CN111978198A - Lapterostigmatic acid derivative and preparation method and application thereof - Google Patents
Lapterostigmatic acid derivative and preparation method and application thereof Download PDFInfo
- Publication number
- CN111978198A CN111978198A CN202010814976.8A CN202010814976A CN111978198A CN 111978198 A CN111978198 A CN 111978198A CN 202010814976 A CN202010814976 A CN 202010814976A CN 111978198 A CN111978198 A CN 111978198A
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- Prior art keywords
- formula
- reaction
- pterodontic
- acid derivative
- acid
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- 239000002253 acid Substances 0.000 title claims abstract description 234
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 27
- 241001269712 Laggera Species 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 293
- 238000006243 chemical reaction Methods 0.000 claims description 180
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 151
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 114
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 109
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 80
- 229910052757 nitrogen Inorganic materials 0.000 claims description 76
- -1 methylamino, ethylamino Chemical group 0.000 claims description 67
- 238000001914 filtration Methods 0.000 claims description 64
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 61
- 230000002829 reductive effect Effects 0.000 claims description 61
- 239000007832 Na2SO4 Substances 0.000 claims description 60
- 239000012074 organic phase Substances 0.000 claims description 60
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 60
- 238000001035 drying Methods 0.000 claims description 59
- 235000019439 ethyl acetate Nutrition 0.000 claims description 57
- 238000010898 silica gel chromatography Methods 0.000 claims description 57
- 239000002904 solvent Substances 0.000 claims description 57
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 45
- 150000001875 compounds Chemical class 0.000 claims description 44
- 238000010791 quenching Methods 0.000 claims description 41
- 238000007865 diluting Methods 0.000 claims description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 36
- 230000000171 quenching effect Effects 0.000 claims description 34
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- 239000003795 chemical substances by application Substances 0.000 claims description 29
- 239000003054 catalyst Substances 0.000 claims description 28
- 239000012295 chemical reaction liquid Substances 0.000 claims description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical group NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 27
- 238000005406 washing Methods 0.000 claims description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 21
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 21
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 21
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- WBWCSJIHCFSYOG-UHFFFAOYSA-N pteridine-2-carboxylic acid Chemical compound N1=CC=NC2=NC(C(=O)O)=NC=C21 WBWCSJIHCFSYOG-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 229940079593 drug Drugs 0.000 claims description 15
- 238000010992 reflux Methods 0.000 claims description 15
- 235000009518 sodium iodide Nutrition 0.000 claims description 15
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 14
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 13
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 11
- RQJDUEKERVZLLU-UHFFFAOYSA-N 4-Hydroxybenzylamine Chemical group NCC1=CC=C(O)C=C1 RQJDUEKERVZLLU-UHFFFAOYSA-N 0.000 claims description 11
- 238000004440 column chromatography Methods 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
- 239000007800 oxidant agent Substances 0.000 claims description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 9
- 238000000338 in vitro Methods 0.000 claims description 9
- XCRBXWCUXJNEFX-UHFFFAOYSA-N peroxybenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 claims description 9
- KDDNKZCVYQDGKE-UHFFFAOYSA-N (2-chlorophenyl)methanamine Chemical group NCC1=CC=CC=C1Cl KDDNKZCVYQDGKE-UHFFFAOYSA-N 0.000 claims description 8
- HMTSWYPNXFHGEP-UHFFFAOYSA-N (4-methylphenyl)methanamine Chemical group CC1=CC=C(CN)C=C1 HMTSWYPNXFHGEP-UHFFFAOYSA-N 0.000 claims description 8
- 238000006482 condensation reaction Methods 0.000 claims description 8
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical group CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 claims description 8
- 238000007254 oxidation reaction Methods 0.000 claims description 8
- 230000001590 oxidative effect Effects 0.000 claims description 8
- BJFPYGGTDAYECS-UHFFFAOYSA-N (3-chlorophenyl)methanamine Chemical group NCC1=CC=CC(Cl)=C1 BJFPYGGTDAYECS-UHFFFAOYSA-N 0.000 claims description 7
- XRNVSPDQTPVECU-UHFFFAOYSA-N (4-bromophenyl)methanamine Chemical group NCC1=CC=C(Br)C=C1 XRNVSPDQTPVECU-UHFFFAOYSA-N 0.000 claims description 7
- IIFVWLUQBAIPMJ-UHFFFAOYSA-N (4-fluorophenyl)methanamine Chemical group NCC1=CC=C(F)C=C1 IIFVWLUQBAIPMJ-UHFFFAOYSA-N 0.000 claims description 7
- ZDBWYUOUYNQZBM-UHFFFAOYSA-N 3-(aminomethyl)aniline Chemical group NCC1=CC=CC(N)=C1 ZDBWYUOUYNQZBM-UHFFFAOYSA-N 0.000 claims description 7
- DRUIESSIVFYOMK-UHFFFAOYSA-N Trichloroacetonitrile Chemical compound ClC(Cl)(Cl)C#N DRUIESSIVFYOMK-UHFFFAOYSA-N 0.000 claims description 7
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 7
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 7
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- KPBSJEBFALFJTO-UHFFFAOYSA-N propane-1-sulfonyl chloride Chemical compound CCCS(Cl)(=O)=O KPBSJEBFALFJTO-UHFFFAOYSA-N 0.000 claims description 7
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 claims description 7
- 229960005055 sodium ascorbate Drugs 0.000 claims description 7
- 241000712431 Influenza A virus Species 0.000 claims description 6
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 6
- 150000003141 primary amines Chemical class 0.000 claims description 6
- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical group COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 claims description 5
- 125000006325 2-propenyl amino group Chemical group [H]C([H])=C([H])C([H])([H])N([H])* 0.000 claims description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 5
- 150000001345 alkine derivatives Chemical class 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 5
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 235000010378 sodium ascorbate Nutrition 0.000 claims description 5
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 claims description 5
- VWSLLSXLURJCDF-UHFFFAOYSA-N 2-methyl-4,5-dihydro-1h-imidazole Chemical compound CC1=NCCN1 VWSLLSXLURJCDF-UHFFFAOYSA-N 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 4
- 230000003647 oxidation Effects 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 230000003612 virological effect Effects 0.000 claims description 4
- 238000006845 Michael addition reaction Methods 0.000 claims description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 238000006352 cycloaddition reaction Methods 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 239000012044 organic layer Substances 0.000 claims description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims 4
- 238000000605 extraction Methods 0.000 claims 4
- 229920006395 saturated elastomer Polymers 0.000 claims 3
- 208000027418 Wounds and injury Diseases 0.000 claims 1
- 238000009833 condensation Methods 0.000 claims 1
- 230000005494 condensation Effects 0.000 claims 1
- 230000006378 damage Effects 0.000 claims 1
- 208000014674 injury Diseases 0.000 claims 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 1
- 241000700605 Viruses Species 0.000 abstract description 19
- 206010022000 influenza Diseases 0.000 abstract description 13
- 230000000694 effects Effects 0.000 abstract description 9
- 201000010740 swine influenza Diseases 0.000 abstract description 4
- 208000035473 Communicable disease Diseases 0.000 abstract description 3
- 208000037801 influenza A (H1N1) Diseases 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 216
- 239000000243 solution Substances 0.000 description 55
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 54
- 238000005160 1H NMR spectroscopy Methods 0.000 description 54
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 48
- 235000011152 sodium sulphate Nutrition 0.000 description 48
- 230000015572 biosynthetic process Effects 0.000 description 39
- 238000003786 synthesis reaction Methods 0.000 description 39
- 238000004809 thin layer chromatography Methods 0.000 description 34
- 239000003208 petroleum Substances 0.000 description 33
- 238000012544 monitoring process Methods 0.000 description 31
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 27
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- 210000004027 cell Anatomy 0.000 description 20
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- 238000001228 spectrum Methods 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 230000000120 cytopathologic effect Effects 0.000 description 12
- 241000712461 unidentified influenza virus Species 0.000 description 10
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 150000001408 amides Chemical class 0.000 description 9
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- 239000002356 single layer Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 7
- SJUKJZSTBBSGHF-UHFFFAOYSA-N (2,4-dichlorophenyl)methanamine Chemical compound NCC1=CC=C(Cl)C=C1Cl SJUKJZSTBBSGHF-UHFFFAOYSA-N 0.000 description 6
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 6
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 6
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 6
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- YKNZTUQUXUXTLE-UHFFFAOYSA-N [3-(trifluoromethyl)phenyl]methanamine Chemical compound NCC1=CC=CC(C(F)(F)F)=C1 YKNZTUQUXUXTLE-UHFFFAOYSA-N 0.000 description 6
- PRDBLLIPPDOICK-UHFFFAOYSA-N [4-(trifluoromethyl)phenyl]methanamine Chemical compound NCC1=CC=C(C(F)(F)F)C=C1 PRDBLLIPPDOICK-UHFFFAOYSA-N 0.000 description 6
- 230000000840 anti-viral effect Effects 0.000 description 6
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- ZWLPBLYKEWSWPD-UHFFFAOYSA-N o-toluic acid Chemical compound CC1=CC=CC=C1C(O)=O ZWLPBLYKEWSWPD-UHFFFAOYSA-N 0.000 description 6
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- 239000003153 chemical reaction reagent Substances 0.000 description 4
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 4
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- LFOIDLOIBZFWDO-UHFFFAOYSA-N 2-methoxy-6-[6-methoxy-4-[(3-phenylmethoxyphenyl)methoxy]-1-benzofuran-2-yl]imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=C2SC(OC)=NN2C=C1C(OC1=CC(OC)=C2)=CC1=C2OCC(C=1)=CC=CC=1OCC1=CC=CC=C1 LFOIDLOIBZFWDO-UHFFFAOYSA-N 0.000 description 3
- WGTASENVNYJZBK-UHFFFAOYSA-N 3,4,5-trimethoxyamphetamine Chemical compound COC1=CC(CC(C)N)=CC(OC)=C1OC WGTASENVNYJZBK-UHFFFAOYSA-N 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 3
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- 206010069767 H1N1 influenza Diseases 0.000 description 3
- 101710154606 Hemagglutinin Proteins 0.000 description 3
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 3
- MQUQNUAYKLCRME-INIZCTEOSA-N N-tosyl-L-phenylalanyl chloromethyl ketone Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N[C@H](C(=O)CCl)CC1=CC=CC=C1 MQUQNUAYKLCRME-INIZCTEOSA-N 0.000 description 3
- 102000005348 Neuraminidase Human genes 0.000 description 3
- 108010006232 Neuraminidase Proteins 0.000 description 3
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- C07D295/16—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 acylated on ring nitrogen atoms
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Abstract
The invention relates to a pterodontic acid derivative and a preparation method and application thereof, belonging to the technical field of natural medicinal chemistry. The method prepares a series of laggera acid derivatives comprising C-5-position, C-12-position, C-13-position derivatives and the like, and the laggera acid derivatives prepared by the method have the advantages of good effect of resisting influenza A (H1N 1) virus, good stability, high yield and the like. Plays an important role in preparing medicaments for treating virus infectious diseases such as influenza and the like. Meanwhile, the preparation method is simple and easy to implement, has strong universality, has the derivative yield more than or equal to 80 percent, and is easy to popularize and apply.
Description
Technical Field
The invention belongs to the technical field of natural medicinal chemistry, and particularly relates to a pterodontic acid derivative and a preparation method and application thereof.
Background
The influenza virus is a specific respiratory virus, is an RNA virus of orthomyxoviridae causing influenza of human beings and poultry, has variable transmission due to the change of internal antigens and seasonal transmission, is concentrated in children and old people for susceptible people, and has high mortality rate due to infection of the old people with chronic diseases. Influenza viruses are classified into a type A, a type B and a type C according to different internal proteins and antigens, wherein the type A influenza virus is the type with the most frequent variation and brings difficulty to prevention and treatment. Influenza a viruses are divided into 18 different HA subtypes and 11 different NA subtypes according to surface glycoproteins of Hemagglutinin (HA) and Neuraminidase (NA), so that the viruses are subjected to gene fragment recombination in vivo cells, virus antigen variation can be caused, novel influenza virus strains are generated, and wide infection of human viral influenza is caused. Therefore, the search and development of safe and effective novel anti-influenza virus drugs become the key point for preventing and treating influenza diseases.
The laggera acid (Pterospondic acid) belongs to eudesmane type sesquiterpene compounds, is colorless to off-white blocky crystals in appearance, is easily soluble in a small polar organic solvent but insoluble in water, mainly exists in overground parts such as branches and leaves of laggera, is a main active ingredient in the plant, and has multiple biological activities of resisting inflammation, easing pain, immunosuppression, bacteria, tumors, influenza viruses and the like. Experimental research shows that: the pterodontic acid can obviously inhibit the proliferation of a plurality of influenza viruses such as H1N 1A in vivo and in vitro. The laggerac acid has obvious effect in resisting influenza, has small toxic and side effect and has a unique anti-influenza virus mechanism, so the laggerac acid can be used as an auxiliary medicament for clinical influenza virus infection and can even be developed into a novel antiviral medicament.
Currently, the kinds of drugs on the market for treating influenza virus infectious diseases are rare, and some drugs have developed drug resistance to viruses, such as amantadine and rimantadine. Meanwhile, the synthetic medicine has large toxic and side effects on organisms, and is easy to cause complications or other diseases. Therefore, by adopting the method of optimizing the structure of the medicine, the medicine with good antiviral effect in the natural product is modified, and the semisynthetic medicine with a novel structure and a novel antiviral mechanism is expected to be obtained, so that the research and development of the antiviral medicine are promoted.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide a pterodontic acid derivative, a preparation method of the pterodontic acid derivative and an application of the pterodontic acid derivative, and provides a new choice for development and utilization of pterodontic acid and treatment of influenza diseases caused by viruses.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
a pterodontic acid derivative has a structural formula shown as a formula (I), a formula (II), a formula (III), (IV), a formula (V), a formula (VI), a formula (VII), a formula (VIII), a formula (IX) or a formula (X):
wherein R1 is methylamino, ethylamino, allylamino, dimethylamino, diethylamino, diallylamino, 2, 4-dimethylhexylamino, cyclohexylamino, 2-methyl-2-imidazoline, 4-pyridylmethylamino, 4-methoxybenzylamino, 3-aminobenzylamino, methylbenzylamino, 3-chlorobenzylamino, 4-fluorobenzylamino, 4-bromobenzylamine group, 4-hydroxybenzylamine group, diphenylmethylamino group, benzylamino group, 4-methylbenzylamine group, 2-phenethylamino group, 2-furanmethylamino group, 4- (trifluoromethyl) benzylamino group, 3- (trifluoromethyl) benzylamino group, 2-chlorobenzylamine group, 2, 4-dichlorobenzylamino group, acetamido group, guanylamine, morpholine, methylpiperazine;
wherein R2 is methyl, n-pentyl or benzyl;
wherein R3 is methyl, n-pentyl, benzyl, -H;
wherein R4 is morpholine and methylpiperazine;
wherein R is5is-OH;
wherein R6 is-OH, -Cl, morpholine, methyl piperazine or benzylamine;
wherein R is7Is n-butyl, phenyl, 2-methylphenyl;
wherein R is8Is propyl;
wherein R9 is phenyl, 4-methylphenyl, 2-N-pyridine.
The invention also discloses a preparation method of the pterodontic acid derivative, which has the following reaction formula:
the method comprises the following steps:
reaction (i): dissolving the pterodontic acid with the structure shown in the formula (A) in a dichloromethane solution, taking EDCI as a condensing agent and DMAP as a catalyst, and carrying out condensation reaction with a primary amine or secondary amine compound at room temperature to obtain the pterodontic acid derivative shown in the formula (I);
reaction (ii): dissolving the pterodontic acid with the structure of formula (A) in a dichloromethane solution, taking DCC as a condensing agent and DMAP as a catalyst, and carrying out condensation reaction on the pterodontic acid and different hydroxyl-containing compounds at room temperature to obtain a pterodontic acid derivative shown in formula (II);
reaction (iii): taking the pterodontic acid derivative shown in the formula (II) in a dichloromethane solution, and carrying out an oxidation reaction under the oxidation action of peroxybenzoic acid at room temperature to obtain the pterodontic acid derivative with the R3 being methyl, n-amyl or benzyl structure in the formula (III);
reaction (iv): dissolving the pterodontic acid with the structure shown in the formula (A) in a dichloromethane solution, and carrying out oxidation reaction under the oxidation action of peroxybenzoic acid at room temperature to obtain the pterodontic acid derivative with the structure R3-H in the formula (III);
reaction (v): taking a ozonic acid derivative with R3 as-H in the formula (III) to perform Michael addition reaction with a secondary amine compound in a dichloromethane solution by taking EDCI as a condensing agent and DMAP as a catalyst under the nitrogen protection room temperature condition to obtain a ozonic acid derivative shown in the formula (IV);
reaction (vi): taking a laggerac acid derivative with R3 being-H in the formula (III), introducing nitrogen for protection under the acidic condition of boron trifluoride-diethyl ether, and reacting in an ice bath condition to obtain a laggerac acid derivative shown in the formula (V);
reaction (vii): dissolving the pterodontic acid with the structure shown in the formula (A) in an anhydrous tetrahydrofuran solvent, and reducing the mixture by lithium aluminum hydride under the reflux condition to obtain a pterodontic acid derivative with the structure of-OH R6 in the formula (VI);
reaction (viii): taking a pterodontic acid derivative with R6 as-OH structure in a formula (VI), and carrying out condensation reaction with a carboxyl-containing compound in a dichloromethane solvent by using DCC as a condensing agent and DMAP as a catalyst to obtain the pterodontic acid derivative shown in the formula (VII);
reaction (ix): taking a pterodontic acid derivative with R6 as-OH structure in a formula (VI), and carrying out substitution reaction with triphenylphosphine and trichloroacetonitrile in a dichloromethane solvent under the ice bath condition of nitrogen protection to obtain the pterodontic acid derivative with R6 as-Cl structure in the formula (VI);
reaction (x): taking a pterodontic acid derivative with R6 in a-Cl substructure in a formula (VI), adding sodium iodide into an anhydrous tetrahydrofuran solvent, and carrying out a condensation reaction with a primary amine or secondary amine compound to obtain the pterodontic acid derivative with R6 in a morpholine, methylpiperazine and benzylamine structure in the formula (VI);
reaction (xi): taking a pterodontic acid derivative with R6 as-OH structure in a formula (VI), adding triethylamine and propyl sulfonyl chloride in a dichloromethane solvent under an ice bath condition, and carrying out a substitution reaction under the protection of nitrogen and a reflux condition to obtain the pterodontic acid derivative shown in a formula (VIII);
reaction (xii): taking a laggera derivative with a structure shown in a formula (VIII), and reacting the laggera derivative with sodium azide in an anhydrous N, N-dimethylformamide solvent under the protection of nitrogen to obtain a laggera derivative shown in a formula (IX);
reaction (xiii): adding copper acetate, sodium ascorbate and water into a tetrahydrofuran solvent to perform cycloaddition reaction with a monosubstituted alkyne compound to obtain the pterodontic acid derivative shown in the formula (X).
