CN107141289A - The preparation method of piperidines with antineoplastic function and chloro-pyridine compounds - Google Patents
The preparation method of piperidines with antineoplastic function and chloro-pyridine compounds Download PDFInfo
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- CN107141289A CN107141289A CN201710411814.8A CN201710411814A CN107141289A CN 107141289 A CN107141289 A CN 107141289A CN 201710411814 A CN201710411814 A CN 201710411814A CN 107141289 A CN107141289 A CN 107141289A
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- 150000003053 piperidines Chemical class 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 230000000118 anti-neoplastic effect Effects 0.000 title claims abstract description 19
- 150000005753 chloropyridines Chemical class 0.000 title claims abstract description 12
- 230000000694 effects Effects 0.000 claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims description 103
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 53
- 238000000034 method Methods 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 29
- 150000001875 compounds Chemical class 0.000 claims description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 26
- 230000008569 process Effects 0.000 claims description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- TZIHFWKZFHZASV-UHFFFAOYSA-N anhydrous methyl formate Natural products COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 18
- 239000000460 chlorine Substances 0.000 claims description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 13
- 239000007787 solid Substances 0.000 claims description 13
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 12
- 229910052801 chlorine 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
- 238000012544 monitoring process Methods 0.000 claims description 11
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 10
- 238000001035 drying Methods 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
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 9
- -1 chloroformyl ethyl Chemical group 0.000 claims description 9
- 229910019213 POCl3 Inorganic materials 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 8
- 239000000047 product Substances 0.000 claims description 8
- 150000003222 pyridines Chemical class 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 239000011780 sodium chloride Substances 0.000 claims description 6
- 238000001291 vacuum drying Methods 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- 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
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims description 5
- 235000019257 ammonium acetate Nutrition 0.000 claims description 5
- 229940043376 ammonium acetate Drugs 0.000 claims description 5
- 239000012295 chemical reaction liquid Substances 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000003368 amide group Chemical group 0.000 claims description 4
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 4
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000000967 suction filtration Methods 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 3
- 239000012065 filter cake Substances 0.000 claims description 3
- 230000036571 hydration Effects 0.000 claims description 3
- 238000006703 hydration reaction Methods 0.000 claims description 3
- 230000005012 migration Effects 0.000 claims description 3
- 238000013508 migration Methods 0.000 claims description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 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 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 238000005917 acylation reaction Methods 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 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
- 238000010438 heat treatment Methods 0.000 claims description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 150000004702 methyl esters Chemical class 0.000 claims description 2
- 229960003742 phenol Drugs 0.000 claims description 2
- 230000002633 protecting effect Effects 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- 229940125773 compound 10 Drugs 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
- 239000004519 grease Substances 0.000 claims 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 238000010791 quenching Methods 0.000 claims 1
- 230000000171 quenching effect Effects 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- 206010073071 hepatocellular carcinoma Diseases 0.000 abstract description 3
- 231100000844 hepatocellular carcinoma Toxicity 0.000 abstract description 3
- 230000008901 benefit Effects 0.000 abstract description 2
- 238000010189 synthetic method Methods 0.000 abstract description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 239000002994 raw material Substances 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 239000003905 agrochemical Substances 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- 0 *S(N(CC1)CC(C(Cl)=C2)=C1N1C2=NNCC1=O)(=O)=O Chemical compound *S(N(CC1)CC(C(Cl)=C2)=C1N1C2=NNCC1=O)(=O)=O 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000004009 herbicide Substances 0.000 description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000005060 rubber Substances 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000012360 testing method Methods 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
