CN107286160A - A kind of preparation method of the piperidines of Antihepatitis medicament and pyrido pyrazoles Zn complex - Google Patents
A kind of preparation method of the piperidines of Antihepatitis medicament and pyrido pyrazoles Zn complex Download PDFInfo
- Publication number
- CN107286160A CN107286160A CN201710413835.3A CN201710413835A CN107286160A CN 107286160 A CN107286160 A CN 107286160A CN 201710413835 A CN201710413835 A CN 201710413835A CN 107286160 A CN107286160 A CN 107286160A
- Authority
- CN
- China
- Prior art keywords
- reaction
- boc
- added
- piperidines
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000003814 drug Substances 0.000 title claims abstract description 24
- 150000003053 piperidines Chemical class 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims description 14
- AMFYRKOUWBAGHV-UHFFFAOYSA-N 1h-pyrazolo[4,3-b]pyridine Chemical class C1=CN=C2C=NNC2=C1 AMFYRKOUWBAGHV-UHFFFAOYSA-N 0.000 title abstract 2
- 230000000694 effects Effects 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims description 126
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 54
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 52
- 150000001875 compounds Chemical class 0.000 claims description 35
- 238000000034 method Methods 0.000 claims description 31
- 230000008569 process Effects 0.000 claims description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 21
- TZIHFWKZFHZASV-UHFFFAOYSA-N anhydrous methyl formate Natural products COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 20
- 238000001035 drying Methods 0.000 claims description 19
- 239000007787 solid Substances 0.000 claims description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 18
- 239000012065 filter cake Substances 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 17
- 238000012544 monitoring process Methods 0.000 claims description 16
- 239000002994 raw material Substances 0.000 claims description 15
- 239000011701 zinc Substances 0.000 claims description 14
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 12
- 230000004044 response Effects 0.000 claims description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 11
- 238000000967 suction filtration Methods 0.000 claims description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 10
- 239000007788 liquid Substances 0.000 claims description 10
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 9
- 239000000047 product Substances 0.000 claims description 9
- 229910019213 POCl3 Inorganic materials 0.000 claims description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 8
- -1 chloroformyl ethyl Chemical group 0.000 claims description 8
- 238000001291 vacuum drying Methods 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- 239000011592 zinc chloride Substances 0.000 claims description 7
- 235000005074 zinc chloride Nutrition 0.000 claims description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 5
- 239000005695 Ammonium acetate Substances 0.000 claims description 5
- 235000019257 ammonium acetate Nutrition 0.000 claims description 5
- 229940043376 ammonium acetate Drugs 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical class O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 claims description 5
- 230000009467 reduction Effects 0.000 claims description 5
- 239000011780 sodium chloride Substances 0.000 claims description 5
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical class CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 claims description 5
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 4
- 125000003368 amide group Chemical group 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 4
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 239000013078 crystal Substances 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 230000036571 hydration Effects 0.000 claims description 2
- 238000006703 hydration reaction Methods 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 claims description 2
- 230000002633 protecting effect Effects 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- 241000165940 Houjia Species 0.000 claims 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- 238000004458 analytical method Methods 0.000 claims 1
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 claims 1
- 239000000835 fiber Substances 0.000 claims 1
- ZTQSADJAYQOCDD-UHFFFAOYSA-N ginsenoside-Rd2 Natural products C1CC(C2(CCC3C(C)(C)C(OC4C(C(O)C(O)C(CO)O4)O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC(C(C(O)C1O)O)OC1COC1OCC(O)C(O)C1O ZTQSADJAYQOCDD-UHFFFAOYSA-N 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 238000010791 quenching Methods 0.000 claims 1
- 238000007363 ring formation reaction Methods 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 claims 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 abstract description 13
- YTGJWQPHMWSCST-UHFFFAOYSA-N Tiopronin Chemical compound CC(S)C(=O)NCC(O)=O YTGJWQPHMWSCST-UHFFFAOYSA-N 0.000 abstract description 7
- 108010058907 Tiopronin Proteins 0.000 abstract description 7
- 229960004402 tiopronin Drugs 0.000 abstract description 7
- 230000001154 acute effect Effects 0.000 abstract description 6
- 230000001225 therapeutic effect Effects 0.000 abstract description 5
- 231100000012 chronic liver injury Toxicity 0.000 abstract description 4
- 238000001647 drug administration Methods 0.000 abstract description 3
- 238000002347 injection Methods 0.000 abstract description 3
- 239000007924 injection Substances 0.000 abstract description 3
- 230000002265 prevention Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 230000008901 benefit Effects 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000010189 synthetic method Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 34
- 206010067125 Liver injury Diseases 0.000 description 11
- 0 C=*(CC1)CC(C(Cl)=C2)=C1NC2=O Chemical compound C=*(CC1)CC(C(Cl)=C2)=C1NC2=O 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 231100000753 hepatic injury Toxicity 0.000 description 6
- WQZGKKKJIJFFOK-SVZMEOIVSA-N (+)-Galactose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-SVZMEOIVSA-N 0.000 description 5
- 230000003908 liver function Effects 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- 239000003905 agrochemical Substances 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 230000001681 protective effect Effects 0.000 description 4
- 230000008859 change Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 239000000575 pesticide Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 102000003929 Transaminases Human genes 0.000 description 2
- 108090000340 Transaminases Proteins 0.000 description 2
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229920001971 elastomer Polymers 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 231100000234 hepatic damage Toxicity 0.000 description 2