Further, it is preferable that the reaction (i) is specifically: dissolving 50.0-80.0mg of laggerac acid with a structure shown in a formula (A) in 5.0-8.0mL of anhydrous dichloromethane solvent, adding 0.27-0.43mmol of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride serving as a condensing agent, adding 0.1-0.2mmol of 4-dimethylaminopyridine catalyst, adding 0.25-0.40mmol of primary amine or secondary amine compound, reacting at room temperature for 4-6H under the protection of nitrogen, diluting a reaction solution with 4.0-5.0mL of EtOAc, adding 1.0-2.0mL of HCl with the volume concentration of 5% to quench, extracting for three times by DCM/H2O, drying an organic phase by anhydrous Na2SO4, filtering, concentrating under reduced pressure, and separating and purifying by column chromatography to obtain the laggerac acid derivative shown in the formula (I);
the reaction (ii) is specifically: dissolving 50.0-80.0mg of the ozonic acid with the structure of the formula (A) in 5.0-8.0mL of anhydrous dichloromethane solvent, adding 1.2-1.9mmol of dicyclohexylcarbodiimide as a condensing agent, adding 0.1-0.2mmol of 4-dimethylaminopyridine catalyst, adding 0.13-0.21mmol of an-OH-containing compound, reacting at room temperature for 3-5H under the protection of nitrogen, diluting the reaction liquid with 4.0-5.0mL of EtOAc, adding 1.0-2.0mL of hydrochloric acid with the volume concentration of 5% to quench, washing with H2O for three times, drying the collected organic phase with anhydrous Na2SO4, filtering, concentrating under reduced pressure, and purifying by silica gel column chromatography to obtain the ozonic acid derivative shown in the formula (II).
Further, it is preferable that the reaction (iii) is specifically: dissolving 50.0-80.0mg of the pterodontic acid derivative shown in the formula (II) in 4.0-6.0mL of anhydrous dichloromethane solvent, adding 0.24-0.38mmol of peroxybenzoic acid as an oxidant, and reacting at room temperature for 0.5-1.0h under the protection of nitrogen; adding 1.0-2.0mL of saturated NaHCO3 into the reaction solution for quenching, washing with DCM/H2O for three times, drying an organic phase by using anhydrous Na2SO4, filtering, concentrating under reduced pressure, and purifying by silica gel column chromatography to obtain a pterodontic acid derivative with a structure of a formula (III) R3 of methyl, n-amyl or benzyl;
reaction (iv) is specifically: dissolving 500.0-600.0mg of laggerac acid with the structure of formula (A) in 10.0-12.0mL of anhydrous dichloromethane solvent, adding 2.57-3.08mmol of oxidizing agent m-chloroperoxybenzoic acid, and reacting at room temperature for 1.0-1.5h under the protection of nitrogen; adding 2.0-3.0mL of saturated NaHCO3 into the reaction solution for quenching, washing with DCM/H2O for three times, drying an organic phase by anhydrous Na2SO4, filtering, concentrating under reduced pressure, and purifying by silica gel column chromatography to obtain a pterodontic acid derivative with a structure of-H as R3 in a formula (III);
further, it is preferable that the reaction (v) is specifically: dissolving 50.0-80.0mg of the pterodontic acid derivative with R3 being-H in 5.0-8.0mL of anhydrous dichloromethane solvent, adding 0.2-0.3mmol of condensing agent 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 0.1-0.2mmol of catalyst 4-dimethylaminopyridine, adding 0.25-0.40mmol of secondary amine compound, reacting at room temperature for 4-5H under the protection of nitrogen, diluting the reaction liquid with 4.0-5.0mL of EtOAc, quenching with 1.0-2.0mL of HCl with volume concentration of 5%, extracting for three times with DCM/H2O, drying the organic phase with anhydrous Na2SO4, filtering, concentrating under reduced pressure, separating and purifying by column chromatography to obtain the pterodontic acid derivative shown in formula (IV);
the reaction (vi) is specifically: dissolving 50.0-80.0mg of the pterodontic acid derivative with R3 of-H in 5.0-8.0mL of anhydrous dichloromethane solvent, adding 0.2-0.3mmol of boron trifluoride-diethyl ether into ice bath, reacting for 4-5H in ice bath under the protection of nitrogen, diluting the reaction liquid with 4.0-5.0mL of EtOAc, adding 1.0-2.0mL of saturated NH4Cl solution for quenching, extracting the EtOAc/H2O for three times, drying an organic phase by anhydrous Na2SO4, filtering, concentrating under reduced pressure, and separating and purifying by column chromatography to obtain the pterodontic acid derivative shown in formula (V).
Further, it is preferable that the reaction (vii) is specifically: dissolving 100.0-300.0mg of laggerac acid with a structure shown in a formula (A) in 10.0-20.0mL of anhydrous tetrahydrofuran solvent, evenly adding 0.45-1.34mmol of lithium aluminum hydride into 3 batches in ice bath under the protection of nitrogen, carrying out reflux reaction at 70 ℃ for 12-18H after complete mixing, adding 3.0-6.0mL of sodium hydroxide solution with a mass concentration of 15% and 3.0-6.0mL of H2O under ice bath, quenching, filtering by using kieselguhr, extracting for three times by using EtOAc/H2O, drying an organic phase by using anhydrous Na2SO4, filtering, carrying out reduced pressure concentration, and carrying out silica gel column chromatography purification to obtain the laggerac acid derivative with a structure shown in a formula (VI) R6 of-OH.
Reaction (viii) is specifically: dissolving 20.0-50.0mg of the pterodontic acid derivative with R6 of-OH structure in 2.0-4.0mL of anhydrous dichloromethane solvent, adding 1.08-2.70mmol of dicyclohexylcarbodiimide and 0.018-0.045mmol of 4-dimethyl aminopyridine as catalyst, adding 0.135-0.338mmol of-COOH-containing compounds, reacting at room temperature for 3-5H under the protection of nitrogen, diluting the reaction liquid with 2.0-4.0mL of EtOAc, adding 1.0-2.0mL of hydrochloric acid with volume concentration of 5% for quenching, washing with EtOAc/H2O for three times, drying the collected organic phase with anhydrous Na2SO4, filtering, concentrating under reduced pressure, and purifying by silica gel column chromatography to obtain the pterodontic acid derivative shown in the formula (VII).
Further, it is preferable that reaction (ix) is specifically: dissolving 50.0-80.0mg of a pterodontic acid derivative with R6 as-OH structure in a formula (VI) in 5.0-8.0mL of anhydrous dichloromethane solution, adding 0.34-0.54mmol of trichloroacetonitrile, averagely dividing into 3 batches under ice bath, adding 0.34-0.54mmol of triphenylphosphine, rotating under the protection of nitrogen, reacting at room temperature for 6-8h, and purifying by silica gel column chromatography after the reaction is finished to obtain the pterodontic acid derivative with R6 as-Cl structure in the formula (VI);
the reaction (x) is specifically: dissolving 24.0-50.0mg of the pterodontic acid derivative with the R6 structure of-Cl in 4.4-6.0mL of anhydrous tetrahydrofuran solvent, adding 0.2-0.4mmol of sodium iodide, adding 0.2-0.4mmol of amine compound under ice bath after the sodium iodide is dissolved, reacting at room temperature for 12-18H under the protection of nitrogen, extracting the reaction solution for three times by DCM/H2O, drying the organic phase by anhydrous Na2SO4, filtering, concentrating under reduced pressure, and separating and purifying by column chromatography to obtain the pterodontic acid derivative with the R6 structure of morpholine, methylpiperazine and benzylamine in the formula (VI).
Further, it is preferable that the reaction (xi) is specifically: dissolving 70.0-100.0mg of a pterodontic acid derivative with R6 of-OH structure in 5.0-8.0mL of anhydrous dichloromethane solvent, adding 0.95-1.38mmol of triethylamine and 0.95-1.38mmol of propyl sulfonyl chloride under ice bath, carrying out reflux reaction for 6-8H under the protection of nitrogen, diluting the reaction liquid with 4.0-5.0mL of DCM, adding 1.0-2.0mL of saturated NaHCO3 for quenching, extracting for three times with DCM/H2O, drying the collected organic phase with anhydrous Na2SO4, filtering, concentrating under reduced pressure, and purifying by silica gel column chromatography to obtain the pterodontic acid derivative shown in formula (VIII);
reaction (xii) is specifically: dissolving 75.5-100.0mg of the pterodontic acid derivative with the structure of formula (VIII) in 2.0-3.0mL of anhydrous N, N-dimethylformamide solvent, slowly adding 0.51-0.68mmol of sodium azide, reacting for 2-3H at room temperature under the protection of nitrogen, diluting the reaction liquid with 2.0-3.0mL of EtOAc, adding 4.0-5.0mL of saturated NaCl solution, extracting for three times with EtOAc/H2O, drying the collected organic phase with anhydrous Na2SO4, filtering, concentrating under reduced pressure, and purifying by silica gel column chromatography to obtain the pterodontic acid derivative shown in formula (IX);
reaction (xiii) is specifically: dissolving 10.0-30.0mg of the pterodontic acid derivative with the structure of formula (IX) in 2.0-5.0mL of anhydrous tetrahydrofuran solvent, adding 0.08-0.24mmol of monosubstituted alkyne, 0.06-0.18mmol of anhydrous copper acetate, 0.08-0.24mmol of L-sodium ascorbate and 0.5-1.25mL of H2O, reacting at room temperature for 6-10H under the protection of nitrogen, diluting the reaction liquid with 2.0-5.0mL of EtOAc, washing an organic layer H2O twice, washing saturated NaCl twice, drying the collected organic phase with anhydrous Na2SO4, filtering, concentrating under reduced pressure, and purifying by silica gel column chromatography to obtain the pterodontic acid derivative shown in formula (X).
It will be understood by those skilled in the art that the specific amounts are not intended to limit the present invention, and that the same or similar amounts may be scaled up or down to fall within the scope of the present invention, e.g., by 100 times, by 2 times, etc.
The invention also provides application of the pterodontic acid derivative in preparing in-vitro anti-H1N 1 influenza A virus diseases.
Further, it is preferable that the drug for treating an influenza a H1N1 virus disease is a drug for treating viral lesions caused by an influenza a H1N1 virus.
Compared with the prior art, the invention has the beneficial effects that:
(1) the laggera acid derivative provided by the invention has better stability, shows good anti-influenza virus activity in vivo and in vitro, but cannot be directly used for treating influenza diseases. Therefore, the structure of the pterodontic acid is modified, and C-5, C-12 carbon-carbon double bond (C ═ C) and C-13 carboxylic acid (COOH) functional groups in the structure are modified, so that the pterodontic acid contributes to improving antiviral activity. The synthetic route has the advantages that: firstly, various groups such as amidation, esterification and the like can be introduced into carboxyl, the reaction rate is high, the efficiency is high, various groups are selected, and meanwhile, the invention uses condensing agents EDCI and DCC to synthesize the laggeramine derivative, so that the reaction steps are reduced and only 1 step is needed; the preparation method does not need heating reflux, and is carried out at room temperature, so that the universality is strong. Secondly, double bonds in the structure can be subjected to ring opening after being oxidized, and further undergo cyclization reaction with carboxylic acid in the structure, so that a plurality of reaction sites are provided. Thirdly, the pterodontic acid derivative which is synthesized by introducing hetero atoms and cyclization has novel structure and widens the design thought.
(2) The synthesis method is simple and easy to implement, and the yield is high and is about 80%.
(3) The pterodontic acid derivative synthesized by the invention has obvious significance in preparing drugs for treating influenza virus infectious diseases, has good inhibition effect and good stability, and is particularly used for treating influenza diseases caused by influenza A H1N1 virus (PR8 strain).
Drawings
FIG. 1 shows the structural formula and carbon number of Laggera acid;
FIG. 2 is a nuclear magnetic hydrogen spectrum of Compound 4;
FIG. 3 is a nuclear magnetic carbon spectrum of Compound 4;
FIG. 4 is the nuclear magnetic hydrogen spectrum of Compound 19;
FIG. 5 is a nuclear magnetic carbon spectrum of Compound 19;
FIG. 6 is a nuclear magnetic hydrogen spectrum of Compound 36;
FIG. 7 is a nuclear magnetic carbon spectrum of compound 36;
FIG. 8 is a nuclear magnetic hydrogen spectrum of Compound 39;
FIG. 9 is a nuclear magnetic carbon spectrum of Compound 39;
FIG. 10 is the nuclear magnetic hydrogen spectrum of compound 42;
FIG. 11 is a nuclear magnetic carbon spectrum of Compound 42;
FIG. 12 is a nuclear magnetic hydrogen spectrum of compound 44;
FIG. 13 is a nuclear magnetic carbon spectrum of compound 44;
FIG. 14 is a nuclear magnetic hydrogen spectrum of Compound 47;
FIG. 15 is a nuclear magnetic carbon spectrum of Compound 47;
FIG. 16 is a nuclear magnetic hydrogen spectrum of compound 54;
fig. 17 is a nuclear magnetic carbon spectrum of compound 54.
Detailed Description
The present invention will be described in further detail with reference to examples. But are not intended to limit the invention in any manner.
It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples do not specify particular techniques or conditions, and are performed according to the techniques or conditions described in the literature in the art or according to the product specifications. The materials or equipment used are not indicated by manufacturers, and all are conventional products available by purchase.
The ratio of the column chromatography eluting solvent in the present embodiment is not limited as long as separation and purification of the target substance can be achieved.
Instruments and materials:
the instrument comprises the following steps: BSA124S-CW electron analytical balance, from Sartorius, Germany; rotary evaporator, available from japan (EYELA-N-1100); SHZ-D (III) circulating water type vacuum pump, purchased from Zhang Yunhua instruments, Inc.; DLSB-5/25 cryogenic cooling circulation pump, available from Zhaohua instruments, Inc., of Onyuan city; a heated magnetic stirrer (RCT basic type) available from germany (Ika eca); AVANCE-400 NMR spectrometer, available from Bruker.
Materials: the laggera acid raw material is extracted and separated from laggera odorata in the subject group, and a GF-254 thin-layer chromatography plate is purchased from Qingdao ocean chemical engineering; column chromatography silica gel (200-; the chemical reactions all used analytically pure reagents, purchased from Shanghai Tantake technologies, Inc.; the column chromatography uses a redistilled technical grade reagent, purchased from Kunming Kernel reagent company; the color developing agent adopts 5% phosphomolybdic acid ethanol solution, improved bismuth potassium iodide solution and 5% sulfuric acid ethanol solution which are all self-made, and is heated and dried after being sprayed.
The structural formula of the pterodontic acid derivative is shown in the table 1.
TABLE 1 Lapteroguanic acid derivatives structural formula
EXAMPLE 1 Synthesis of Lapterostin acid 13-amidated derivative
Reaction (i) was carried out in this example: dissolving 50.0mg of tolindac with the structure of formula (A) in 5.0mL of anhydrous Dichloromethane (DCM) solvent, adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI,0.27mmol) as a condensing agent, 4-Dimethylaminopyridine (DMAP) catalyst (0.1mmol), and adding 0.25mmol of methylamine hydrochloride, ethylamine hydrochloride, allylamine, dimethylamine hydrochloride, diethylamine hydrochloride, diallylamine, 2, 4-dimethylhexylamine, cyclohexylamine, 2-methyl-2-imidazoline, 4-picolylamine, 4-methoxybenzylamine, 3-aminobenzylamine, methylbenzylamine, 3-chlorobenzylamine, 4-fluorobenzylamine, 4-bromobenzylamine, 4-hydroxybenzylamine, diphenylmethylamine, benzylamine, 4-methylbenzylamine, Phenethylamine, 2-furanmethylamine, 4- (trifluoromethyl) benzylamine, 3- (trifluoromethyl) benzylamine, 2-chlorobenzylamine, 2, 4-dichlorobenzylamine, acetamide, guanidine, morpholine and methylpiperazine, reacting for 4 hours at room temperature under the protection of nitrogen, monitoring the reaction process by thin layer chromatography, diluting the reaction solution with 4.0mL of EtOAc, adding 1.0mL of HCl with the volume concentration of 5%, extracting for three times with DCM/H2O, drying the organic phase with anhydrous Na2SO4, filtering, concentrating under reduced pressure, performing 200-300 mesh silica gel column chromatography, and separating and purifying by using petroleum ether-ethyl acetate to obtain compounds of formula (I) R1, wherein R1 is methylamino, ethylamino, allylamino, dimethylamino, diethylamino, diallylamino, 2, 4-dimethylhexylamino, cyclohexylamino, 2-methyl-2 imidazoline, 4-picolyl amino, 4-methoxybenzylamine group, 3-aminobenzylamine group, methylbenzylamine group, 3-chlorobenzylamine group, 4-fluorobenzylamine group, 4-bromobenzylamine group, 4-hydroxybenzylamine group, benzhydrylamine group, benzylamine group, 4-methylbenzylamine group, 2-phenethylamine group, 2-furanmethylamino group, 4- (trifluoromethyl) benzylamine group, 3- (trifluoromethyl) benzylamine group, 2-chlorobenzylamine group, 2, 4-dichlorobenzylamine group, acetamide group, guanylamine, morpholine and amide series compounds of methylpiperazine structure 1-31, the yield is more than or equal to 90%.
