CN107759607A - Triazole with antitumor activity and phenodiazine Zhuo compound and preparation method thereof - Google Patents
Triazole with antitumor activity and phenodiazine Zhuo compound and preparation method thereof Download PDFInfo
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- CN107759607A CN107759607A CN201711220507.8A CN201711220507A CN107759607A CN 107759607 A CN107759607 A CN 107759607A CN 201711220507 A CN201711220507 A CN 201711220507A CN 107759607 A CN107759607 A CN 107759607A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 23
- 150000003852 triazoles Chemical class 0.000 title claims abstract description 20
- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- -1 diazepine compound Chemical class 0.000 claims abstract description 39
- 230000000118 anti-neoplastic effect Effects 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 144
- VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 claims description 94
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 60
- 239000000243 solution Substances 0.000 claims description 59
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 53
- 239000002994 raw material Substances 0.000 claims description 37
- 238000012544 monitoring process Methods 0.000 claims description 35
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 23
- 239000012074 organic phase Substances 0.000 claims description 23
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 22
- 229940049706 benzodiazepine Drugs 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 238000004440 column chromatography Methods 0.000 claims description 14
- 230000008569 process Effects 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 239000007788 liquid Substances 0.000 claims description 13
- 238000000926 separation method Methods 0.000 claims description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000012295 chemical reaction liquid Substances 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 12
- 239000012043 crude product Substances 0.000 claims description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- OFLXLNCGODUUOT-UHFFFAOYSA-N acetohydrazide Chemical class C\C(O)=N\N OFLXLNCGODUUOT-UHFFFAOYSA-N 0.000 claims description 9
- 230000000694 effects Effects 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 229940057874 phenyl trimethicone Drugs 0.000 claims description 9
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical class O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 claims description 7
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 claims description 6
- 239000012065 filter cake Substances 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N sodium azide Substances [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 6
- 241000736199 Paeonia Species 0.000 claims description 5
- 235000006484 Paeonia officinalis Nutrition 0.000 claims description 5
- 238000012545 processing Methods 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- BEBCJVAWIBVWNZ-UHFFFAOYSA-N glycinamide Chemical compound NCC(N)=O BEBCJVAWIBVWNZ-UHFFFAOYSA-N 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 230000004913 activation 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
- 229940117975 chromium trioxide Drugs 0.000 claims description 2
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 2
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 claims description 2
- XGISHOFUAFNYQF-UHFFFAOYSA-N pentanoyl chloride Chemical compound CCCCC(Cl)=O XGISHOFUAFNYQF-UHFFFAOYSA-N 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- UYRUJOSOEXZYLW-UHFFFAOYSA-N acetohydrazide;hydrochloride Chemical compound Cl.CC(=O)NN UYRUJOSOEXZYLW-UHFFFAOYSA-N 0.000 claims 2
- WCBVOPMSONYWEB-UHFFFAOYSA-N 2-aminoacetyl chloride Chemical compound NCC(Cl)=O WCBVOPMSONYWEB-UHFFFAOYSA-N 0.000 claims 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims 1
- 238000007259 addition reaction Methods 0.000 claims 1
- 150000001408 amides Chemical class 0.000 claims 1
- 239000004202 carbamide Substances 0.000 claims 1
- 238000004587 chromatography analysis Methods 0.000 claims 1
- 238000012650 click reaction Methods 0.000 claims 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims 1
- 125000000468 ketone group Chemical group 0.000 claims 1
- XIPFMBOWZXULIA-UHFFFAOYSA-N pivalamide Chemical compound CC(C)(C)C(N)=O XIPFMBOWZXULIA-UHFFFAOYSA-N 0.000 claims 1
- 238000010025 steaming Methods 0.000 claims 1
- 206010006187 Breast cancer Diseases 0.000 abstract description 4
- 208000026310 Breast neoplasm Diseases 0.000 abstract description 4
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 abstract description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- SYOANZBNGDEJFH-UHFFFAOYSA-N 2,5-dihydro-1h-triazole Chemical class C1NNN=C1 SYOANZBNGDEJFH-UHFFFAOYSA-N 0.000 abstract 1
- 238000010189 synthetic method Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 6
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 239000000370 acceptor Substances 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 0 *1N=C2N=C(c3ccncc3)c(cccc3)c3NC2=N1 Chemical compound *1N=C2N=C(c3ccncc3)c(cccc3)c3NC2=N1 0.000 description 1
- WKNMKGVLOWGGOU-UHFFFAOYSA-N 2-aminoacetamide;hydron;chloride Chemical compound Cl.NCC(N)=O WKNMKGVLOWGGOU-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical group C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 229960004538 alprazolam Drugs 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 150000001557 benzodiazepines Chemical class 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 230000002508 compound effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 1
- 230000007831 electrophysiology Effects 0.000 description 1
- 238000002001 electrophysiology Methods 0.000 description 1
- CDCHDCWJMGXXRH-UHFFFAOYSA-N estazolam Chemical compound C=1C(Cl)=CC=C(N2C=NN=C2CN=2)C=1C=2C1=CC=CC=C1 CDCHDCWJMGXXRH-UHFFFAOYSA-N 0.000 description 1
- 229960002336 estazolam Drugs 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- DDLIGBOFAVUZHB-UHFFFAOYSA-N midazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F DDLIGBOFAVUZHB-UHFFFAOYSA-N 0.000 description 1
- 229960003793 midazolam Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 238000012360 testing method Methods 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
- LINXHFKHZLOLEI-UHFFFAOYSA-N trimethyl-[phenyl-bis(trimethylsilyloxy)silyl]oxysilane Chemical compound C[Si](C)(C)O[Si](O[Si](C)(C)C)(O[Si](C)(C)C)C1=CC=CC=C1 LINXHFKHZLOLEI-UHFFFAOYSA-N 0.000 description 1
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of triazole with antitumor activity and phenodiazine Zhuo compound and preparation method thereof, belong to medical synthesis technical field.Technical key point is：
Description
Technical field
The invention belongs to medical synthesis technical field, and in particular to a kind of triazole with antitumor activity and phenodiazine Zhuo
Compound and preparation method thereof.
