CN1651418A - Human epidermis growth factor acceptor 2 tyrosinase inhibitor - Google Patents
Human epidermis growth factor acceptor 2 tyrosinase inhibitor Download PDFInfo
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- CN1651418A CN1651418A CN 200410052496 CN200410052496A CN1651418A CN 1651418 A CN1651418 A CN 1651418A CN 200410052496 CN200410052496 CN 200410052496 CN 200410052496 A CN200410052496 A CN 200410052496A CN 1651418 A CN1651418 A CN 1651418A
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- aryl
- triazole
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- itrile group
- growth factor
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- 239000003102 growth factor Substances 0.000 title description 3
- 101710147108 Tyrosinase inhibitor Proteins 0.000 title description 2
- 210000002615 epidermis Anatomy 0.000 title description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 21
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 claims abstract description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 13
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 claims abstract description 10
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims abstract description 8
- -1 Methyl benzenesulfonyl Chemical group 0.000 claims description 24
- 239000000243 solution Substances 0.000 claims description 23
- SYOANZBNGDEJFH-UHFFFAOYSA-N 2,5-dihydro-1h-triazole Chemical compound C1NNN=C1 SYOANZBNGDEJFH-UHFFFAOYSA-N 0.000 claims description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 12
- 238000001953 recrystallisation Methods 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 238000000605 extraction Methods 0.000 claims description 9
- 238000001556 precipitation Methods 0.000 claims description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 claims description 8
- 239000005483 tyrosine kinase inhibitor Substances 0.000 claims description 8
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- 239000011541 reaction mixture Substances 0.000 claims description 7
- 238000010189 synthetic method Methods 0.000 claims description 7
- 238000012546 transfer Methods 0.000 claims description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 6
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 6
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 claims description 5
- 235000010288 sodium nitrite Nutrition 0.000 claims description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 150000001540 azides Chemical class 0.000 claims description 4
- 239000008367 deionised water Substances 0.000 claims description 4
- 229910021641 deionized water Inorganic materials 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 235000019270 ammonium chloride Nutrition 0.000 claims description 3
- UDLLFLQFQMACJB-UHFFFAOYSA-N azidomethylbenzene Chemical compound [N-]=[N+]=NCC1=CC=CC=C1 UDLLFLQFQMACJB-UHFFFAOYSA-N 0.000 claims description 3
- 229960005181 morphine Drugs 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- 239000012429 reaction media Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 6
- WRFPVMFCRNYQNR-UHFFFAOYSA-N 2-hydroxyphenylalanine Chemical compound OC(=O)C(N)CC1=CC=CC=C1O WRFPVMFCRNYQNR-UHFFFAOYSA-N 0.000 abstract 1
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 abstract 1
- 230000000994 depressogenic effect Effects 0.000 abstract 1
- 238000010992 reflux Methods 0.000 abstract 1
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
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Abstract
A depressant of human epidermal growth factor receptor 2 tyrosine knase is disclosed. The process for synthesizing it includes reaction of 1-aryl-2-nitrile-2-triphenylphosphino ethanone on butyl lithium in tetrahydrofuran at -50--70 deg.C for 15 min under N2 protection, reacting on p-methylphenyl sulfonyl azo to obtain 1-p-methylphenylsulfonyl-4-aryl-5-nitil- 1H-1,2,3-triazazole, dissolving it in alcohol, thermal reflux, and adding cold water to educe out the deposit.
Description
Technical field the present invention relates to human epidermal growth factor receptor 2's tyrosine kinase inhibitor.Be specifically related to comprise 5-itrile group-1H-1,2, the molecular designing and the synthetic method of 3-triazole derivative.
Background technology human epidermal growth factor receptor 2's (writing a Chinese character in simplified form HER2/neu) Tyrosylprotein kinase is one of the highest oncogene of frequency that changes in tumour, studies show that, at many epithelial tumors, 25%-30% mammary cancer, 25%-32% ovarian cancer, 30%-40% primary renal cell carcinoma, with part prostate cancer, small cell lung cancer and rhinitis cancer in can see the HER2/neu overexpression, the activation of HER2/neu signal transduction pathway has strengthened kinds of tumors and has shifted correlated performance, also cause tumour cell to the conventional treatment drug resistance, facilitate conversion to malignant tumour.The overexpression of HER2/neu is patient's poor prognosis and the high partly cause of mortality ratio at least, and it is very important to think that receptor tyrosine kinase and family's tyrosine kinase receptor thereof and polypeptide growth factor play a part in the generation of tumour, evolution.Therefore, suppress propagation and transfer that the HER2/neu receptor tyrosine kinase can stop tumour cell effectively, prevent that tumour is to vicious transformation and generation resistance.The objective of the invention is screening and have the active compound of HER2/neu receptor tyrosine kinase inhibition.