- 239000004009 herbicide Substances 0.000 description 2
- 229960002591 hydroxyproline Drugs 0.000 description 2
- 230000008818 liver damage Effects 0.000 description 2
- 238000011866 long-term treatment Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 230000003449 preventive effect Effects 0.000 description 2
- 239000005060 rubber Substances 0.000 description 2
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 2
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- 102000049773 5-HT2A Serotonin Receptor Human genes 0.000 description 1
- 108010072564 5-HT2A Serotonin Receptor Proteins 0.000 description 1
- 102100027211 Albumin Human genes 0.000 description 1
- 101710153593 Albumin A Proteins 0.000 description 1
- 241001566735 Archon Species 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- KEUVTQPNJYHEHS-UHFFFAOYSA-N CCOC(C(C(C(CN(CC1)C(OC(C)(C)C)=O)=C1N1)=O)C1=O)=O Chemical compound CCOC(C(C(C(CN(CC1)C(OC(C)(C)C)=O)=C1N1)=O)C1=O)=O KEUVTQPNJYHEHS-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- KSLMFMQDWTXTQW-UHFFFAOYSA-N ClC1C(CNCC2)=C2Nc2n[nH]c(C3CCNCC3)c12 Chemical compound ClC1C(CNCC2)=C2Nc2n[nH]c(C3CCNCC3)c12 KSLMFMQDWTXTQW-UHFFFAOYSA-N 0.000 description 1
- PADPURGFWVMRMN-UHFFFAOYSA-N Clc1c(CNCC2)c2nc(Cl)c1 Chemical compound Clc1c(CNCC2)c2nc(Cl)c1 PADPURGFWVMRMN-UHFFFAOYSA-N 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 102000007665 Extracellular Signal-Regulated MAP Kinases Human genes 0.000 description 1
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- DMJZETNFCJMPCJ-QBFSEMIESA-N N/C(/C1CCNCC1)=C(/C(C(CNCC1)=C1N1)Cl)\C1=N Chemical compound N/C(/C1CCNCC1)=C(/C(C(CNCC1)=C1N1)Cl)\C1=N DMJZETNFCJMPCJ-QBFSEMIESA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- GBWJABCKRQVFDK-UHFFFAOYSA-N O=C1NC(CCNC2)=C2C(Cl)=C1 Chemical compound O=C1NC(CCNC2)=C2C(Cl)=C1 GBWJABCKRQVFDK-UHFFFAOYSA-N 0.000 description 1
- 102100037602 P2X purinoceptor 7 Human genes 0.000 description 1
- 101710189965 P2X purinoceptor 7 Proteins 0.000 description 1
- SMTZFNFIKUPEJC-UHFFFAOYSA-N Roxane Chemical compound CC(=O)OCC(=O)NCCCOC1=CC=CC(CN2CCCCC2)=C1 SMTZFNFIKUPEJC-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 235000010716 Vigna mungo Nutrition 0.000 description 1
- 244000042295 Vigna mungo Species 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 231100000439 acute liver injury Toxicity 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- WMNMMTGBUYIWTA-UHFFFAOYSA-N carbamic acid;piperidine Chemical compound NC(O)=O.C1CCNCC1 WMNMMTGBUYIWTA-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- BWUPSGJXXPATLU-UHFFFAOYSA-N dimepiperate Chemical compound C=1C=CC=CC=1C(C)(C)SC(=O)N1CCCCC1 BWUPSGJXXPATLU-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012990 dithiocarbamate Substances 0.000 description 1
- 150000004659 dithiocarbamates Chemical class 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000010562 histological examination Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 239000010985 leather Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- IPOVLZSJBYKHHU-UHFFFAOYSA-N piperidin-3-ylmethanamine Chemical class NCC1CCCNC1 IPOVLZSJBYKHHU-UHFFFAOYSA-N 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229960003320 roxatidine Drugs 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 150000003560 thiocarbamic acids Chemical class 0.000 description 1
- 229940101671 tiopronin 100 mg Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 238000004073 vulcanization Methods 0.000 description 1
- 238000009333 weeding Methods 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of piperidines of Antihepatitis medicament and pyrido pyrazoles Zn complex, belong to pharmaceutical chemistry synthesis technical field.Technical scheme main points are：The present invention has the advantages that compared with prior art：Synthetic method of the present invention is simple, molecular structure is novel and resulting compound
Description
Technical field
The invention belongs to pharmaceutical chemical synthesis technical field, and in particular to a kind of piperidines of Antihepatitis medicament and pyrido
The preparation method of pyrazoles-Zn complex.
Background technology
The synthesis of organic heterocyclic molecule is that organic chemistry filed develops fast one branch in recent years with application, in doctor
Occupy highly important status in medicine, the development of agricultural chemicals.It is used as the important heterocyclic compound of a class, o-diazepamate class
Compound all plays very important effect in medicine, agricultural chemicals.The pyrazole derivatives spy such as have effect wide spectrum, drug effect strong
Point, has been received more and more attention.In field of medicaments, o-diazepamate class compound is to including cancer, asthma, joint
Many diseases including inflammation have curative effect；In pesticide field, there is o-diazepamate class compound desinsection, sterilization and weeding to live
Property.In addition, o-diazepamate analog derivative has also all been applied in industries such as papermaking, leather, washing, plastics, coating, with wide
Wealthy research and development prospect.Pyridine is also a kind of important nitrogen heterocyclic ring, because there is good bioactivity extensively should for it
For medical research.For example, its derivative can suppress as 5HT2A receptor antagonists, extracellular signal-regulated kinase
Agent, mammal P2X7 conditioning agents, and with anti-breast cancer cell MDA-MB-231 proliferation activities and suppress liver cancer cells
HepG2 propagation.Fluorine-containing aromatic ring group, occurs very frequently in many insecticide pesticides, such as double trifluoro worm urides.Piperidines is main
For synthesizing medicine, agricultural chemicals and rubber chemicals, it is mainly used in synthesizing herbicides for use in paddy dimepiperate in pesticide industry, is a kind of selection
The non-hormone-type thiocarbamic acid class herbicide of property, very with development prospect.It is used to synthesize digestive system in pharmaceuticals industry
Medicine hydrochloric acid acetyl Roxatidine, cardiovascular disease medicine Dipyridmole etc..It is used to synthesize thiurams in Rubber Chemicals Industries
Super vulcanization accelerator bis-pentamethylenethiuram tetrasulfide, the super sulphur of accelerator pentamethylene two of dithiocarbamates
For carbamic acid piperidinium salt etc..Other piperidines can also synthesize various new fine-chemical intermediate, and many products are belonged to newly
The intermediate of small tonnage, the medicine of high added value, agricultural chemicals and the auxiliary agent developed, such as pipecoline, 3- aminomethylpiperidines, 4- hydroxyls
Phenylpiperidines etc..
