAP (15mg) at room temperature, moving to 120 ℃ for reflux reaction, counting a spot plate to monitor the reaction is complete, adding ethyl acetate, adding water for washing, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, evaporating to dryness under reduced pressure, and purifying by column chromatography to obtain compound 15.1H NMR(400MHz,CDCl3)δ6.06(s,1H),5.49(s,1H),2.23–2.05(m,2H),2.03–1.93(m,2H),1.85–1.66(m,4H),1.56–1.38(m,5H),1.27(s,3H),1.26–1.19(m,3H),1.05(dd,J＝13.5,4.0Hz,1H),1.01(s,3H),0.86(td,J＝12.9,4.1Hz,1H),0.68(s,3H).
(7) And 7: preparation of Compound 16
Weighing compound 15(50mg) into a 10mL round-bottom flask, adding anhydrous DMF (3mL) to dissolve, sequentially adding potassium carbonate (40mg) and 1, 4-dibromobutane (180 mu L), reacting at room temperature for 4h, adding water, extracting with ethyl acetate, and washing with saturated brine after the reaction is monitored by a dot plate. Drying with anhydrous sodium sulfate, filtering, evaporating to dryness under reduced pressure, and purifying by column chromatography to obtain compound 16.1H NMR(400MHz,CDCl3)δ6.05(s,1H),5.45(s,1H),4.06(t,J＝6.4Hz,2H),3.44(t,J＝6.6Hz,2H),2.18(d,J＝12.4Hz,1H),2.10–1.92(m,5H),1.86–1.65(m,6H),1.60(d,J＝3.0Hz,1H),1.55–1.38(m,5H),1.30(dd,J＝12.9,3.6Hz,1H),1.22(s,3H),1.18(dd,J＝7.7,5.3Hz,1H),1.05(dd,J＝13.5,3.9Hz,1H),1.01(s,3H),0.86(td,J＝12.8,3.6Hz,1H),0.61(s,3H).
(8) And 8: preparation of Compound II-1
Weighing compound 16(30mg) and placing the compound in a 10mL round-bottom flask, adding DMF (2mL) for dissolving, adding potassium carbonate (18mg) and 4,4, 4-trifluoro butenoic acid, stirring at room temperature overnight, monitoring the reaction by a dot plate, adding water, adding ethyl acetate for extraction, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, decompressing and evaporating to dryness, and purifying by column chromatography to obtain compound II-1.1H NMR(400MHz,CDCl3)δ6.78(dq,J＝15.8,6.5Hz,1H),6.49(ddd,J＝15.7,3.7,1.8Hz,1H),6.04(s,1H),5.42(s,1H),4.25(t,J＝6.2Hz,2H),4.07(t,J＝5.8Hz,2H),2.18(d,J＝13.0Hz,1H),2.12–1.92(m,3H),1.84–1.64(m,8H),1.56–1.38(m,5H),1.30(dd,J＝12.8,3.6Hz,1H),1.22(s,3H),1.20–1.16(m,1H),1.05(dd,J＝13.5,3.9Hz,1H),1.01(s,3H),0.92–0.81(m,1H),0.61(s,3H).
Example 8: preparation of Compound II-2
Weighing compound 16(20mg) and placing the compound in a 10mL round-bottom flask, adding 1.5mL anhydrous DMF to dissolve the compound, adding potassium carbonate (12mg) and trans-cinnamic acid (7mg), stirring the mixture at room temperature for 48 hours, adding water and ethyl acetate to extract the mixture after the reaction is monitored by a dot plate, washing the mixture with saturated saline, drying the mixture with anhydrous sodium sulfate, filtering the mixture, evaporating the mixture to dryness under reduced pressure, and purifying the mixture by column chromatography to obtain compound II-2.1H NMR(400MHz,CDCl3)δ7.69(d,J＝16.0Hz,1H),7.59–7.48(m,2H),7.45–7.34(m,3H),6.43(d,J＝16.0Hz,1H),6.05(s,1H),5.44(s,1H),4.25(t,J＝6.0Hz,2H),4.10(t,J＝5.7Hz,2H),2.24–2.16(m,1H),2.16–2.03(m,1H),2.03–1.93(m,2H),1.83–1.64(m,8H),1.53–1.38(m,5H),1.30(dd,J＝12.9,3.7Hz,2H),1.23(s,3H),1.22–1.17(m,2H),1.05(dd,J＝13.5,4.0Hz,1H),1.01(s,3H),0.62(s,3H).
Example 9: preparation of Compound II-3
Weighing compound 16(30mg) and placing the compound in a 10mL round-bottom flask, adding anhydrous DMF (1.5mL) to dissolve the compound, adding potassium carbonate (18mg) and trans-4- (trifluoromethyl) cinnamic acid (17mg) at room temperature, stirring the mixture at room temperature overnight, monitoring the reaction by a dot plate, adding water, extracting the mixture by ethyl acetate, washing the mixture by saturated saline solution, drying the mixture by anhydrous sodium sulfate, filtering the mixture, evaporating the mixture under reduced pressure to dryness, and purifying the mixture by column chromatography to obtain compound II-3.1H NMR(400MHz,CDCl3)δ7.69(d,J＝16.0Hz,1H),7.66–7.57(m,4H),6.50(d,J＝16.0Hz,1H),6.05(s,1H),5.44(s,1H),4.26(t,J＝6.1Hz,2H),4.10(t,J＝6.1Hz,2H),2.19(d,J＝13.3Hz,1H),2.13–1.93(m,3H),1.83–1.65(m,7H),1.54–1.37(m,5H),1.30(dd,J＝12.9,3.7Hz,1H),1.23(s,3H),1.22–1.14(m,2H),1.05(dd,J＝13.4,4.0Hz,1H),1.01(s,3H),0.91–0.80(m,2H),0.62(s,3H).
Example 10: preparation of Compound II-4
Weighing compound 16(30mg) and placing in a 10mL round-bottom flask, dissolving with anhydrous DMF (1.5mL), adding potassium carbonate (18mg) and 4-Cl-cinnamic acid (15mg) at room temperature, stirring overnight at room temperature, monitoring reaction completion with a dot plate, adding water, extracting with ethyl acetate, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and subtractingEvaporating to dryness under pressure, and purifying by column chromatography to obtain compound II-4.1H NMR(400MHz,CDCl3)δ7.63(d,J＝16.0Hz,1H),7.49–7.42(m,2H),7.39–7.32(m,2H),6.40(d,J＝16.0Hz,1H),6.05(s,1H),5.43(s,1H),4.25(t,J＝6.0Hz,2H),4.09(t,J＝6.0Hz,2H),2.19(d,J＝13.2Hz,1H),2.13–1.93(m,3H),1.81–1.65(m,7H),1.64–1.39(m,5H),1.30(dd,J＝12.8,3.7Hz,1H),1.23(s,3H),1.21–1.14(m,2H),1.05(dd,J＝13.5,4.0Hz,1H),1.01(s,3H),0.91–0.82(m,2H),0.61(s,3H).
Example 11: preparation of Compound II-5
Weighing compound 16(30mg) and placing the compound in a 10mL round-bottom flask, adding anhydrous DMF (1.5mL) to dissolve the compound, adding potassium carbonate (18mg) and 2,4, 5-trifluorophenylacrylic acid (16mg) at room temperature, stirring the mixture at room temperature overnight, monitoring the reaction by a dot plate, adding water and ethyl acetate to extract the mixture, washing the mixture with saturated saline solution, drying the mixture with anhydrous sodium sulfate, filtering the mixture, evaporating the mixture under reduced pressure to dryness, and purifying the mixture by column chromatography to obtain compound II-5.1HNMR(400MHz,CDCl3)δ7.69(d,J＝16.2Hz,1H),7.35(ddd,J＝10.4,8.6,6.8Hz,1H),6.98(td,J＝9.8,6.5Hz,1H),6.44(d,J＝16.2Hz,1H),6.04(s,1H),5.43(s,1H),4.25(t,J＝6.1Hz,2H),4.09(t,J＝6.0Hz,2H),2.19(d,J＝13.2Hz,1H),2.13–1.93(m,3H),1.85–1.65(m,8H),1.56–1.39(m,5H),1.30(dd,J＝12.9,3.6Hz,1H),1.23(s,3H),1.21–1.14(m,2H),1.05(dd,J＝13.4,4.0Hz,1H),1.01(s,3H),0.87(td,J＝12.8,4.2Hz,1H),0.62(s,3H).