Background technology
The important heterocyclic compound with pharmacological activity of Benzodiazepines compound Shi ー kinds, have calmness, hypnosis,
The effect such as of flaccid muscles of anti-epileptic, central, when it acts on human body, has the characteristics of rapid-action, safe.Central nervous system
It is middle the binding site to Benzodiazepine with high-affinity, stereospecificity and saturability to be present.And most of benzene phenodiazines
Tall and erect class medicine is related to the affinity of binding site and their pharmacological action, and its central action has with Benzodiazepine binding site
Close.Further investigation is it has also been found that distribution situation and the CNS inhibition neurotransmitter GABA of Benzodiazepine binding site
(GABA) distribution of GABAA acceptors is basically identical.Electro physiology is it is demonstrated experimentally that Benzodiazepines can strengthen GABA energy neurotransmissions
Function and cynapse depression effect；The effect that GABA is combined with GABAA acceptors can also be strengthened.
Triazole has certain physiologically active, in terms of as antiseptic medicine research, due to its efficient, hypotoxicity, secondary work
With it is small the advantages of, increasingly paid close attention to by scientist.Imidazoles or triazole ring etc. are introduced on Benzodiazepine parent nucleus 1,2
The compound of heterocycle, clinically extensive use, mainly there is alprazolam, estazolam, midazolam etc..At present for
1, the 2 introducing heterocycle modifications of Benzodiazepine parent nucleus and the derivative to 4,5 introducing heterocycle modifications, the existing more report of document
Road.This research, in 2,3 introducing triazole rings of Benzodiazepine parent nucleus, obtains novel diazo by designing synthetic route
And benzodiazepine compound.
The content of the invention
Present invention solves the technical problem that it there is provided a kind of novel triazole with antitumor activity of molecular structure
And phenodiazine Zhuo compound and preparation method thereof.
A kind of triazole with antitumor activity and phenodiazine Zhuo compound, the compound are shown below：
The preparation method of a kind of triazole with antitumor activity and phenodiazine Zhuo compound, it is characterised in that concretely comprise the following steps：
A, acylation reaction generation N- phenyl trimethicone acetamides occur in pyridine or dichloromethane for aniline and pivaloyl chloride；
B, under n-BuLi effect after activation ortho-hydrogens with 4- pyridine carboxaldehydes addition occurs for N- phenyl trimethicones acetamide
Reaction obtains N- (2- (hydroxyl (4- pyridine radicals) methyl) phenyl) pivaloyl amine；
C, N- (2- (hydroxyl (4- pyridine radicals) methyl) phenyl) pivaloyl amine is aoxidized by manganese dioxide or chromium trioxide,
Secondary carbon and the hydroxyl connected generate carbonyl after sloughing a molecule hydrogen in its structure, obtain N- (2- (4- piperidone bases) phenyl)
Pivaloyl amine；
D, N- (2- (4- piperidone bases) phenyl) pivaloyl amine sloughs tertiary bytyry and obtains 2- (4- in acid condition
Piperidone base) aniline；Substitution reaction generation N- occurs under DCC effects with Boc glycyls chlorine for 2- (4- piperidone bases) aniline
(2- (4- piperidone bases) phenyl) Boc amino acetamides；
E, N- (2- (4- piperidone bases) phenyl) Boc amino acetamides react with HCl in Isosorbide-5-Nitrae-dioxane or THF,
While sloughing Boc groups N- (2- (4- piperidone bases) phenyl) glycyl amine hydrochlorate is obtained into salt；
F, N- (2- (4- piperidone bases) phenyl) glycyl amine hydrochlorates occur ketoamine and are condensed under sodium methoxide effect
To tall and erect -2 (3H) -one of 5- (4- pyridine radicals) -1H- benzos [e] [1,4] phenodiazine；
G, tall and erect -2 (3H) -one of 5- (4- pyridine radicals) -1H- benzos [e] [1,4] phenodiazine and TMSN3Or NaN3Click is occurring
Reaction obtains
Further limit, step A detailed process is：In reaction bulb, aniline is added in pyridine, in room temperature condition
Under, pivaloyl chloride is slowly added dropwise, continues to react at ambient temperature after dripping, TLC monitoring raw material reactions are complete, to reaction solution
It is middle to add a certain amount of HCl solution, strong stirring for a period of time after washed reaction liquid, be finally concentrated to give under vacuum
N- phenyl trimethicone acetamides；Or in reaction bulb, aniline and potassium carbonate are added in dichloromethane and stirred, in room temperature condition
Under, pivaloyl chloride is slowly added dropwise, continues to react at ambient temperature after dripping, TLC monitoring raw material reactions are complete, to reaction solution
It is middle to add a certain amount of HCl solution, strong stirring for a period of time after washed reaction liquid, be finally concentrated to give N- under vacuum
Phenyl trimethicone acetamide.