Summary of the invention the present invention has designed itrile group-1H-1 with 5-, and 2, the 3-triazole is precursor structure, has the compound of general formula of molecular structure as depicted in figs. 1 and 2, and designed synthetic method.
Through testing the activity that these compounds have good inhibition HER2/neu receptor tyrosine kinase, its half inhibiting rate (IC
50) between 10nmole/L～100nmole/L.
Description of drawings Fig. 1 and Fig. 2 for the present invention designed with 5-itrile group-1H-1,2, the 3-triazole is human epidermal growth factor receptor 2's tyrosine kinase inhibitor of precursor structure.
Among Fig. 1, R
1, R
2, R
3Respectively or be H simultaneously, NO
2, CN, F, Cl, Br, CH
3O, C
6H
5O, 4-CH
3C
6H
4, 3-CH
3C
6H
4, 2-CH
3C
6H
4, HO, NH
2, CH
3NH, (CH
3)
2N, CH
3COO, CH
3CH
2COO, (CH
3)
2CHCOO, (CH
3)
3CCOO, CF
3COO, (CF
3)
2CHCOO, (CF
3)
3CCOO, CH
3, CH
3CH
2, (CH
3)
2CH, (CH
3)
3C, CF
3
Among Fig. 2, R
4, R
5Respectively or be H simultaneously, NO
2, CN, F, Cl, Br, CH
3O, C
6H
5O, 4-CH
3C
6H
4, 3-CH
3C
6H
4, 2-CH
3C
6H
4, HO, NH
2, CH
3NH, (CH
3)
2N, CH
3COO, CH
3CH
2COO, (CH
3)
2CHCOO, (CH
3)
3CCOO, CF
3COO, (CF
3)
2CHCOO, (CF
3)
3CCOO, CH
3, CH
3CH
2, (CH
3)
2CH, (CH
3)
3C, CF
3
The present invention designed with 5-itrile group-1H-1,2,3-triazole is the human epidermis growth factor acceptor 2 tyrosinase inhibitor of precursor structure, synthetic method is as follows:
Method one:
1-aryl-2-itrile group-2-triphenylphosphinyl ethyl ketone; with the exsiccant tetrahydrofuran (THF) is solvent; under nitrogen protection ,-50 ℃～-70 ℃; through the butyllithium effect of 1: 1.1 mol ratio after 15 minutes; with 1: 1.1 mol ratio to Methyl benzenesulfonyl base azide reaction 6～12 hours; get 1-to Methyl benzenesulfonyl base-4-aryl-5-itrile group-1H-1,2,3-triazole.1-is to Methyl benzenesulfonyl base-4-aryl-5-itrile group-1H-1,2,3-triazole; with 90% ethanol it is dissolved, reheat refluxed 1 hour, then solution in the bottle was imported cold water and allowed precipitation separate out; get compound shown in Fig. 1, Fig. 2, yield is respectively 55%～86%.
Method two:
1-itrile group-2-aryl-2-heterocyclic radical ethene, heterocyclic radical are respectively piperidino, 1-piperazinyl or 4-morphine quinoline base, with methylene dichloride dissolving, with equimolar to Methyl benzenesulfonyl base azide reaction 2～4 days.Get 1-to Methyl benzenesulfonyl base-4-aryl-5-itrile group-1H-1,2,3-triazole.The 1-of gained is to Methyl benzenesulfonyl base-4-aryl-5-itrile group-1H-1,2,3-triazole; with 90% ethanol it is dissolved, reheat refluxed 1 hour, then solution in the bottle was imported cold water and allowed precipitation separate out; compound shown in Fig. 1, Fig. 2, yield is respectively 30%～45%.