Example 12: preparation of Compound II-6
Weighing compound 16(30mg) and placing the compound in a 10mL round-bottom flask, adding anhydrous DMF (1.5mL) for dissolving, adding potassium carbonate (18mg) and 4-nitrocinnamic acid (15mg) at room temperature, stirring overnight at room temperature, monitoring the reaction by a dot plate, adding water, extracting by ethyl acetate, washing by saturated saline, drying by anhydrous sodium sulfate, filtering, evaporating to dryness under reduced pressure, and purifying by column chromatography to obtain compound II-6.1H NMR(400MHz,CDCl3)δ8.25(d,J＝8.7Hz,2H),7.82–7.62(m,3H),6.55(d,J＝16.0Hz,1H),6.04(s,1H),5.43(s,1H),4.27(t,J＝6.1Hz,2H),4.10(t,J＝6.1Hz,2H),2.19(d,J＝13.2Hz,1H),2.12–1.92(m,3H),1.87–1.64(m,8H),1.55–1.37(m,5H),1.30(dd,J＝12.8,3.7Hz,1H),1.23(s,3H),1.21–1.11(m,2H),1.06(dd,J＝13.4,4.0Hz,1H),1.01(s,3H),0.87(td,J＝13.1,4.2Hz,1H),0.62(s,3H).
Example 13: preparation of Compound II-7
Weighing compound 16(30mg) and placing the compound in a 10mL round-bottom flask, adding anhydrous DMF (1.5mL) to dissolve the compound, adding potassium carbonate (27mg) and trans-indole-3-acrylic acid (19mg) at room temperature, stirring the mixture at room temperature overnight, monitoring the reaction by a dot plate, adding water, extracting by ethyl acetate, washing the mixture by saturated saline, drying the mixture by anhydrous sodium sulfate, filtering the dried mixture, evaporating the dried mixture under reduced pressure, and purifying the dried mixture by column chromatography to obtain compound II-7.1HNMR(400MHz,CDCl3)δ8.79(s,1H),7.99–7.82(m,2H),7.48(d,J＝2.7Hz,1H),7.43(dd,J＝6.8,1.6Hz,1H),7.30–7.21(m,2H),6.43(d,J＝16.0Hz,1H),6.06(s,1H),5.48(s,1H),4.27–4.04(m,4H),2.21(d,J＝13.2Hz,1H),2.15–2.06(m,1H),2.02–1.91(m,2H),1.83–1.63(m,8H),1.54–1.35(m,6H),1.30(dd,J＝12.7,3.7Hz,1H),1.24(s,3H),1.22–1.16(m,2H),1.05(dd,J＝13.5,4.0Hz,1H),1.01(s,3H),0.65(s,3H).
Example 14: preparation of Compound II-8
Weighing compound 16(17mg) and placing the compound in a 10mL round-bottom flask, adding anhydrous DMF (1.5mL) to dissolve the compound, adding potassium carbonate (12mg) and 3-pyridylacrylic acid (8mg) at room temperature, stirring the mixture at room temperature overnight, monitoring the reaction by a dot plate, adding water and ethyl acetate to extract the mixture, washing the mixture by saturated saline, drying the mixture by anhydrous sodium sulfate, filtering the dried mixture, evaporating the dried mixture under reduced pressure, and purifying the dried mixture by column chromatography to obtain compound II-8.1HNMR(400MHz,CDCl3)δ8.75(s,1H),8.61(d,J＝3.5Hz,1H),7.85(d,J＝8.0Hz,1H),7.67(d,J＝16.1Hz,1H),7.35(dd,J＝7.8,4.8Hz,1H),6.50(d,J＝16.1Hz,1H),6.04(s,1H),5.43(s,1H),4.26(t,J＝6.1Hz,2H),4.09(t,J＝6.0Hz,2H),2.19(d,J＝13.9Hz,1H),2.13–1.92(m,3H),1.85–1.64(m,8H),1.53–1.38(m,5H),1.30(dd,J＝12.8,3.6Hz,2H),1.23(s,3H),1.21–1.65(m,2H),1.09–1.02(m,1H),1.01(s,3H),0.61(s,3H).
Example 15: preparation of Compound II-9
Weighing compound 16(17mg) and placing in a 10mL round-bottom flask, dissolving with anhydrous DMF (1.5mL), adding potassium carbonate (12mg) and 2-furanacrylic acid (7mg) at room temperature, stirring at room temperature overnight, monitoring reaction completion by dot plate, adding water, and extracting with ethyl acetateWashing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, evaporating to dryness under reduced pressure, and purifying by column chromatography to obtain compound II-9.1H NMR(400MHz,CDCl3)δ7.48(s,1H),7.42(d,J＝15.7Hz,1H),6.61(d,J＝3.3Hz,1H),6.46(dd,J＝3.2,1.8Hz,1H),6.30(d,J＝15.7Hz,1H),6.05(s,1H),5.43(s,1H),4.22(t,J＝5.9Hz,2H),4.08(t,J＝5.5Hz,2H),2.19(d,J＝13.7Hz,1H),2.12–1.93(m,3H),1.80–1.65(m,8H),1.54–1.39(m,5H),1.29(dd,J＝12.9,3.5Hz,2H),1.22(s,3H),1.21–1.58(m,2H),1.05(dd,J＝13.5,3.9Hz,1H),1.01(s,3H),0.62(s,3H).
Example 16: preparation of Compound II-10
Weighing compound 16(30mg) and placing the compound in a 10mL round-bottom flask, adding anhydrous DMF (1.5mL) for dissolving, adding potassium carbonate (18mg) and 2-pyrrole acrylic acid (11mg) at room temperature, stirring overnight at room temperature, monitoring the reaction by a dot plate, adding water, extracting by ethyl acetate, washing by saturated saline, drying by anhydrous sodium sulfate, filtering, evaporating to dryness under reduced pressure, and purifying by column chromatography to obtain compound II-10.1HNMR(400MHz,CDCl3)δ8.97(s,1H),7.54(d,J＝15.9Hz,1H),6.98–6.89(m,1H),6.61–6.51(m,1H),6.27(dd,J＝6.0,2.5Hz,1H),6.06(s,1H),5.98(d,J＝15.9Hz,1H),5.45(s,1H),4.21(t,J＝5.6Hz,2H),4.12(q,J＝7.1Hz,2H),2.23–2.16(m,1H),2.09(dd,J＝12.1,3.3Hz,1H),2.02–1.92(m,3H),1.72–1.64(m,5H),1.55–1.38(m,8H),1.32–1.23(m,4H),1.08–1.02(m,1H),1.01(s,3H),0.90–0.81(m,2H),0.61(s,3H).
Example 17: preparation of Compound II-11
Weighing compound 16(30mg) and placing the compound in a 10mL round-bottom flask, adding anhydrous DMF (1.5mL) to dissolve the compound, adding potassium carbonate (27mg) and trans-4-dimethylaminocrotonate (16mg) at room temperature, stirring the mixture at room temperature overnight, monitoring the reaction by a dot plate, adding water and ethyl acetate to extract the mixture, washing the mixture with saturated saline solution, drying the mixture with anhydrous sodium sulfate, filtering the mixture, evaporating the mixture under reduced pressure to dryness, and purifying the mixture by column chromatography to obtain compound II-11.1H NMR(400MHz,CDCl3)δ6.93(dt,J＝15.7,6.2Hz,1H),6.03(s,1H),5.96(dt,J＝15.7,1.6Hz,1H),5.42(s,1H),4.16(t,J＝6.1Hz,2H),4.05(t,J＝5.9Hz,2H),3.07(dd,J＝6.2,1.5Hz,2H),2.25(s,6H),2.17(d,J＝12.8Hz,1H),2.10–2.03(m,1H),2.02–1.91(m,2H),1.80–1.65(m,8H),1.56–1.38(m,5H),1.32–1.24(m,3H),1.21(s,3H),1.16(dd,J＝7.7,5.3Hz,1H),1.04(dd,J＝13.4,4.0Hz,1H),1.00(s,3H),0.60(s,3H).