Further limit, step B detailed process is：In reaction bulb, N- phenyl trimethicone acetamides be added to through
In the THF of Non-aqueous processing, nitrogen protection reaction system, it is placed under the conditions of 0 DEG C, n-butyllithium solution, keeping temperature is slowly added dropwise
Below 5 DEG C, 2h is stirred after dripping, the THF solution dissolved with 4- pyridine carboxaldehydes is slowly dropped in reaction solution, makes reaction temperature
Degree is no more than 5 DEG C, and it is in peony to drip rear reaction solution；Continue to react 3h, TLC monitoring raw material unreacteds are complete, make reaction exist
Temperature continues to add a certain amount of frozen water after reacting 8h reaction is quenched under the conditions of being -20 DEG C~60 DEG C, then is extracted with ethyl acetate
Reaction solution, the crude product of N- (2- (hydroxyl (4- pyridine radicals) methyl) phenyl) pivaloyl amine is obtained after organic phase is evaporated off, then passed through
Column chromatography for separation obtains sterling.
Further limit, step C detailed process is：In reaction bulb, N- (2- (hydroxyl (4- pyridine radicals) methyl) benzene
Base) pivaloyl amine and MnO2It is added in chloroform, heating reflux reaction 10h, TLC monitoring raw material reaction is complete, and filtering is anti-
Liquid is answered, N- (2- (4- piperidone bases) phenyl) pivaloyl amine is obtained after filtrate concentration；Or in reaction bulb, N- (2- (hydroxyls
Base (4- pyridine radicals) methyl) phenyl) pivaloyl amine and CrO3It is added in chloroform, reacts at room temperature 5h, TLC monitoring raw materials is anti-
Should be complete, reaction solution is extracted with ethyl acetate after filtering, N- (2- (4- piperidone bases) phenyl) front three is obtained after organic phase is evaporated off
Yl acetamide.
Further limit, step D detailed process is：In reaction bulb, N- (2- (4- piperidone bases) phenyl) front three
Yl acetamide is added in the mixed solution of ethanol and hydrochloric acid, is stirred reaction at ambient temperature, is heated to after stirring 2h
Backflow, continue to react 6h, TLC monitoring raw material reactions are complete；Ethanol is evaporated off in vacuum concentration, then is adjusted instead with saturated sodium carbonate solution
It is 7~8 to answer liquid pH, then, 2- (4- piperidone bases) benzene is concentrated to give after merging organic phase with dichloromethane extractive reaction liquid three times
The crude product of amine, then obtain sterling through column chromatography for separation；Resulting 2- (4- piperidone bases) aniline is added in dichloromethane,
Compound Boc glycyls chlorine and DCC are added, reacts 10h at ambient temperature, TLC monitoring raw material reactions are complete, and filtering is anti-
Liquid is answered to remove dicyclohexylurea, reaction solution is washed with 10% HCl solution and saturated sodium carbonate solution respectively again, after separating organic phase
N- (2- (4- piperidone bases) phenyl) Boc amino acetamide crude products are concentrated to give, then sterling is obtained through column chromatography for separation.
Further limit, step E detailed process is：In reaction bulb, N- (2- (4- piperidone bases) phenyl) Boc ammonia
Yl acetamide is added in Isosorbide-5-Nitrae-dioxane containing 4M HCl, at ambient temperature stirring reaction 2h, and TLC monitoring raw materials are anti-
Should be complete, filtering reacting liquid, filter cake is N- (2- (4- piperidone bases) phenyl) glycyl amine hydrochlorate；Or in reaction bulb,
N- (2- (4- piperidone bases) phenyl) Boc amino acetamides are added in the THF containing 4M HCl, stirred under heated reflux condition
Mix the reaction of reaction 2h, TLC monitoring raw material completely, filtering reacting liquid, filter cake is N- (2- (4- piperidone bases) phenyl) glycyl
Amine hydrochlorate.