Method three:
Sodium azide or nitrine potassium are suspended in exsiccant N; in the dinethylformamide solvent; under the nitrogen protection; reaction medium is heated to 50 ℃～90 ℃; reacted 1～3 hour with the 1-itrile group-2-aryl ethane of 1.5: 1 mol ratios; react the residual thing deionized water dissolving that heats up in a steamer, the dilute hydrochloric acid with 10% transfers to pH value of solution about 2～4.Again with ether with aqueous solution extraction.The residual thing that heats up in a steamer got 4-itrile group-5-aryl-1H-1 with solvent recrystallization after extraction liquid steamed and desolventizes, and 2, the 3-triazole, the compound yield is respectively 40%～64% shown in Fig. 1, Fig. 2.
Method four:
Equimolar aryl benzyl cyanide and benzyl azide dissolve with the exsiccant tetrahydrofuran (THF); the following potassium tert.-butoxide with 1: 1.1 mole of nitrogen protection reacted 24～48 hours, reaction mixture is poured into to place in the frozen water separate out precipitation, got 1-benzyl-4-aryl-5-amino-1H-1; 2, the 3-triazole.Again with 1-benzyl-4-aryl-5-amino-1H-1,2, the 3-triazole dissolves in-70 ℃ the liquefied ammonia, with the sodium Metal 99.5 effect of 1: 2 mol ratio.Decompose with excessive ammonium chloride, with the sodium hydroxide solution of 4M residual heating up in a steamer in the bottle washed out, with methylene dichloride insolubles is come together and remove, the clarifying aqueous solution transfers to pH about 2～4 with 10% hydrochloric acid, uses ethyl acetate extraction then.Extraction liquid steams and desolventizes, and the residual thing that heats up in a steamer gets 4-aryl-5-amino-1H-1,2,3-triazole with solvent recrystallization.4-aryl-5-amino-1H-1,2, the 3-triazole is with 95% dissolve with ethanol and use sulfuric acid acidation.Be lower than below 5 ℃ and excessive Sodium Nitrite effect after 30～40 minutes, then with the cuprous reaction of the nitrilation of 1: 1.1 mol ratio 3～12 hours.Use the ethyl acetate extraction reaction mixture.Extraction liquid steams and desolventizes, and the residual thing that heats up in a steamer gets 4-aryl-5-itrile group-1H-1,2,3-triazole with solvent recrystallization.The compound yield is respectively 35%～53% shown in Fig. 1, Fig. 2.
Embodiment
Embodiment 1
1-(4-the p-methoxy-phenyl)-2-itrile group-2-triphenylphosphinyl ethyl ketone that adds 0.15mol in the three-necked bottle of 250mL, with the dissolving of vial matter, stirring is immersed three-necked bottle in the dry ice bath down and is cooled to-70 ℃ with 150mL exsiccant tetrahydrofuran (THF).The butyllithium pentane solution that will contain 0.165mol under nitrogen protection through dropping funnel, the rate-controlling of dropping temperature in making bottle is no more than-50 ℃, continues to keep in the dry ice bath cooling and stirring after adding 15 minutes.Under agitation will contain 0.165mol Methyl benzenesulfonyl base nitrine tetrahydrofuran solution is slowly added then, and maintain after adding about-50 ℃ and continued stirring reaction 6～12 hours through dropping funnel.The bottle reaction mixture is overanxious, and filtrate decompression concentrates.The residue solvent recrystallization gets 1-to Methyl benzenesulfonyl base-4-(4-p-methoxy-phenyl)-5-itrile group-1H-1,2,3-triazole.
In the three-necked bottle of 250mL, add the 1-of 0.1mol to Methyl benzenesulfonyl base-4-(4-p-methoxy-phenyl)-5-itrile group-1H-1,2,3-triazole; with 100mL90% ethanol it is dissolved; reheat refluxed 1 hour, then solution in the bottle was imported in the 500mL water, and cooling allows precipitation separate out.Overanxious collection solid, drying gets 4-(4-p-methoxy-phenyl)-5-itrile group-1H-1, and 2,3-triazole, yield 86%.
Embodiment 2
Add the 100mL methylene dichloride in the flask of 250mL successively, the 1-itrile group-2-to Methyl benzenesulfonyl base nitrine and 0.1mol of 0.1mol (4-p-methoxy-phenyl)-2-heterocyclic radical ethene, heterocyclic radical are respectively piperidino, 1-piperazinyl or 4-morphine quinoline base.Mixture reacted under stirring at room 2～4 days.Then with the reaction mixture concentrating under reduced pressure.The residue solvent recrystallization gets 1-to Methyl benzenesulfonyl base-4-(4-p-methoxy-phenyl)-5-itrile group-1H-1,2,3-triazole.