Example 2 Synthesis of Lapterostimul acid 13-amidated derivative
Reaction (i) was carried out in this example: dissolving 80.0mg of tolindac with the structure of formula (A) in 8.0mL of anhydrous Dichloromethane (DCM) solvent, adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI,0.43mmol) as a condensing agent, 4-Dimethylaminopyridine (DMAP) catalyst (0.2mmol), and adding 0.40mmol of methylamine hydrochloride, ethylamine hydrochloride, allylamine, dimethylamine hydrochloride, diethylamine hydrochloride, diallylamine, 2, 4-dimethylhexylamine, cyclohexylamine, 2-methyl-2-imidazoline, 4-picolylamine, 4-methoxybenzylamine, 3-aminobenzylamine, methylbenzylamine, 3-chlorobenzylamine, 4-fluorobenzylamine, 4-bromobenzylamine, 4-hydroxybenzylamine, diphenylmethylamine, benzylamine, 4-methylbenzylamine, Phenethylamine, 2-furanmethylamine, 4- (trifluoromethyl) benzylamine, 3- (trifluoromethyl) benzylamine, 2-chlorobenzylamine, 2, 4-dichlorobenzylamine, acetamide, guanidine, morpholine and methylpiperazine, reacting at room temperature for 6H under the protection of nitrogen, monitoring the reaction process by thin-layer chromatography, diluting the reaction solution with 5.0mL of EtOAc, adding 2.0mL of HCl with the volume concentration of 5%, extracting for three times with DCM/H2O, drying the organic phase with anhydrous Na2SO4, filtering, concentrating under reduced pressure, performing 200-300-mesh silica gel column chromatography, and separating and purifying by using petroleum ether-ethyl acetate to obtain compounds of formula (I) R1, wherein R1 is methylamino, ethylamino, allylamino, dimethylamino, diethylamino, diallylamino, 2, 4-dimethylhexylamino, cyclohexylamino, 2-methyl-2 imidazoline, 4-picolylamino, or the like, 4-methoxybenzylamine group, 3-aminobenzylamine group, methylbenzylamine group, 3-chlorobenzylamine group, 4-fluorobenzylamine group, 4-bromobenzylamine group, 4-hydroxybenzylamine group, benzhydrylamine group, benzylamine group, 4-methylbenzylamine group, 2-phenethylamine group, 2-furanmethylamino group, 4- (trifluoromethyl) benzylamine group, 3- (trifluoromethyl) benzylamine group, 2-chlorobenzylamine group, 2, 4-dichlorobenzylamine group, acetamide group, guanylamine, morpholine and amide series compounds of methylpiperazine structure 1-31, the yield is more than or equal to 90%.
EXAMPLE 3 Synthesis of Lapterostin acid 13-amidated derivative
Reaction (i) was carried out in this example: dissolving 60.0mg of tolindac with the structure of formula (A) in 6.0mL of anhydrous Dichloromethane (DCM) solvent, adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI,0.3mmol) as a condensing agent, 4-Dimethylaminopyridine (DMAP) catalyst (0.15mmol), and adding 0.35mmol of methylamine hydrochloride, ethylamine hydrochloride, allylamine, dimethylamine hydrochloride, diethylamine hydrochloride, diallylamine, 2, 4-dimethylhexylamine, cyclohexylamine, 2-methyl-2-imidazoline, 4-picolylamine, 4-methoxybenzylamine, 3-aminobenzylamine, methylbenzylamine, 3-chlorobenzylamine, 4-fluorobenzylamine, 4-bromobenzylamine, 4-hydroxybenzylamine, diphenylmethylamine, benzylamine, 4-methylbenzylamine, Phenethylamine, 2-furanmethylamine, 4- (trifluoromethyl) benzylamine, 3- (trifluoromethyl) benzylamine, 2-chlorobenzylamine, 2, 4-dichlorobenzylamine, acetamide, guanidine, morpholine and methylpiperazine, reacting at room temperature for 5 hours under the protection of nitrogen, monitoring the reaction process by thin layer chromatography, diluting the reaction solution with 4.5mL of EtOAc, adding 1.5mL of HCl with the volume concentration of 5%, extracting for three times with DCM/H2O, drying the organic phase with anhydrous Na2SO4, filtering, concentrating under reduced pressure, performing 200-300 mesh silica gel column chromatography, and separating and purifying by using petroleum ether-ethyl acetate to obtain compounds of formula (I) R1, wherein R1 is methylamino, ethylamino, allylamino, dimethylamino, diethylamino, diallylamino, 2, 4-dimethylhexylamino, cyclohexylamino, 2-methyl-2 imidazoline, 4-picolyl amino, 4-methoxybenzylamine group, 3-aminobenzylamine group, methylbenzylamine group, 3-chlorobenzylamine group, 4-fluorobenzylamine group, 4-bromobenzylamine group, 4-hydroxybenzylamine group, benzhydrylamine group, benzylamine group, 4-methylbenzylamine group, 2-phenethylamine group, 2-furanmethylamino group, 4- (trifluoromethyl) benzylamine group, 3- (trifluoromethyl) benzylamine group, 2-chlorobenzylamine group, 2, 4-dichlorobenzylamine group, acetamide group, guanylamine, morpholine and amide series compounds of methylpiperazine structure 1-31, the yield is more than or equal to 90%.
1H NMR(400MHz,CDCl3)6.17(1H,s),5.65(1H,s),5.26(1H,s),5.25(1H,s),3.28(1H,t,J＝8.1Hz),2.85(3H,d,J＝4.3Hz),2.45-2.49(1H,m),1.78-1.83(2H,m),1.52-1.58(4H,m),1.42-1.48(3H,m),1.15(3H,d,J＝8.2Hz),1.15(3H,s).
13C NMR(100MHz,CDCl3)169.4,149.7,149.2,123.2,117.5,41.8,41.2,40.3,38.1,34.4,33.1,27.0,26.1,25.6,23.1,17.4.
1H NMR(400MHz,CDCl3)6.10(1H,s),5.66(1H,s),5.26(2H,s),3.28-3.43(3H,m),2.46-2.49(1H,m),1.78-1.81(2H,m),1.52-1.57(4H,m),1.43-1.47(3H,m),1.16-1.19(9H,m).
13C NMR(100MHz,CDCl3)168.5,149.7,149.2,123.2,117.7,41.9,41.3,40.6,38.1,34.4,33.1,27.1,25.5,23.0,17.4,14.8.
The compound 3, N-allyl pterodonamide, C18H27NO was a colorless oil in 92% yield.
1H NMR(400MHz,CDCl3)6.10(1H,s),5.74-5.87(1H,m),5.62(1H,s),5.22(1H,s),5.19(1H,s),5.05(1H,t,J＝12.3Hz),3.86(2H,t,J＝4.4Hz),3.22-3.26(1H,m),2.38-2.41(1H,m),1.70(1H,m),1.45-1.52(4H,m),1.36-1.38(1H,m),1.08(3H,s),1.07(3H,d,J＝4.5Hz).
13C NMR(100MHz,CDCl3)168.4,149.8,149.1,134.1,123.1,118.0,116.6,42.03,41.9,41.3,40.6,38.1,34.4,33.1,27.1,25.6,23.0,17.4.
1H NMR(400MHz,CDCl3)5.18(1H,s),5.12(1H,s),4.95(1H,s),3.07-3.11(1H,m),2.97(1H,s),2.37-2.39(1H,m),1.71-1.78(2H,m),1.42-1.52(4H,m),1.32-1.37(3H,m),1.08(3H,s),1.07(3H,d,J＝4.4Hz).
13C NMR(100MHz,CDCl3)172.5,149.2,149.1,121.9,112.3,41.8,41.3,40.5,38.8,38.2,34.6,34.4,33.1,27.2,25.1,23.1,17.5.
1H NMR(400MHz,CDCl3)5.67-5.71(2H,m),5.01-5.18(7H,m),3.87-3.96(4H,m),3.09-3.13(1H,m),2.36-2.39(1H,m),1.69-1.78(2H,m),1.42-1.49(4H,m),1.33-1.39(3H,m),1.07(3H,s),1.06(3H,d,J＝8.2Hz).
13C NMR(100MHz,CDCl3)172.3,149.1,148.8,133.4,132.7,121.8,117.6,117.4,111.9,50.2,46.0,41.8,41.3,40.8,38.2,34.4,33.1,27.2,25.2,23.1,17.4.
13C NMR(100MHz,CDCl3)167.8,149.5,123.1,117.4,116.8,43.1,41.9,41.3,38.1,34.4,33.2,31.4,29.6,27.1,25.5,23.0,19.1,19.0,17.4,11.2,11.2,11.1.
The compound 7, N-cyclohexyl pterodonamide, C21H33NO was a white solid with a yield of 92%.
1H NMR(400MHz,CDCl3)5.81(1H,d,J＝8.3Hz),5.57(1H,s),5.19(1H,s),5.17(1H,s),3.74-3.78(1H,m),3.19-3.23(1H,m),2.39-2.41(1H,m),1.89-1.91(2H,m),1.63-1.74(5H,m),1.54-1.58(6H,m),1.25-1.38(6H,m),1.10(3H,s),1.09(3H,d,J＝8.5Hz).
13C NMR(100MHz,CDCl3)167.6,149.5,149.4,123.2,117.6,42.0,41.3,40.8,38.1,34.4,33.3,33.2,27.2,25.5,25.4,25.0,23.0,17.4.
1H NMR(400MHz,CDCl3)6.23(s,1H),5.61(s,1H),5.11(s,1H),3.22(s,1H),2.39(dd,J＝7.1,3.5Hz,1H),1.90(d,J＝9.7Hz,1H),1.74(s,1H),1.53–1.46(m,3H),1.44(s,1H),1.41–1.32(m,4H),1.18(s,4H),1.09(d,J＝7.7Hz,8H),0.81(s,1H).
13C NMR(100MHz,CDCl3)172.5,149.1,145.0,125.7,122.8,41.8,41.5,38.1,38.1,34.4,33.2,29.7,27.2,26.6,23.1,17.5.
1H NMR(400MHz,CDCl3)8.56(1H,s),8.52(1H,d,J＝4.6Hz),7.71(1H,d,J＝8.2Hz),7.30(1H,q,J＝4.2Hz),6.57(1H,s),5.74(1H,s),5.34(1H,s),5.24(1H,s),4.47-4.58(2H,m),3.29-3.33(1H,m),2.42-2.45(1H,m),1.74-1.82(2H,m),1.50-1.56(4H,m),1.41-1.45(3H,m),1.06(3H,s),1.04(3H,d,J＝8.3Hz).
13C NMR(100MHz,CDCl3)168.7,150.2,148.5,148.4,148.1,136.5,134.4,123.9,122.8,118.9,41.1,40.9,40.6,38.1,34.3,33.1,26.9,25.6,22.9,20.9,17.4.
1H NMR(400MHz,CDCl3)7.12(2H,d,J＝8.5Hz),6.75(2H,d,J＝8.2Hz),6.31(1H,s),5.61(1H,s),5.20(1H,s),5.15(1H,s),4.27-4.39(2H,m),3.70(3H,s),3.21-3.24(1H,m),2.32-2.355(1H,m),1.64-1.74(2H,m),1.40-1.46(4H,m),1.32-1.355(3H,m),1.03(1H,td,J＝12.2Hz,4Hz),0.97(3H,s),0.94(3H,d,J＝4.2Hz).
13C NMR(100MHz,CDCl3)168.3,159.0,149.8,149.1,130.4,129.3,123.0,118.0,114.0,55.2,43.1,41.9,41.3,40.6,38.1,34.3,33.1,26.9,25.6,22.9,17.4.
1H NMR(400MHz,CDCl3)7.02-6.98(1H,t,J＝8.6Hz),6.58-6.56(1H,d,J＝8.2Hz),6.52(1H,s),6.52-6.49(1H,d,J＝12.3Hz),6.29(1H,s),5.60(1H,s),5.21(1H,s),5.16(1H,s),4.30(2H,s),3.58(2H,s),3.25-3.22(1H,m),2.36-2.33(1H,m),1.75-1.69(2H,m),1.46-1.41(5H,m),1.35-1.33(3H,m),1.18(1H,s),1.11-1.03(1H,td,J＝12.2Hz,4Hz),0.99(3H,s),0.99-0.97(3H,d,J＝8.5Hz).
13C NMR(100MHz,CDCl3)168.5,149.8,149.2,146.8,139.3,129.6,123.0,118.0,117.9,114.6,114.2,43.7,41.9,41.3,40.5,38.1,34.3,33.1,27.0,25.7,22.9,17.4.
1H NMR(400MHz,CDCl3)7.24(5H,s),5.61-5.59(1H,d,J＝12.2Hz),5.19-5.15(3H,m),3.23-3.20(1H,m),2.37-2.34(1H,m),1.73-1.67(2H,m),1.47-1.43(7H,m),1.40-1.33(5H,m),1.08-1.04(5H,m),0.97-0.92(3H,m).
13C NMR(100MHz,CDCl3)167.7,149.8,149.1,143.0,128.6,127.3,126.3,126.2,123.0,118.1,48.7,42.0,41.3,40.7,38.1,34.4,33.2,27.2,25.6,22.8,21.3,17.4.
1H NMR(400MHz,CDCl3)7.18(1H,s),7.16-7.14(1H,m),7.10-7.07(1H,m),6.52(1H,s),5.64(1H,s),5.23(1H,m),5.16(1H,s),4.42-4.31(2H,m),3.25-3.21(1H,m),2.37-2.33(1H,m),1.74-1.66(2H,m),1.46-1.41(5H,m),1.35-1.33(3H,m),1.11-1.03(2H,td,J＝12.2Hz,4.3Hz),0.98(3H,s),0.97-0.95(3H,d,J＝8.5Hz).
13C NMR(100MHz,CDCl3)168.5,149.9,148.8,140.4,134.4,129.9,127.9,127.6,126.0,122.9,117.4,43.0,41.9,41.2,40.5,38.1,34.3,33.1,26.9,25.6,22.9,17.4.
1H NMR(400MHz,CDCl3)7.20-7.18(2H,d,J＝8.3Hz),7.13-7.11(2H,d,J＝8.2Hz),6.49(1H,s),5.62(1H,s),5.22(1H,s),5.15(1H,s),4.41-4.29(2H,m),3.24-3.20(1H,m),2.35-2.33(1H,m),1.71-1.66(2H,m),1.47-1.41(5H,m),1.35-1.32(3H,m),1.18(1H,s),1.11-1.03(1H,td,J＝12.4Hz,4Hz),0.97(3H,s),0.97-0.95(3H,d,J＝8.4Hz).
13C NMR(100MHz,CDCl3)168.5,149.9,148.9,136.9,133.2,129.2,128.7,122.9,118.3,42.8,41.9,41.2,40.5,38.1,34.3,33.1,26.9,25.6,22.9,17.4.
1H NMR(400MHz,CDCl3)7.35-7.33(2H,d,J＝8.5Hz),7.08-7.06(2H,d,J＝8.3Hz),6.49(1H,s),5.62(1H,s),5.22(1H,s),5.15(1H,s),4.39-4.28(2H,m),3.24-3.20(1H,m),2.26-2.33(1H,m),1.74-1.67(2H,m),1.47-1.41(5H,m),1.36-1.32(3H,m),1.18(1H,s),1.11-1.03(1H,td,J＝12.2Hz,4Hz),0.98(3H,s),0.98-0.96(3H,d,J＝8.4Hz).
13C NMR(100MHz,CDCl3)168.5,149.9,148.9,137.4,131.7,129.6,122.9,121.3,118.3,42.9,41.9,41.2,40.5,38.1,34.3,33.1,27.0,25.6,22.9,17.4.
Compound 16, N- (4-bromo) benzyl pterodonamide, C22H28BrNO white solid, 91% yield.
1H NMR(400MHz,CDCl3)7.21-7.17(2H,t,J＝8.2Hz),6.95-6.91(2H,t,J＝8.3Hz),6.27(1H,s),5.66(1H,s),5.24(1H,s),5.17(1H,s),4.45-4.33(2H,m),3.26-3.22(1H,m),2.36-2.33(1H,m),1.74-1.71(2H,m),1.47-1.42(5H,m),1.36-1.34(3H,m),1.18(1H,s),1.12-1.04(1H,td,J＝12.4Hz,4Hz),0.97(3H,s),0.96-0.94(3H,d,J＝8.3Hz).
13C NMR(100MHz,CDCl3)168.3,150.1,148.8,134.0,129.7,129.6,123.0,118.6,115.6,115.4,42.9,41.9,41.2,40.8,38.1,34.3,33.1,29.7,26.9,25.5,22.8,17.4.
Compound 17, N- (4-hydroxy) benzyl pterodonamide, C22H29NO2 as a white solid in 93% yield.
1H NMR(400MHz,CDCl3)7.25-7.23(2H,d,J＝8.6Hz),7.02-7.00(2H,d,J＝8.5Hz),6.31(1H,s),5.67(1H,s),5.23(1H,s),5.17(1H,s),4.47-4.36(2H,m),3.26-3.23(1H,m),2.38-2.34(1H,m),1.77-1.70(2H,m),1.47-1.45(5H,m),1.39-1.34(3H,m),1.18(1H,s),0.99(3H,s),0.99-0.97(3H,d,J＝8.3Hz).
13C NMR(100MHz,CDCl3)168.4,149.9,149.2,135.7,129.1,125.3,122.9,121.9,118.1,43.0,41.9,40.5,38.7,38.1,34.4,33.2,27.2,25.7,22.9,17.4.
Compound 18, N-benzhydryl pterodonamide, C28H33NO as a white solid in 91% yield.