Further limit, step F detailed process is：In reaction bulb, N- (2- (4- piperidone bases) phenyl) amino
Acetamide hydrochloride and sodium methoxide are added in methanol, and the stirring reaction 2h at 50 DEG C, LCMS monitoring raw material reaction are complete, true
Reaction dissolvent is evaporated off under empty condition, adds a certain amount of water and dichloromethane, separates organic phase, 5- (4- pyrroles are obtained after concentration
Piperidinyl) tall and erect -2 (3H) -one of -1H- benzos [e] [1,4] phenodiazine.
Further limit, step G detailed process is：In reaction bulb, 5- (4- pyridine radicals) -1H- benzos [e] [1,
4] tall and erect -2 (3H) -one of phenodiazine and TMSN3It is added in acetone, adds a certain amount of potassium carbonate, room temperature is anti-under nitrogen protection
2h is answered, TLC monitoring raw material reactions are complete, and reaction solution is extracted after adding certain water with dichloromethane, is concentrated after merging organic phase,
Obtained again through column chromatography for separationOr in reaction bulb, 5- (4- pyridine radicals) -1H- benzos [e] [Isosorbide-5-Nitrae] two
Nitrogen -2 (3H) -one of Zhuo and NaN3It is added in DMF, adds a certain amount of CuI and potassium carbonate, be heated under air conditionses
120 DEG C, TLC monitoring raw material reactions are complete after reacting 6h, and reaction solution is extracted after adding certain water with dichloromethane, merges organic phase
After concentrate, then obtained through column chromatography for separation
Embodiment
The above of 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, aniline (10g, 0.107mol) is added in pyridine 50mL, at ambient temperature, spy is slowly added dropwise
Valeric chloride (14.24g, 0.118mol), continuing to react 3h at ambient temperature after dripping, TLC monitoring raw material reactions are complete, to
Add a certain amount of 6N HCl solutions in reaction solution, strong stirring for a period of time after washed reaction liquid, finally under vacuum
It is concentrated to give N- phenyl trimethicone acetamides (18g, yield:95.23%) .MS (ESI) m/z:177.1(M+H+). HNMR:
(CDCl3) δ 7.38 (brs, 1H, NH), 7.55 (d, J=8Hz, 2H, Ar-H), 7.36 (t, J=8Hz, 2H, Ar-H), 7.20
(t, J=4Hz, 1H, Ar-H), 1.40 (s, 9H)
Embodiment 2
In reaction bulb, aniline (10g, 0.107mol) and potassium carbonate (27.6g, 0.20mol) are added dichloromethane
Stirred in 50ml, at ambient temperature, pivaloyl chloride (14.24g, 0.118mol) is slowly added dropwise, continued after dripping in room temperature
Under the conditions of react 3h, TLC monitoring raw material reactions are complete, and a certain amount of 6N HCl solutions, strong stirring one are added into reaction solution
Washed reaction liquid after the section time, is finally concentrated to give N- phenyl trimethicone acetamides (15.7g, yield under vacuum:
82.78%) .MS (ESI) m/z:177.1(M+H+).
Embodiment 3
In reaction bulb, N- phenyl trimethicones acetamide (10g, 0.056mol) is added to the THF through Non-aqueous processing
In 100mL, nitrogen protection reaction system, be placed under the conditions of 0 DEG C, n-butyllithium solution be slowly added dropwise, maintain the temperature at 5 DEG C with
Under, about 30min is added dropwise complete；After stirring 2h, the THF solution 50mL dissolved with 4- pyridine carboxaldehydes 12g, reaction solution is slowly dropped to
In, reaction temperature is no more than 5 DEG C, it is in peony to drip rear reaction solution；Continue to react 3h, TLC monitoring raw material unreacteds are complete
Entirely, reaction is added a certain amount of frozen water after reaction 8h is continued under the conditions of temperature is 60 DEG C and reaction is quenched, then use ethyl acetate
Extractive reaction liquid, the crude product of N- (2- (hydroxyl (4- pyridine radicals) methyl) phenyl) pivaloyl amine is obtained after organic phase is evaporated off,
Again sterling (3.4g, yield are obtained through column chromatography for separation:21.38%) .MS (ESI) m/z:285.4 (M+H+).HNMR:
(CDCl3) δ 8.94 (brs, 1H, NH), 8.27 (d, J=6Hz, 2H, Ar-H), 8.09 (d, J=8Hz, 1H, Ar-H), 7.24-
7.34 (m, 1H, Ar-H), 8.29 (d, J=6Hz, 2H, Ar-H), 7.22 (d, J=5.2Hz, 2H, Ar-H), 8.38 (d, J=
6Hz, 2H, Ar-H), 7.01 (d, J=3.6Hz, 2H, Ar-H), 5.65 (s, 1H), 1.04 (s, 9H)