In the three-necked bottle of 100mL, add the 1-of 0.02mol to Methyl benzenesulfonyl base-4-(4-p-methoxy-phenyl)-5-itrile group-1H-1,2,3-triazole; with 50mL90% ethanol it is dissolved; reheat refluxed 1 hour, then solution in the bottle was imported in the 200mL water, and cooling allows precipitation separate out.Overanxious collection solid, drying gets 4-(4-p-methoxy-phenyl)-5-itrile group-1H-1, and 2,3-triazole, yield 45%.
Embodiment 3
The sodium azide or the nitrine potassium that in the three-necked bottle of 250mL, add 0.15mol; add 100mL exsiccant N; dinethylformamide; be heated with stirring to 50 ℃～90 ℃ under the nitrogen protection, 1-itrile group-2-(4-p-methoxy-phenyl) acetylene that adds 0.1mol then is dissolved in 30mL exsiccant N, dinethylformamide solution; keep heating and continue reaction 1～3 hour; remove solvent under reduced pressure, the residual thing 200mL deionized water dissolving that heats up in a steamer transfers to pH value of solution about 2～4 at the dilute hydrochloric acid with 10%.With aqueous solution extraction three times, merge diethyl ether solution with the 100mL ether, use twice of 50mL deionized water wash again.Steaming desolventized after diethyl ether solution spent the night with anhydrous magnesium sulfate drying, and the residual thing that heats up in a steamer gets 4-aryl-5-(4-p-methoxy-phenyl)-1H-1,2,3-triazole, yield 64% with solvent recrystallization.
Embodiment 4
In the three-necked bottle of 500mL, add the potassium tert.-butoxide of 300mL exsiccant tetrahydrofuran (THF), 0.22mol, the aryl benzyl cyanide of 0.2mol and the benzyl azide of 0.2mol successively; stirring reaction is 24～48 hours under the room temperature nitrogen protection; reaction mixture is slowly poured in the frozen water of 3L; place and separate out precipitation after 1 hour; overanxious collection solid, dry back solvent recrystallization gets 1-benzyl-4-(4-p-methoxy-phenyl)-5-amino-1H-1; 2, the 3-triazole.
1-benzyl-4-(4-the p-methoxy-phenyl)-5-amino-1H-1 that in the three-necked bottle of 500mL, adds 0.07mol, 2, the 3-triazole immerses three-necked bottle in the dry ice bath and to cool off, the liquefied ammonia that adds 250mL-70 ℃, the sodium Metal 99.5 fritter with 0.14mol under stirring adds in the bottle.After treating sodium Metal 99.5 all the blueness of dissolving and bottle internal reaction thing disappearing, the ammonium chloride of 0.28mol divided for several times add in the bottle, under agitation reacted again 30 minutes.Removing the dry ice bath then slowly volatilizees by liquefied ammonia, sodium hydroxide solution 100mL with 4M washes out residual heating up in a steamer in the bottle, with the 50mL methylene dichloride insolubles collection is removed, the clarifying aqueous solution transfers to pH about 2～4 with 10% hydrochloric acid, uses the 50mL ethyl acetate extraction then three times again.Steaming desolventized after ethyl acetate solution spent the night with anhydrous magnesium sulfate drying, and the residual thing that heats up in a steamer gets 4-aryl-5-amino-1H-1,2,3-triazole with solvent recrystallization.
4-(4-the p-methoxy-phenyl)-5-amino-1H-1 that in the three-necked bottle of 250mL, adds 0.02mol, 2, the 3-triazole is chilled to-5 ℃ with 100mL95% ethanol with its dissolving and with the cryosel bath, adds the sulfuric acid of 10mL6M again.Under agitation slowly add then, guarantee that a bottle interior temperature is lower than below 5 ℃, reacted again after sodium nitrite solution adds 30 minutes, add a spot of urea then unreacted Sodium Nitrite is removed through the sodium nitrite solution of dropping funnel with 22mL 1M.The cuprous solution of nitrilation that contains 0.022mol at 0 ℃ of 10mL that will prepare in advance through dropping funnel slowly adds in the bottle, keeps the interior temperature of bottle to be lower than and reacts below 5 ℃ 0.5～3 hour, rises to room temperature reaction again 3～12 hours.Use 50mL ethyl acetate extraction three times after removing ethanol under reduced pressure.Steaming desolventized after ethyl acetate solution spent the night with anhydrous magnesium sulfate drying, and the residual thing that heats up in a steamer gets 4-(4-p-methoxy-phenyl)-5-itrile group-1H-1,2,3-triazole, yield 53% with solvent recrystallization.