This seminar has designed and synthesized a kind of piperidines of Antihepatitis medicament by the method for Computer-Aided Drug Design
And the preparation method of pyrido pyrazoles-Zn complex, and related activity test has been carried out to it.
The content of the invention
Present invention solves the technical problem that there is provided, a kind of synthetic method is simple, a kind of novel anti-hepatitis of molecular structure
The piperidines of medicine and the preparation method of pyrido pyrazoles-Zn complex.
The present invention adopts the following technical scheme that a kind of piperidines of new Antihepatitis medicament is simultaneously to solve above-mentioned technical problem
The preparation method of pyrido pyrazoles-Zn complex, it is characterised in that concretely comprise the following steps：
A, N-Boc-4- piperidones and dimethyl carbonate react in the presence of potassium tert-butoxide obtains N-Boc-3- formic acid first
Ester -4- piperidones
B, N-Boc-3- methyl formate -4- piperidones are under ammonium acetate effect, and ketone carbonyl redox is changed into amino
Compound N-Boc-3- methyl formate -4- amino -3- alkene-piperidines
C, N-Boc-3- methyl formate -4- amino -3- alkene-piperidines and chloroformyl ethyl acetate take under TEA effects
Generation reaction obtains compound N-Boc-3- methyl formate -4- carbamyl ethyl acetate -3- alkene-piperidines
D, N-Boc-3- methyl formate -4- carbamyl ethyl acetate -3- alkene-piperidines occur in the presence of potassium tert-butoxide
Intramolecular cyclization obtains compoundThen the compound carries out intramolecular in acid condition
Hydrogen migration and carbonyl reduction obtain compound
E、Under strongly acidic conditions, ester group and Boc groups are sloughed in heating, obtain compound
F、Under POCl3 effect, hydroxyl is replaced by chlorine obtains compound
G、Chloro carbon-to-nitrogen double bon is changed into amido link under concentrated hydrochloric acid effect and obtain compound
H、In the basic conditions, Boc amido protectings are carried out and obtains compound
I、Under cesium carbonate effect compound is obtained with iodomethane reaction
J、Reduction carbon-carbon double bond is obtained under Pd/C effects
K、Occur condensation with 4- pyridine carboxaldehydes and obtain compound
L、Compound is obtained with hydration hydrazine reaction
M、Intramolecular cyclization is carried out under Oxygen Condition and obtains compound
N、Slough Boc groups and obtain compound
O、Occur complex reaction with zinc chloride to obtain
Further limit, step A detailed process is：In reaction bulb, 1eq N-Boc-4- piperidones is added to 10V volumes
In toluene, 2eq dimethyl carbonate and 2eq potassium tert-butoxide are added, 70 DEG C of reaction 1h is heated to, is cooled to room temperature, adds water
It is quenched, it is 7 to adjust reaction solution pH with 1mol/L HCl, ethyl acetate extraction, after anhydrous sodium sulfate drying, is spin-dried for obtaining yellow
Grease N-Boc-3- methyl formate -4- piperidones
Further limit, step B detailed process is：1eq N-Boc-3- methyl formate -4- piperidones is added to 10
In the methanol of times volume, 3eq ammonium acetate is added, reaction is stayed overnight, be spin-dried for methanol, add the water of 3 times of volumes, dichloromethane extraction
Anhydrous sodium sulfate drying is used after extracting reaction solution, red oily liquids N-Boc-3- methyl formate -4- amino -3- is obtained after being spin-dried for
Alkene-piperidines
Further limit, step C detailed process is：By 1eq N-Boc-3- methyl formate -4- amino -3- alkene-piperidines
In the DCM for being added to 8 times of volumes, 1.05eq TEA is added, 10 DEG C are cooled to, 1.05eq 4- chloromethane ethyl acetoacetic acid second is added dropwise
Ester, room temperature reaction is stayed overnight, and adds the DCM dilute reaction solutions of 8 times of volumes, twice, anhydrous sodium sulfate drying is spin-dried for both obtaining for washing
Red oil product N-Boc-3- methyl formate -4- carbamyl ethyl acetate -3- alkene-piperidines
Further limit, step D detailed process is：1eq N-Boc-3- methyl formate -4- carbamyl acetic acid second
Ester -3- alkene-piperidines is added in the THF of 10 times of volumes, then is added portionwise 2.0eq t-BuOK, reaction temperature control less than
25 DEG C, frozen water is added after reaction 1h and is quenched, it is 3 to adjust reaction solution pH with 2mol/L HCl, filtering, and it is white that vacuum drying obtains class
Color solid product
Further limit, step E detailed process is：In 10eq 6mol/L HCl solution, it is added portionwise 1.0eq's100 DEG C are heated to, reaction is stayed overnight, are spin-dried for reaction dissolvent, then washed with ether, is dried in vacuo
Obtain off-white powder
Further limit, step F detailed process is：To 5eq POCl3In be added portionwise 1.0eq's100 DEG C are heated to, reaction is stayed overnight, are spin-dried for POCl3Obtain Red oil product
Further limit, step G detailed process is：It is added to the 1,4- dioxies six of 4 times of volumes
In ring, the concentrated hydrochloric acid of 4 times of volumes is added, 100 DEG C are heated to, back flow reaction 2 days is spin-dried for adding the second of 10 times of volumes after solvent
Acetoacetic ester, is washed three times, is dried and is obtained brown solid after being spin-dried for
Further limit, step H detailed process is：1eq'sIt is added to the 1,4- of 10 times of volumes
In dioxane and the water of 10 times of volumes, then 3.0eq sodium carbonate and 1.5eq (Boc) is added portionwise2O, reacts at room temperature 10h
Afterwards, filter, then wash with ethyl acetate reaction solution is extracted with ethyl acetate after filter cake, then washed with sodium chloride solution, dried, revolved
Reaction solution is obtained
Further limit, step I detailed process is：1.0eq'sIt is added to 10 times of volumes
DMF in, add 1.5eq Cs2CO3, 1.3eq KI, room temperature reaction stays overnight, and adds frozen water and reaction solution, acetic acid is quenched
Ethyl ester extractive reaction liquid, sodium chloride solution washing, dries, is spin-dried for, then is beaten with ether, filters, and it is solid that vacuum drying obtains white