1H NMR(400MHz,CDCl3)7.23-7.14(10H,m),6.50-6.48(1H,d,J＝8.4Hz),6.26-6.24(1H,d,J＝8.3Hz),5.63(1H,s),5.22(1H,s),5.18(1H,s),3.26-3.23(1H,m),2.36-2.32(1H,m),1.74-1.71(2H,m),1.53-1.39(4H,m),1.34-1.32(3H,m),1.18(1H,s),1.09-1.01(1H,td,J＝12.3Hz,4.2Hz),0.94-0.92(3H,d,J＝8.1Hz),0.90(3H,s).
13C NMR(100MHz,CDCl3)167.7,149.8,149.1,141.5,141.3,128.7,128.6,127.7,127.5,127.4,122.8,118.2,57.1,42.0,41.4,40.6,38.2,34.4,33.2,27.0,25.7,23.0,17.4.
Compound 19, N-benzyl pterodonamide, C22H29NO as a white solid in 91% yield.
1H NMR(400MHz,CDCl3)7.25-7.17(5H,m),6.35(1H,s),5.62(1H,s),5.21(1H,s),5.16(1H,s),4.46-4.34(2H,m),3.26-3.22(1H,m),2.36-2.32(1H,m),1.76-1.66(2H,m),1.50-1.40(4H,m),1.35-1.33(3H,m),1.18(1H,s),1.10-1.03(1H,td,J＝12.3Hz,4.4Hz),0.97(3H,s),0.96-0.94(3H,d,J＝8.4Hz).
13C NMR(100MHz,CDCl3)168.4,149.8,149.1,138.2,128.6,127.9,127.5,123.0,118.1,43.6,41.9,41.3,40.6,38.1,27.0,25.6,22.9,17.4.
1H NMR(400MHz,CDCl3)7.10-7.08(2H,d,J＝8.4Hz),7.05-7.03(2H,d,J＝8.3Hz),6.28(1H,s),5.60(1H,s),5.20(1H,s),5.15(1H,s),4.41-4.30(2H,m),3.25-3.21(1H,m),2.36-2.32(1H,m),2.24(3H,s),1.76-1.66(2H,m),1.46-1.41(4H,m),1.35-1.32(3H,m),1.18(1H,s),1.10-1.03(1H,td,J＝12.5Hz,4.2Hz),0.97(3H,s),0.96-0.94(3H,d,J＝8.1Hz).
13C NMR(100MHz,CDCl3)168.4,149.7,149.2,137.2,135.2,129.3,128.0,123.0,117.9,43.4,41.9,41.3,40.5,38.1,34.3,33.1,27.0,25.6,22.9,21.1,17.4.
The compound 21, N-phenethyl pterodonamide, C23H31NO was a colorless oil in 92% yield.
1H NMR(400MHz,CDCl3)7.23-7.10(5H,m),6.04(1H,s),5.47(1H,s),5.14(1H,s),5.12(1H,s),3.52-3.44(2H,m),3.21-3.18(1H,s),2.79-2.76(2H,m),2.35-2.33(1H,m),1.73-1.69(2H,m),1.47-1.45(3H,m),1.41-1.40(1H,m),1.37-1.32(4H,m),1.18(1H,s),1.11-1.04(1H,td,J＝12.4Hz,4Hz),1.03-1.02(3H,d,J＝4.2Hz),1.02(3H,s).
13C NMR(100MHz,CDCl3)168.8,149.6,149.5,139.0,128.8,128.6,126.5,122.9,117.0,41.9,41.3,40.8,40.0,38.1,35.7,34.4,33.1,27.1,25.7,23.1,17.4.
1H NMR(400MHz,CDCl3)6.36(1H,s),6.23-6.16(1H,d,J＝28.4Hz),5.66(1H,s),5.23(1H,s),5.17(1H,s),4.47-4.34(2H,m),3.24-3.20(1H,m),2.37-2.35(1H,m),1.73-1.69(2H,m),1.48-1.42(4H,m),1.38-1.34(3H,m),1.18(1H,s),1.10-1.00(3H,d,J＝4.4Hz),1.00(3H,s).
13C NMR(100MHz,CDCl3)168.2,151.0,150.1,148.5,142.1,123.0,118.9,110.4,107.7,41.9,41.2,40.8,38.1,36.5,34.3,33.1,26.9,25.5,22.8,17.4.
Compound 23, N- (4-trifluoromethyl) benzyl pterodonamide, C23H28F3NO was a yellow oil in 94% yield.
1H NMR(400MHz,CDCl3)7.50-7.48(2H,d,J＝8.3Hz),7.32-7.30(2H,d,J＝8.4Hz),6.54(1H,s),5.66(1H,s),5.25(1H,s),5.16(1H,s),4.4.47-4.43(2H,m),3.25-3.21(1H,m),2.35-2.33(1H,m),1.72-1.66(2H,m),1.47-1.41(5H,m),1.37-1.33(3H,m),1.18(1H,s),0.97(3H,s),0.96-0.94(3H,d,J＝8.3Hz).
13C NMR(100MHz,CDCl3)168.7,150.2,148.6,142.4,128.0,125.6,125.5,122.8,118.8,43.0,41.8,41.2,40.6,38.1,34.3,33.0,29.6,26.9,25.6,22.8,17.3.
Compound 24, N- (3-trifluoromethyl) benzyl pterodamine, C23H28F3NO as a yellow oil in 93% yield.
1H NMR(400MHz,CDCl3)7.44-7.35(4H,m),6.57(1H,s),5.66(1H,s),5.24(1H,s),5.16(1H,s),4.51-4.38(2H,m),3.25-3.21(1H,m),2.35-2.32(1H,m),1.72-1.64(2H,m),1.46-1.41(5H,m),1.35-1.32(3H,m),1.18(1H,s),1.10-1.03(1H,m),0.95(3H,s),0.94-0.92(3H,d,J＝8.4Hz).
13C NMR(100MHz,CDCl3)168.6,150.2,148.5,139.3,131.3,129.1,124.5,124.2,122.8,118.8,43.0,41.8,41.2,40.7,38.0,34.3,33.0,26.8,25.5,22.8,17.3.
1H NMR(400MHz,CDCl3)7.29-7.26(2H,m),7.14-7.12(2H,m),6.45(1H,s),5.60(1H,s),5.21(1H,s),5.14(1H,s),4.54-4.43(2H,m),3.24-3.20(1H,m),2.36-2.32(1H,m),1.75-1.66(2H,m),1.46-1.40(4H,m),1.36-1.32(3H,m),1.17(1H,s),1.10-1.03(1H,td,J＝12.3Hz,4.Hz),0.98(3H,s),0.98-0.96(3H,d,J＝8.1Hz).
13C NMR(100MHz,CDCl3)168.6,149.7,149.2,135.6,133.6,130.1,129.5,128.8,127.0,122.9,117.8,41.9,41.5,41.3,40.3,38.1,34.3,33.1,27.0,25.7,23.0,17.4.
Compound 26, N- (2, 4-dichloro) benzyl pterodonamide, C22H27Cl2NO as a white solid in 92% yield.
1H NMR(400MHz,CDCl3)7.28(1H,s),7.23-7.21(1H,d,J＝8.4Hz),7.12-7.10(1H,d,J＝8.3Hz),6.52(1H,s),5.60(1H,s),5.22(1H,s),5.13(1H,s),4.45-4.42(2H,m),3.23-3.19(1H,m),2.37-2.33(1H,m),1.72-1.67(2H,m),1.47-1.41(4H,m),1.36-1.32(3H,m),1.17(1H,s),1.10-1.03(1H,td,J＝12.1Hz,4.3Hz),1.00-0.99(3H,d,J＝4.2Hz),1.00(3H,s).
13C NMR(100MHz,CDCl3)168.7,149.9,149.0,134.3,134.1,133.9,130.9,129.2,127.3,122.8,118.0,41.9,41.2,40.9,40.2,38.1,34.3,33.1,27.0,25.7,23.0,17.4.
Compound 27, N-acetylpterostilbene amide, C17H25NO2 as a yellow solid, 92% yield.
1H NMR(400MHz,CDCl3)6.23(1H,s),5.61(1H,s),5.11(1H,s),3.24(1H,d,J＝9.5Hz),2.47–2.28(1H,m),2.00–1.81(1H,m),1.73(2H,dd,J＝10.9,5.6Hz),1.46(8H,dd,J＝28.2,23.1Hz),1.29–0.95(14H,m),0.82(1H,dd,J＝19.0,13.3Hz).
13C NMR(100MHz,CDCl3)172.5,149.1,145.0,125.8,122.8,41.8,41.5,38.1,38.1,34.4,33.2,29.7,27.2,26.6,23.1,17.5.
Compound 28, N-guanidinoitrinidamide, C16H25N3O as a yellow solid in 93% yield.
1H NMR(400MHz,CDCl3)6.30(1H,s),5.68(1H,s),5.19(1H,s),3.31(1H,d,J＝9.7Hz),2.53–2.42(1H,m),2.36(1H,s),1.96(1H,d,J＝9.2Hz),1.81(1H,s),1.67–1.53(4H,m),1.49(1H,d,J＝12.6Hz),1.43(4H,d,J＝7.0Hz),1.27(9H,d,J＝11.8Hz),1.16(8H,d,J＝7.7Hz),0.88(2H,s).
13C NMR(100MHz,CDCl3)172.1,149.1,144.9,125.7,122.8,41.8,41.5,38.2,38.1,34.4,33.2,29.7,27.2,26.6,23.1,17.5.
Compound 29, N-moroxydine tolfenpyrad, C19H29NO2 as a yellow oil in 93% yield.
1H NMR(400MHz,CDCl3)5.24(1H,s),5.22(1H,s),5.01(1H,s),3.68(9H,s),3.22–3.11(1H,m),2.56–2.38(1H,m),1.82(2H,d,J＝2.9Hz),1.55(5H,dd,J＝6.4,3.5Hz),1.44(3H,s),1.22–1.07(8H,m).
13C NMR(100MHz,CDCl3)170.9,141.5,119.5,84.0,77.3,77.0,76.7,74.0,41.3,39.3,36.5,35.7,35.5,29.2,24.7,19.9,16.8,16.7.
1H NMR(400MHz,CDCl3)5.26(1H,s),5.12(1H,),5.01(1H,s),3.43(4H,d,J＝5.9Hz),3.15(1H,dd,J＝9.1,7.2Hz),2.45(1H,dd,J＝7.2,3.8Hz),1.83(3H,dd,J＝5.8,3.4Hz),1.54(5H,dd,J＝6.2,3.3Hz),1.44(3H,d,J＝3.7Hz),1.14(14H,d,J＝5.7Hz).13C NMR(100MHz,CDCl3)153.6,148.6,123.4,108.6,77.3,77.2,77.0,76.7,64.6,41.9,41.6,41.3,38.1,34.3,33.2,27.2,25.9,23.1,17.5.
Compound 31, N- (4-methylpiperazine) pterodane amide, C20H32N2O brown oil, 94% yield.
1H NMR(400MHz,CDCl3)5.23(1H,d,J＝13.2Hz),5.19(1H,s),5.00(1H,s),3.80–3.52(4H,m),3.22–3.08(1H,m),2.59–2.38(5H,m),2.33(3H,s),2.03(1H,d,J＝12.1Hz),1.88–1.72(2H,m),1.62–1.47(4H,m),1.46–1.36(3H,m),1.25(1H,dd,J＝21.7,14.0Hz),1.18–1.02(7H,m).
13C NMR(100MHz,CDCl3)171.0,149.4,148.5,121.6,112.5,45.72,41.8,41.2,40.6,38.2,34.4,33.1,27.2,25.0,23.1,17.4.
Example 4 Synthesis of 13-esterified Lapterolic acid derivative
Reaction (ii) was carried out in this example: dissolving 50.0mg of laggerac acid with a structure shown in a formula (A) in 5.0mL of anhydrous dichloromethane solvent, adding dicyclohexylcarbodiimide (DCC,1.2mmol) serving as a condensing agent, adding 0.13mmol of methanol, n-amyl alcohol and benzyl alcohol into 4-Dimethylaminopyridine (DMAP) catalyst (0.1mmol), reacting at room temperature for 3 hours under the protection of nitrogen, monitoring the reaction process by thin-layer chromatography, diluting the reaction liquid with 4.0mL of EtOAc, adding 1.0mL of hydrochloric acid with a volume concentration of 5%, quenching, washing with EtOAc/H2O for three times, drying the collected organic phase by anhydrous Na2SO4, filtering, concentrating under reduced pressure, performing 200-300-mesh silica gel column chromatography, and separating and purifying by using petroleum ether-ethyl acetate to obtain 32-34 of laggerac acid ester series compounds with a structure shown in a formula (II) R2 being methyl, n-amyl and benzyl, wherein the yield is not less than 90%.
EXAMPLE 5 Synthesis of 13-esterified Lapterolic acid derivative
Reaction (ii) was carried out in this example: dissolving 80.0mg of pteridinium acid with a structure shown in formula (A) in 8.0mL of anhydrous dichloromethane solvent, adding dicyclohexylcarbodiimide (DCC,1.9mmol) serving as a condensing agent, adding 0.21mmol of methanol, n-amyl alcohol and benzyl alcohol into 4-Dimethylaminopyridine (DMAP) catalyst (0.2mmol), reacting at room temperature for 5 hours under the protection of nitrogen, monitoring the reaction process by thin-layer chromatography, diluting the reaction liquid with 5.0mL of EtOAc, adding 2.0mL of hydrochloric acid with the volume concentration of 5%, quenching, washing with EtOAc/H2O for three times, drying the collected organic phase by anhydrous Na2SO4, filtering, concentrating under reduced pressure, performing 200-300-mesh silica gel column chromatography, and separating and purifying by using petroleum ether-ethyl acetate to obtain 32-34 pteridinium acid ester series compounds with the structures shown in formula (II) R2 being methyl, n-amyl and benzyl, wherein the yield is not less than 90%.
EXAMPLE 6 Synthesis of 13-esterified Lapterolic acid derivative
Reaction (ii) was carried out in this example: dissolving 60.0mg of laggerac acid with a structure shown in a formula (A) in 7.0mL of anhydrous dichloromethane solvent, adding dicyclohexylcarbodiimide (DCC,1.7mmol) serving as a condensing agent, adding 0.2mmol of methanol, n-amyl alcohol and benzyl alcohol into 4-Dimethylaminopyridine (DMAP) catalyst (0.18mmol), reacting at room temperature for 4 hours under the protection of nitrogen, monitoring the reaction process by thin-layer chromatography, diluting the reaction liquid with 4.5mL of EtOAc, adding 1.5mL of hydrochloric acid with a volume concentration of 5%, quenching, washing with EtOAc/H2O for three times, drying the collected organic phase by anhydrous Na2SO4, filtering, concentrating under reduced pressure, performing 200-300-mesh silica gel column chromatography, and separating and purifying by using petroleum ether-ethyl acetate to obtain 32-34 of laggerac acid ester series compounds with a structure shown in a formula (II) R2 being methyl, n-amyl and benzyl, wherein the yield is not less than 90%.
Compound 32, methyl pterodontate, C16H24O2 white solid, yield 93%.
1H NMR(400MHz,CDCl3)6.14(1H,s),5.56(1H,s),5.17(1H,s),3.76(3H,s),3.30-3.32(1H,m),2.44-2.47(1H,m),1.90-1.94(1H,m),1.75-1.87(1H,m),1.54-1.57(3H,m),1.43-1.46(4H,m),1.15(3H,d,J＝8.2Hz),1.15(3H,s).
13C NMR(100MHz,CDCl3)167.7,148.7,145.6,123.3,123.0,51.7,41.8,41.5,38.6,38.1,34.3,33.2,27.2,26.6,23.2,17.5.
Compound 33, pterodontic acid pentyl ester, C20H32O2 as a colorless oil, 94% yield.
1H NMR(400MHz,CDCl3)6.13(1H,d,J＝0.8Hz),5.54(1H,d,J＝8.7Hz),5.18(1H,s),4.15(2H,t,J＝6.7Hz),3.76(1H,s),3.32(1H,d,J＝9.7Hz),2.52–2.37(1H,m),2.00–1.87(1H,m),1.87–1.72(1H,m),1.67(2H,dt,J＝17.4,8.7Hz),1.59–1.52(2H,m),1.49(1H,d,J＝9.6Hz),1.47–1.39(4H,m),1.37(4H,dd,J＝11.1,7.6Hz),1.16(7H,d,J＝8.3Hz),0.91(3H,dd,J＝13.6,6.6Hz).
13C NMR(100MHz,CDCl3)167.3,148.7,145.9,123.1,122.9,64.7,41.8,41.5,38.5,38.1,34.4,33.2,28.3,28.1,27.2,26.6,23.2,22.3,17.5,13.9.
Compound 34, benzol pterodontate, C22H28O2 as a colorless oil in 95% yield.
1H NMR(400MHz,CDCl3)7.32-7.38(5H,m),6.19(1H,s),5.58(1H,s),5.21(2H,s),5.17(1H,s),3.30-3.36(1H,m),2.43-2.47(1H,m),1.92-1.96(1H,m),1.74-1.83(2H,m),1.54-1.56(3H,m),1.40-1.45(4H,m),1.14(3H,d,J＝8.2Hz),1.13(3H,s).
13C NMR(100MHz,CDCl3)167.0,148.3,145.6,136.1,128.5,128.1,128.0,123.7,123.0,66.3,41.8,41.5,38.5,38.1,34.4,33.2,27.2,26.7,23.2,17.5.
Example 7 Synthesis of derivatives of modified pterodontic acid with double bond at position 5
Reaction (iii) was carried out in this example: dissolving 50.0mg of the pteridinoic acid derivative with the structure of methyl, n-amyl or benzyl in 4.0mL of anhydrous dichloromethane solvent, adding an oxidant of peroxybenzoic acid (m-CPBA,0.24mmol), and reacting at room temperature for 0.5h under the protection of nitrogen. Adding 1.0mL of saturated NaHCO3 into the reaction liquid for quenching, washing the reaction liquid for three times by DCM/H2O, drying an organic phase by anhydrous Na2SO4, filtering, concentrating under reduced pressure, carrying out silica gel column chromatography by 200-300 meshes, and separating and purifying by using petroleum ether-ethyl acetate to obtain 35-37 of the pterodontic acid oxidized ester compound with the R3 of the formula (III) being methyl, n-pentyl and benzyl structures, wherein the yield is more than or equal to 90%.