Example 18: preparation of Compound II-12
Weighing compound 16(10mg), adding DMF (1mL) for dissolving, adding potassium carbonate (6.1mg) and artesunic acid (9.3mg), stirring at room temperature, reacting overnight, adding water and ethyl acetate for extraction after complete reaction, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, evaporating to dryness under reduced pressure, and purifying by column chromatography to obtain compound II-12.1H NMR(400MHz,CDCl3)δ6.05(s,1H),5.79(d,J＝9.9Hz,1H),5.43(s,2H),4.13–4.03(m,4H),2.76–2.69(m,2H),2.66(dd,J＝7.5,5.3Hz,1H),2.64–2.51(m,2H),2.37(td,J＝14.1,3.9Hz,1H),2.18(d,J＝13.0Hz,1H),2.03–1.93(m,3H),1.89(ddd,J＝13.5,6.2,3.3Hz,1H),1.80–1.57(m,12H),1.55–1.43(m,5H),1.42(s,3H),1.40–1.34(m,2H),1.33–1.23(m,7H),1.22(s,3H),1.19–1.15(m,1H),1.01(s,3H),0.96(d,J＝5.9Hz,3H),0.85(d,J＝7.1Hz,3H),0.61(s,3H).
Example 19: preparation of Compound II-13
(1) Step 1: preparation of Compound 17
Weighing compound 15(300mg) and placing the compound in a 10mL round-bottom flask, adding anhydrous DMF (5mL) to dissolve the compound, adding potassium carbonate (126mg) and propargyl bromide (197 mu L) at room temperature, stirring the mixture at room temperature for 2 hours, monitoring the reaction by a dot plate, adding water, extracting by ethyl acetate, washing the mixture by saturated saline, drying the mixture by anhydrous sodium sulfate, filtering the dried mixture, evaporating the dried mixture under reduced pressure, and purifying the dried mixture by column chromatography to obtain compound 17.1H NMR(400MHz,CDCl3)δ6.05(s,1H),5.48(s,1H),4.74(dd,J＝15.6,2.4Hz,1H),4.58(dd,J＝15.6,2.4Hz,1H),2.43(t,J＝2.4Hz,1H),2.25–2.07(m,2H),2.04–1.91(m,2H),1.86–1.64(m,4H),1.55–1.38(m,5H),1.30(dd,J＝12.8,3.6Hz,1H),1.24(s,3H),1.23–1.12(m,2H),1.06(dd,J＝13.5,4.1Hz,1H),1.01(s,3H),0.86(td,J＝13.2,4.1Hz,1H),0.63(s,3H).
(2) Step 1: preparation of Compound II-13
Compound 17(20mg) was weighed, dissolved in anhydrous dichloromethane (0.5mL), and benzyl azide (8mg), DIPEA (0.5. mu.L) and HOAc (0.1) were added in that order6 mu L), adding CuI (0.6mg) under the protection of nitrogen, stirring at room temperature for reaction for 2h, completely reacting, adding water, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, evaporating to dryness under reduced pressure, and purifying by column chromatography to obtain compound II-13.1H NMR(400MHz,CDCl3)δ7.47(s,1H),7.39–7.30(m,3H),7.26–7.19(m,2H),6.00(s,1H),5.51(d,J＝14.8Hz,1H),5.46(d,J＝14.8Hz,1H),5.30(d,J＝9.2Hz,1H),5.26(d,J＝12.5Hz,1H),5.09(d,J＝12.5Hz,1H),2.14(d,J＝13.3Hz,1H),1.99–1.86(m,3H),1.76–1.52(m,4H),1.50–1.32(m,5H),1.26–1.19(m,1H),1.18(s,3H),1.15–1.01(m,2H),1.00(s,3H),0.99–0.94(m,1H),0.79(td,J＝13.2,4.0Hz,1H),0.19(s,3H).
Example 20: preparation of Compound II-14
Weighing compound 15(50mg), adding anhydrous THF (2mL) for dissolving, adding oxalyl chloride (20 mu L) dropwise under ice bath under nitrogen protection, adding one drop of anhydrous DMF dropwise, reacting at room temperature for 1h, adding water for quenching after complete reaction, extracting with ethyl acetate, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, evaporating to dryness under reduced pressure, and purifying by column chromatography to obtain compound II-14.1H NMR(400MHz,CDCl3)δ6.05(s,1H),5.39(s,1H),2.20(d,J＝13.3Hz,1H),2.15–2.05(m,1H),2.03–1.93(m,2H),1.81–1.66(m,4H),1.56–1.41(m,5H),1.32(s,3H),1.31–1.12(m,4H),1.01(s,3H),0.94–0.84(m,1H),0.75(s,3H).
Example 21: preparation of Compound II-15
Weighing compound 15(52mg), adding anhydrous DMF (2mL) for dissolving, adding potassium carbonate (42mg) and 1, 2-dibromoethane (6.8 mu L), stirring overnight at room temperature, adding water for quenching after complete reaction, extracting with ethyl acetate, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, decompressing and evaporating to dryness, and purifying by column chromatography to obtain compound II-15.1H NMR(400MHz,CDCl3)δ6.04(s,1H),5.43(s,1H),4.33–4.16(m,2H),2.18(d,J＝13.3Hz,1H),2.12–2.01(m,1H),2.01–1.89(m,2H),1.81–1.62(m,4H),1.58–1.37(m,6H),1.30(dd,J＝12.8,3.4Hz,2H),1.25–1.20(m,4H),1.06(dd,J＝13.5,3.9Hz,1H),1.01(s,3H),0.61(s,3H).
Example 22: preparation of Compound II-16
WeighingDissolving the compound 15(50mg) in anhydrous DMF (2mL), adding potassium carbonate (42mg) and 1, 3-dibromopropane (7.8 mu L), stirring at room temperature for 5h, adding water for quenching after complete reaction, extracting with ethyl acetate, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, evaporating to dryness under reduced pressure, and purifying by column chromatography to obtain the compound II-16.1H NMR(400MHz,CDCl3)δ6.04(s,1H),5.43(s,1H),4.22–4.02(m,2H),2.17(d,J＝13.2Hz,1H),2.10–1.92(m,4H),1.78–1.63(m,4H),1.55–1.38(m,6H),1.33–1.24(m,3H),1.21(s,3H),1.19–1.14(m,1H),1.05(dd,J＝13.6,4.0Hz,1H),1.01(s,3H),0.59(s,3H).
Example 23: preparation of Compound II-17
Weighing compound 15(50mg), adding anhydrous DMF (2mL) for dissolving, adding potassium carbonate (42mg) and 1, 4-dibromobutane (8.7 mu L), stirring at room temperature for 5h, adding water for quenching after complete reaction, extracting with ethyl acetate, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, evaporating to dryness under reduced pressure, and purifying by column chromatography to obtain compound II-17.1H NMR(400MHz,CDCl3)δ6.04(s,1H),5.42(s,1H),4.19–3.96(m,2H),2.17(d,J＝13.2Hz,1H),2.11–1.93(m,3H),1.82–1.64(m,6H),1.56–1.38(m,5H),1.28(td,J＝12.6,3.0Hz,2H),1.21(s,3H),1.20–1.16(m,1H),1.05(dd,J＝13.4,3.9Hz,1H),1.01(s,3H),0.84(dd,J＝12.9,4.2Hz,1H),0.60(s,3H).