Body
Further limit, step J detailed process is：In autoclave, by 1.0eq'sAdd
To the methanol of 10 times of volumes, a certain amount of Pd/C is passed through hydrogen, reacting kettle inner pressure is reached 0.2MPa, is heated to 50
DEG C, back flow reaction 5h, TLC monitoring raw material reaction is complete, and filtering reacting liquid is spin-dried for after solvent obtaining brown solid
Further limit, step K detailed process is：By compoundAdd in DMF, add
4- pyridine carboxaldehydes and a certain amount of triethylamine, are heated to backflow, complete through TLC monitoring raw material reactions after reaction a period of time,
Reaction solution, which is poured into frozen water, has a large amount of solids to separate out, and filter cake drying is obtained compound after suction filtration
Further limit, step L detailed process is：In reaction bulb, compoundAdd
In DMSO, a certain amount of hydrazine hydrate is added, at ambient temperature reaction a period of time, it is complete through TLC monitoring raw material reactions,
Reaction solution, which is poured into frozen water, has a large amount of solids to separate out, and filter cake drying is obtained compound after suction filtration
Further limit, step M detailed process is：In reaction bulb, compoundPlus
Enter in DMSO, backflow is heated under Oxygen Condition, it is reaction a period of time, complete through TLC monitoring raw material reactions, reaction solution is fallen
Enter in frozen water to have a large amount of solids to separate out, filter cake drying is obtained compound after suction filtration
Further limit, step K detailed process is：1.0eqIt is added to 10 times of volumes
Methanol and 10 volumes 12mol/L HCl/1, in 4- dioxane, room temperature reaction is stayed overnight, and is spin-dried for, ether washing, is obtained
Further limit, step L detailed process is：Nitrogen is passed through into the ultrasonic response container for being provided with agitating device
Gas, then add dissolved withDichloromethane solution, add ammoniacal liquor after, hold in 25 DEG C to ultrasonic response
The methanol solution dissolved with zinc chloride is added dropwise in device, agitating device and ultrasonic generator, ultrasonic wave hair are opened during dropwise addition
The setpoint frequency of generating apparatus is 80KHz, drips rear solution for clear state, stops stirring, keep ultrasonic generator after
Continuous work, is cooled to 0 DEG C of standing reaction solution, opens the steam vent on ultrasonic response container, keeps the nitrogen that is passed through from exhaust
Hole is discharged, and nitrogen is discharged ultrasonic response container with reaction dissolvent, has crystallization after clear crystal precipitation, 5h complete, suction filtration
Reaction solution, filter cake is washed repeatedly with methanol to wash away unnecessary zinc chloride, and filter cake is obtained after drying at room temperature
The synthetic route of the piperidines of Antihepatitis medicament of the present invention a kind of and pyrido pyrazoles-Zn complex is：
The present invention has synthesized a kind of piperidines and pyrido pyrazoles-Zn complex and has carried out antihepatitic activity test, finds
The complex has good antihepatitic activity.
Embodiment
The above to the present invention is described in further details by the following examples, but this should not be interpreted as to this
The scope for inventing above-mentioned theme is only limitted to following embodiment, and all technologies realized based on the above of the present invention belong to this hair
Bright scope.
Embodiment 1
In reaction bulb, N-Boc-4- piperidones 20g (0.1mol) is added in toluene 200mL, carbonic acid two is added
Methyl esters 18g (0.2mol) and potassium tert-butoxide 22g (0.2mol), is heated to 70 DEG C of reaction 1h, is cooled to room temperature, the 100mL that adds water quenches
Go out, it is 7 to adjust reaction solution pH with 1mol/L HCl, ethyl acetate extraction, after anhydrous sodium sulfate drying, be spin-dried for obtaining yellow oil
Shape thing N-Boc-3- methyl formate -4- piperidones 25g
Embodiment 2
In reaction bulb, N-Boc-3- methyl formate -4- piperidones 25g (0.1mol) are added in methanol 300mL, then
Ammonium acetate 22g (0.3mol) is added, reaction is stayed overnight, TLC monitoring raw material reactions are complete, are spin-dried for methanol, water 900mL added, with two
Chloromethanes 300mL extractive reactions liquid three times, merges and anhydrous sodium sulfate drying is used after organic phase, red oily liquids is obtained after being spin-dried for
N-Boc-3- methyl formate -4- amino -3- alkene-piperidines 25g
Embodiment 3
In reaction bulb, N-Boc-3- methyl formate -4- amino -3- alkene-piperidines 26g (0.1mol) is added to dichloromethane
In alkane 200mL, TEA11g (0.11mol) is added, 10 DEG C are cooled to, 4- chloroformyl ethyl acetate 16g is slowly added dropwise
(0.105mol), room temperature reaction is stayed overnight, and TLC monitoring raw material reactions are complete, add dichloromethane 200mL dilute reaction solutions, water
Wash twice, anhydrous sodium sulfate drying, be spin-dried for both obtaining Red oil product N-Boc-3- methyl formate -4- carbamyl acetic acid second
Ester -3- alkene-piperidines 25g
Embodiment 4
In reaction bulb, N-Boc-3- methyl formate -4- carbamyl ethyl acetate -3- alkene-piperidines 37g (0.1mol)
It is added in THF400mL, then t-BuOK 23g (0.2mol) is added portionwise, reaction temperature control is reacted after 1h less than 25 DEG C
Add frozen water 300mL to be quenched, it is 3 to adjust reaction solution pH with 2mol/L HCl, and filtering, vacuum drying obtains off-white powder production
Product32g
Embodiment 5
In reaction bulb, the HCl solution 200mL in 6mol/L is added, then be added portionwise
34g (0.1mol), is heated to 100 DEG C, reaction is stayed overnight, and is spin-dried for reaction dissolvent, then is washed with ether, and vacuum drying obtains off-white color
Solid15g
Embodiment 6
In closed reaction bulb, it is added portionwise into POCl3 50g (0.5mol)16g
(0.1mol), is slowly heated to 100 DEG C, reaction is stayed overnight, and vacuum is spin-dried for POCl3 and obtains Red oil product16g