EXAMPLE 8 Synthesis of modified Laggera acid 5-position double bond derivative
Reaction (iii) was carried out in this example: 80.0mg of the pteridinoic acid derivative with the structure of methyl, n-amyl or benzyl in the formula (II) R2 is dissolved in 6.0mL of anhydrous dichloromethane solvent, an oxidant of peroxybenzoic acid (m-CPBA,0.38mmol) is added, and the reaction is carried out for 1.0h at room temperature under the protection of nitrogen. Adding 2.0mL of saturated NaHCO3 into the reaction liquid for quenching, washing the reaction liquid for three times by DCM/H2O, drying an organic phase by anhydrous Na2SO4, filtering, concentrating under reduced pressure, carrying out silica gel column chromatography by 200-300 meshes, and separating and purifying by using petroleum ether-ethyl acetate to obtain 35-37 of the pterodontic acid oxidized ester compound with the R3 of the formula (III) being methyl, n-pentyl and benzyl structures, wherein the yield is more than or equal to 90%.
EXAMPLE 9 Synthesis of modified Laggera acid 5-position double bond derivative
Reaction (iii) was carried out in this example: dissolving 65.0mg of the pterodontic acid derivative with the structure of methyl, n-amyl or benzyl in 5.0mL of anhydrous dichloromethane solvent, adding an oxidant of peroxybenzoic acid (m-CPBA,0.30mmol), and reacting at room temperature for 0.8h under the protection of nitrogen. Adding 1.5mL of saturated NaHCO3 into the reaction liquid for quenching, washing the reaction liquid for three times by DCM/H2O, drying an organic phase by anhydrous Na2SO4, filtering, concentrating under reduced pressure, carrying out silica gel column chromatography by 200-300 meshes, and separating and purifying by using petroleum ether-ethyl acetate to obtain 35-37 of the pterodontic acid oxidized ester compound with the R3 of the formula (III) being methyl, n-pentyl and benzyl structures, wherein the yield is more than or equal to 90%.
1H NMR(400MHz,CDCl3)6.23(1H,s),5.65(1H,s),3.79(3H,s),3.04-3.09(1H,m),2.83(1H,s),1.82-1.92(2H,m),1.57-1.70(3H,m),1.43-1.52(4H,m),1.33(2H,d,J＝12.3Hz),1.22(3H,s),1.19(3H,d,J＝8.1Hz).
13C NMR(100MHz,CDCl3)166.9,143.6,125.3,67.7,63.3,51.8,38.1,37.8,37.62,35.7,33.1,29.7,23.9,21.6,17.6,17.3.
Compound 36, benzyl 5, 6-epoxy-ozonide benzoate, C22H28O3 was a pale yellow oil, yield 94%.
1H NMR(400MHz,CDCl3)7.33-7.38(5H,m),6.28(1H,s),5.66(1H,s),5.22(2H,s),3.09(1H,t,J＝8.3Hz),2.84(1H,s),1.77-1.90(2H,m),1.62-1.72(2H,m),1.41-1.51(4H,m),1.33-1.36(2H,d,J＝12.2Hz),1.20(3H,s),1.16(3H,d,J＝4.1Hz).
13C NMR(100MHz,CDCl3)166.2,143.9,135.9,128.5,128.5,128.2,128.1,128.1,125.2,67.8,66.5,63.2,38.1,37.6,37.3,35.7,33.1,29.8,24.1,21.7,17.7,17.3.
The compound 37, 5, 6-epoxy pterodontic acid amyl ester, C20H32O3 was a pale yellow oil, 93% yield.
1H NMR(400MHz,CDCl3)6.22(1H,s),5.63(1H,s),4.17(2H,t,J＝6.7Hz),3.09(1H,dd,J＝10.2,8.5Hz),2.84(1H,s),1.86(3H,d,J＝8.6Hz),1.78–1.56(6H,m),1.46(5H,ddd,J＝14.6,14.0,7.7Hz),1.41–1.26(8H,m),1.18(3H,d,J＝7.7Hz),0.92(4H,t,J＝6.8Hz).
13C NMR(100MHz,CDCl3)166.5,144.2,124.5,67.7,64.9,63.3,38.0,37.6,37.2,35.7,33.1,29.7,28.3,28.1,24.1,22.3,21.7,17.6,17.3,13.9.
Example 10 Synthesis of Lapterostilic acid derivative of formula (III) wherein R3 is-H
Reaction (iv) was carried out in this example: dissolving 500.0mg of the pterodontic acid with the structure of the formula (A) in 10.0mL of anhydrous dichloromethane solvent, adding an oxidant m-chloroperoxybenzoic acid (m-CPBA,2.57mmol), and reacting at room temperature for 1.0h under the protection of nitrogen. Adding 2.0mL of saturated NaHCO3 into the reaction liquid for quenching, washing the reaction liquid for three times by DCM/H2O, drying an organic phase by anhydrous Na2SO4, filtering, concentrating under reduced pressure, carrying out silica gel column chromatography by 200-300 meshes, and separating and purifying by using petroleum ether-ethyl acetate to obtain the pterodontic acid derivative with the structure of-H in the formula (III) R3. C15H22O3 white solid, and the yield is more than or equal to 90 percent.
Example 11 Synthesis of Lapterolic acid derivative of formula (III) wherein R3 is-H
Reaction (iv) was carried out in this example: dissolving 600.0mg of the pterodontic acid with the structure of the formula (A) in 12.0mL of anhydrous dichloromethane solvent, adding an oxidant m-chloroperoxybenzoic acid (m-CPBA,3.08mmol), and reacting for 1.5h at room temperature under the protection of nitrogen. Adding 3.0mL of saturated NaHCO3 into the reaction liquid for quenching, washing the reaction liquid for three times by DCM/H2O, drying an organic phase by anhydrous Na2SO4, filtering, concentrating under reduced pressure, carrying out silica gel column chromatography by 200-300 meshes, and separating and purifying by using petroleum ether-ethyl acetate to obtain the pterodontic acid derivative with the structure of-H in the formula (III) R3. C15H22O3 white solid, and the yield is more than or equal to 90 percent.
Example 12 Synthesis of Lapterostilic acid derivative of formula (III) wherein R3 is-H
Reaction (iv) was carried out in this example: 550.0mg of the pterodontic acid with the structure of the formula (A) is dissolved in 11.0mL of anhydrous dichloromethane solvent, an oxidant m-chloroperoxybenzoic acid (m-CPBA,2.8mmol) is added, and the reaction is carried out for 1.3h at room temperature under the protection of nitrogen. Adding 2.5mL of saturated NaHCO3 into the reaction liquid for quenching, washing the reaction liquid for three times by DCM/H2O, drying an organic phase by anhydrous Na2SO4, filtering, concentrating under reduced pressure, carrying out silica gel column chromatography by 200-300 meshes, and separating and purifying by using petroleum ether-ethyl acetate to obtain the pterodontic acid derivative with the structure of-H in the formula (III) R3. C15H22O3 white solid, and the yield is more than or equal to 90 percent.
1H NMR(400MHz,CDCl3)6.07(1H,s),5.53(1H,s),3.99(1H,d,J＝4.2Hz),3.24-3.30(1H,m),1.98-2.06(1H,m),1.75-1.92(4H,m),1.51-1.68(4H,m),1.42-1.45(3H,m),1.36(3H,d,J＝8.0Hz),1.19(3H,s),0.92(1H,dd,J＝60.2Hz,12.1Hz).
13C NMR(100MHz,CDCl3)170.9,141.5,119.5,84.0,74.0,41.3,39.3,36.5,35.7,35.5,29.2,24.7,19.9,16.8,16.7.
Example 13 Synthesis of Lapterostimulic acid derivative represented by formula (IV)
This example was run for reaction (v): dissolving 50.0mg of pteridinoic acid derivative with a structure R3 of-H in 5.0mL of anhydrous dichloromethane solvent, adding a condensing agent 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI,0.2mmol) and a catalyst 4-dimethylaminopyridine (DMAP,0.1mmol), respectively adding 0.25mmol of morpholine and methylpiperazine, reacting at room temperature for 4 hours under the protection of nitrogen, monitoring the reaction process by thin layer chromatography, diluting the reaction solution with 4.0mL of EtOAc, adding 1.0mL of HCl with the volume concentration of 5% for quenching, extracting for three times with DCM/H2O, drying an organic phase with anhydrous Na2SO4, filtering, concentrating under reduced pressure, carrying out silica gel column chromatography with 200-300 meshes, separating and purifying by dichloromethane-methanol to obtain (IV) pterosin series compounds 39-40 with the structure of R4 of morpholine and methylpiperazine, wherein the yield is more than or equal to 90%.
EXAMPLE 14 Synthesis of a Lapterostilic acid derivative represented by the formula (IV)
This example was run for reaction (v): dissolving 80.0mg of pteridinoic acid derivative with a structure R3 of-H in 8.0mL of anhydrous dichloromethane solvent, adding a condensing agent 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI,0.3mmol) and a catalyst 4-dimethylaminopyridine (DMAP,0.2mmol), respectively adding 0.40mmol of morpholine and methylpiperazine, reacting at room temperature for 5 hours under the protection of nitrogen, monitoring the reaction process by thin layer chromatography, diluting the reaction solution with 5.0mL of EtOAc, adding 2.0mL of HCl with the volume concentration of 5% for quenching, extracting for three times with DCM/H2O, drying an organic phase with anhydrous Na2SO4, filtering, concentrating under reduced pressure, carrying out silica gel column chromatography with 200-300 meshes, separating and purifying by dichloromethane-methanol to obtain (IV) pterosin series compounds 39-40 with the structure of R4 of morpholine and methylpiperazine, wherein the yield is more than or equal to 90%.
EXAMPLE 15 Synthesis of a Lapterostilic acid derivative represented by the formula (IV)
This example was run for reaction (v): dissolving 75.0mg of pteridinoic acid derivative with a structure R3 of-H in 6.0mL of anhydrous dichloromethane solvent, adding a condensing agent 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI,0.25mmol) and a catalyst 4-dimethylaminopyridine (DMAP,0.17mmol), respectively adding 0.33mmol of morpholine and methylpiperazine, reacting at room temperature for 4.5H under the protection of nitrogen, monitoring the reaction process by thin layer chromatography, diluting the reaction solution with 4.5mL of EtOAc, adding 1.5mL of HCl with the volume concentration of 5% for quenching, extracting for three times with DCM/H2O, drying an organic phase with anhydrous Na2SO4, filtering, concentrating under reduced pressure, performing 200-300-mesh silica gel column chromatography, and separating and purifying by dichloromethane-methanol to obtain (IV) pteridamine series compounds with the structure of morpholine and methylpiperazine, wherein R4 is 39-40, and the yield is not less than 90%.
The compound 39, 5, 6-epoxy-12-N-morpholine-pterodontic acid, C19H31NO4 was a colorless oil in 92% yield.
1H NMR(400MHz,CDCl3)3.96(1H,d,J＝4.2Hz),3.67-3.74(4H,m),2.80-2.89(2H,m),2.71(1H,dd,J＝16.1Hz,4.3Hz),2.55-2.58(2H,m),2.41-2.43(2H,m),1.97-2.05(1H,m),1.76-1.87(3H,m),1.59-1.65(2H,m),1.36-1.45(2H,m),1.31(3H,d,J＝8.0Hz),1.17(3H,s).
13C NMR(100MHz,CDCl3)177.7,85.1,74.3,66.8,53.6,44.0,41.2,37.4,36.4,36.1,35.7,29.1,19.9,18.5,16.8,16.7.
The compound 40, 5, 6-epoxy-12-N- (4-methylpiperazine) pterodontic acid, C20H34N2O3 was yellow oil in 91% yield.
1H NMR(400MHz,CDCl3)8.20(1H,s),6.51(1H,s),3.97(1H,d,J＝3.5Hz),3.01(4H,s),2.91–2.65(3H,m),2.58(3H,dd,J＝12.7,10.3Hz),2.45(4H,s),2.28(2H,s),2.05(1H,ddd,J＝13.6,11.5,4.6Hz),1.82(2H,td,J＝13.5,3.8Hz),1.64(1H,ddd,J＝12.8,9.9,3.0Hz),1.41(1H,dd,J＝13.5,10.1Hz),1.33–1.21(3H,m),1.16(2H,s),1.01(2H,dd,J＝36.8,12.9Hz).
13C NMR(101MHz,CDCl3)178.0,85.2,77.3,77.0,76.7,74.2,55.0,52.8,45.9,44.4,41.1,39.0,37.5,36.4,36.1,35.7,29.1,20.0,18.5,16.8,16.7.
EXAMPLE 16 Synthesis of pterodontic acid derivative represented by the formula (V)
This example was run for reaction (vi): dissolving 50.0mg of the pterodontic acid derivative with the structure R3 of-H in 5.0mL of anhydrous dichloromethane solvent, adding boron trifluoride-diethyl ether (BF3-Et2O,0.2mmol) in an ice bath, reacting for 4 hours in the ice bath under the protection of nitrogen, monitoring the reaction process by thin layer chromatography, diluting the reaction liquid with 4.0mL of EtOAc, quenching with 1.0mL of saturated NH4Cl solution, extracting for three times with EtOAc/H2O, drying the organic phase with anhydrous Na2SO4, filtering, concentrating under reduced pressure, performing 200-300-mesh silica gel column chromatography, and separating and purifying by using petroleum ether-ethyl acetate to obtain the pterodontic acid derivative with the structure R5 of-OH, C15H22O3, a yellow oily substance and the yield of 82%.
EXAMPLE 17 Synthesis of pterodontic acid derivative represented by the formula (V)
This example was run for reaction (vi): dissolving 80.0mg of the pterodontic acid derivative with the structure R3 of-H in 8.0mL of anhydrous dichloromethane solvent, adding boron trifluoride-diethyl ether (BF3-Et2O,0.3mmol) in an ice bath, reacting for 5H in the ice bath under the protection of nitrogen, monitoring the reaction process by thin layer chromatography, diluting the reaction liquid with 5.0mL of EtOAc, quenching with 2.0mL of saturated NH4Cl solution, extracting for three times with EtOAc/H2O, drying the organic phase with anhydrous Na2SO4, filtering, concentrating under reduced pressure, performing 200-300-mesh silica gel column chromatography, and separating and purifying by using petroleum ether-ethyl acetate to obtain the pterodontic acid derivative with the structure R5 of-OH, C15H22O3, a yellow oily substance and the yield of 81%.
EXAMPLE 18 Synthesis of pterodontic acid derivative represented by the formula (V)
This example was run for reaction (vi): 60.0mg of the pterodontic acid derivative with the structure R3 of-H in the formula (III) is dissolved in 7.0mL of anhydrous dichloromethane solvent, boron trifluoride-diethyl ether (BF3-Et2O,0.25mmol) is added in an ice bath, the mixture reacts in the ice bath for 4.6H under the protection of nitrogen, the reaction process is monitored by thin layer chromatography, the reaction solution is diluted by 4.5mL of EtOAc, 1.3mL of saturated NH4Cl solution is quenched, the EtOAc/H2O is extracted for three times, an organic phase is dried by anhydrous Na2SO4, filtered, concentrated under reduced pressure, subjected to 200-300 meshes of silica gel column chromatography and separated and purified by petroleum ether-ethyl acetate to obtain the pterodontic acid derivative with the structure R5 of-OH in the formula (V), C15H22O3, yellow oily matter and 82% yield.
The compound 41, 5-hydroxy-6-O-laggera lactone, C15H22O3 was a yellow oil in 82% yield.
1H NMR(400MHz,CDCl3)6.46(1H,s),5.54(1H,s),2.93(1H,s),2.21(1H,ddd,J＝12.6,6.4,4.1Hz),2.04(1H,dd,J＝14.0,2.8Hz),1.97–1.75(4H,m),1.71–1.60(2H,m),1.54(4H,t,J＝12.4Hz),1.28–1.14(4H,m),1.08(4H,d,J＝7.9Hz),0.88(3H,d,J＝6.7Hz).
13C NMR(100MHz,CDCl3)166.5,139.1,127.2,87.9,38.5,34.8,34.3,34.1,32.7,31.3,29.2,24.8,21.9,20.8,15.1.
Example 19 Synthesis of a derivative of pterodontic acid of formula (VI) wherein R6 is-OH
This example carried out reaction (vii): dissolving 100.0mg of pteridinoic acid with the structure of formula (A) in 10.0mL of anhydrous Tetrahydrofuran (THF) solvent, adding 0.45mmol of reducing agent lithium aluminum hydride (LAH.) in 3 batches averagely in an ice bath under the protection of nitrogen, carrying out reflux reaction at 70 ℃ for 12h after completely mixing, and monitoring the reaction process by thin-layer chromatography. Adding 3.0mL of 15% sodium hydroxide solution and 3.0mL of H2O under ice bath for quenching, filtering by using kieselguhr, extracting by using EtOAc/H2O for three times, drying an organic phase by using anhydrous Na2SO4, filtering, concentrating under reduced pressure, performing 200-300-mesh silica gel column chromatography, and separating and purifying by using petroleum ether-ethyl acetate to obtain the pterodontic acid derivative with the structure of-OH as R6 in the formula (VI), wherein C15H24O is colorless oily matter, and the yield is 73%.
Example 20 Synthesis of a derivative of pterodontic acid of formula (VI) wherein R6 is-OH
This example carried out reaction (vii): dissolving 300.0mg of pteridinoic acid with the structure of formula (A) in 20.0mL of anhydrous Tetrahydrofuran (THF) solvent, adding 1.34mmol of reducing agent lithium aluminum hydride (LAH.) in 3 batches averagely in an ice bath under the protection of nitrogen, carrying out reflux reaction at 70 ℃ for 18h after completely mixing, and monitoring the reaction process by thin layer chromatography. Adding 6.0mL of 15% sodium hydroxide solution and 6.0mL of H2O under ice bath for quenching, filtering by using kieselguhr, extracting by using EtOAc/H2O for three times, drying an organic phase by using anhydrous Na2SO4, filtering, concentrating under reduced pressure, performing 200-300-mesh silica gel column chromatography, and separating and purifying by using petroleum ether-ethyl acetate to obtain the pterodontic acid derivative with the structure of-OH as R6 in the formula (VI), wherein C15H24O is colorless oily matter, and the yield is 72%.