Example 24: preparation of Compound II-18
Weighing compound 15(52mg), adding anhydrous DMF (2mL) for dissolving, adding potassium carbonate (45mg) and 1, 5-dibromo-n-pentane (10.7 mu L), stirring at room temperature for 5h, adding water for quenching after complete reaction, extracting with ethyl acetate, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, evaporating to dryness under reduced pressure, and purifying by column chromatography to obtain compound II-18.1H NMR(400MHz,CDCl3)δ6.04(s,1H),5.43(s,1H),4.03(t,J＝6.6Hz,2H),2.17(d,J＝13.2Hz,1H),2.12–1.91(m,3H),1.81–1.63(m,6H),1.56–1.37(m,6H),1.30(dd,J＝12.8,3.6Hz,1H),1.21(s,3H),1.20–1.14(m,2H),1.04(dd,J＝13.6,4.1Hz,1H),1.01(s,3H),0.91–0.81(m,1H),0.60(s,3H).
Example 25: preparation of Compound II-19
Weighing Compound 15(50mg) and adding to anhydrous DMDissolving F (2mL), adding potassium carbonate (42mg) and 1, 6-dibromohexane (11.6 mu L), stirring at room temperature for reacting overnight, after the reaction is completed, adding water for quenching, extracting by ethyl acetate, washing by saturated saline solution, drying by anhydrous sodium sulfate, filtering, evaporating to dryness under reduced pressure, and purifying by column chromatography to obtain a compound II-19.1H NMR(400MHz,CDCl3)δ6.03(s,1H),5.42(s,1H),4.02(t,J＝6.5Hz,2H),2.17(d,J＝13.3Hz,1H),2.11–2.02(m,1H),2.02–1.90(m,2H),1.79–1.58(m,6H),1.52–1.36(m,7H),1.33–1.23(m,2H),1.20(s,3H),1.18–1.15(m,1H),1.00(s,3H),0.90–0.79(m,2H),0.60(s,3H).
Example 26: preparation of Compound II-20
Weighing a compound 15(50mg), adding anhydrous DMF (2mL) for dissolving, adding potassium carbonate (42mg) and 1, 8-dibromooctane (14.3 mu L), stirring at room temperature for reacting overnight, adding water for quenching after complete reaction, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, decompressing and evaporating to dryness, and purifying by column chromatography to obtain a compound II-20.1H NMR(400MHz,CDCl3)δ6.04(s,1H),5.43(s,1H),4.01(t,J＝6.6Hz,2H),2.17(d,J＝13.3Hz,1H),2.11–1.90(m,3H),1.80–1.57(m,6H),1.56–1.26(m,11H),1.20(s,3H),1.19–1.14(m,2H),1.07–1.01(m,1H),1.00(s,3H),0.60(s,3H).
Example 27: preparation of Compound II-21
Weighing compound 15(47mg), adding anhydrous DMF (2mL) for dissolving, adding potassium carbonate (42mg) and 1, 9-dibromononane (15 mu L), stirring at room temperature for reaction overnight, adding water for quenching after complete reaction, extracting with ethyl acetate, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, decompressing and evaporating to dryness, and purifying by column chromatography to obtain compound II-21.1H NMR(400MHz,CDCl3)δ6.04(s,1H),5.43(s,1H),4.01(t,J＝6.6Hz,2H),2.17(d,J＝13.2Hz,1H),2.12–1.90(m,3H),1.80–1.56(m,6H),1.54–1.26(m,12H),1.21(s,3H),1.19–1.13(m,2H),1.07–1.01(m,1H),1.01(s,3H),0.89–0.83(m,1H),0.60(s,3H).
Example 28: preparation of Compound II-22
Weighing compound 15(56mg), adding anhydrous THF (2mL) for dissolving, adding oxalyl chloride (22 mu L) and one drop of DMF under nitrogen protection, and reacting at room temperature1h, after the reaction is completed, evaporating the solvent to dryness, adding anhydrous THF (tetrahydrofuran) for dissolution, dropwise adding a mixture of triethylamine (70 mu L) and ethylenediamine (5.7 mu L), reacting at room temperature for 6h, monitoring the reaction completion by a dot plate, adding water for quenching, extracting by ethyl acetate, washing by saturated saline solution, drying by anhydrous sodium sulfate, filtering, decompressing and evaporating to dryness, and purifying by column chromatography to obtain a compound II-22.1H NMR(600MHz,CDCl3)δ6.51(s,1H),6.03(s,1H),5.48(s,1H),3.40(d,J＝8.4Hz,1H),3.29(d,J＝8.2Hz,1H),2.25–2.14(m,1H),2.02–1.95(m,2H),1.71(dd,J＝29.1,14.6Hz,4H),1.51–1.35(m,6H),1.31–1.14(m,8H),1.00(s,3H),0.65(s,3H).
Example 29: preparation of Compound II-23
(1) Step 1: preparation of Compound 18
Weighing compound 15(50mg), dissolving in anhydrous THF (2mL), adding oxalyl chloride and one drop of DMF under nitrogen protection, reacting for 30 min, evaporating, dissolving in anhydrous dichloromethane, adding triethylamine (117 μ L), and N1,N5Reacting bis-Boc-spermidine (78mg) for 30 minutes, adding water for quenching, extracting with ethyl acetate, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, evaporating to dryness under reduced pressure, and purifying by column chromatography to obtain compound 18.1H NMR(400MHz,CDCl3)δ7.04(s,1H),6.03(s,1H),5.51(s,1H),4.55(s,1H),4.05(t,J＝6.7Hz,2H),3.38–3.19(m,2H),3.15–3.07(m,4H),2.23(d,J＝15.3Hz,1H),2.20–2.06(m,2H),2.01–1.94(m,1H),1.91–1.82(m,1H),1.76–1.66(m,3H),1.62–1.56(m,3H),1.53–1.47(m,3H),1.44(s,9H),1.43(s,9H),1.40–1.34(m,2H),1.33–1.24(m,3H),1.21(s,3H),1.19–1.12(m,2H),1.00(s,3H),0.92(t,J＝7.4Hz,2H),0.86(dd,J＝12.5,4.1Hz,1H),0.67(s,3H).
(2) Step 2: preparation of Compound II-23
Compound 18(73mg) was weighed out and dissolved in anhydrous dichloromethane (2mL), and trifluoroacetic acid (33. mu.L) was added dropwise to react at room temperature overnight. And (3) counting a plate to monitor the reaction is complete, evaporating to dryness, adding a small amount of methanol and sodium bicarbonate solution to adjust the mixture to be alkaline, adding dichloromethane for extraction, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, evaporating to dryness, and purifying by column chromatography to obtain a compound II-23.1H NMR(400MHz,MeOD)δ6.00(s,1H),5.53(s,1H),3.35(s,2H),3.28(d,J＝6.8Hz,1H),3.09–2.94(m,6H),2.31–2.04(m,3H),2.02–1.89(m,3H),1.87–1.63(m,8H),1.62–1.45(m,4H),1.43–1.37(m,2H),1.30–1.25(m,1H),1.23(s,3H),1.21–1.12(m,1H),1.04–0.99(m,1H),0.98(s,3H),0.69(s,3H).
Example 30: preparation of Compound II-24
Weighing compound 15(30mg), adding anhydrous DMF (2mL) for dissolving, adding potassium carbonate (28mg) and corresponding triphenylphosphine salt (70mg), reacting at room temperature overnight, monitoring the reaction by a dot plate, adding water, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, evaporating to dryness, and purifying by column chromatography to obtain compound II-24.1H NMR(400MHz,MeOD)δ7.96–7.89(m,3H),7.87–7.74(m,12H),5.86(s,1H),5.27(s,1H),4.34–4.10(m,2H),3.60–3.42(m,2H),2.18–2.11(m,1H),2.08–1.97(m,4H),1.92(dt,J＝13.5,3.1Hz,1H),1.79–1.63(m,4H),1.62–1.50(m,3H),1.45–1.36(m,3H),1.32–1.26(m,2H),1.22(s,3H),1.16–1.05(m,2H),0.98(s,3H),0.52(s,3H).