Embodiment 7
In the reaction bulb with thermometer and stirring,20g is added to 1,4- dioxane
In 100mL, concentrated hydrochloric acid 100mL is slow added into, 100 DEG C are heated to, back flow reaction 2 days is spin-dried for after solvent adding 10 times of volumes
Ethyl acetate, wash three times, dry be spin-dried for after obtain brown solid
Embodiment 8
In reaction bulb,18g (0.1mol) is added to 1,4- dioxane 200mL and water 200mL
In, then sodium carbonate 30g (0.3mol) and (Boc) is added portionwise2After O 33g (0.15mol), room temperature reaction 10h, TLC monitoring is former
Material reaction is complete, filtering reacting liquid, then is washed with ethyl acetate 100mL after filter cake with ethyl acetate 200mL extractive reactions liquid three
It is secondary, then washed with sodium chloride solution, dry, rotation reaction solution is obtained20g
Embodiment 9
In reaction solution,28g (0.1mol) is added in DMF 300mL, adds carbonic acid
Caesium 50g (0.15mol), KI 20g (0.13mol), room temperature reaction is stayed overnight, and TLC monitoring raw material reactions are complete, add frozen water
Reaction solution is quenched in 100mL, and ethyl acetate 200mL extractive reactions liquid three times, saturated nacl aqueous solution 200mL washing reaction liquids are done
It is dry, it is spin-dried for, then be beaten with ether, filter, vacuum drying obtains white solid26g embodiments 10
, will in autoclave30g (0.1mol) is added in methanol 300mL, adds catalysis
Agent Pd/C 6g, are passed through hydrogen, reacting kettle inner pressure is reached 0.2MPa, are heated to 50 DEG C, back flow reaction 5h, TLC monitoring raw material
Reaction is complete, and filtering reacting liquid is spin-dried for after solvent obtaining brown solid27g
Embodiment 12
In reaction bulb, by compound30g (0.1mol) is added in DMF200mL, adds 4-
Pyridine carboxaldehyde 12.5 (0.12mol) and triethylamine 10mL, are heated to backflow, monitor former through TLC after reaction a period of time
Material reaction is complete, and reaction solution, which is poured into frozen water, has a large amount of solids to separate out, and filter cake drying is obtained compound after suction filtration
Embodiment 13
In reaction bulb, compound40g (0.1mol) is added in DMSO 150mL, then is added
Enter hydrazine hydrate 50mL, at ambient temperature reaction a period of time, it is complete through TLC monitoring raw material reactions, reaction solution is poured into frozen water
In there are a large amount of solids to separate out, filter cake drying is obtained compound after suction filtration36g
Embodiment 14
In reaction bulb, compound41g (0.1mol) is added in DMSO 150mL,
Backflow is heated under Oxygen Condition, reaction a period of time, complete through TLC monitoring raw material reactions, reaction solution, which is poured into frozen water, to be had
A large amount of solids are separated out, and filter cake drying is obtained compound after suction filtration33g
Embodiment 15
, will in reaction bulb40g (0.1mol) is added to methanol 400mL's and 12mol/L
In HCl/1,4- dioxane 400mL, room temperature reaction is stayed overnight, and TLC monitoring raw material reactions are complete, are spin-dried for, ether washing concentrate,
Obtain
Embodiment 16
Nitrogen is being passed through in the ultrasonic response container for being reversely provided with agitating device, is then being added dissolved with compound51g dichloromethane solution 500mL, adds after ammoniacal liquor 100mL, holds in 25 DEG C to ultrasonic response
The methanol solution 500mL dissolved with zinc chloride 50g is slowly added dropwise in device, opens agitating device during dropwise addition and ultrasonic wave is filled
Put, the setpoint frequency of ultrasonic generator is 80KHz, drip rear solution for clear state, stop stirring, keep ultrasonic wave
Generating means works on, and slow cooling opens the steam vent on ultrasonic response container to 0 DEG C of standing reaction solution, keeps logical
The nitrogen entered is discharged from steam vent, nitrogen is discharged ultrasonic response container with a certain amount of reaction dissolvent, gradually has colourless
Crystal is separated out, and completely, suction filtration reaction solution, filter cake is washed repeatedly to wash away unnecessary zinc salt crystallization with methanol, and filter cake is in room after 5h
Obtained after being dried under temperature48g。
Embodiment 15
Pharmacodynamic study
In order to evaluate and compare Tiopronin andPharmacodynamics, using four
Chlorination carbon, D-Gal (DAG) cause acute and chronic liver injury model, with transaminase GOT, GPT in serum, total protein T-
Hydroxyproline, sialic acid, the change of liver collagen content are turned to liver function change in P, albumin A LB, Archon ratio A/G and tissue
Change, the evaluation index of liver tissue fibrosis, and binding of pathological histological examination, are evaluated the pharmacodynamics of the two.Medicine is set
Count a series of Isodoses and be compared observation, be administered with injecting pathway, observed in preventive administration and chronic treatment
The operative condition of the two, as a result shows under administering mode：
Effect to acute hepatic injury model：
(1) effect of acute liver is caused to carbon tetrachloride：Through note
Penetrate after administration, 37.5-150mg/kg can substantially suppress CCl4The rise of serum GOT and GPT caused by caused acute liver damage
(P<0.05、P<0.01), showTo CCl4Caused acute liver damage has significantly
Protective effect.Under same experimental condition, Tiopronin 150mg/kg is to CCl4Caused acute liver damage equally has notable
Protective effect.
(2) effect of acute liver is caused to D-Gal (DAG)
Prevention effect：After being administered through preventive vaccination, high dose 150mg/
Kg can substantially suppress the rise (P of the serum GOT and GPT caused by acute liver damage caused by DAG<0.05、P<0.01), showAcute liver damage caused by DAG can be suppressed, there is significant protective effect.Equally
Under experimental condition, Tiopronin 75-150mg/kg equally has significant protective effect to acute liver damage caused by DAG.