- ZFUJHNBYZWRGBI-UHFFFAOYSA-N CC(C(CNCC1)=C1N12)=CC1=NNCC2=O Chemical compound CC(C(CNCC1)=C1N12)=CC1=NNCC2=O ZFUJHNBYZWRGBI-UHFFFAOYSA-N 0.000 description 1
- FBYYPSJQLWGETF-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CC(C(Cl)=C2)=C1N(C(CNN)=O)C2=O)=O Chemical compound CC(C)(C)OC(N(CC1)CC(C(Cl)=C2)=C1N(C(CNN)=O)C2=O)=O FBYYPSJQLWGETF-UHFFFAOYSA-N 0.000 description 1
- KZBCVTXDTVKVJK-UHFFFAOYSA-N CCC(N1C(CCN(C2)C(OC(C)(C)C)=O)=C2C(Cl)=CC2OC12)=O Chemical compound CCC(N1C(CCN(C2)C(OC(C)(C)C)=O)=C2C(Cl)=CC2OC12)=O KZBCVTXDTVKVJK-UHFFFAOYSA-N 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
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- KBNZTUBAXWACLZ-UHFFFAOYSA-N O=C1N2C(CCNC3)=C3C(Cl)=CC2NNC1 Chemical compound O=C1N2C(CCNC3)=C3C(Cl)=CC2NNC1 KBNZTUBAXWACLZ-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
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 230000002508 compound effect Effects 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 238000001514 detection method Methods 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
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- IXSZQYVWNJNRAL-UHFFFAOYSA-N etoxazole Chemical compound CCOC1=CC(C(C)(C)C)=CC=C1C1N=C(C=2C(=CC=CC=2F)F)OC1 IXSZQYVWNJNRAL-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 102000034356 gene-regulatory proteins Human genes 0.000 description 1
- 108091006104 gene-regulatory proteins Proteins 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- IPOVLZSJBYKHHU-UHFFFAOYSA-N piperidin-3-ylmethanamine Chemical class NCC1CCCNC1 IPOVLZSJBYKHHU-UHFFFAOYSA-N 0.000 description 1
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical class OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 1
- 239000003909 protein kinase inhibitor Substances 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
- 210000002966 serum Anatomy 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- 150000003560 thiocarbamic acids Chemical class 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000004073 vulcanization Methods 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 the preparation method of a kind of piperidines with antineoplastic function and chloro-pyridine compounds, belong to the synthesis technical field of antineoplastic.Technical scheme main points are：
Description
Technical field
The invention belongs to pharmaceutical chemical synthesis technical field, and in particular to a kind of piperidines with antineoplastic function
And preparation method of the chlorine with pyridine compounds and their.
Background technology
In recent years, heterocyclic compound is because structure is changeable, active high, toxicity is low and turns into the master of medicine and agricultural chemicals innovation
Stream, plurality of new varieties just continuously put goods on the market, and study on the synthesis is more towards baroque condensed hetero ring, double miscellaneous
Ring and poly-heterocyclic compounds.Piperidines and azole compounds are all the nitrogen-containing heterocycle compounds with good biological activity, extensively should
For medicine and the study on the synthesis of agricultural chemicals.Piperidines is mainly used in synthesis medicine, agricultural chemicals and rubber chemicals, is mainly used in pesticide industry
It is a kind of selective non-hormone-type thiocarbamic acid class herbicide, very with hair in synthesis herbicides for use in paddy dimepiperate
Exhibition prospect.It is used to synthesize medicine for digestive system hydrochloric acid acetyl Roxatidine, cardiovascular disease medicine Dipyridmole in pharmaceuticals industry
Deng.It is used to synthesize the super vulcanization accelerator bis-pentamethylenethiuram tetrasulfide of thiurams in Rubber Chemicals Industries, two is thio
Super accelerator pentamethylene aminodithioformic acid piperidinium salt of Carbamates etc..Other piperidines can also synthesize a variety of new
Type fine-chemical intermediate, many products belong to the centre of small tonnage newly developed, the medicine of high added value, agricultural chemicals and auxiliary agent
Body, such as pipecoline, 3- aminomethylpiperidines, 4- hydroxy piperidines.Pyridine is also a kind of important nitrogen heterocyclic ring, because it has
Good bioactivity is widely used in medical research.For example, its derivative can be used as 5HT2A receptor antagonists, cell
External signal regulatory protein kinase inhibitor, mammal P2X7 conditioning agents, and increase with anti-breast cancer cell MDA-MB-231
Grow activity and suppress the propagation of hepatocellular carcinoma H22.We have synthesized a series of with antitumor in laboratory by new method
Piperidines and chlorine the band pyridine compounds and their of pharmic function, and carried out corresponding bioactivity detection.
The content of the invention
Present invention solves the technical problem that there is provided, a kind of synthetic method is simple, and having for molecular structure novelty is antitumor
The piperidines and preparation method of the chlorine with pyridine compounds and their of pharmic function.