Example 21 Synthesis of a derivative of pterodontic acid of formula (VI) wherein R6 is-OH
This example carried out reaction (vii): dissolving 200.0mg of pteridinoic acid with the structure of formula (A) in 15.0mL of anhydrous Tetrahydrofuran (THF) solvent, adding 1.10mmol of reducing agent lithium aluminum hydride (LAH.) in 3 batches averagely in an ice bath under the protection of nitrogen, carrying out reflux reaction at 70 ℃ for 14h after completely mixing, and monitoring the reaction process by thin-layer chromatography. Adding 5.0mL of 15% sodium hydroxide solution and 5.0mL of H2O under ice bath for quenching, filtering by using kieselguhr, extracting by using EtOAc/H2O for three times, drying an organic phase by using anhydrous Na2SO4, filtering, concentrating under reduced pressure, performing 200-300-mesh silica gel column chromatography, and separating and purifying by using petroleum ether-ethyl acetate to obtain the pterodontic acid derivative with the structure of-OH as R6 in the formula (VI), wherein C15H24O is colorless oily matter, and the yield is 73%.
Compound 42, prodigiosin, C15H24O as a colorless oil in 73% yield.
1H NMR(400MHz,CDCl3)5.21(1H,s),5.02(1H,d,J＝4.3Hz),4.93(1H,s),4.14(2H,d,J＝4.2Hz),2.87-2.91(1H,m),2.42-2.46(1H,m),1.74-1.83(2H,m),1.50-1.56(4H,m),1.38-1.45(4H,m),1.16 3H,s),1.14(3H,d,J＝8.0Hz),0.87(1H,m).
13C NMR(100MHz,CDCl3)153.6,148.6,123.4,108.6,64.6,41.9,41.6,41.3,38.1,34.3,33.2,27.2,25.9,23.1,17.5.
EXAMPLE 22 Synthesis of pteridinoate derivatives of formula (VII)
This example carried out reaction (viii): dissolving 20.0mg of a pteridinoic acid derivative with a structure represented by formula (VI) R6-OH in 2.0mL of anhydrous dichloromethane solvent, adding a condensing agent dicyclohexylcarbodiimide (DCC,1.08mmol) and a catalyst 4-dimethylaminopyridine (DMAP,0.018mmol), respectively adding n-butyric acid, benzoic acid and 2-methylbenzoic acid (0.135mmol), reacting at room temperature for 3H under the protection of nitrogen, monitoring the reaction process by thin-layer chromatography, diluting the reaction solution with 2.0mL of EtOAc, quenching with 2.0mL of hydrochloric acid with the volume concentration of 5%, washing with EtOAc/H2O for three times, drying the collected organic phase with anhydrous Na2SO4, filtering, concentrating under reduced pressure, performing 200-300-mesh silica gel column chromatography, and separating and purifying by using petroleum ether-ethyl acetate to obtain a pteridinoic acid ester series compound 43-45 with a structure represented by formula (VII) R7 of n-butyl, phenyl and 2-methylphenyl, the yield is more than or equal to 90 percent.
EXAMPLE 23 Synthesis of pteridinoate derivatives of formula (VII)
This example carried out reaction (viii): dissolving 50.0mg of a pteridinoic acid derivative with a structure represented by formula (VI) R6-OH in 4.0mL of anhydrous dichloromethane solvent, adding a condensing agent dicyclohexylcarbodiimide (DCC,2.70mmol) and a catalyst 4-dimethylaminopyridine (DMAP,0.045mmol), respectively adding n-butyric acid, benzoic acid and 2-methylbenzoic acid (-0.338mmol), reacting at room temperature for 5 hours under the protection of nitrogen, monitoring the reaction process by thin-layer chromatography, diluting the reaction solution with 4.0mL of EtOAc, quenching with 2.0mL of hydrochloric acid with the volume concentration of 5%, washing with EtOAc/H2O for three times, drying the collected organic phase with anhydrous Na2SO4, filtering, concentrating under reduced pressure, performing 200-300-mesh silica gel column chromatography, separating and purifying by using petroleum ether-ethyl acetate to obtain pteridinoic acid ester series compounds 43-45 with the structure represented by formula (VII) R7 of n-butyl, phenyl and 2-methylphenyl, the yield is more than or equal to 90 percent.
EXAMPLE 24 Synthesis of pteridinoate derivatives of formula (VII)
This example carried out reaction (viii): dissolving 40.0mg of a pteridinoic acid derivative with a structure represented by formula (VI) R6-OH in 3.0mL of anhydrous dichloromethane solvent, adding a condensing agent dicyclohexylcarbodiimide (DCC,2mmol) and a catalyst 4-dimethylaminopyridine (DMAP,0.035mmol), respectively adding n-butyric acid, benzoic acid and 2-methylbenzoic acid (0.200mmol), reacting at room temperature for 4H under the protection of nitrogen, monitoring the reaction process by thin-layer chromatography, diluting the reaction solution with 3.0mL of EtOAc, quenching 1.5mL of hydrochloric acid with the volume concentration of 5%, washing with EtOAc/H2O for three times, drying the collected organic phase with anhydrous Na2SO4, filtering, concentrating under reduced pressure, performing silica gel column chromatography with 200-300 meshes, and separating and purifying by using petroleum ether-ethyl acetate to obtain a pteridinic acid ester series compound 43-45 with the structure represented by formula (VII) R7 being n-butyl, phenyl and 2-methylphenyl, the yield is more than or equal to 90 percent.
Compound 43, valeryl pterodontol, C20H32O2 as a colorless oil in 93% yield.
1H NMR(400MHz,CDCl3)5.21(1H,s),5.00(1H,s),4.98(1H,s),4.52-4.62(2H,m),2.85-2.89(1H,m),2.42-2.44(1H,m),2.29-2.37(2H,m),1.78-1.80(2H,m),1.59-1.65(2H,m),1.50-1.56(4H,m),1.41-1.45(3H,m),1.35-1.39(2H,m),1.15(3H,s),1.14(3H,d,J＝4.3Hz),0.90(1H,t,J＝8.2Hz).
13C NMR(100MHz,CDCl3)173.5,148.8,148.6,123.0,111.3,65.3,41.9,41.5,38.1,34.1,33.2,27.2,27.0,23.1,22.2,17.5,13.7.
Compound 44, benzoylozonidanol, C22H28O2 as a colorless oil in 93% yield.
1H NMR(400MHz,CDCl3)8.17–7.98(3H,m),8.12–7.99(3H,m),7.56(2H,t,J＝6.8Hz),7.56(2H,t,J＝6.8Hz),7.45(2H,d,J＝7.3Hz),7.44(3H,t,J＝7.4Hz),5.27(1H,s),5.27(1H,s),5.12(1H,s),5.12(1H,s),5.05(1H,s),5.05(1H,s),4.83(2H,q,J＝13.5Hz),4.83(2H,q,J＝13.5Hz),3.92(1H,s),3.92(1H,s),2.96(1H,dd,J＝9.0,7.3Hz),2.96(1H,dd,J＝9.0,7.3Hz),2.44(1H,dd,J＝6.9,3.1Hz),2.44(1H,dd,J＝6.9,3.1Hz),1.92–1.73(3H,m),1.90–1.72(3H,m),1.68–1.58(2H,m),1.67–1.58(2H,m),1.59–1.48(5H,m),1.52(5H,dd,J＝24.1,9.4Hz),1.44(4H,t,J＝12.5Hz),1.44(4H,t,J＝12.5Hz),1.32–1.24(2H,m),1.30–1.22(2H,m),1.16(10H,dd,J＝11.1,8.5Hz),1.16(10H,dd,J＝11.1,8.5Hz).
13C NMR(100MHz,CDCl3)166.3,148.9,148.5,132.9,132.9,130.2,129.6,129.5,129.5,128.3,123.0,111.7,66.0,41.9,41.5,41.4,38.1,34.3,33.2,27.2,25.9,23.1,17.5.
Compound 45, 2-methyl-benzoylozonidanol, C23H30O2 as a colorless oil in 93% yield.
1H NMR(400MHz,CDCl3)8.05(1H,d,J＝7.8Hz),8.04–7.88(1H,m),7.50(1H,t,J＝7.4Hz),7.40(1H,t,J＝7.3Hz),7.35–7.30(2H,m),7.27–7.19(2H,m),5.26(1H,s),5.11(1H,s),5.04(1H,s),4.80(2H,q,J＝13.5Hz),3.89(1H,s),2.96(1H,dd,J＝8.8,6.8Hz),2.70(3H,s),2.66–2.57(4H,m),2.44(1H,dd,J＝6.9,3.0Hz),1.95–1.72(2H,m),1.61(1H,dd,J＝11.0,3.6Hz),1.54(4H,dd,J＝11.6,9.6Hz),1.44(4H,dd,J＝14.2,11.2Hz),1.25(1H,s),1.16(8H,t,J＝9.4Hz).
13C NMR(100MHz,CDCl3)167.2,162.9,148.9,148.6,142.6,140.3,133.6,132.2,132.0,131.7,131.6,131.4,130.6,130.5,129.5,127.7,126.1,125.7,125.7,123.0,111.5,65.8,41.9,41.5,41.4,38.1,34.3,33.2,27.2,25.9,23.1,22.0,21.8,17.5.
Example 25 Synthesis of a derivative of pterodontic acid of formula (VI) R6-Cl
This example carried out reaction (ix): dissolving 50.0mg of the pterodontic acid derivative with R6 as-OH structure in the formula (VI) in 5.0mL of anhydrous dichloromethane solution, adding trichloroacetonitrile (0.34mmol), averagely adding 0.34mmol of triphenylphosphine in 3 batches under ice bath, rotating under the protection of nitrogen and reacting at room temperature for 6H, monitoring the reaction process by thin-layer chromatography, adding 0.8g of silica gel after the reaction is finished, stirring, performing 200-300-mesh silica gel column chromatography, and separating and purifying by using petroleum ether to obtain the pterodontic acid derivative with R6 as-Cl structure in the formula (VI), C15H23Cl, colorless oily matter and yield of 91%.
Example 26 Synthesis of a derivative of pterodontic acid of formula (VI) wherein R6 is-Cl
This example carried out reaction (ix): dissolving 80.0mg of the pterodontic acid derivative with R6 as-OH structure in the formula (VI) in 8.0mL of anhydrous dichloromethane solution, adding trichloroacetonitrile (0.54mmol), averagely adding 0.54mmol of triphenylphosphine in 3 batches under ice bath, rotating under the protection of nitrogen and reacting at room temperature for 8H, monitoring the reaction process by thin-layer chromatography, adding 1.5g of silica gel after the reaction is finished, stirring, performing 200-300-mesh silica gel column chromatography, and separating and purifying by using petroleum ether to obtain the pterodontic acid derivative with R6 as-Cl structure in the formula (VI), C15H23Cl, colorless oily matter and yield of 92%.
Example 27 Synthesis of a derivative of pterodontic acid of formula (VI) R6-Cl
This example carried out reaction (ix): 60.0mg of the pterodontic acid derivative with R6 as-OH structure in the formula (VI) is dissolved in 7.0mL of anhydrous dichloromethane solution, trichloroacetonitrile (0.40mmol) is added, 0.45mmol of triphenylphosphine is added in 3 batches averagely under ice bath, the mixture is turned down under the protection of nitrogen and reacted for 7 hours at room temperature, the reaction process is monitored by thin layer chromatography, 1g of silica gel is added after the reaction is finished, the mixture is stirred, and is subjected to 200-300-mesh silica gel column chromatography and petroleum ether separation and purification to obtain the pterodontic acid derivative with the R6 as-Cl structure in the formula (VI), C15H23Cl, colorless oily matter and the yield of 92 percent.
Compound 46, chloroozonedianol, C15H23Cl as a colorless oil in 92% yield.
1H NMR(400MHz,CDCl3)5.21(1H,s),5.14(1H,s),5.03(1H,s),4.09(2H,s),2.99-3.04(1H,m),2.45-2.46(1H,m),1.82-1.85(2H,m),1.50-1.56(4H,m),1.38-1.45(4H,m),1.16 3H,s),1.14(3H,d,J＝8.2Hz).
13C NMR(100MHz,CDCl3)149.8,148.8,123.1,113.7,47.0,41.5,40.9,38.1,34.4,33.2,29.7,27.2,26.0,23.1,17.5.
Example 28 Synthesis of a derivative of formula (VI) R6 with morpholine, methylpiperazine, benzylamino structure
This example carried out reaction (x): dissolving 24.0mg of a pteridinoic acid derivative with a structure represented by formula (VI) R6-Cl structure in 4.4mL of anhydrous tetrahydrofuran solvent, adding sodium iodide (NaI,0.2mmol), after the sodium iodide is dissolved, respectively adding 0.2mmol of morpholine, methylpiperazine and benzylamine under ice bath, reacting at room temperature for 12H under the protection of nitrogen, monitoring the reaction process by thin-layer chromatography, extracting the reaction solution for three times by DCM/H2O, drying an organic phase by anhydrous Na2SO4, filtering, concentrating under reduced pressure, performing 200-300-mesh silica gel column chromatography, and separating and purifying by dichloromethane-methanol to obtain 47-49 pteridinoic acid amine series compounds with structures represented by R6 of morpholine, methylpiperazine and benzylamine in formula (VI), wherein the yield is not less than 90%.
Example 29 Synthesis of a derivative of formula (VI) R6 with morpholine, methylpiperazine, benzylamino structure
This example carried out reaction (x): dissolving 50.0mg of a pteridinoic acid derivative with a structure represented by formula (VI) R6-Cl structure in 6.0mL of anhydrous tetrahydrofuran solvent, adding sodium iodide (NaI,0.4mmol), after the sodium iodide is dissolved, respectively adding 0.4mmol of morpholine, methylpiperazine and benzylamine under ice bath, reacting at room temperature for 18H under the protection of nitrogen, monitoring the reaction process by thin-layer chromatography, extracting the reaction solution for three times by DCM/H2O, drying an organic phase by anhydrous Na2SO4, filtering, concentrating under reduced pressure, performing 200-300-mesh silica gel column chromatography, and separating and purifying by dichloromethane-methanol to obtain 47-49 pteridinoic acid amine series compounds with structures represented by R6 of morpholine, methylpiperazine and benzylamine in formula (VI), wherein the yield is not less than 90%.
Example 30 Synthesis of a derivative of formula (VI) R6 with morpholine, methylpiperazine, benzylamino structure
This example carried out reaction (x): dissolving 40.0mg of a pteridinoic acid derivative with a structure represented by formula (VI) R6-Cl structure in 5.0mL of anhydrous tetrahydrofuran solvent, adding sodium iodide (NaI,0.3mmol), after the sodium iodide is dissolved, respectively adding 0.3mmol of morpholine, methylpiperazine and benzylamine under ice bath, rotating under the protection of nitrogen for reaction at room temperature for 15H, monitoring the reaction process by thin-layer chromatography, extracting the reaction solution for three times by DCM/H2O, drying an organic phase by anhydrous Na2SO4, filtering, concentrating under reduced pressure, performing 200-300-mesh silica gel column chromatography, and separating and purifying by dichloromethane-methanol to obtain 47-49 pteridinoic acid amine series compounds with structures represented by R6 of morpholine, methylpiperazine and benzylamine in formula (VI), wherein the yield is not less than 90%.
Compound 47, N-morpholine pteridinium, C19H31NO as a yellow oil in 92% yield.
1H NMR(400MHz,CDCl3)5.19(1H,s),4.92(2H,s),3.68-3.71(4H,m),3.00(1H,d,J＝12.0Hz),2.90-2.93(1H,m),2.78(1H,d,J＝16.2Hz),2.41-2.43(4H,m),1.77-1.83(2H,m),1.51-1.58(4H,m),1.40-1.45(3H,m),1.16(3H,s),1.14(3H,d,J＝8.3Hz).
13C NMR(100MHz,CDCl3)150.5,147.7,124.2,111.6,67.1,67.1,63.3,53.7,53.7,42.0,41.8,41.3,38.1,34.4,33.2,27.2,26.1,23.2,17.5.
Compound 48, N- (4-methyl) pterodonidine, C20H34N2 as a yellow oil, 92% yield.
1H NMR(400MHz,CDCl3)5.19(1H,s),4.92(1H,s),4.90(1H,s),3.01(1H,d,J＝12.3Hz),2.87-2.91(1H,m),2.79(1H,d,J＝12.1Hz),2.43-2.45(8H,m),1.77-1.80(2H,m),1.49-1.55(4H,m),1.39-1.45(3H,m),1.15(3H,s),1.14(3H,d,J＝4.1Hz).
13C NMR(100MHz,CDCl3)151.0,147.6,124.3,111.2,62.8,62.8,55.2,55.2,53.1,46.0,42.0,41.8,41.4,38.1,34.4,33.2,27.2,26.1,23.2,17.5.
Compound 49, N-benzyl pterodonamine, C22H31N as a yellow oil in 93% yield.
1H NMR(400MHz,CDCl3)7.40–7.14(1H,m),5.21(1H,s),4.95(1H,s),4.92(1H,s),3.78(1H,s),3.25(1H,s),2.88(1H,dd,J＝8.5,6.9Hz),2.52–2.33(1H,m),1.85–1.67(1H,m),1.58–1.45(1H,m),1.41(1H,dd,J＝9.9,6.6Hz),1.25(1H,s),1.20–1.00(2H,m).
13C NMR(100MHz,CDCl3)152.3,148.1,140.4,128.3,128.2,126.8,124.0,109.2,53.3,52.1,42.3,42.0,41.7,38.1,34.3,33.2,27.2,26.0,23.1,17.5.