Example 31: preparation of Compound II-25
Weighing a compound 15(32mg), adding anhydrous DMF (2mL) for dissolving, adding potassium carbonate (28mg) and corresponding triphenylphosphine salt (72mg), reacting at room temperature overnight, monitoring the reaction by a dot plate, adding water, extracting by ethyl acetate, washing by saturated saline solution, drying by anhydrous sodium sulfate, filtering, evaporating to dryness, and purifying by column chromatography to obtain a compound II-25.1H NMR(400MHz,MeOD)δ7.94–7.71(m,15H),5.95(s,1H),5.38(s,1H),4.15(dt,J＝12.3,6.2Hz,1H),4.05(dt,J＝11.4,5.8Hz,1H),3.55–3.42(m,2H),2.09–1.99(m,2H),1.98–1.85(m,4H),1.82–1.48(m,9H),1.41–1.28(m,4H),1.24(dd,J＝12.2,2.2Hz,1H),1.11(s,3H),1.10–1.00(m,2H),0.98(s,3H),0.53(s,3H).
Example 32: preparation of Compound II-26
Weighing compound 15(30mg), adding anhydrous DMF (2mL) for dissolving, adding potassium carbonate (28mg) and corresponding triphenylphosphine salt (72mg), reacting at room temperature overnight, monitoring the reaction by a dot plate, adding water, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, evaporating to dryness, and purifying by column chromatography to obtain compound II-26.1H NMR(600MHz,MeOD)δ7.92–7.86(m,3H),7.83–7.73(m,12H),5.96(s,1H),5.44(d,J＝0.6Hz,1H),4.04(dt,J＝11.0,6.4Hz,1H),3.99(dt,J＝10.9,6.5Hz,1H),3.44–3.35(m,2H),2.21–2.07(m,2H),2.04–1.98(m,1H),1.94(dt,J＝13.6,3.2Hz,1H),1.83–1.72(m,2H),1.70–1.61(m,6H),1.60–1.54(m,4H),1.42–1.36(m,6H),1.34–1.27(m,6H),1.21(s,3H),1.18–1.05(m,2H),0.99(s,3H),0.61(s,3H).
Example 33: preparation of Compound II-27
Weighing compound 15(30mg), adding anhydrous DMF (2mL) for dissolving, adding potassium carbonate (28mg) and corresponding triphenylphosphine salt (85mg), reacting at room temperature overnight, monitoring the reaction by a dot plate, adding water, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, evaporating to dryness, and purifying by column chromatography to obtain compound II-27.1H NMR(400MHz,MeOD)δ7.92–7.87(m,3H),7.84–7.76(m,12H),5.98(s,1H),5.46(d,J＝0.7Hz,1H),4.15–3.95(m,2H),3.48–3.37(m,2H),2.20–2.10(m,2H),2.04–1.92(m,2H),1.82–1.52(m,16H),1.43–1.30(m,12H),1.21(s,3H),1.18–1.08(m,2H),0.97(s,3H),0.63(s,3H).
Example 34: preparation of Compound II-28
(1) Step 1: preparation of Compound 19
Weighing compound 15(510mg), adding anhydrous DMF (10mL) for dissolving, adding potassium carbonate (443mg) and 1, 2-dibromoethane (1.4mL), stirring at room temperature for 3h, monitoring the reaction completion by a dot plate, adding water, extracting with ethyl acetate, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, evaporating to dryness, and purifying by column chromatography to obtain compound 19.1H NMR(400MHz,CDCl3)δ6.05(s,1H),5.52(s,1H),4.49–4.21(m,2H),3.53(t,J＝5.7Hz,2H),2.26–2.07(m,2H),2.05–1.93(m,2H),1.88–1.65(m,4H),1.56–1.37(m,5H),1.30(dd,J＝12.8,3.6Hz,1H),1.25(s,3H),1.19(ddd,J＝18.6,12.7,4.0Hz,2H),1.07(dd,J＝13.5,4.0Hz,1H),1.01(s,3H),0.87(td,J＝13.3,4.1Hz,1H),0.63(s,3H).
(2) Step 2: preparation of Compound II-28
Weighing compound 19(50mg) and anhydrous DMF (3mL) to dissolve, adding potassium carbonate (34mg) and methylpiperazine (40 μ L), stirring at room temperature for reaction overnight, and spottingAnd (3) detecting that the reaction is complete, adding water, extracting by ethyl acetate, washing by saturated saline solution, drying by anhydrous sodium sulfate, filtering, evaporating to dryness, and purifying by column chromatography to obtain a compound II-28.1H NMR(400MHz,MeOD)δ6.02(s,1H),5.51(s,1H),4.31–4.09(m,2H),3.07–2.64(m,10H),2.61(s,3H),2.23–2.09(m,2H),2.06–1.94(m,2H),1.89–1.65(m,4H),1.63–1.51(m,3H),1.46–1.36(m,3H),1.30(dd,J＝12.1,2.2Hz,1H),1.24(s,3H),1.22–1.06(m,2H),0.98(s,3H),0.94(dd,J＝13.3,4.1Hz,1H),0.66(s,3H).
Example 35: preparation of Compound II-29
Weighing compound 19(100mg), adding anhydrous DMF (5mL) for dissolving, adding potassium carbonate (64mg) and piperazine (397 mu L), stirring at room temperature for reacting overnight, monitoring the reaction on a spot plate, adding water, extracting with ethyl acetate, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, evaporating to dryness, and purifying by column chromatography to obtain compound II-29.1H NMR(600MHz,CDCl3)δ9.55(s,1H),6.04(s,1H),5.42(s,1H),4.23–4.06(m,2H),3.21(t,J＝4.6Hz,4H),2.90–2.76(m,4H),2.74–2.65(m,2H),2.14(d,J＝13.2Hz,1H),2.10–2.01(m,2H),1.99–1.93(m,2H),1.77–1.64(m,4H),1.53–1.38(m,5H),1.29(dd,J＝12.8,3.9Hz,1H),1.20(s,3H),1.20–1.10(m,2H),1.07–1.01(m,1H),1.00(s,3H),0.86(td,J＝13.2,3.9Hz,1H),0.59(s,3H).
Example 36: preparation of Compound II-30
(1) Step 1: preparation of Compound 20
Weighing compound 15(50mg) into a 10mL round-bottom flask, adding anhydrous DMF (3mL) to dissolve, sequentially adding potassium carbonate (40mg) and 1, 4-dibromobutane (180 mu L), reacting at room temperature for 4h, adding water, extracting with ethyl acetate, and washing with saturated brine after the reaction is monitored by a dot plate. Drying with anhydrous sodium sulfate, filtering, evaporating to dryness under reduced pressure, and purifying by column chromatography to obtain compound 20.1H NMR(400MHz,CDCl3)δ6.05(s,1H),5.45(s,1H),4.06(t,J＝6.4Hz,2H),3.44(t,J＝6.6Hz,2H),2.18(d,J＝12.4Hz,1H),2.10–1.92(m,5H),1.86–1.65(m,6H),1.60(d,J＝3.0Hz,1H),1.55–1.38(m,5H),1.30(dd,J＝12.9,3.6Hz,1H),1.22(s,3H),1.18(dd,J＝7.7,5.3Hz,1H),1.05(dd,J＝13.5,3.9Hz,1H),1.01(s,3H),0.86(td,J＝12.8,3.6Hz,1H),0.61(s,3H).