Embodiment 4
In reaction bulb, N- phenyl trimethicones acetamide (10g, 0.056mol) is added to the THF through Non-aqueous processing
In 100mL, nitrogen protection reaction system, be placed under the conditions of 0 DEG C, n-butyllithium solution be slowly added dropwise, maintain the temperature at 5 DEG C with
Under, about 30min is added dropwise complete；After stirring 2h, the THF solution 50mL dissolved with 4- pyridine carboxaldehydes 12g, reaction solution is slowly dropped to
In, reaction temperature is no more than 5 DEG C, it is in peony to drip rear reaction solution；Continue to react 3h, TLC monitoring raw material unreacteds are complete
Entirely, reaction is added a certain amount of frozen water after reaction 8h is continued under the conditions of temperature is -20 DEG C and reaction is quenched, then use ethyl acetate
Extractive reaction liquid, the crude product of N- (2- (hydroxyl (4- pyridine radicals) methyl) phenyl) pivaloyl amine is obtained after organic phase is evaporated off,
Again sterling (12.7g, yield are obtained through column chromatography for separation:79.21%) .MS (ESI) m/z:285.4 (M+H+)。
Embodiment 5
In reaction bulb, N- phenyl trimethicones acetamide (10g, 0.056mol) is added to the THF through Non-aqueous processing
In 100mL, nitrogen protection reaction system, be placed under the conditions of 0 DEG C, n-butyllithium solution be slowly added dropwise, maintain the temperature at 5 DEG C with
Under, about 30min is added dropwise complete；After stirring 2h, the THF solution 50mL dissolved with 4- pyridine carboxaldehydes 12g, reaction solution is slowly dropped to
In, reaction temperature is no more than 5 DEG C, it is in peony to drip rear reaction solution；Continue to react 3h, TLC monitoring raw material unreacteds are complete
Entirely, reaction is added a certain amount of frozen water after reaction 8h is continued under the conditions of temperature is 10 DEG C and reaction is quenched, then use ethyl acetate
Extractive reaction liquid, the crude product of N- (2- (hydroxyl (4- pyridine radicals) methyl) phenyl) pivaloyl amine is obtained after organic phase is evaporated off,
Again sterling (13.3g, yield are obtained through column chromatography for separation:83.23%) .MS (ESI) m/z:285.4 (M+H+)。
Embodiment 6
In reaction bulb, N- (2- (hydroxyl (4- pyridine radicals) methyl) phenyl) pivaloyl amine (6g, 0.021mol)
And MnO2(9.2g, 0.021mol) is added in chloroform 50mL, and heating reflux reaction 10h, TLC monitoring raw material reaction is complete, mistake
Reaction solution is filtered, N- (2- (4- piperidone bases) phenyl) pivaloyl amine (4.8g, yield is obtained after filtrate concentration:
82.11%) .MS (ESI) m/z:283.4(M+H+).MS(ESI)m/z:283.4(M+H+).HNMR:(CDCl3)δ11.35
(brs, 1H, NH), 8.77-8.79 (m, 3H, Ar-H), 7.60 (t, J=7.6Hz, 1H, Ar-H), 7.50-7.49 (m, 3H, Ar-
), H 7.03 (t, J=7.2Hz, 1H, Ar-H), 1.06 (s, 9H)
Embodiment 7
In reaction bulb, N- (2- (hydroxyl (4- pyridine radicals) methyl) phenyl) pivaloyl amine (6g, 0.021mol)
And CrO3(2.1g, 0.021mol) is added in chloroform 50mL, reacts at room temperature 5h, TLC monitoring raw material reactions are complete, after filtering
Reaction solution is extracted with ethyl acetate, be evaporated off obtaining after organic phase N- (2- (4- piperidone bases) phenyl) pivaloyl amine (5.4g,
yield:92.30%) .MS (ESI) m/z:283.4(M+H+).
Embodiment 8
In reaction bulb, N- (2- (4- piperidone bases) phenyl) pivaloyl amine (4.2g, 0.0154mol) is added to
In ethanol 35mL and hydrochloric acid 14mL mixed solution, reaction is stirred at ambient temperature, is heated to flowing back after stirring 2h,
Continue to react 6h, TLC monitoring raw material reactions are complete；Ethanol is evaporated off in vacuum concentration, then adjusts reaction solution with saturated sodium carbonate solution
PH is 7~8, then, 2- (4- piperidone bases) aniline is concentrated to give after merging organic phase with dichloromethane extractive reaction liquid three times
Crude product, then obtain sterling (2.5g, yield through column chromatography for separation:83%) .MS (ESI) m/z:199.2(M+H+).HNMR:
(CDCl3) δ 8.75-8.76 (m, 2H, Ar-H), 7.44 (d, 2H, Ar-H), 7.43 (d, 2H, Ar-H), 6.75 (d, 1H, J=
8Hz,Ar-H),6.57-6.61(m,1H,Ar-H),6.32(brs,2H,NH).