The present invention adopts the following technical scheme that to solve above-mentioned technical problem, and a kind of new have antineoplastic function
Piperidines and preparation method of the chlorine with pyridine compounds and their, it is characterised in that its molecular structure is：R
For benzene, to methylbenzene, para hydroxybenzene
The present invention adopts the following technical scheme that to solve above-mentioned technical problem, and a kind of new have antineoplastic function
Piperidines and preparation method of the chlorine with pyridine compounds and their, 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, are obtained while carrying out intramolecular hydrogen migration
Compound
I、Compound is obtained with chloracetyl chloride reaction
J、Hydrazine is set to replace chlorine to obtain with hydration hydrazine reaction
K、Carry out intramolecular condensation cyclization and obtain compound
L、Slough Boc groups and obtain compound
M、Occur acylation reaction from different sulfonic acid and obtain compound
Further limit, step A detailed process is：In reaction bulb, 1eq N-Boc-4- piperidones is added to
In the toluene of 10V volumes, 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 is quenched, and it is 7 to adjust reaction solution pH with 1mol/L HCl, ethyl acetate extraction, after anhydrous sodium sulfate drying, is spin-dried for
Obtain yellow oil 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's
100 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：In reaction bulb, 1.0eq'sAdd
Into the dichloromethane of 10 times of volumes, 1.5eq K is added2CO3, 3.0eq chloracetyl chloride is added dropwise, room temperature reaction is stayed overnight, plus
Enter frozen water and reaction solution is quenched, ethyl acetate extractive reaction liquid, sodium chloride solution washing is dried, is spin-dried for, then be beaten with ether, mistake
Filter, vacuum drying obtains white solid
Further limit, step J detailed process is：In reaction bulb, by 1.0eq'sAdd
Into the THF of 20 times of volumes, 10eq hydrazine hydrate and 5eq triethylamine are added, 70 DEG C are heated to, reaction is stayed overnight, acetic acid second
Ester is extracted, and is dried, is spin-dried for rear column chromatography for separation and obtains
Further limit, step K detailed process is：In reaction bulb, by 1.0eq's
In the DMSO for being added to 10 times of volumes, 80 DEG C are heated under air conditionses, after TLC monitoring raw material reactions completely, reaction solution
Pour into frozen water, there are a large amount of solids to separate out, suction filtration solid is obtained
Further limit, step M detailed process is：1.0eqIt is added to 10 times of volumes
In the HCl/1 of methanol and the 12mol/L of 10 volumes, 4- dioxane, room temperature reaction is stayed overnight, and is spin-dried for, ether washing, is obtained
Further limit, step J detailed process is：In reaction bulb,It is added in DMF,
Triethylamine and sulfoacid compound are added, 70 DEG C are heated to, reaction a period of time obtains compound
The conjunction of piperidines of the present invention with antineoplastic function and preparation method of the chlorine with pyridine compounds and their
It is into route：
The present invention has synthesized a series of piperidines and chlorine band and has carried out antitumor activity test at pyridine compounds and their, and finding should
Class compound has inhibitory activity to breast cancer cell MCF-7 and liver cancer HepG2.
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；1HNMR(400MHz,CD3Cl)δ:3.81 (s, 1H), 3.71 (d, J=
8.4Hz, 1H), 3.68 (d, J=8.4Hz, 1H), 3.45 (s, 3H), 3.07-3.05 (m, 2H), 2.76-2.73 (m, 2H), 1.37
(s,9H).MS-ESI(m/z):258.3[M+H+]。
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；1HNMR(400MHz,CD3Cl)δ:8.56(s,2H),3.93(s,
2H),3.77(s,3H),3.57-3.55(m,2H),2.16-2.13(m,2H),1.37(s,9H).MS-ESI(m/z):257.3[M
+H+]。
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；1HNMR(400MHz,CD3Cl)δ:4.71(s,2H),3.93(s,2H),3.79(s,3H),3.57-
3.55(m,2H),3.53(s,2H),2.16-2.13(m,2H),1.37(s,9H),1.29(s,3H).MS-ESI(m/z):371.4
[M+H+]。
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, filtering, and it is white that vacuum drying obtains class
Color solid product32g；1H NMR(400MHz,DMSO-d6)δ:11.51(s,
1H), 5.35 (s, 1H), 4.71 (s, 2H), 4.33 (d, J=4.0Hz, 2H), 3.66-3.62 (m, 2H), 3.25 (d, J=
12.0Hz,2H),1.41-1.39(m,9H),1.33-1.32(m,3H)。
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；1H NMR(400MHz,DMSO-d6)δ:11.47(s,1H),5.95(s,1H),5.41(s,
1H), 3.86-3.85 (m, 2H), 3.71 (d, J=12.0Hz, 2H), 3.11-3.09 (m, 2H), 1.90 (s, 1H).