(2) Step 2: preparation of Compound II-30
Weighing compound 20(50mg), adding anhydrous DMF (3mL) for dissolving, adding potassium carbonate (30mg) and piperazine (190 mu L), stirring at room temperature for reacting overnight, performing dot-matrix monitoring on the reaction, adding water, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, evaporating to dryness, and purifying by column chromatography to obtain compound II-30.1H NMR(600MHz,MeOD)δ6.01(s,1H),5.48(s,1H),4.07(t,J＝6.4Hz,2H),3.22(t,J＝5.1Hz,4H),2.71(s,4H),2.50(t,J＝7.2Hz,2H),2.19–2.09(m,2H),2.06–2.00(m,1H),1.97(dt,J＝13.5,3.1Hz,1H),1.85–1.68(m,6H),1.65–1.53(m,5H),1.44–1.38(m,3H),1.30(dd,J＝12.2,2.2Hz,2H),1.23(s,3H),1.16(ddd,J＝16.5,12.2,4.8Hz,1H),1.09(dd,J＝13.5,4.0Hz,1H),0.98(s,3H),0.95(dd,J＝13.3,4.1Hz,1H),0.65(s,3H).
Example 37: preparation of Compound II-31
(1) Step 1: preparation of Compound 21
Weighing compound 15(50mg) into a 10mL round-bottom flask, adding anhydrous DMF (3mL) to dissolve, sequentially adding potassium carbonate (42mg) and 1, 10-dibromodecane (337 uL), reacting at room temperature for 4h, adding water, extracting with ethyl acetate, and washing with saturated brine after the reaction is monitored by a dot plate. Drying with anhydrous sodium sulfate, filtering, evaporating to dryness under reduced pressure, and purifying by column chromatography to obtain compound 21.1H NMR(400MHz,CDCl3)δ6.04(s,1H),5.44(s,1H),4.02(t,J＝6.5Hz,2H),3.40(t,J＝6.8Hz,2H),2.18(d,J＝13.3Hz,1H),2.13–2.03(m,1H),2.02–1.92(m,2H),1.89–1.80(m,2H),1.80–1.58(m,7H),1.55–1.26(m,18H),1.21(s,3H),1.20–1.15(m,1H),1.07–1.02(m,1H),1.01(s,3H),0.86(td,J＝13.1,4.0Hz,1H),0.61(s,3H).
(2) Step 2: preparation of Compound II-31
Weighing compound 21(167mg), dissolving with anhydrous DMF (4mL), adding potassium carbonate (86mg) and piperazine (533 uL), stirring at room temperature for reaction overnight, performing dot-on-plate monitoring for complete reaction, adding water, extracting with ethyl acetate, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, evaporating to dryness, and purifying by column chromatography to obtain compound II-31.1H NMR(600MHz,CDCl3)δ6.04(s,1H),5.43(s,1H),4.08–3.97(m,2H),3.52–3.12(m,4H),3.10–2.68(m,4H),2.66–2.30(m,2H),2.18(d,J＝13.2Hz,1H),2.13–2.03(m,1H),2.02–1.92(m,2H),1.82–1.65(m,4H),1.64–1.58(m,2H),1.54–1.33(m,9H),1.31–1.24(m,11H),1.21(s,3H),1.20–1.15(m,2H),1.05–1.02(m,1H),1.01(s,3H),0.86(td,J＝13.3,3.9Hz,1H),0.60(s,3H).
Example 38: preparation of Compound II-32
Weighing a compound II-29(45mg), adding anhydrous DMF (3mL) for dissolving, adding potassium carbonate (31mg) and corresponding triphenylphosphine salt (77mg), reacting at room temperature overnight, monitoring the reaction by a dot plate, adding water, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, evaporating to dryness, and purifying by column chromatography to obtain a compound II-32.1H NMR(400MHz,MeOD)δ8.04–7.69(m,15H),5.99(s,1H),5.50(d,J＝0.7Hz,1H),4.18(td,J＝5.6,2.1Hz,2H),3.52–3.39(m,2H),2.67(t,J＝5.8Hz,2H),2.60–2.42(m,8H),2.22–2.09(m,2H),2.06–1.93(m,2H),1.89–1.64(m,6H),1.63–1.51(m,3H),1.45–1.37(m,3H),1.32–1.27(m,3H),1.22(s,3H),1.18–1.04(m,2H),0.98(s,3H),0.96–0.87(m,1H),0.64(s,3H).
Example 39: preparation of Compound II-33
Weighing a compound II-29(45mg), adding anhydrous DMF (3mL) for dissolving, adding potassium carbonate (31mg) and corresponding triphenylphosphine salt (79mg), reacting at room temperature overnight, monitoring the reaction by a dot plate, adding water, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, evaporating to dryness, and purifying by column chromatography to obtain a compound II-33.1H NMR(400MHz,MeOD)δ7.95–7.71(m,15H),6.00(s,1H),5.51(d,J＝0.6Hz,1H),4.30–4.10(m,2H),3.56–3.41(m,2H),2.79–2.54(m,10H),2.23–2.09(m,2H),2.05–1.93(m,2H),1.90–1.66(m,8H),1.63–1.52(m,3H),1.46–1.37(m,3H),1.33–1.27(m,3H),1.23(s,3H),1.12(ddd,J＝17.5,13.5,4.8Hz,2H),0.98(s,3H),0.93(dd,J＝13.9,3.4Hz,1H),0.66(s,3H).
Example 40: preparation of Compound II-34
Weighing the compound II-29(30mg), adding anhydrous DMF (3mL) for dissolving, adding potassium carbonate (19mg) and corresponding triphenylphosphine salt (47mg), reacting at room temperature overnight, monitoring the reaction completion by a dot plate, adding waterExtracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, evaporating to dryness, and purifying by column chromatography to obtain compound II-34.1H NMR(600MHz,MeOD)δ7.95–7.85(m,3H),7.85–7.72(m,12H),6.02(s,1H),5.51(s,1H),4.28–4.08(m,2H),3.46–3.37(m,2H),2.96–2.61(m,10H),2.22–2.10(m,2H),2.07–1.93(m,2H),1.87–1.80(m,1H),1.79–1.74(m,1H),1.73–1.65(m,4H),1.64–1.59(m,2H),1.59–1.52(m,5H),1.45–1.38(m,3H),1.36–1.26(m,13H),1.24(s,3H),1.17(dd,J＝13.4,5.6Hz,1H),1.11(td,J＝13.4,4.0Hz,1H),0.98(s,3H),0.95(dd,J＝13.3,4.0Hz,1H),0.67(s,3H).
Example 41: preparation of Compound II-35
Weighing a compound II-30(46mg), adding anhydrous DMF (3mL) for dissolving, adding potassium carbonate (28mg) and corresponding triphenylphosphine salt (85mg), reacting at room temperature overnight, monitoring the reaction by a spot plate, adding water, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, evaporating to dryness, and purifying by column chromatography to obtain a compound II-35.1H NMR(600MHz,MeOD)δ7.94–7.87(m,3H),7.86–7.71(m,12H),6.01(s,1H),5.48(s,1H),4.19–4.00(m,2H),3.45–3.38(m,2H),3.27–2.72(m,8H),2.71–2.58(m,2H),2.22–2.09(m,2H),2.06–1.95(m,2H),1.85–1.63(m,12H),1.61–1.52(m,5H),1.46–1.38(m,3H),1.37–1.27(m,13H),1.24(s,3H),1.20–1.08(m,2H),0.98(s,3H),0.97–0.89(m,1H),0.65(s,3H).
Example 42: preparation of Compound II-36
Weighing a compound II-31(45mg), adding anhydrous DMF (3mL) for dissolving, adding potassium carbonate (22mg) and corresponding triphenylphosphine salt (58mg), reacting at room temperature overnight, monitoring the reaction by a spot plate, adding water, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, evaporating to dryness, and purifying by column chromatography to obtain a compound II-36.1H NMR(400MHz,MeOD)δ7.95–7.72(m,15H),6.00(s,1H),5.48(s,1H),4.14–3.96(m,2H),3.57–3.41(m,2H),3.14–2.66(m,8H),2.57(t,J＝6.6Hz,2H),2.21–2.08(m,2H),1.07–1.93(m,2H),1.88–1.49(m,16H),1.48–1.27(m,17H),1.22(s,3H),1.19–1.05(m,2H),0.98(s,3H),0.94(dd,J＝13.5,4.1Hz,1H),0.64(s,3H).