Therapeutic action：Treat after 32h,37.5-150mg/kg can substantially press down
Rise (the P of serum GPT caused by DAG processed caused by hepatic injury<0.05、P<0.01), showAfter short, there is the restitution of part to the liver function of damage.Same examination
Under the conditions of testing, Tiopronin 75-150mg/kg is to hepatic injury caused by DAG, and after short, the liver function to damage equally has
There is the restitution of part.
Treat after 7d,37.5-150mg/kg can substantially it suppress caused by DAG
Rise (the P of serum GPT, GOT caused by hepatic injury<0.05、P<0.01), show
After long-term treatment, there is preferable restitution to the liver function of damage.Under same experimental condition, Tiopronin 37.5-150mg/
Kg is to hepatic injury caused by DAG, after long-term treatment, equally has preferable restitution to the liver function of damage.
Effect to chronic liver damage model：
Continuous drug administration by injection is after 1 month, and 50-100mg/kg dosage makes liter
High transaminase ALT, AST significantly reduces (P<0.05、P<0.01), 100mg/kg dosage makes the ALB of reduction significantly raise
(P<0.01) ratio (P that, significantly rise A/G is reversed<0.01)；25-100mg/kg dosage significantly reduces elevated sialic acid and contained
Measure (P<0.01), 100mg/kg dosage significantly reduces elevated hydroxyproline content (P<0.01).ShowChronic liver injury is caused to have significant therapeutic effect in carbon tetrachloride.Same experiment
Under the conditions of, Tiopronin 100mg/kg causes chronic liver injury equally to have significant therapeutic effect in carbon tetrachloride.
Conclusion：Drug administration by injection draws for carbon tetrachloride, D-Gal
The acute and chronic hepatic injury risen has significant prevention or therapeutic action, and the dosage and intensity of effect are quite or approximate with Tiopronin.
Embodiment above describes general principle, principal character and the advantage of the present invention, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, the original for simply illustrating the present invention described in above-described embodiment and specification
Reason, under the scope for not departing from the principle of the invention, various changes and modifications of the present invention are possible, and these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (7)
1. a kind of preparation method of piperidines of Antihepatitis medicament and pyrido pyrazoles-Zn complex, it is characterised in that specific steps
For：
A, N-Boc-4- piperidones and dimethyl carbonate react in the presence of potassium tert-butoxide obtains N-Boc-3- methyl formates -4-
Piperidones；
B, N-Boc-3- methyl formate -4- piperidones are under ammonium acetate effect, and ketone carbonyl redox obtains compound into amino
N-Boc-3- methyl formate -4- amino -3- alkene-piperidines；
It is anti-that under TEA effects substitution occurs for C, N-Boc-3- methyl formate -4- amino -3- alkene-piperidines and chloroformyl ethyl acetate
Compound N-Boc-3- methyl formate -4- carbamyl ethyl acetate -3- alkene-piperidines should be obtained；
Molecule occurs in the presence of potassium tert-butoxide for D, N-Boc-3- methyl formate -4- carbamyl ethyl acetate -3- alkene-piperidines
Interior cyclization obtains compoundThen the compound carries out intramolecular hydrogen turn in acid condition
Move and carbonyl reduction obtains compound
E、Under strongly acidic conditions, ester group and Boc groups are sloughed in heating, obtain compound
F、Under POCl3 effect, hydroxyl is replaced by chlorine obtains compound
G、Chloro carbon-to-nitrogen double bon is changed into amido link under concentrated hydrochloric acid effect and obtain compound
H、In the basic conditions, Boc amido protectings are carried out and obtains compound
I、Under cesium carbonate effect compound is obtained with iodomethane reaction
J、Reduction carbon-carbon double bond is obtained under Pd/C effects
K、Occur condensation with 4- pyridine carboxaldehydes and obtain compound
L、Compound is obtained with hydration hydrazine reaction
M、Intramolecular cyclization is carried out under Oxygen Condition and obtains compound
N、Slough Boc groups and obtain compound
O、Occur complex reaction with zinc chloride to obtain
2. the preparation method of a kind of piperidines of Antihepatitis medicament according to claim 1 and pyrido pyrazoles-Zn complex,
It is characterized in that step A detailed process is：In reaction bulb, 1eq N-Boc-4- piperidones is added to the first of 10V volumes
In benzene, 2eq dimethyl carbonate and 2eq potassium tert-butoxide are added, 70 DEG C of reaction 1h is heated to, is cooled to room temperature, adds water and quench
Go out, it is 7 to adjust reaction solution pH with 1mol/L HCl, ethyl acetate extraction, after anhydrous sodium sulfate drying, be spin-dried for obtaining yellow oil
Shape thing N-Boc-3- methyl formate -4- piperidones；Described step B detailed process is：By 1eq N-Boc-3- formic acid first
Ester -4- piperidones is added in the methanol of 10 times of volumes, adds 3eq ammonium acetate, and reaction is stayed overnight, and is spin-dried for methanol, adds 3 times
Anhydrous sodium sulfate drying is used after the water of volume, dichloromethane extractive reaction liquid, red oily liquids N-Boc-3- is obtained after being spin-dried for
Methyl formate -4- amino -3- alkene-piperidines；Described step C detailed process is：By 1eq N-Boc-3- methyl formates -4-
Amino -3- alkene-piperidines is added in the DCM of 8 times of volumes, adds 1.05eq TEA, is cooled to 10 DEG C, is added dropwise 1.05eq's
4- chloroformyl ethyl acetate, room temperature reaction is stayed overnight, and adds the DCM dilute reaction solutions of 8 times of volumes, is washed twice, anhydrous slufuric acid
Sodium is dried, and is spin-dried for both obtaining Red oil product N-Boc-3- methyl formate -4- carbamyl ethyl acetate -3- alkene-piperidines；It is described
Step D detailed process be：1eq N-Boc-3- methyl formate -4- carbamyl ethyl acetate -3- alkene-piperidines is added