Embodiment 9
In reaction bulb, 2- (4- piperidone bases) aniline (2g, 0.01mol) is added in dichloromethane 50mL, then added
Enter Boc glycyls chlorine (3.8g, 0.02mol) and DCC (4.12g, 0.02mol), react 7h, TLC prisons at ambient temperature
It is complete to control raw material reaction, filtering reacting liquid removes dicyclohexylurea, reaction solution again respectively with 10% HCl solution and saturated sodium carbonate
Solution is washed, and N- (2- (4- piperidone bases) phenyl) Boc amino acetamide crude products are concentrated to give after separating organic phase, then through post layer
Analyse isolated sterling (2.2g.yield:60%) .MS (ESI) m/z:356.4(M+H+).HNMR:(CDCl3)δ 11.46
(brs, 1H, NH), 8.79 (t, 3H, J=4Hz, Ar-H), 8.72 (d, 1H, J=4Hz, Ar-H), 7.45-7.61 (m, 4H, Ar-
), H 5.36 (brs, 1H, NH), 4.00 (d, J=8Hz, 2H), 1.45 (s, 9H)
Embodiment 10
In reaction bulb, N- (2- (4- piperidone bases) phenyl) Boc amino acetamides (2g, 0.0056mol) are added to
In Isosorbide-5-Nitrae-dioxane containing 4M HCl, stirring reaction 2h, the reaction of TLC monitoring raw materials at ambient temperature completely, is filtered anti-
Liquid is answered, filter cake is N- (2- (4- piperidone bases) phenyl) glycyl amine hydrochlorate (1.2g, yield:75%) .MS (ESI) m/
z: 256.4(M+H+).HNMR:(CDCl3) δ 8.66 (t, 3H, J=4Hz, Ar-H), 8.43 (d, 1H, J=4Hz, Ar-H),
7.38-7.61 (m, 4H, Ar-H), 7.23 (brs, 1H, NH), 3.85 (d, J=8Hz, 2H), 1.53 (s, 2H)
Embodiment 11
In reaction bulb, N- (2- (4- piperidone bases) phenyl) Boc amino acetamides (2g, 0.0056mol) are added to
In THF containing 4M HCl, stirring reaction 2h under heated reflux condition, TLC monitoring raw material reaction are complete, filtering reacting liquid, filter
Cake is N- (2- (4- piperidone bases) phenyl) glycyl amine hydrochlorate (1.5g, yield:93.56%) .MS (ESI) m/z:
256.4 (M+H+).
Embodiment 12
In reaction bulb, N- (2- (4- piperidone bases) phenyl) glycyl amine hydrochlorates (700mg, 2.41mmol) and
Sodium methoxide (155.8mg, 2.88mmol) is added in methanol 20mL, the stirring reaction 2h under the conditions of 50 DEG C, LC-MS monitoring reaction
Completely, reaction dissolvent is evaporated off under vacuum, adds a certain amount of water and dichloromethane, separates organic phase, after concentration
To -2 (3H) -one (450mg, yield of 5- (4- pyridine radicals) -1H- benzos [e] [1,4] phenodiazine Zhuo:78.81%) .MS (ESI) m/
z: 238.3(M+H+).HNMR:(CDCl3) δ 9.37 (brs, 1H, NH), 8.68 (s, 2H, Ar-H), 7.54 (d, 1H, J=8Hz,
Ar-H),7.45(s,2H,Ar-H),7.20-7.27(m,3H,Ar-H),4.38(s,2H).
Embodiment 13
In reaction bulb, tall and erect -2 (3H) -one of 5- (4- pyridine radicals) -1H- benzos [e] [Isosorbide-5-Nitrae] phenodiazine (300mg,
1.26mmol) and TMSN3(130mg, 1.52mmol) is added in acetone 20mL, add potassium carbonate (170mg,
1.26mmol), 2h is reacted at room temperature under nitrogen protection, and TLC monitoring raw material reactions are complete, and reaction solution is poured into water 50mL, used
Dichloromethane 20mL extractive reactions liquid three times, merges organic phase, solvent is evaporated off and obtains(299mg,
yield:90.55%) MS (ESI) m/z:262.1(M+H+).HNMR:(DMSO-d6)δ11.79(s,1H,NH),8.68(s,
2H,Ar-H), 7.88(m,2H,Ar-H),7.58(m,1H,Ar-H),6.68-7.22(m,3H,Ar-H),4.22(s,1H).
Embodiment 14
In reaction bulb, tall and erect -2 (3H) -one of 5- (4- pyridine radicals) -1H- benzos [e] [Isosorbide-5-Nitrae] phenodiazine (300mg,
1.26mmol) and NaN3(99mg, 1.52mmol) is added in DMF20mL, adds CuI (71.5mg, 0.50mmol) and carbon
Sour potassium (68.97mg, 0.50mmol), 120 DEG C being heated under air conditionses, TLC monitoring raw material reactions are complete after reacting 6h,
Reaction solution is extracted after adding certain water with dichloromethane, is concentrated after merging organic phase, then obtained through column chromatography for separation(258mg,yield:77.8%) .MS (ESI) m/z:262.1(M+H+).
Embodiment 15
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.After acting on 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 determines.
Preliminary biological activity test shows that the compound has suppression to make breast cancer cell MCF-7 and liver cancer HepG2
With, but it is better than the inhibitory action to breast cancer cell MCF-7 to the inhibitory action of hepatocellular carcinoma H22.