Example 43: preparation of Compound II-37
Weighing a compound II-31(45mg), adding anhydrous DMF (3mL) for dissolving, adding potassium carbonate (22mg) and corresponding triphenylphosphine salt (68mg), reacting at room temperature overnight, monitoring the reaction by a spot plate, adding water, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, evaporating to dryness, and purifying by column chromatography to obtain a compound II-37.1H NMR(400MHz,MeOD)δ7.94–7.71(m,15H),6.00(s,1H),5.47(s,1H),4.17–3.90(m,2H),3.47–3.36(m,2H),3.05–2.68(m,10H),2.21–2.09(m,2H),2.06–1.94(m,2H),1.83–1.53(m,18H),1.44–1.27(m,27H),1.22(s,3H),1.18–1.14(m,1H),1.08(dd,J＝13.4,4.0Hz,1H),0.98(s,3H),0.94(dd,J＝13.3,4.0Hz,1H),0.64(s,3H).
Example 44: preparation of Compound II-38
(1) Step 1: preparation of Compound 22
Weighing compound 15(30mg), adding anhydrous DMF (2mL) for dissolving, adding potassium carbonate (25mg) and bis (2-bromoethyl) ether at room temperature, stirring at room temperature for reaction overnight, monitoring the reaction completion by a dot plate, adding water, extracting with ethyl acetate, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, evaporating to dryness, and purifying by column chromatography to obtain compound 22.1H NMR(400MHz,CDCl3)δ6.05(s,1H),5.49(s,1H),4.20(t,J＝4.7Hz,2H),3.79(td,J＝6.2,1.7Hz,2H),3.71(dd,J＝9.5,4.5Hz,2H),3.44(t,J＝6.2Hz,2H),2.26–2.06(m,2H),2.03–1.92(m,2H),1.87–1.64(m,4H),1.56–1.38(m,5H),1.30(dd,J＝12.9,3.6Hz,1H),1.23(s,3H),1.20(dd,J＝12.3,2.6Hz,1H),1.05(dd,J＝13.5,4.1Hz,1H),1.01(s,3H),0.86(td,J＝13.2,4.5Hz,2H),0.62(s,3H).
(2) Step 2: preparation of Compound II-38
Weighing the compound 22(36mg) in a 10mL round-bottom flask, adding anhydrous toluene (4mL) for dissolving, adding triphenylphosphine (59mg), carrying out reflux reaction at 112 ℃ for 12h, carrying out spot-plate monitoring reaction, evaporating to dryness, and carrying out column chromatography purification to obtain the compound II-38.1HNMR(600MHz,MeOD)δ7.91–7.86(m,3H),7.84–7.78(m,6H),7.74(ddd,J＝8.2,3.6,2.0Hz,6H),5.96(s,1H),5.44(s,1H),3.94(t,J＝4.6Hz,2H),3.85(dt,J＝20.4,5.7Hz,2H),3.80–3.74(m,2H),3.49–3.39(m,2H),2.15–2.05(m,2H),2.01–1.93(m,2H),1.74(ddd,J＝13.4,8.7,3.8Hz,2H),1.70–1.66(m,2H),1.60–1.53(m,3H),1.40(dd,J＝11.5,2.6Hz,2H),1.28(dd,J＝12.6,2.5Hz,2H),1.17(s,3H),1.14(dd,J＝13.4,5.6Hz,1H),1.09(td,J＝13.4,4.0Hz,1H),0.99(s,3H),0.95(dd,J＝13.1,4.0Hz,1H),0.58(s,3H).
Example 45: preparation of Compound II-39
(1) Step 1: preparation of Compound 23
Weighing compound 15(33mg) in a 10mL round-bottom flask, adding anhydrous DMF (3mL) to dissolve, adding potassium carbonate (28mg) and di-p-toluenesulfonic acid triexate (230mg), reacting at room temperature for 4h, monitoring the reaction completion by using a dot plate, adding ethyl acetate, washing with water, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, evaporating to dryness under reduced pressure, and purifying by column chromatography to obtain compound 26.1HNMR(400MHz,CDCl3)δ7.79(d,J＝8.3Hz,2H),7.34(d,J＝8.0Hz,2H),6.03(s,1H),5.47(s,1H),4.24–4.10(m,4H),3.74–3.62(m,4H),3.57(s,4H),2.45(s,3H),2.23–2.06(m,2H),2.02–1.91(m,2H),1.85–1.64(m,4H),1.55–1.38(m,5H),1.30(dd,J＝12.9,3.7Hz,1H),1.22(s,3H),1.19(dd,J＝12.3,2.7Hz,2H),1.08–1.03(m,1H),1.02(s,3H),0.86(td,J＝13.2,3.9Hz,1H),0.61(s,3H).
(2) Step 2: preparation of Compound II-39
Weighing compound 23(41mg) in a 10mL round-bottom flask, adding acetone (4mL) to dissolve, adding lithium bromide monohydrate (8.5mg), refluxing for 2 days, performing dot-on-board monitoring on complete reaction, adding ethyl acetate, washing with water, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and evaporating under reduced pressure to obtain compound 24. And (3) adding anhydrous toluene (4mL) to dissolve the compound 24 without purification, adding triphenylphosphine, carrying out reflux reaction for 2 days, carrying out treatment reaction, adding ethyl acetate, washing with water, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, and carrying out reduced pressure evaporation to dryness to obtain a compound II-39.1H NMR(600MHz,MeOD)δ7.89–7.80(m,9H),7.74(td,J＝7.9,3.4Hz,6H),5.95(s,1H),5.48(s,1H),4.12(ddd,J＝11.4,6.3,3.2Hz,1H),4.03(ddd,J＝12.0,5.8,3.2Hz,1H),3.82(t,J＝5.8Hz,1H),3.80–3.76(m,2H),3.75(t,J＝5.8Hz,1H),3.53–3.43(m,2H),3.35(s,4H),2.21–2.12(m,2H),2.02–1.92(m,2H),1.86–1.72(m,2H),1.68(d,J＝12.7Hz,2H),1.61–1.52(m,3H),1.45–1.37(m,3H),1.36–1.32(m,1H),1.22(s,3H),1.11(ddd,J＝17.5,13.7,4.8Hz,2H),0.99(s,3H),0.95(td,J＝13.2,4.2Hz,1H),0.62(s,3H).
Example 46: evaluation of antitumor Activity of the above series of Compounds
The test method comprises the following steps: in vitro anti-tumor activity test method:
a) the principle is as follows: succinate dehydrogenase in mitochondria of living cells can reduce exogenous thiazole blue (MTT) to water-insoluble blue-violet crystalline formazan and deposit it in cells, while dead cells do not. Dimethyl sulfoxide can dissolve formazan in cells, and its light absorption value is measured by ELISA detector, which can indirectly reflect the number of living cells.
b) Cell: a549, MCF-7 and K562.
c) The experimental steps are as follows: taking the three tumor cell strains, 2 × 104After culturing for 48 hours, 5mg/mL MTT 20. mu.L per well was added to each well, and incubation was continued for 4 hours, followed by centrifugation, the supernatant was carefully aspirated, 200. mu. LDMSO was added thereto, and gentle shaking was performed to completely dissolve and develop formazan, and OD was measured at 570nm using a Bio-Rad model550Microplate Reader. The experiments were performed 3 times each, and the average value was calculated. The specific results of doxorubicin as a positive control are shown in table 1.