Into the THF of 10 times of volumes, then 2.0eq t-BuOK is added portionwise, reaction temperature control is added less than 25 DEG C after reaction 1h
Frozen water is quenched, and it is 3 to adjust reaction solution pH with 2mol/L HCl, and filtering, vacuum drying obtains off-white powder productDescribed step E detailed process is：In 10eq 6mol/L HCl solution, add in batches
Enter 1.0eq's100 DEG C are heated to, reaction is stayed overnight, are spin-dried for reaction dissolvent, then washed with ether
Wash, vacuum drying obtains off-white powder
3. the preparation method of a kind of piperidines of Antihepatitis medicament according to claim 1 and pyrido pyrazoles-Zn complex,
It is characterized in that step F detailed process is：To 5eq POCl3In be added portionwise 1.0eq'sIt is heated to
100 DEG C, reaction is stayed overnight, and is spin-dried for POCl3Obtain Red oil productDescribed step G detailed process
For：In the Isosorbide-5-Nitrae-dioxane for being added to 4 times of volumes, the concentrated hydrochloric acid of 4 times of volumes is added, is heated to
100 DEG C, back flow reaction 2 days is spin-dried for adding the ethyl acetate of 10 times of volumes after solvent, washed three times, dries and obtain palm fibre after being spin-dried for
Color solidDescribed step H detailed process is：1eq'sIt is added to 10 times of bodies
In long-pending Isosorbide-5-Nitrae-dioxane and the water of 10 times of volumes, then 3.0eq sodium carbonate and 1.5eq (Boc) is added portionwise2O, room temperature
React after 10h, filtering, then washed with ethyl acetate reaction solution is extracted with ethyl acetate after filter cake, then washed with sodium chloride solution,
Dry, rotation reaction solution is obtainedDescribed step I detailed process is：1.0eq'sIn the DMF for being added to 10 times of volumes, 1.5eq Cs is added2CO3, 1.3eq KI, room temperature is anti-
It should stay overnight, add frozen water and reaction solution is quenched, ethyl acetate extractive reaction liquid, sodium chloride solution washing is dried, is spin-dried for, then use second
Ether is beaten, and filtering, vacuum drying obtains white solid
4. the preparation method of a kind of piperidines of Antihepatitis medicament according to claim 1 and pyrido pyrazoles-Zn complex,
It is characterized in that step J detailed process is：In autoclave, by 1.0eq'sIt is added to 10 times of bodies
Long-pending methanol, a certain amount of Pd/C, is passed through hydrogen, reacting kettle inner pressure is reached 0.2MPa, is heated to 50 DEG C, back flow reaction
5h, TLC monitoring raw material reaction are complete, and filtering reacting liquid is spin-dried for after solvent obtaining brown solidIt is described
Step K detailed process be：By compoundAdd in DMF, add 4- pyridine carboxaldehydes and certain
The triethylamine of amount, is heated to backflow, complete through TLC monitoring raw material reactions after reaction a period of time, and reaction solution is poured into frozen water
There are a large amount of solids to separate out, filter cake drying is obtained compound after suction filtration
5. the preparation method of a kind of piperidines of Antihepatitis medicament according to claim 1 and pyrido pyrazoles-Zn complex,
It is characterized in that step L detailed process is：In reaction bulb, compoundAdd in DMSO, then
A certain amount of hydrazine hydrate is added, at ambient temperature reaction a period of time, it is complete through TLC monitoring raw material reactions, reaction solution is fallen
Enter in frozen water to have a large amount of solids to separate out, filter cake drying is obtained compound after suction filtrationDescribed step
Suddenly M detailed process is：In reaction bulb, compoundAdd in DMSO, under Oxygen Condition
Backflow is heated to, reaction a period of time, complete through TLC monitoring raw material reactions, reaction solution, which is poured into frozen water, there are a large amount of solids to analyse
Go out, filter cake drying is obtained compound after suction filtrationDescribed step N detailed process is：
1.0eqIt is added to the methanol of 10 times of volumes and the 12mol/L of 10 volumes HCl/1,4- dioxies
In six rings, room temperature reaction is stayed overnight, and is spin-dried for, ether washing, is obtained
6. the preparation method of a kind of piperidines of Antihepatitis medicament according to claim 1 and pyrido pyrazoles-Zn complex,
It is characterized in that step O detailed process is：Nitrogen, Ran Houjia are passed through into the ultrasonic response container for being provided with agitating device
Enter dissolved withDichloromethane solution, add ammoniacal liquor after, in 25 DEG C into ultrasonic response container be added dropwise
Dissolved with the methanol solution of zinc chloride, agitating device and ultrasonic generator, ultrasonic generator are opened during dropwise addition
Setpoint frequency be 80KHz, drip rear solution for clear state, stop stirring, keep ultrasonic generator to continue
Work, is cooled to 0 DEG C of standing reaction solution, opens the steam vent on ultrasonic response container, keep the nitrogen that is passed through from exhaust
Hole is discharged, and nitrogen is discharged ultrasonic response container with reaction dissolvent, has crystallization after clear crystal precipitation, 5h completely, to take out
Reaction solution is filtered, filter cake is washed repeatedly with methanol to wash away unnecessary zinc chloride, and filter cake is obtained after drying at room temperature
7. the preparation method of a kind of piperidines of Antihepatitis medicament according to claim 1 and pyrido pyrazoles-Zn complex,
It is characterized in that the specific synthetic route in preparation process is：
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710413835.3A CN107286160A (en) | 2017-06-05 | 2017-06-05 | A kind of preparation method of the piperidines of Antihepatitis medicament and pyrido pyrazoles Zn complex |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710413835.3A CN107286160A (en) | 2017-06-05 | 2017-06-05 | A kind of preparation method of the piperidines of Antihepatitis medicament and pyrido pyrazoles Zn complex |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107286160A true CN107286160A (en) | 2017-10-24 |