Embodiment above describes the general principle of the present invention, main features and advantages, 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. triazole and phenodiazine Zhuo compound with antitumor activity, it is characterised in that its molecular structural formula is：
2. the preparation method of the triazole with antitumor activity and phenodiazine Zhuo compound described in a kind of claim 1, it is special
Sign is to concretely comprise the following steps：
A, acylation reaction generation N- phenyl trimethicone acetamides occur in pyridine or dichloromethane for aniline and pivaloyl chloride；
B, under n-BuLi effect after activation ortho-hydrogens with 4- pyridine carboxaldehydes addition reaction occurs for N- phenyl trimethicones acetamide
Obtain N- (2- (hydroxyl (4- pyridine radicals) methyl) phenyl) pivaloyl amine；
C, N- (2- (hydroxyl (4- pyridine radicals) methyl) phenyl) pivaloyl amine is aoxidized by manganese dioxide or chromium trioxide, and it is tied
Secondary carbon and the hydroxyl connected generate carbonyl after sloughing a molecule hydrogen on structure, obtain N- (2- (4- piperidone bases) phenyl) front three
Yl acetamide；
D, N- (2- (4- piperidone bases) phenyl) pivaloyl amine sloughs tertiary bytyry and obtains 2- (4- piperidines in acid condition
Ketone group) aniline；Substitution reaction generation N- (2- occur under DCC effects with Boc glycyls chlorine for 2- (4- piperidone bases) aniline
(4- piperidone bases) phenyl) Boc amino acetamides；
E, N- (2- (4- piperidone bases) phenyl) Boc amino acetamides react in Isosorbide-5-Nitrae-dioxane or THF with HCl, sloughed
While Boc groups N- (2- (4- piperidone bases) phenyl) glycyl amine hydrochlorate is obtained into salt；
F, N- (2- (4- piperidone bases) phenyl) glycyl amine hydrochlorates occur ketoamine and are condensed to yield 5- under sodium methoxide effect
(4- pyridine radicals) -1H- benzos [e] [1,4] phenodiazine -2 (3H) -one of Zhuo；
G, tall and erect -2 (3H) -one of 5- (4- pyridine radicals) -1H- benzos [e] [1,4] phenodiazine and TMSN3Or NaN3Click reactions are occurring
Obtain
3. the preparation method of a kind of triazole with antitumor activity according to claim 2 and phenodiazine Zhuo compound,
It is characterized in that step A detailed process is：In reaction bulb, aniline is added in pyridine, at ambient temperature, is slowly added dropwise
Pivaloyl chloride, continue to react at ambient temperature after dripping, TLC monitoring raw material reactions are complete, add into reaction solution certain
The HCl solution of amount, strong stirring for a period of time after washed reaction liquid, be finally concentrated to give N- phenyl trimethicones under vacuum
Acetamide；Or in reaction bulb, aniline and potassium carbonate are added in dichloromethane and stirred, at ambient temperature, spy is slowly added dropwise
Valeric chloride, continue to react at ambient temperature after dripping, TLC monitoring raw material reactions are complete, add into reaction solution a certain amount of
HCl solution, strong stirring for a period of time after washed reaction liquid, be finally concentrated to give N- phenyl trimethicone second under vacuum
Acid amides.
4. the preparation method of a kind of triazole with antitumor activity according to claim 2 and phenodiazine Zhuo compound,
It is characterized in that step B detailed process is：In reaction bulb, N- phenyl trimethicone acetamides are added to through Non-aqueous processing
In THF, nitrogen protection reaction system, it is placed under the conditions of 0 DEG C, n-butyllithium solution is slowly added dropwise, maintain the temperature at less than 5 DEG C,
2h is stirred after dripping, the THF solution dissolved with 4- pyridine carboxaldehydes is slowly dropped in reaction solution, reaction temperature is no more than 5
DEG C, it is in peony to drip rear reaction solution；Continue react 3h, TLC monitoring raw material unreacted it is complete, make reaction temperature be -20
DEG C~40 DEG C under the conditions of continue to add a certain amount of frozen water after reacting 8h reaction is quenched, then reaction solution is extracted with ethyl acetate, steaming
Except the crude product that N- (2- (hydroxyl (4- pyridine radicals) methyl) phenyl) pivaloyl amine is obtained after organic phase, then through column chromatography for separation
Obtain sterling.
5. the preparation method of a kind of triazole with antitumor activity according to claim 2 and phenodiazine Zhuo compound,
It is characterized in that step C detailed process is：In reaction bulb, N- (2- (hydroxyl (4- pyridine radicals) methyl) phenyl) trimethyl
Acetamide and MnO2It is added in chloroform, heating reflux reaction 10h, TLC monitoring raw material reaction is complete, filtering reacting liquid, filtrate
N- (2- (4- piperidone bases) phenyl) pivaloyl amine is obtained after concentration；Or in reaction bulb, N- (2- (hydroxyl (4- pyridines
Base) methyl) phenyl) pivaloyl amine and CrO3It is added in chloroform, reacts at room temperature 5h, TLC monitoring raw material reactions are complete, mistake
Reaction solution is extracted with ethyl acetate after filter, N- (2- (4- piperidone bases) phenyl) pivaloyl amine is obtained after organic phase is evaporated off.