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；1H NMR(400MHz,DMSO-d6)δ:7.61 (s, 1H), 3.81 (s, 2H), 3.37 (d, J=
12.0Hz,2H),3.13-3.12(m,2H),1.87(s,1H)。
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, TLC monitoring raw material reactions are complete, rotation
The ethyl acetate of 10 times of volumes is added after dry solvent, is washed three times, organic phase is separated, dries and obtains brown solid after being spin-dried for16g；1H NMR(400MHz,CDCl3)δ:8.17(s,1H),6.62(s,1H),3.35(s,2H),2.96
(d, J=12.0Hz, 2H), 2.07-2.05 (m, 2H) .MS-ESI (m/z):185.6[M+H+]。
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；1H NMR(400MHz,
DMSO-d6)δ:6.61 (s, 1H), 3.93 (s, 2H), 3.54 (s, 3H), 3.57 (d, J=12.0Hz, 2H), 2.07-2.05 (m,
2H),1.39(s,9H)。
Embodiment 9
In reaction bulb, 1.0eq's28g (0.1mol) is added to the dichloromethane of 10 times of volumes
In alkane, 1.5eq K is added2CO3, 3.0eq chloracetyl chloride is added dropwise, room temperature reaction is stayed overnight, TLC monitoring raw material reactions are complete,
Add frozen water and reaction solution be quenched, ethyl acetate extractive reaction liquid, sodium chloride solution washing is dried, is spin-dried for, then is beaten with ether,
Filtering, vacuum drying obtains white solid34g；1H NMR(400MHz,CDCl3)δ:6.61(s,1H),
(s, the 9H) .MS-ESI of 4.21 (s, 2H), 3.93 (s, 2H), 3.55 (d, J=4.0Hz, 2H), 2.07-2.05 (m, 2H), 1.37
(m/z):362.2[M+H+]。
Embodiment 10
, will in reaction bulb36g (0.1mol) is added in THF 500mL, adds hydration
Hydrazine 50g (1mol) and triethylamine 50g (0.5mol), is heated to 70 DEG C, reaction is stayed overnight, and TLC monitoring raw material reactions are complete, acetic acid second
Ester extractive reaction liquid, separates and is dried after organic phase, be spin-dried for rear column chromatography for separation and obtain33g
Embodiment 11
, will in reaction bulb35g (0.1mol) is added in DMSO300mL, in air
Under the conditions of be heated to 80 DEG C, after TLC monitoring raw material reaction completely, reaction solution is poured into frozen water, has a large amount of solids to separate out, suction filtration
Solid is obtained30g；1H NMR(400MHz,CDCl3)δ:7.11(s,1H),6.25(s,1H),3.93
(s, 2H), 3.55 (d, J=4.0Hz, 2H), 3.53 (d, J=4.0Hz, 2H), 2.09-2.08 (m, 2H), 1.36 (s, 9H) .MS-
ESI(m/z):339.8[M+H+]。
Embodiment 12
In reaction bulb,34g (0.1mol) is added to methanol 300mL's and 12mol/L
In HCl/1,4- dioxane 300mL, room temperature reaction is stayed overnight, and TLC monitoring raw material reactions are complete, are spin-dried for solvent, and ether washing is dense
Contracting thing, suction filtration drying is obtained20g；1H NMR(400MHz,CDCl3)δ:7.09(s,1H),6.23(s,
1H), 3.55 (d, J=4.0Hz, 2H), 3.33 (d, J=4.0Hz, 2H), 2.91 (d, J=4.0Hz, 2H), 2.07 (s, 2H)
.MS-ESI(m/z):239.6[M+H+]。
Embodiment 13
In reaction bulb,24g (0.1mol) is added in DMF, adds triethylamine 20g
(0.2mol) and benzene sulfonic acid 16g (0.1mol), is heated to after 70 DEG C, reaction 3h through the reaction of TLC monitoring raw materials completely, fall reaction solution
Enter in water, with chloroform 200mL extractive reactions liquid three times, be spin-dried for obtaining compound after merging organic phase
35g；1H NMR(400MHz,CDCl3)δ:7.86-7.85(m,2H),7.71-7.69(m,3H),7.11(s,1H),6.24(s,
1H), 3.55 (d, J=4.0Hz, 2H), 3.31 (d, J=4.0Hz, 2H), 2.99 (d, J=4.0Hz, 2H), 2.07 (s, 2H)
.MS-ESI(m/z):379.8[M+H+]。
Embodiment 14
Antitumor activity is tested
Growth period breast cancer cell MCF-7 and liver cancer HepG2 are collected, the active anticancer of compound is determined with MTS methods,
By cell with (every milliliter 4 × 10 of debita spissitudo4Individual cell) it is added in 96 porocyte culture plates and (must trains containing 10% tire calf serum
Nutrient solution is made into individual cells suspension), after cultivating 24 hours, in 37 DEG C, the CO that volumetric concentration is 5%2Under the conditions of with various concentrations