Embodiment 5
The cell of taking the logarithm vegetative period adds in 96 orifice plates, 2000 cells in every hole, 100 μ l/ holes.Adding is by the 4-aryl-5-itrile group-1H-1 of preparation among the embodiment 1～4,2, the 3-triazole, establish 3 parallel holes for every group, put 37 ℃ of cultivations, experiment stops preceding 4 hours adding 10 μ l5mg/mlMTT liquid, cultivated again 4 hours, discard nutrient solution, add 0.2ml DMSO, the OD value in every hole under the 570mm wavelength is detected in dissolving to be crystallized back on enzyme connection instrument, press: growth inhibition ratio (%)=((1-medication group OD value)/average OD value of control group) * 100%, obtaining half inhibiting rate (%) by BLISS method computer program again is 6.6 μ mole/L.5-itrile group-the 1H-1 of structure as shown in Figure 1 and Figure 2,2,3-triazole derivative is to the half inhibiting rate (IC of HER2/neu receptor tyrosine kinase
50) between 10nmole/L～100nmole/L.
Claims (5)
1. human epidermal growth factor receptor 2's tyrosine kinase inhibitor, the compound of it is characterized in that having formula (1) or formula (2) structure:
In the formula (1), R
1, R
2, R
3Respectively or be H simultaneously, NO
2, CN, F, Cl, Br, CH
3O, C
6H
5O, 4-CH
3C
6H
4, 3-CH
3C
6H
4, 2-CH
3C
6H
4, HO, NH
2, CH
3NH, (CH
3)
2N, CH
3COO, CH
3CH
2COO, (CH
3)
2CHCOO, (CH
3)
3CCOO, CF
3COO, (CF
3)
2CHCOO, (CF
3)
3CCOO, CH
3, CH
3CH
2, (CH
3)
2CH, (CH
3)
3C, CF
3In the formula (2), R
4, R
5Respectively or be H simultaneously, NO
2, CN, F, Cl, Br, CH
3O, C
6H
5O, 4-CH
3C
6H
4, 3-CH
3C
6H
4, 2-CH
3C
6H
4, HO, NH
2, CH
3NH, (CH
3)
2N, CH
3COO, CH
3CH
2COO, (CH
3)
2CHCOO, (CH
3)
3CCOO, CF
3COO, (CF
3)
2CHCOO, (CF
3)
3CCOO, CH
3, CH
3CH
2, (CH
3)
2CH, (CH
3)
3C, CF
3
2. the synthetic method of human epidermal growth factor receptor 2's tyrosine kinase inhibitor, it is characterized in that: 1-aryl-2-itrile group-2-triphenylphosphinyl ethyl ketone, with the exsiccant tetrahydrofuran (THF) is solvent, under nitrogen protection ,-50 ℃～-70 ℃, through the butyllithium effect of 1: 1.1 mol ratio after 15 minutes, with 1: 1.1 mol ratio to Methyl benzenesulfonyl base azide reaction 6～12 hours, 1-to Methyl benzenesulfonyl base-4-aryl-5-itrile group-1H-1,2, the 3-triazole; 1-is to Methyl benzenesulfonyl base-4-aryl-5-itrile group-1H-1,2, the 3-triazole dissolves it with 90% ethanol, reheat refluxed 1 hour, then solution in the bottle is imported cold water and allows precipitation separate out, compound shown in formula (1) or the formula (2).
3. the synthetic method of human epidermal growth factor receptor 2's tyrosine kinase inhibitor, it is characterized in that: 1-itrile group-2-aryl-2-heterocyclic radical ethene, heterocyclic radical is respectively piperidino, 1-piperazinyl or 4-morphine quinoline base, with methylene dichloride dissolving, with equimolar to Methyl benzenesulfonyl base azide reaction 2～4 days; Get 1-to Methyl benzenesulfonyl base-4-aryl-5-itrile group-1H-1,2,3-triazole.The 1-of gained is to Methyl benzenesulfonyl base-4-aryl-5-itrile group-1H-1,2, the 3-triazole dissolves it with 90% ethanol, reheat refluxed 1 hour, then solution in the bottle is imported cold water and allows precipitation separate out, compound shown in formula (1) or the formula (2).