6. the preparation method of a kind of triazole with antitumor activity according to claim 2 and phenodiazine Zhuo compound,
It is characterized in that step D detailed process is：In reaction bulb, N- (2- (4- piperidone bases) phenyl) pivaloyl amine is added
Enter into the mixed solution of ethanol and hydrochloric acid, be stirred reaction at ambient temperature, be heated to flowing back after stirring 2h, continue anti-
5h is answered, the reaction of TLC monitoring raw materials is completely；Ethanol is evaporated off in vacuum concentration, then adjusts reaction solution pH with saturated sodium carbonate solution>7, then
With dichloromethane extractive reaction liquid three times, the crude product of 2- (4- piperidone bases) aniline is concentrated to give after merging organic phase, then through post
Chromatography obtains sterling；Resulting 2- (4- piperidone bases) aniline is added in dichloromethane, adds compound Boc
Glycyl chlorine and DCC, 10h are reacted at ambient temperature, TLC monitoring raw material reactions are complete, and filtering reacting liquid removes two hexamethylenes
Urea, reaction solution are washed with 10% HCl solution and saturated sodium carbonate solution respectively again, and N- (2- are concentrated to give after separating organic phase
(4- piperidone bases) phenyl) Boc amino acetamide crude products, then obtain sterling through column chromatography for separation.
7. the preparation method of a kind of triazole with antitumor activity according to claim 2 and phenodiazine Zhuo compound,
It is characterized in that step E detailed process is：In reaction bulb, N- (2- (4- piperidone bases) phenyl) Boc amino acetamides
It is added in Isosorbide-5-Nitrae-dioxane containing 4M HCl, at ambient temperature stirring reaction 2h, TLC monitoring raw material reactions are complete,
Filtering reacting liquid, filter cake are N- (2- (4- piperidone bases) phenyl) glycyl amine hydrochlorate；Or in reaction bulb, N- (2-
(4- piperidone bases) phenyl) Boc amino acetamides are added in the THF containing 4M HCl, stirring reaction under heated reflux condition
2h, TLC monitoring raw material reaction are complete, and filtering reacting liquid, filter cake is N- (2- (4- piperidone bases) phenyl) amino acetamide hydrochloric acid
Salt.
8. the preparation method of a kind of triazole with antitumor activity according to claim 2 and phenodiazine Zhuo compound,
It is characterized in that step F detailed process is：In reaction bulb, N- (2- (4- piperidone bases) phenyl) amino acetamide hydrochloric acid
Salt and sodium methoxide are added in methanol, and the stirring reaction 2h at 50 DEG C, LCMS monitoring raw material reaction are complete, steam under vacuum
Except reaction dissolvent, a certain amount of water and dichloromethane are added, separates organic phase, 5- (4- pyridine radicals) -1H- benzene is obtained after concentration
And tall and erect -2 (3H) -one of [e] [1,4] phenodiazine.
9. the preparation method of a kind of triazole with antitumor activity according to claim 2 and phenodiazine Zhuo compound,
It is characterized in that step G detailed process is：In reaction bulb, 5- (4- pyridine radicals) -1H- benzos [e] [Isosorbide-5-Nitrae] phenodiazine Zhuo -2
(3H) -one and TMSN3It is added in acetone, adds a certain amount of potassium carbonate, reacts at room temperature 2h, TLC prisons under nitrogen protection
It is complete to control raw material reaction, is extracted with dichloromethane after the certain water of reaction solution addition, is concentrated after merging organic phase, then through column chromatography point
From obtainingOr in reaction bulb, -2 (3H) of 5- (4- pyridine radicals) -1H- benzos [e] [Isosorbide-5-Nitrae] phenodiazine Zhuo -
Ketone and NaN3It is added in DMF, adds a certain amount of CuI and potassium carbonate, 120 DEG C are heated under air conditionses, reacts 6h
TLC monitors raw material reaction completely afterwards, and reaction solution is extracted after adding certain water with dichloromethane, is concentrated after merging organic phase, then pass through
Column chromatography for separation obtains
10. simultaneously phenodiazine Zhuo compound is preparing antineoplastic to the triazole with antitumor activity as claimed in claim 1
In application.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113527334A (en) * | 2020-04-13 | 2021-10-22 | 济南爱思医药科技有限公司 | Triazole derivative capable of influencing calcium ion channel of tumor cell and preparation method and application thereof |
| CN113527334B (en) * | 2020-04-13 | 2022-04-29 | 济南爱思医药科技有限公司 | Triazole derivative capable of influencing calcium ion channel of tumor cell and preparation method and application thereof |
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| CN107759607B (en) | 2019-08-23 |
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