Family
ID=60095193
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710413835.3A Withdrawn CN107286160A (en) | 2017-06-05 | 2017-06-05 | A kind of preparation method of the piperidines of Antihepatitis medicament and pyrido pyrazoles Zn complex |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107286160A (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102574861A (en) * | 2009-08-26 | 2012-07-11 | 奈科明有限责任公司 | Methylpyrrolopyrimidinecarboxamides |
| CN102917703A (en) * | 2010-03-08 | 2013-02-06 | 科研制药株式会社 | Novel EP4 agonist |
| CN103058982A (en) * | 2011-10-19 | 2013-04-24 | 四川大学 | Bifendate derivative containing halogen substituent, preparation method and application |
| CN104610240A (en) * | 2015-01-28 | 2015-05-13 | 南京工业大学 | Bicyclol-carnosine conjugate and preparation method and application thereof |
| CN104781272A (en) * | 2012-06-19 | 2015-07-15 | 英特塞普特医药品公司 | Preparation, use and solid form of obeticholic acid |
| CN106083976A (en) * | 2012-04-12 | 2016-11-09 | 弗吉尼亚联邦大学 | For treating dysbolismus, hyperlipemia, diabetes, Fatty Liver Disease and atherosclerotic new cholesterol metabolism thing 5 cholestene 3 β, 25 disulfate (25HCDS) |
| CN106279332A (en) * | 2016-07-29 | 2017-01-04 | 北京大学 | Triterpenoid compound Antcin K and liver-protecting activity thereof and application |
-
2017
- 2017-06-05 CN CN201710413835.3A patent/CN107286160A/en not_active Withdrawn
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102574861A (en) * | 2009-08-26 | 2012-07-11 | 奈科明有限责任公司 | Methylpyrrolopyrimidinecarboxamides |
| CN102917703A (en) * | 2010-03-08 | 2013-02-06 | 科研制药株式会社 | Novel EP4 agonist |
| CN103058982A (en) * | 2011-10-19 | 2013-04-24 | 四川大学 | Bifendate derivative containing halogen substituent, preparation method and application |
| CN106083976A (en) * | 2012-04-12 | 2016-11-09 | 弗吉尼亚联邦大学 | For treating dysbolismus, hyperlipemia, diabetes, Fatty Liver Disease and atherosclerotic new cholesterol metabolism thing 5 cholestene 3 β, 25 disulfate (25HCDS) |
| CN104781272A (en) * | 2012-06-19 | 2015-07-15 | 英特塞普特医药品公司 | Preparation, use and solid form of obeticholic acid |
| CN104610240A (en) * | 2015-01-28 | 2015-05-13 | 南京工业大学 | Bicyclol-carnosine conjugate and preparation method and application thereof |
| CN106279332A (en) * | 2016-07-29 | 2017-01-04 | 北京大学 | Triterpenoid compound Antcin K and liver-protecting activity thereof and application |
Non-Patent Citations (1)
| Title |
|---|
| RONG-GENG FU: "Design, synthesis and bioevaluation of dihydropyrazolo [3,4-b]pyridine and benzo[4,5]imidazo[1,2-a]pyrimidine compounds as dual KSP and Aurora-A kinase inhibitors for anti-cancer agents", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104130212B (en) | A kind of applicable hydrobromic acid irrigates the synthetic method for western spit of fland industrialized production | |
| CN107286131A (en) | A kind of Kinase Selectivity inhibitor | |
| CN103896970B (en) | 2-piconol copper complex and preparation method and application | |
| CN103073514A (en) | Rupestonic acid heterocyclic amide derivative, and preparation method and application of derivative | |
| CN107286160A (en) | A kind of preparation method of the piperidines of Antihepatitis medicament and pyrido pyrazoles Zn complex | |
| CN107260719A (en) | A kind of preparation method of Antihepatitis medicament piperidines and the diazetidine Zn complex of pyrido 1,2 | |
| CN107235973A (en) | The preparation method of the adjoining fluorobenzene calcium composition of piperidones chain with pharmaceutical activity | |
| CN107445938A (en) | Crystal form, preparation method and the Pharmaceutical composition containing the crystal form of the tartrates of Yi Ligelusita half | |
| CN107163046A (en) | The preparation method of pyrido o-diazepamate derivative with anti-tumor function | |
| CN107383070A (en) | The preparation method of piperidines with anti-hepatitis function and the adjoining fluorobenzene Zn complex of pyridine chain | |
| CN107325099A (en) | The preparation method of piperidines with insecticidal activity and the triazole derivative of 4,5 dihydro of pyrido 1,2,3 | |
| CN107245077A (en) | The preparation method of piperidines with insecticidal activity and the adjoining fluorobenzene analog derivative of pyridine chain | |
| CN107266442A (en) | The preparation method of piperidines with antitumor activity and pyridine compounds and their | |
| CN107286159A (en) | The preparation method of piperidines with pharmaceutical activity and chloro-pyridine calcium composition | |
| CN106938989A (en) | N- (5- benzyls thiazol-2-yl) acetamide derivative and preparation method and application | |
| CN107266444A (en) | The preparation method of piperidines with pharmaceutical activity and pyridine calcium composition | |
| CN110183377A (en) | A kind of synthetic method of anticancer drug Rui Gefeini | |
| CN107266443A (en) | The preparation method of piperidines with PVC stabilizer function and pyridone tin complex | |
| CN107286161A (en) | The preparation method of medicament for resisting platelet aggregation piperidines and the triazole calcium composition of 4,5 dihydro of pyrido 1,2,3 | |
| CN107325100A (en) | The preparation method of piperidines with insecticidal activity and pyridinone derivatives | |
| CN108329236B (en) | A kind of preparation method of enzalutamide intermediate | |
| CN107151247A (en) | The preparation method of the adjoining fluorophenyl compound of piperidones chain with bioactivity | |
| CN107151248A (en) | The preparation method of piperidine sulfonamide class compound with bioactivity | |
| CN107266445A (en) | The piperidines and the preparation method of the triazole tin complex of pyrido 1,2,3 acted on PVC stabilizer | |
| CN107325094A (en) | A kind of preparation method of antifungal drug piperidines and the diazetidine derivative of pyrido 1,2 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20171024 |
|
| WW01 | Invention patent application withdrawn after publication |