4. the synthetic method of human epidermal growth factor receptor 2's tyrosine kinase inhibitor, it is characterized in that: sodium azide or nitrine potassium are suspended in exsiccant N, in the dinethylformamide solvent, under the nitrogen protection, reaction medium is heated to 50 ℃～90 ℃, reacted 1～3 hour with the 1-itrile group-2-aryl ethane of 1.5: 1 mol ratios, react the residual thing deionized water dissolving that heats up in a steamer, the dilute hydrochloric acid with 10% transfers to pH value of solution about 2～4; Again with ether with aqueous solution extraction; The residual thing that heats up in a steamer got 4-itrile group-5-aryl-1H-1 with solvent recrystallization after extraction liquid steamed and desolventizes, and 2, the 3-triazole gets compound shown in formula (1) or the formula (2).
5. the synthetic method of human epidermal growth factor receptor 2's tyrosine kinase inhibitor; it is characterized in that: equimolar aryl benzyl cyanide and benzyl azide dissolve with the exsiccant tetrahydrofuran (THF); the following potassium tert.-butoxide with 1: 1.1 mole of nitrogen protection reacted 24～48 hours; reaction mixture poured in the frozen water to place separate out precipitation; get 1-benzyl-4-aryl-5-amino-1H-1; 2, the 3-triazole.Again with 1-benzyl-4-aryl-5-amino-1H-1,2, the 3-triazole dissolves in-70 ℃ the liquefied ammonia, with the sodium Metal 99.5 effect of 1: 2 mol ratio.Decompose with excessive ammonium chloride, with the sodium hydroxide solution of 4M residual heating up in a steamer in the bottle washed out, with methylene dichloride insolubles is come together and remove, the clarifying aqueous solution transfers to pH about 2～4 with 10% hydrochloric acid, uses ethyl acetate extraction then.Extraction liquid steams and desolventizes, and the residual thing that heats up in a steamer gets 4-aryl-5-amino-1H-1,2,3-triazole with solvent recrystallization; 4-aryl-5-amino-1H-1,2, the 3-triazole is with 95% dissolve with ethanol and use sulfuric acid acidation.Be lower than below 5 ℃ and excessive Sodium Nitrite effect after 30～40 minutes, then with the cuprous reaction of the nitrilation of 1: 1.1 mol ratio 3～12 hours; Use the ethyl acetate extraction reaction mixture.Extraction liquid steams and desolventizes, and the residual thing that heats up in a steamer gets 4-aryl-5-itrile group-1H-1,2,3-triazole with solvent recrystallization; Get compound shown in formula (1) or the formula (2).
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410052496 CN1651418A (en) | 2004-12-06 | 2004-12-06 | Human epidermis growth factor acceptor 2 tyrosinase inhibitor |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410052496 CN1651418A (en) | 2004-12-06 | 2004-12-06 | Human epidermis growth factor acceptor 2 tyrosinase inhibitor |
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ID=34868736
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|---|---|---|---|
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20160030995A (en) | 2013-07-17 | 2016-03-21 | 오츠카 세이야쿠 가부시키가이샤 | Cyanotriazole compounds |
| CN106866484A (en) * | 2015-12-10 | 2017-06-20 | 中国科学院大连化学物理研究所 | It is a kind of to prepare pyrroles, the method for imidazoles, oxazole derivatives |
-
2004
- 2004-12-06 CN CN 200410052496 patent/CN1651418A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20160030995A (en) | 2013-07-17 | 2016-03-21 | 오츠카 세이야쿠 가부시키가이샤 | Cyanotriazole compounds |
| US10626095B2 (en) | 2013-07-17 | 2020-04-21 | Otsuka Pharmaceutical Co., Ltd. | Cyanotriazole compounds |
| EP4219477A1 (en) | 2013-07-17 | 2023-08-02 | Otsuka Pharmaceutical Co., Ltd. | Cyanotriazole compounds |
| CN106866484A (en) * | 2015-12-10 | 2017-06-20 | 中国科学院大连化学物理研究所 | It is a kind of to prepare pyrroles, the method for imidazoles, oxazole derivatives |
| CN106866484B (en) * | 2015-12-10 | 2019-04-09 | 中国科学院大连化学物理研究所 | A method of preparing pyrroles, imidazoles, oxazole derivatives |
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