Compound effects 72 hours, then by MTS (final mass concentration 2mg/mL) and DMS (final 30 μM of molar concentration) mixing
Thing is directly added into celliferous culture medium, continues to put incubator incubation 4h.Act on after 4h, abandoning supernatant, 150 are added per hole
μ LDMSO, vibration, suction of the metabolin that cell survival rate is acted on MTS by it under enzyme linked immunological monitor 490nm wavelength
Yield is determined.
Preliminary biological activity test shows that such compound has inhibitory action in hepatocellular carcinoma H22 to cancer cell,
HepG2 is less than to MCF-7 inhibiting rate.
In summary, the invention provides a kind of new piperidines with antineoplastic function and chloro-pyridine class
Compound and preparation method thereof, this is the discovery first of such compound purposes, with great research and development potentiality.
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 (10)
1. the preparation method of piperidines and chloro-pyridine compounds with antineoplastic function, 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, while carrying out intramolecular hydrogen migration obtains compound
I、Compound is obtained with chloracetyl chloride reaction
J、Hydrazine is set to replace chlorine to obtain with hydration hydrazine reaction
K、Carry out intramolecular condensation cyclization and obtain compound
L、Slough Boc groups and obtain compound
M、Occur acylation reaction from different sulfonic acid and obtain compoundR is
Benzene, to methylbenzene, para hydroxybenzene.
2. the preparation side of the piperidines according to claim 1 with antineoplastic function and chloro-pyridine compounds
Method, it is characterised in that step A detailed process is：In reaction bulb, 1eq N-Boc-4- piperidones is added to 10V volumes
Toluene in, add 2eq dimethyl carbonate and 2eq potassium tert-butoxide, be heated to 70 DEG C reaction 1h, be cooled to room temperature, plus
Water quenching is gone out, and 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 Huang
Color grease N-Boc-3- methyl formate -4- piperidones；Step B detailed process is：By 1eq N-Boc-3- methyl formates-
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 of bodies
Anhydrous sodium sulfate drying is used after long-pending water, dichloromethane extractive reaction liquid, red oily liquids N-Boc-3- first is obtained after being spin-dried for
Sour methyl esters -4- amino -3- alkene-piperidines；Step C detailed process is：By 1eq N-Boc-3- methyl formate -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, and 1.05eq 4- chloroformyls are added dropwise
Ethyl acetate, room temperature reaction is stayed overnight, and adds the DCM dilute reaction solutions of 8 times of volumes, twice, anhydrous sodium sulfate drying is revolved for washing
It is dry both to obtain Red oil product N-Boc-3- methyl formate -4- carbamyl ethyl acetate -3- alkene-piperidines；Step D specific mistake
Cheng Wei：1eq N-Boc-3- methyl formate -4- carbamyl ethyl acetate -3- alkene-piperidines is added to the THF of 10 times of volumes
In, then 2.0eq t-BuOK is added portionwise, reaction temperature control is less than 25 DEG C, and addition frozen water is quenched after reaction 1h, uses 2mol/L
HCl regulations reaction solution pH be 3, filtering, vacuum drying obtains off-white powder product
3. the preparation side of the piperidines according to claim 1 with antineoplastic function and chloro-pyridine compounds
Method, it is characterised in that 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 powderStep 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
4. the preparation side of the piperidines according to claim 1 with antineoplastic function and chloro-pyridine compounds
Method, it is characterised in that step G detailed process is：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, 100 DEG C are heated to, back flow reaction 2 days is spin-dried for adding the acetic acid second of 10 times of volumes after solvent