TABLE 1 evaluation of the antitumor Activity of the above Compounds, specifically by the median Inhibitory Concentration (IC)50Value) to represent
TABLE 1 evaluation of antitumor Activity of isosteviol derivatives
Example 47: evaluation of antifungal Activity of the above series of Compounds
The MIC values of the test strains were determined by the fungal susceptibility test method (M27-A3) established by the American society for Clinical and Laboratory Standards (CLSI) using microdilution.
a) Strain: wild type 5314.
b) The experimental steps are as follows: adjusting the concentration of the strain to be detected to 0.5-2.5 multiplied by 10 by using RPMI1640 culture medium3cells/mL; adding 200 mu L of bacterial liquid containing the highest-concentration drug to be detected into the first hole of a 96-hole plate, and adding 100 mu L of blank bacterial liquid containing no drug into each of the other holes; diluting the bacterial liquid to a series of concentration gradients by a two-fold gradient dilution method; standing and culturing at constant temperature of 35 ℃ for 24 hours; and detecting the absorbance (OD value) of each concentration gradient at 570nm by using a microplate reader, deducting the absorbance of the blank culture medium, dividing the OD value of each well by the OD value of a control group to obtain the growth rate, and taking the minimum concentration with the inhibition rate (1-growth rate) of more than 80% as the Minimum Inhibitory Concentration (MIC) value. The experiments were performed 3 times, the average was calculated, amphotericin B was used as the positive control, and the specific results are shown in table 2.
TABLE 2 results of the evaluation of the antifungal activity of the above compounds, expressed in terms of 80% inhibitory concentration (MIC value).
TABLE 2 evaluation of antifungal Activity of isosteviol derivatives
A series of synthesized isosteviol derivatives show good antitumor activity, and the derivative triphenylphosphine salt series compounds show antifungal activity equivalent to amphotericin B, while the prepared compound 2 isosteviol has neither antitumor activity nor antifungal activity.
The above description is only a preferred embodiment of the present application and is not intended to limit the present application, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present application shall be included in the protection scope of the present application.
Claims (3)
1. Isosteviol derivative having antitumor activity, characterized by being selected from the following compounds:
2. the process for the preparation of isosteviol derivative according to claim 1, comprising the steps of:
weighing 4.0g stevioside, placing in a round bottom flask, adding 10% H2SO4Dissolving, heating and stirring for reaction, cooling the system to room temperature after the reaction is finished, filtering, and washing with water to obtain a white solid compound 2;
weighing 200mg of compound 2, placing in a round bottom flask, adding 5mL of anhydrous dichloromethane for dissolution, N2Protecting, adding 60 mu L of oxalyl chloride and 1 mu L of anhydrous DMF under ice bath, reacting at room temperature, and after the reaction is finished, evaporating to dryness under reduced pressure to obtain a yellow solid 3; adding 3mL of anhydrous toluene for dissolving, adding 110mg of sodium pyrithione and 7.6mg of DMAP at room temperature, cooling to room temperature after the reaction is finished, carrying out suction filtration, and evaporating the filtrate under reduced pressure to dryness to obtain a brown-yellow oily liquid 4; adding 1.5mL of anhydrous dichloromethane, N2Under protection, 108mg of m-CPBA is added, after reaction for 1 hour, the mixture is moved to room temperature, 4mL of toluene is added, and the reaction is carried out overnight; after the reaction is finished, adding water, extracting a water layer by using dichloromethane, combining organic layers, drying by using magnesium sulfate, filtering, evaporating a solvent under reduced pressure, and purifying by using column chromatography to obtain a white solid 5;
weighing 136mg of compound 5 in a round-bottom flask, adding 5mL of cyclohexane for dissolving, adding 0.5mL of ethylene glycol and 2mg of camphorsulfonic acid, carrying out water division reflux on a water separator, adding ethyl acetate after complete reaction, washing with water in sequence, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, filtering, carrying out reduced pressure rotary evaporation, and purifying by column chromatography to obtain a compound 6;
weighing 550mg of compound 6 in a three-necked bottle, adding 30mL of anhydrous dichloromethane and 30mL of anhydrous methanol for dissolving, introducing ozone at-78 ℃, stopping introducing the ozone when the solution turns blue, introducing nitrogen to empty the ozone, slowly adding 2.5mL of dimethyl sulfide, slowly heating to room temperature for reacting overnight; monitoring the reaction progress by using a point plate, and after the reaction is finished, evaporating to dryness under reduced pressure, and purifying by using column chromatography to obtain a compound 7;
weighing 653mg of compound 7 in a double-mouth bottle, adding 15mL of anhydrous THF for dissolving, adding 3.2mL of LiHMDS dropwise under the protection of nitrogen, reacting for 1h, adding 630 mu L of CS2, moving to room temperature for reaction, adding methyl iodide, and reacting overnight; after the reaction is completely monitored by a point plate, adding water for quenching, extracting by ethyl acetate, washing by saturated sodium chloride, drying by anhydrous sodium sulfate, filtering, decompressing and rotary steaming, and purifying by column chromatography to obtain a compound 8;
weighing 46.5mg of trimethyl sulfur iodide in a double-mouth bottle, adding 1mL of anhydrous THF (tetrahydrofuran) -20 ℃, dropwise adding 96 mu L of n-butyl lithium, continuing to react for 2h, dropwise adding 20mg of anhydrous THF solution of a compound 8, continuing to react for 1h, monitoring the complete reaction by a point plate, adding water, extracting with ethyl acetate, washing with water, drying with anhydrous sodium sulfate, and evaporating to dryness under reduced pressure to obtain a compound 9;
compound 9 was added 3mL of 0.5M H2SO4/CH3Reacting the OH solution for 4 hours, adding water, extracting with ethyl acetate, washing with water, washing with saturated saline solution, filtering, carrying out reduced pressure rotary evaporation, and purifying by column chromatography to obtain a compound I-1;
weighing 68mg of the compound I-1 in a double-mouth bottle, adding 2mL of anhydrous THF for dissolving, dropwise adding bis (trimethylsilyl) aminolithium under the protection of nitrogen, adding 123mg of (N, N-dimethylmethylene) ammonium iodide, and continuing to react for 1 h; monitoring reaction completion by a point plate, adding water for quenching, adding dichloromethane for extraction, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, evaporating to dryness under reduced pressure, and purifying by column chromatography to obtain a compound I-2;
weighing 23mg of compound I-2 in a round-bottom flask, adding 0.5mL of anhydrous dichloromethane and 1.5mL of anhydrous ether for dissolving, dropwise adding 100 mu L of iodomethane, stirring at room temperature for reaction, evaporating the solvent, adding 2mL of anhydrous dichloromethane and 100mg of alumina, reacting at room temperature, monitoring by using a dot plate to complete the reaction, evaporating the solvent, and performing neutral alumina column chromatography to obtain a compound I-3;
weighing 40mg of compound I-3 in a round-bottom flask, adding 2mL of anhydrous THF for dissolving, dropwise adding 200 mu LLIHMDS under the protection of nitrogen, continuing to react for 1h, adding 74mg of (N, N-dimethyl) methylene ammonium iodide, reacting at room temperature for 2h, adding water for quenching after the reaction is finished, extracting with dichloromethane, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, evaporating to dryness under reduced pressure, and purifying by column chromatography to obtain a compound I-4;
weighing 20mg of compound I-4 in a round-bottom flask, adding 0.5mL of anhydrous dichloromethane and 1.5mL of anhydrous ether for dissolving, dropwise adding 82 mu L of iodomethane, stirring at room temperature for reaction, evaporating the solvent, adding 2mL of anhydrous dichloromethane and 100mg of alumina, reacting at room temperature, monitoring by using a dot plate, evaporating the solvent, and performing neutral alumina column chromatography to obtain a compound I-5;
wherein the compound 2, the yellow solid 3, the yellow oily liquid 4, the white solid 5, the compound 6, the compound 7, the compound 8 and the compound 9 are sequentially:
3. use of isosteviol derivative as claimed in claim 1 for preparing antitumor agent.
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| Synthesis and cytotoxic activity of nitric oxide-releasing isosteviol derivatives;Ting-ting Wang等;《Bioorganic & Medicinal Chemistry Letters》;20140312;第24卷;2202-2205 * |
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