EXAMPLE 31 Synthesis of a Lapterostilic acid derivative represented by the formula (VIII)
This example was run for reaction (xi)): dissolving 70.0mg of the pterodontic acid derivative with R6 as-OH structure in a formula (VI) in 5.0mL of anhydrous dichloromethane solvent, adding triethylamine (TEA,0.95mmol) and propyl sulfonyl chloride (0.95mmol) in ice bath, carrying out reflux reaction for 6H under the protection of nitrogen, monitoring the reaction process by thin layer chromatography, diluting the reaction solution with 4.0mL of DCM, adding 1.0mL of saturated NaHCO3 for quenching, extracting DCM/H2O for three times, drying the collected organic phase by anhydrous Na2SO4, filtering, carrying out reduced pressure concentration, carrying out 200-300-mesh silica gel column chromatography, and separating and purifying by using petroleum ether-ethyl acetate to obtain the pterodontic acid derivative with the formula (VIII) R8 as propyl structure, C18H30O3S, a brown oily substance and 82% yield.
EXAMPLE 32 Synthesis of a Lapterostilic acid derivative represented by the formula (VIII)
This example was run for reaction (xi)): dissolving 100.0mg of the pterodontic acid derivative with R6 as-OH structure in the formula (VI) in 8.0mL of anhydrous dichloromethane solvent, adding triethylamine (TEA,1.38mmol) and propyl sulfonyl chloride (1.38mmol) in ice bath, carrying out reflux reaction for 8H under the protection of nitrogen, monitoring the reaction process by thin layer chromatography, diluting the reaction solution with 5.0mL of DCM, adding 2.0mL of saturated NaHCO3 for quenching, extracting DCM/H2O for three times, drying the collected organic phase by anhydrous Na2SO4, filtering, carrying out reduced pressure concentration, carrying out 200-300-mesh silica gel column chromatography, and carrying out separation and purification by adopting petroleum ether-ethyl acetate to obtain the pterodontic acid derivative with the formula (VIII) R8 as propyl structure, C18H30O3S, a brown oily substance and the yield of 81%.
Example 33 Synthesis of Lapterostilic acid derivative represented by formula (VIII)
This example was run for reaction (xi)): dissolving 80.0mg of the pterodontic acid derivative with R6 as-OH structure in a formula (VI) in 7.0mL of anhydrous dichloromethane solvent, adding triethylamine (TEA,1.10mmol) and propyl sulfonyl chloride (1.12mmol) in ice bath, carrying out reflux reaction for 7H under the protection of nitrogen, monitoring the reaction process by thin layer chromatography, diluting the reaction solution with 4.5mL of DCM, adding 1.5mL of saturated NaHCO3 for quenching, extracting DCM/H2O for three times, drying the collected organic phase by anhydrous Na2SO4, filtering, carrying out reduced pressure concentration, carrying out 200-300-mesh silica gel column chromatography, and carrying out separation and purification by adopting petroleum ether-ethyl acetate to obtain the pterodontic acid derivative with R8 as propyl structure in a formula (VIII), C18H30O3S, a brown oily substance and 82% yield.
Compound 50, pterodontate propanesulfonate, C18H30O3S brown oil, yield 82%.
1H NMR(400MHz,CDCl3)5.18(1H,s),5.16(1H,s),5.11(1H,s),4.68(2H,q,J＝12.1Hz),3.08(2H,dt,J＝13.2,5.7Hz),2.99–2.82(1H,m),2.50–2.36(1H,m),1.90(2H,dt,J＝10.2,7.6Hz),1.86–1.78(2H,m),1.59–1.48(5H,m),1.44(4H,ddd,J＝14.0,7.9,3.5Hz),1.16(8H,t,J＝3.7Hz),1.09(5H,dd,J＝14.6,7.2Hz).
13C NMR(100MHz,CDCl3)149.4,146.9,122.4,114.4,77.3,77.0,76.7,72.3,70.5,52.5,41.9,41.4,40.7,38.1,34.3,33.2,27.2,25.8,23.1,17.4,17.2,12.9.
EXAMPLE 34 Synthesis of a Lapterostin derivative of formula (IX)
This example carried out reaction (xii): dissolving 75.5mg of the pterodontic acid derivative with the structure of formula (VIII) in 2.0mL of anhydrous N, N-Dimethylformamide (DMF) solvent, slowly adding sodium azide (NaN3,0.51mmol), reacting for 2H at room temperature under the protection of nitrogen, monitoring the reaction process by thin-layer chromatography, diluting the reaction liquid with 2.0mL of EtOAc, adding 4.0mL of saturated NaCl solution, extracting for three times with EtOAc/H2O, drying the collected organic phase with anhydrous Na2SO4, filtering, concentrating under reduced pressure, carrying out 200-300-mesh silica gel column chromatography, and separating and purifying by using petroleum ether to obtain the pterodontic acid derivative shown in formula (IX), C15H23N3, a colorless oily substance, wherein the yield is 80%.
EXAMPLE 35 Synthesis of a Lapterostin derivative of formula (IX)
This example carried out reaction (xii): dissolving 100.0mg of the pterodontic acid derivative with the structure of formula (VIII) in 3.0mL of anhydrous N, N-Dimethylformamide (DMF) solvent, slowly adding sodium azide (NaN3,0.68mmol), reacting for 3H at room temperature under the protection of nitrogen, monitoring the reaction process by thin-layer chromatography, diluting the reaction liquid with 3.0mL of EtOAc, adding 5.0mL of saturated NaCl solution, extracting for three times with EtOAc/H2O, drying the collected organic phase with anhydrous Na2SO4, filtering, concentrating under reduced pressure, carrying out 200-300-mesh silica gel column chromatography, and separating and purifying by using petroleum ether to obtain the pterodontic acid derivative shown in formula (IX), C15H23N3, a colorless oily substance, wherein the yield is 81%.
EXAMPLE 36 Synthesis of a Lapterostin derivative of formula (IX)
This example carried out reaction (xii): dissolving 90.0mg of the pterodontic acid derivative with the structure of formula (VIII) in 2.5mL of anhydrous N, N-Dimethylformamide (DMF) solvent, slowly adding sodium azide (NaN3,0.60mmol), reacting at room temperature for 2.5H under the protection of nitrogen, monitoring the reaction process by thin-layer chromatography, diluting the reaction liquid with 2.5mL of EtOAc, adding 4.5mL of saturated NaCl solution, extracting for three times with EtOAc/H2O, drying the collected organic phase with anhydrous Na2SO4, filtering, concentrating under reduced pressure, carrying out 200-300-mesh silica gel column chromatography, and separating and purifying by using petroleum ether to obtain the pterodontic acid derivative shown in formula (IX), C15H23N3, a colorless oily substance, wherein the yield is 81%.
Compound 51, ozonedianol azide, C15H23N3 as a colorless oil in 81% yield.
1H NMR(400MHz,CDCl3)5.18(1H,s),5.06(1H,s),5.03(1H,s),3.72-3.80(2H,m),2.87-2.91(1H,m),2.43-2.46(1H,m),1.76-1.83(2H,m),1.49-1.59(5H,m),1.39-1.46(3H,m),1.16(3H,s),1.14(3H,d,J＝8.2Hz).
13C NMR(100MHz,CDCl3)149.1,147.8,122.9,113.1,54.3,42.0,41.9,41.4,38.1,34.3,33.2,27.2,25.6,23.1,17.5.
EXAMPLE 37 Synthesis of triazole-based derivative of Latrogen acid
This example carried out reaction (xiii): dissolving 10.0mg of a pterodontic acid derivative with a structure shown in formula (IX) in 2.0mL of anhydrous tetrahydrofuran solvent, adding different monosubstituted alkynes (0.08mmol), anhydrous copper acetate (0.06mmol), L sodium ascorbate (0.08mmol) and H2O (0.5mL), reacting at room temperature for 6H under the protection of nitrogen, monitoring the reaction process by thin-layer chromatography, diluting the reaction solution with 2.0mL of EtOAc, washing with several layers of H2O twice, washing with saturated NaCl twice, drying the collected organic phase with anhydrous Na2SO4, filtering, concentrating under reduced pressure, carrying out 200-300-mesh silica gel column chromatography, and separating and purifying by using petroleum ether-ethyl acetate to obtain a pterodontic acid 1,2, 3-triazole series compound 52-54 with a structure shown in formula (X) R9 being phenyl, 4-methylphenyl and 2-N-pyridine, wherein the yield is 100%.
EXAMPLE 38 Synthesis of triazole-based derivatives of Latrogen acid
This example carried out reaction (xiii): dissolving 30.0mg of a pterodontic acid derivative with a structure shown in a formula (IX) in 5.0mL of anhydrous tetrahydrofuran solvent, adding different single substituted alkyne (0.24mmol), anhydrous copper acetate (0.18mmol), L sodium ascorbate (0.24mmol) and H2O (1.25mL), reacting at room temperature for 6-10H under the protection of nitrogen, monitoring the reaction process by thin-layer chromatography, diluting the reaction solution with 5.0mL of EtOAc, washing with several layers of H2O twice, washing with saturated NaCl twice, drying the collected organic phase by anhydrous Na2SO4, filtering, concentrating under reduced pressure, carrying out 200-300-mesh silica gel column chromatography, and separating and purifying by using petroleum ether-ethyl acetate to obtain a pterodontic acid 1,2, 3-triazole series compound with a structure shown in a formula (X) R9, namely phenyl, 4-methylphenyl and 2-N-pyridine, wherein the yield is 100%.
EXAMPLE 39 Synthesis of triazole-based derivative of Lapterocarpus pterodontoid
This example carried out reaction (xiii): dissolving 20.0mg of a pterodontic acid derivative with a structure shown in a formula (IX) in 4.0mL of anhydrous tetrahydrofuran solvent, adding different monosubstituted alkyne (0.15mmol), anhydrous copper acetate (0.12mmol), L sodium ascorbate (0.2mmol) and H2O (1mL), reacting at room temperature for 8H under the protection of nitrogen, monitoring the reaction process by thin-layer chromatography, diluting the reaction solution by using 3mL of EtOAc, washing a plurality of layers of H2O twice, washing saturated NaCl twice, drying the collected organic phase by using anhydrous Na2SO4, filtering, concentrating under reduced pressure, performing 200-300-mesh silica gel column chromatography, and separating and purifying by using petroleum ether-ethyl acetate to obtain a pterodontic acid 1,2, 3-triazole series compound 52-54 with a structure shown in a formula (X) R9 being phenyl, 4-methylphenyl and 2-N-pyridine structure, wherein the yield is 100%.
1H NMR(400MHz,CDCl3)7.84(1H,d,J＝7.5Hz),7.76(1H,s),7.42(1H,t,J＝7.6Hz),7.33(1H,t,J＝7.3Hz),5.16(1H,s),5.12(1H,s),5.00(1H,dd,J＝42.8,15.4Hz),4.86(1H,s),2.81(1H,dd,J＝8.9,6.7Hz),2.47–2.35(1H,m),1.86–1.71(1H,m),1.64(1H,s),1.59–1.46 2H,m),1.46–1.37(1H,m),1.26(1H,s),1.14(4H,d,J＝7.4Hz),0.93–0.82(1H,m).
13C NMR(100MHz,CDCl3)149.7,148.3,147.9,130.6,128.8,128.1,125.7,122.3,119.6,113.7,53.6,41.8,41.4,41.3,38.1,34.3,33.1,31.6,27.2,25.6,23.1,22.6,17.4,14.1.
The compound 53, N-1,2, 3-triazole- [4- (4-methyl) phenyl ] pteridinium, C24H31N3, was a white solid in 100% yield.
1H NMR(400MHz,CDCl3)7.73(1H,d,J＝8.0Hz),7.22(1H,d,J＝7.8Hz),5.15(1H,s),5.10(1H,s),4.98(1H,dd,J＝42.3,15.4Hz),4.85(1H,s),2.80(1H,dd,J＝8.9,6.9Hz),2.46–2.32(1H,m),1.79(1H,dd,J＝10.0,2.6Hz),1.57–1.46(1H,m),1.46–1.37(1H,m),1.35(1H,d,J＝1.8Hz),1.22–1.04(3H,m).
13C NMR(100MHz,CDCl3)149.7,148.3,148.0,137.9,129.5,127.8,125.6,122.3,119.3,113.6,53.6,41.8,41.4,41.3,38.1,34.3,33.1,27.2,25.6,23.1,21.3,17.4.
Compound 54, N-1,2, 3-triazole- [4- (2-N-pyridyl) ] pterodonidine, C22H28N4 yellow oil, 100% yield.
1H NMR(400MHz,CDCl3)8.59(1H,d,J＝4.5Hz),8.28–8.12(2H,m),7.78(1H,dd,J＝11.2,4.2Hz),7.28–7.19(1H,m),5.16(1H,s),5.12(1H,s),5.02(2H,dd,J＝42.6,15.3Hz),4.89(1H,s),2.82(1H,dd,J＝8.9,6.8Hz),2.48–2.38(1H,m),1.79(2H,d,J＝12.9Hz),1.51(5H,dd,J＝15.3,5.2Hz),1.46–1.37(3H,m),1.14(8H,d,J＝8.5Hz).
13C NMR(100MHz,CDCl3)150.2,149.7,149.3,148.4,147.9,137.0,122.8,122.3,122.2,120.3,114.1,77.3,77.2,77.0,76.7,53.6,41.8,41.4,41.3,38.1,34.3,33.1,27.2,25.5,23.1,17.4.
Example 14 in vitro inhibition of influenza A H1N1 by pterodontic acid derivatives
1. Apparatus and materials
1.1 drug test drugs
The drug to be tested is dissolved in 2-methyl sulfoxide (DMSO) and diluted by the drug solution and cell culture Medium (MEM) to serve as working mother liquor (400ug/mL, DMSO final concentration is 1%).
Positive control drug: laggera acid, dissolved in MEM to 100. mu.g/mL when used, filtered and stored at 4 ℃.
1.2 cell lines and viruses
Cell: dog Kidney epithelial cell line (Madin-Darby Canine Kidney Cells, MDCK), purchased from American Type Culture Collection (ATCC) and deposited at Guangzhou respiratory health research institute.
Virus: influenza A H1N1 PR8 strain (A/PR/8/34, H1N1) purchased from American Type Culture Collection (ATCC).
1.3 instruments
BS 224S electronic balance, purchased from sydows scientific instruments ltd; HERACELL 150i thermostatted CO2 incubator, available from Thermo corporation, USA; BHC-1300IIA/B3 Secondary Biosafety Cabinet, available from Suzhou clarification Equipment, Inc.; leica DM3000 inverted microscope, purchased from come company; leica D B000B biomicroscope, available from come; an Avanti J-26 high speed refrigerated centrifuge available from BECKMAN COULTER, USA; varioskan Flash full wavelength scanner, available from Thermo corporation, USA.
1.4 reagents
Minimum Essential Medium (MEM) cell culture Medium, purchased from Gibco, usa; fetal bovine serum (FBS, origin of australia), purchased from Gibco, usa; trypsin Trypsin, purchased from Sigma, USA; TPCK pancreatin, purchased from Sigma company, usa; phosphate Buffered Saline (PBS), available from Gibco, usa; distilled water, self-made in laboratories.
2. Drug toxicity test (MTT method)
Inoculating 2.5 multiplied by 104 cells per well into a 96-well plate, after 24-48 h, removing the culture solution after the cells grow into a monolayer, adding 100-10-7 of eight medicaments with different dilution concentrations into each well, adding 100 mu L/well MEM into a normal cell control well, continuously culturing for 2 days at 37 ℃ by 5% CO2, adding 20 mu L of MTT solution (5mg/mL) into each well, placing at 37 ℃, and continuously incubating for 4 hours in a 5% CO2 incubator. The culture supernatant was aspirated off, 100. mu.L of dimethyl sulfoxide (DMSO) was added to each well, and the mixture was shaken at a low speed (200r/min to 500r/min) for 10 minutes to dissolve the crystals sufficiently. The 490nm wavelength is selected, and the absorbance of each pore is measured on an enzyme linked immunosorbent instrument. The inhibition was calculated according to the following formula, and the 50% toxic concentration was calculated as the half-toxic concentration of the drug (TC50) by the Reed-Muench method. 3. Viral titer determination
MDCK cells were seeded at a concentration of 2.5 × 104 per well into 96-well plates, and after the cells grew into a monolayer (about 24h), the culture solution was discarded, and the cell surface was washed 2 times with PBS. The virus is diluted to eight concentrations of 10 < -1 > to 10 < -8 > by 10 times of serum-free culture solution in a gradient manner. Adding virus diluents with different concentrations, wherein the adding amount is 100 mu L/hole, each concentration is 4 multiple holes, incubating in a 5% CO2 incubator at 37 ℃ for 2 hours, discarding the virus solution, adding a culture medium containing 1 mu g/mL TPCK, incubating in a 5% CO2 incubator at 37 ℃ for 48-72 hours, and observing and recording cytopathic effect every day. The degree of lesion appearance was recorded according to the following 6-point criteria (table 1):
TABLE 1 Virus-induced cytopathic Effect (CPE) grade 6 criteria
| Cell morphology | Extent of disease |
| The cells grow normally without the appearance of disease | － |
| Cytopathic effect is less than 10% of the whole monolayer of cells | ± |
| The cytopathic effect is about 25% of the total monolayer of cells | + |
| The cytopathic effect is about 50% of the total monolayer of cells | ++ |
| The cytopathic effect is about 75% of the total monolayer of cells | +++ |
| Cytopathic effect accounts for more than 75% of the whole monolayer | ++++ |
50 μ L of 0.5% chicken red blood cells and 50 μ L of cell supernatant were added, and the results were observed after 30min in a microplate, and 4 wells were filled with physiological saline as a control. The hemagglutination results are represented as +++, +++++, +++, -, respectively: +: the blood cells form a small cluster at the bottom of the hole, but the edge is not smooth, and small agglomerations are arranged around the blood cells; ++: the blood cells form a ring at the bottom of the hole and small agglomerations are arranged around the hole; +++: basically, but the edge is irregular and has a sagging tendency; ++++: a layer of red blood cells is paved on the bottom of the hole; -: the blood cells form a small ball at the bottom of the hole, and the edge is smooth and round. The 50% tissue cell half-infection (TCID50) was calculated by the Reed-Muench method.