Ester, is washed three times, is dried and is obtained brown solid after being spin-dried for
5. the preparation side of the piperidines according to claim 1 with antineoplastic function and chloro-pyridine compounds
Method, it is characterised in that step H detailed process is：1eq'sIt is added to the 1,4- dioxies six of 10 times of volumes
In ring and the water of 10 times of volumes, then 3.0eq sodium carbonate and 1.5eq (Boc) is added portionwise2After O, room temperature reaction 10h, mistake
Filter, then wash with ethyl acetate reaction solution is extracted with ethyl acetate after filter cake, then washed with sodium chloride solution, dry, rotation is reacted
Liquid is obtained
6. the preparation side of the piperidines according to claim 1 with antineoplastic function and chloro-pyridine compounds
Method, it is characterised in that step I detailed process is：In reaction bulb, 1.0eq'sIt is added to 10 times
In the dichloromethane of volume, 1.5eq K is added2CO3, 3.0eq chloracetyl chloride is added dropwise, room temperature reaction is stayed overnight, adds frozen water
Reaction solution is quenched, ethyl acetate extractive reaction liquid, sodium chloride solution washing is dried, is spin-dried for, then is beaten with ether, is filtered, vacuum
It is dried to obtain white solid
7. the preparation side of the piperidines according to claim 1 with antineoplastic function and chloro-pyridine compounds
Method, it is characterised in that step J detailed process is：In reaction bulb, by 1.0eq'sIt is added to 20 times
In the THF of volume, 10eq hydrazine hydrate and 5eq triethylamine are added, 70 DEG C are heated to, reaction is stayed overnight, ethyl acetate extraction is done
It is dry, it is spin-dried for rear column chromatography for separation and obtainsStep K detailed process is：In reaction bulb, by 1.0eq
'sIn the DMSO for being added to 10 times of volumes, 80 DEG C are heated under air conditionses, TLC monitoring is former
After material reaction completely, reaction solution is poured into frozen water, there are a large amount of solids to separate out, suction filtration solid is obtained
8. the preparation side of the piperidines according to claim 1 with antineoplastic function and chloro-pyridine compounds
Method, it is characterised in that step L detailed process is：1.0eqBe added to 10 times of volumes methanol and
In the 12mol/L of 10 volumes HCl/1,4- dioxane, room temperature reaction is stayed overnight, and is spin-dried for, ether washing, is obtained
9. the preparation side of the piperidines according to claim 1 with antineoplastic function and chloro-pyridine compounds
Method, it is characterised in that step M detailed process is：In reaction bulb,It is added in DMF, adds
Triethylamine and sulfoacid compound, are heated to 70 DEG C, reaction a period of time obtains compound
10. the piperidines according to claim 1 with antineoplastic function and preparation side of the chlorine with pyridine compounds and their
Method, it is characterised in that the specific synthetic route in preparation process is：
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH09291034A (en) * | 1996-02-27 | 1997-11-11 | Yoshitomi Pharmaceut Ind Ltd | Condensed pyridine compound and its use as a medicine |
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2017
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH09291034A (en) * | 1996-02-27 | 1997-11-11 | Yoshitomi Pharmaceut Ind Ltd | Condensed pyridine compound and its use as a medicine |
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|---|---|---|---|---|
| CN108069965A (en) * | 2017-12-29 | 2018-05-25 | 河南科技大学 | A kind of piperidones and pyridine compounds and their and the application in antitumor drug is prepared |
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Application publication date: 20170908 |