4. Detection of anti-influenza Virus Activity (CPE method)
The antiviral activity of the drug was measured by Cytopathic effect (CPE). The drug to be tested is dissolved in a culture medium containing 1 mu g/mL TPCK to prepare the maximum nontoxic concentration, and the maximum nontoxic concentration is diluted into eight concentrations of 10 < -1 > to 10 < -8 > by multiple ratio. MDCK cells were seeded into 96-well plates at a concentration of 2.5 × 104 per well, and after the cells grew into a monolayer (about 24h), the culture solution was discarded, and the cell surface was washed 2 times with PBS. Adding 100 mu L/well of virus diluent containing 100TCID50, adding 4 multiple wells per concentration, incubating at 37 ℃ in a 5% CO2 incubator, discarding the virus solution after 2h, adding a culture medium containing a drug to be tested, incubating at 37 ℃ in a 5% CO2 incubator for 48h, and observing and recording cytopathic effect every day. The degree of lesion appearance was recorded according to the scale of table 1. Half maximal inhibitory concentrations (IC50) were calculated by the Reed-Muench method.
5. In-vitro anti-influenza A H1N1 virus effect experiment of pterodontic acid and derivatives thereof
The results of in vitro inhibition experiments of the H1N1 influenza A virus by pterodontic acid and all derivatives in the examples are shown in Table 2, wherein, the compounds 1 to 31 are the laggerac acid derivatives with the structure of formula (I), the compounds 32 to 34 are the laggerac acid derivatives with the structure of formula (II), the compounds 35 to 38 are the laggerac acid derivatives with the structure of formula (III), the compounds 39 to 40 are the laggerac acid derivatives with the structure of formula (IV), the compound 41 is the laggerac acid derivative with the structure of formula (V), the compounds 42 and 46 to 49 are the laggerac acid derivatives with the structure of formula (VI), the compounds 43 to 45 are the laggerac acid derivatives with the structure of formula (VII), the compound 50 is the laggerac acid derivative with the structure of formula (VIII), the compound 51 is the laggerac acid derivative with the structure of formula (IX), and the compounds 52 to 54 are the laggerac acid derivatives with the structure of formula (X).
TABLE 2 Lapterostilic acid derivatives in vitro anti-H1N 1 influenza A virus (PR8) Activity
The results show that various pterodontic acid derivatives can inhibit the proliferation of influenza A virus H1N1 to different degrees, especially amide derivatives and nitrogen heterocyclic derivatives. Wherein partial compound has better inhibitory activity on influenza A virus H1N1 (PR8) than on tolbutate. Among the derivatives, the compounds containing nitrogen atoms have relatively good activity, possibly have good affinity with virus protein receptors, and the pterodontic acid derivatives have the potential of being used for preparing medicaments for treating influenza virus infectious respiratory diseases.
The foregoing shows and describes the general principles, essential features, and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (10)
1. The pterodontic acid derivative is characterized in that: the structural formula of the compound is shown as formula (I), formula (II), formula (III), (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX) or formula (X):
wherein R is1Is methylamino, ethylamino, allylamino, dimethylamino, diethylamino, diallylamino,2, 4-dimethylhexylamino group, cyclohexylamino group, 2-methyl-2 imidazoline, 4-pyridinemethylamino group, 4-methoxybenzylamine group, 3-aminobenzylamine group, methylbenzylamine group, 3-chlorobenzylamine group, 4-fluorobenzylamine group, 4-bromobenzylamine group, 4-hydroxybenzylamine group, diphenylmethylamino group, benzylamino group, 4-methylbenzylamine group, 2-phenethylamino group, 2-furanmethylamino group, 4- (trifluoromethyl) benzylamino group, 3- (trifluoromethyl) benzylamino group, 2-chlorobenzylamine group, 2, 4-dichlorobenzylamino group, acetamido group, guanylamine, morpholine, methylpiperazine;
wherein R is2Is methyl, n-pentyl or benzyl;
wherein R is3Is methyl, n-pentyl, benzyl, -H;
wherein R is4Morpholine and methyl piperazine;
wherein R is5is-OH;
wherein R is6is-OH, -Cl, morpholine, methyl piperazine, benzylamino;
wherein R is7Is n-butyl, phenyl, 2-methylphenyl;
wherein R is8Is propyl;
wherein R is9Is phenyl, 4-methylphenyl, 2-N-pyridine.
2. The process for producing a pterodontic acid derivative according to claim 1, wherein the reaction formula is as follows:
the method comprises the following steps:
reaction (i): dissolving the pterodontic acid with the structure shown in the formula (A) in a dichloromethane solution, taking EDCI as a condensing agent and DMAP as a catalyst, and carrying out condensation reaction with a primary amine or secondary amine compound at room temperature to obtain the pterodontic acid derivative shown in the formula (I);
reaction (ii): dissolving the pterodontic acid with the structure of formula (A) in a dichloromethane solution, taking DCC as a condensing agent and DMAP as a catalyst, and carrying out condensation reaction on the pterodontic acid and different hydroxyl-containing compounds at room temperature to obtain a pterodontic acid derivative shown in formula (II);
reaction (iii): taking the pterodontic acid derivative shown in the formula (II) to perform an oxidation reaction in a dichloromethane solution under the oxidation action of peroxybenzoic acid at room temperature to obtain R in the formula (III)3Pterodontic acid with methyl, n-amyl and benzyl structureA derivative;
reaction (iv): dissolving the tolindac with the structure of formula (A) in a dichloromethane solution, and carrying out an oxidation reaction under the oxidation action of peroxybenzoic acid at room temperature to obtain R in the formula (III)3A laggerac acid derivative having the structure-H;
reaction (v): taking R in formula (III)3Carrying out Michael addition reaction on a-H ozonic acid derivative and a secondary amine compound in a dichloromethane solution by taking EDCI as a condensing agent and DMAP as a catalyst under the room temperature condition of nitrogen protection to obtain an ozonic acid derivative shown as a formula (IV);
reaction (vi): taking R in formula (III)3Leading nitrogen to protect in dichloromethane solution of the laggera acid derivative which is-H under the acidic condition of boron trifluoride-ethyl ether, and reacting in an ice bath condition to obtain the laggera acid derivative shown in the formula (V);
reaction (vii): dissolving pterodontic acid with the structure of formula (A) in an anhydrous tetrahydrofuran solvent, and reducing by lithium aluminum hydride under the reflux condition to obtain R in formula (VI)6A laggerac acid derivative having the structure-OH;
reaction (viii): taking R in formula (VI)6In a dichloromethane solvent, carrying out condensation reaction on a laggera derivative with an-OH structure and a carboxyl-containing compound by using DCC as a condensing agent and DMAP as a catalyst to obtain the laggera derivative shown in a formula (VII);
reaction (ix): taking R in formula (VI)6The pterodontic acid derivative with-OH structure is subjected to substitution reaction with triphenylphosphine and trichloroacetonitrile in a dichloromethane solvent under the ice bath condition of nitrogen protection to obtain R in the formula (VI)6A laggerac acid derivative having a structure of-Cl;
reaction (x): taking R in formula (VI)6The pterodontic acid derivative with-Cl substructure is prepared by adding sodium iodide into anhydrous tetrahydrofuran solvent, and performing condensation reaction with primary amine or secondary amine compound to obtain R in formula (VI)6The pterodontic acid derivatives are morpholine, methyl piperazine and benzylamine structures;
reaction (xi): taking R in formula (VI)6Pterodontic acid derivatives of the-OH structureAdding triethylamine and propyl sulfonyl chloride into a dichloromethane solvent under an ice bath condition, and carrying out a substitution reaction under the protection of nitrogen and under a reflux condition to obtain a pterodontic acid derivative shown as a formula (VIII);
reaction (xii): taking a laggera derivative with a structure shown in a formula (VIII), and reacting the laggera derivative with sodium azide in an anhydrous N, N-dimethylformamide solvent under the protection of nitrogen to obtain a laggera derivative shown in a formula (IX);
reaction (xiii): adding copper acetate, sodium ascorbate and water into a tetrahydrofuran solvent to perform cycloaddition reaction with a monosubstituted alkyne compound to obtain the pterodontic acid derivative shown in the formula (X).
3. The method for preparing pterodontic acid derivative according to claim 2, wherein:
the reaction (i) is specifically: dissolving 50.0-80.0mg of laginella acid with the structure of formula (A) in 5.0-8.0mL of anhydrous dichloromethane solvent, adding 0.27-0.43mmol of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride serving as a condensing agent, adding 0.1-0.2mmol of 4-dimethylaminopyridine catalyst, adding 0.25-0.40mmol of primary amine or secondary amine compound, reacting at room temperature for 4-6H under the protection of nitrogen, diluting the reaction solution with 4.0-5.0mL of EtOAc, adding 1.0-2.0mL of HCl with the volume concentration of 5%, quenching, and adding DCM/H2O extraction three times, passing the organic phase through anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and separating and purifying by column chromatography to obtain pterodontic acid derivative shown in formula (I);
the reaction (ii) is specifically: dissolving 50.0-80.0mg of pteridinoic acid with the structure of formula (A) in 5.0-8.0mL of anhydrous dichloromethane solvent, adding 1.2-1.9mmol of dicyclohexylcarbodiimide as a condensing agent, adding 0.1-0.2mmol of 4-dimethylaminopyridine catalyst, adding 0.13-0.21mmol of-OH-containing compound, reacting at room temperature for 3-5H under the protection of nitrogen, diluting the reaction solution with 4.0-5.0mL of EtOAc, adding 1.0-2.0mL of hydrochloric acid with the volume concentration of 5%, and quenching, wherein the concentration of the hydrochloric acid is 1.0-5%, and the concentration of the hydrochloric acid is H/H2Washing with O three times, collecting organic phase, and passing through anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and purifying by silica gel column chromatography to obtain formula (II)) The pterodontic acid derivative is shown.
4. The method for preparing pterodontic acid derivative according to claim 2, wherein:
reaction (iii) is specifically: dissolving 50.0-80.0mg of the pterodontic acid derivative shown in the formula (II) in 4.0-6.0mL of anhydrous dichloromethane solvent, adding 0.24-0.38mmol of peroxybenzoic acid as an oxidant, and reacting at room temperature for 0.5-1.0h under the protection of nitrogen; adding 1.0-2.0mL of saturated NaHCO into the reaction solution3Quenching, DCM/H2O three times, the organic phase over anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and purifying by silica gel column chromatography to obtain R of formula (III)3The pterodontic acid derivative has methyl, n-amyl and benzyl structures;
reaction (iv) is specifically: dissolving 500.0-600.0mg of laggerac acid with the structure of formula (A) in 10.0-12.0mL of anhydrous dichloromethane solvent, adding 2.57-3.08mmol of oxidizing agent m-chloroperoxybenzoic acid, and reacting at room temperature for 1.0-1.5h under the protection of nitrogen; adding 2.0-3.0mL of saturated NaHCO into the reaction solution3Quenching, DCM/H2O three times, the organic phase over anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and purifying by silica gel column chromatography to obtain R of formula (III)3A laggerac acid derivative having the structure-H;
5. the method for preparing pterodontic acid derivative according to claim 2, wherein:
the reaction (v) is specifically: taking R in formula (III)3Dissolving 50.0-80.0mg of laginella acid derivative of-H in 5.0-8.0mL of anhydrous dichloromethane solvent, adding 0.2-0.3mmol of condensing agent 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, 0.1-0.2mmol of catalyst 4-dimethylaminopyridine, adding 0.25-0.40mmol of secondary amine compound, reacting at room temperature for 4-5H under the protection of nitrogen, diluting the reaction solution with 4.0-5.0mL of EtOAc, quenching with 1.0-2.0mL of HCl with volume concentration of 5%, DCM/H2O extraction three times, passing the organic phase through anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and separating and purifying by column chromatography to obtain the pterodontic acid derivative shown in formula (IV);
the reaction (vi) is specifically: taking R in formula (III)3Dissolving 50.0-80.0mg of laggerac acid derivative of-H in 5.0-8.0mL of anhydrous dichloromethane solvent, adding 0.2-0.3mmol of boron trifluoride-diethyl ether into ice bath, reacting for 4-5H in ice bath under the protection of nitrogen, diluting the reaction solution with 4.0-5.0mL of EtOAc, adding 1.0-2.0mL of saturated NH4Cl solution quench, EtOAc/H2O extraction three times, passing the organic phase through anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and purifying by column chromatography to obtain the pterodontic acid derivative shown in formula (V).
6. The method for preparing pterodontic acid derivative according to claim 2, wherein:
the reaction (vii) is specifically: dissolving 100.0-300.0mg of pterodontic acid with the structure of formula (A) in 10.0-20.0mL of anhydrous tetrahydrofuran solvent, adding 0.45-1.34mmol of lithium aluminum hydride in 3 batches in ice bath under the protection of nitrogen, completely mixing, carrying out reflux reaction at 70 ℃ for 12-18H, adding 3.0-6.0mL of sodium hydroxide solution with the mass concentration of 15% and 3.0-6.0mL of H under ice bath2O quench, celite filtration, EtOAc/H2O extraction three times, passing the organic phase through anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and purifying by silica gel column chromatography to obtain R of formula (VI)6Is a laggera acid derivative with-OH structure.
Reaction (viii) is specifically: taking R in formula (VI)6Dissolving 20.0-50.0mg of lagineolic acid derivative with-OH structure in 2.0-4.0mL of anhydrous dichloromethane solvent, adding 1.08-2.70mmol of condensation agent dicyclohexylcarbodiimide and 0.018-0.045mmol of catalyst 4-dimethylaminopyridine, adding 0.135-0.338mmol of-COOH-containing compound, reacting at room temperature for 3-5H under the protection of nitrogen, diluting the reaction solution with 2.0-4.0mL of EtOAc, adding 1.0-2.0mL of hydrochloric acid with volume concentration of 5%, and quenching, wherein the concentration of hydrochloric acid is H/H2Washing with O three times, collecting organic phase, and passing through anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and purifying by silica gel column chromatography to obtain the pterodontic acid derivative shown in formula (VII).
7. The method for preparing pterodontic acid derivative according to claim 2, wherein:
reaction (ix) is specifically: taking R in formula (VI)6Dissolving 50.0-80.0mg of laggerac acid derivative with-OH structure in 5.0-8.0mL of anhydrous dichloromethane solution, adding 0.34-0.54mmol of trichloroacetonitrile, averagely dividing into 3 batches under ice bath, adding 0.34-0.54mmol of triphenylphosphine, reacting at room temperature for 6-8h under the protection of nitrogen, and purifying by silica gel column chromatography after the reaction is finished to obtain R in (VI)6A laggerac acid derivative having a structure of-Cl;
the reaction (x) is specifically: taking R in formula (VI)6Dissolving 24.0-50.0mg of laginella acid derivative with-Cl structure in 4.4-6.0mL of anhydrous tetrahydrofuran solvent, adding 0.2-0.4mmol of sodium iodide, adding 0.2-0.4mmol of amine compound under ice bath after the sodium iodide is dissolved, reacting at room temperature for 12-18H under the protection of nitrogen, and passing the reaction solution through DCM/H2Extracting with O for three times, and extracting the organic phase with anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and purifying by column chromatography to obtain R in formula (VI)6Is a pterodontic acid derivative with morpholine, methylpiperazine and benzylamine structures.
8. The method for preparing pterodontic acid derivative according to claim 2, wherein:
the reaction (xi) is specifically: taking R in formula (VI)6Dissolving 70.0-100.0mg of laginella acid derivative with-OH structure in 5.0-8.0mL of anhydrous dichloromethane solvent, adding 0.95-1.38mmol of triethylamine and 0.95-1.38mmol of propyl sulfonyl chloride under ice bath, refluxing and reacting for 6-8h under the protection of nitrogen, diluting the reaction solution with 4.0-5.0mL of DCM, adding 1.0-2.0mL of saturated NaHCO3Quenching, DCM/H2Extracting with O for three times, collecting organic phase, and passing through anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and purifying by silica gel column chromatography to obtain pterodontic acid derivative represented by formula (VIII);
reaction (xii) is specifically: dissolving 75.5-100.0mg of the pterodontic acid derivative with the structure of formula (VIII) in 2.0-3.0mL of anhydrous N, N-dimethylformamide solvent, slowly adding 0.51-0.68mmol of sodium azide, reacting for 2-3h at room temperature under the protection of nitrogen, diluting the reaction liquid with 2.0-3.0mL of EtOAc, and adding 4.0-5.0mL saturated NaCl solution, EtOAc/H2Extracting with O for three times, collecting organic phase, and passing through anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and purifying by silica gel column chromatography to obtain pterodontic acid derivative represented by formula (IX);
reaction (xiii) is specifically: dissolving 10.0-30.0mg of pterodontic acid derivative with the structure of formula (IX) in 2.0-5.0mL of anhydrous tetrahydrofuran solvent, adding 0.08-0.24mmol of monosubstituted alkyne, 0.06-0.18mmol of anhydrous copper acetate, 0.08-0.24mmol of L-sodium ascorbate, and 0.5-1.25mL of H2O, reacting at room temperature for 6-10H under the protection of nitrogen, diluting the reaction solution with 2.0-5.0mL of EtOAc, and obtaining an organic layer H2Washing twice with O, twice with saturated NaCl, collecting the organic phase, and passing through anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and purifying by silica gel column chromatography to obtain the pterodontic acid derivative shown in formula (X).
9. The use of the pterodontic acid derivative according to claim 1 for the preparation of a medicament for the treatment of influenza a virus disease H1N1 in vitro.
10. The use of pterodontic acid derivatives according to claim 9 for the preparation of a medicament against influenza a virus H1N1 in vitro, wherein: the drug for resisting influenza A virus H1N1 is a drug for treating viral injury caused by influenza A virus H1N 1.
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| CN115947750B (en) * | 2023-03-14 | 2023-08-18 | 山东东岳有机硅材料股份有限公司 | Carboxylated silane coupling agent and preparation method thereof |
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