CN105153027A - 3-cyano-4-hydroxy-2-pyridone compound and preparation method therefor and application thereof - Google Patents
3-cyano-4-hydroxy-2-pyridone compound and preparation method therefor and application thereof Download PDFInfo
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D213/85—Nitriles in position 3
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Abstract
The invention relates to a 3-cyano-4-hydroxy-2-pyridone compound and a preparation method therefor and application thereof. The compound has a structural formula shown in the description. The preparation method comprises the steps of dissolving a 3-cyano-4-methoxy-2-pyridone compound and alkali in a solvent, carrying out stirring reaction for 1-48 hours at the temperature of 90-100 DEG C, adding water into the reacted material after the reaction ends, dropwise adding hydrochloric acid into the water added reacted material until the pH is 4-5, carrying out stirring for 5-20 minutes, and carrying out suction filtration, thereby obtaining the 3-cyano-4-hydroxy-2-pyridone compound. The compound prepared by the preparation method has relatively good anti-tumor activity; the preparation method for the compound is simple; and the compound can be used for preparing drugs for preventing or treating diseases such as tumors and the like.
Description
Technical field
The invention belongs to 4-hydroxyl-2-pyridine compounds and Synthesis and applications field thereof, particularly a kind of 3-cyano group-4-hydroxyl-2-pyridine compounds and Synthesis and applications thereof.
Background technology
In recent years, along with the raising day by day of people's living standard, modernization of industry process is accelerated, and chemical widely uses the fields such as food, makeup and material, and the aggravation of environmental pollution, the sickness rate of the malignant tumours such as cancer of the stomach, lung cancer, leukemia and mammary cancer is in ascendant trend year by year.At present, the antitumor drug of clinical middle use is as large and lack the shortcomings such as broad-spectrum anti-tumor effect in endoxan (Cyclophosphamide), cis-platinum (Cisplatin), doxifluridine (Doxifluridine) and methotrexate (methotrexate) etc. all exist toxicity.
In recent years, along with developing rapidly of oncobiology and related discipline, people recognize that the essence of cell carcinogenesis is the cell infinite multiplication that the imbalance of intracellular signal transduction pathway causes, and the consequent is that the research and development of antitumor drug and focus just transfer to the specificity a new generation antitumor drug for abnormal signal system target site in tumour cell from conventional cell poison.As acted on the medicine imatinib (Imatinib) of Urogastron Tyrosylprotein kinase (tyrosinekinase), Gefitinib (Gefitinib), Tarceva (Erlotinib) and Ursula for Buddhist nun (Sorafenib) etc.But it is narrow that said medicine still exists antitumor spectra, toxicity is large, the efficient shortcoming such as low, and therefore, the antitumor drug of research and development wide spectrum low toxicity has met clinical demand and had great importance.
Antitumour drug Gimeracil (Gimeracil) chemical name 5-chloro-4-hydroxyl-2 (1H)-pyridone, for dihydropyrimidine dehydrogenase inhibitor, be one of 3 kinds of components (florafur, Gimeracil and Oxonic Acid) of anti-cancer of the stomach medicine cefecone (S1), play an important role in tumour such as treatment cancer of the stomach etc. etc.(Sun Yao, Feng Baotong, Zhang Shiyi pay Yongxing, Wang Ying. observe for the clinical bed of lucky capsule difficult to understand to esophageal carcinoma conformal therapy sensitization, Chinese treatment and prevention of tumour magazine, 2012,19 (18): 1410-1412; Fan Weifei, Wang Jun, Meng Lijuan, Liu Fuyin, Pu Xiaolin, Yang Min. for the clinical study of lucky associating oxaliplatin difficult to understand contrast for lucky combination with cisplatin scheme first-line treatment Senile Advanced cancer of the stomach difficult to understand, Journal of Clinical Oncology, 2103,18 (1): 50-53).Wherein, the structure containing 4-hydroxyl-2-pyridone in Gimeracil structure.
In recent years, the antitumor activity about 4-hydroxyl-2-pyridine compounds is study hotspot always.Cocco in 2000 etc. report 4-hydroxyl-2-pyridine compounds to 60 kinds of cell strain display inhibit activities such as carcinoma of the colon and rectum, nonsmall-cell lung cancer and kidney, have antitumor action (Cocco, M.T.; Congiu, C.; Onnis, V..Synthesisandantitumouractivityof4-hydroxy-2-pyridoned erivatives, Eur.J.Med.Chem., 2000,35 (5): 545-552).Obika in 2008 etc. report 4-hydroxyl-2-pyridone nucleoside compound display anti-tumor activity (Robins, MorrisJ.; Yang, Hong; Miranda, Karl; Peterson, MattA.; DeClercq, Erik; Balzarini, Jan.SynthesisandBiologicalEvaluationof3,3-Difluoropyridine-2,4 (1H, 3H)-dioneand3-Deaza-3-fluorouracilBaseandNucleosideDerivativ es, J.Med.Chem., 2009,52 (9): 3018-3027.Obika, Satoshi; Inohara, Hiroyasu; Hari, Yoshiyuki; Imanishi, Takeshi.RecognitionofTAinterruptionby2', 4'-BNAsbearingheteroaromaticnucleobasesthroughparallelmo tiftriplexformation, Bioorg.Med.Chem, 2008,16 (6): 2945-2954.)
Fuerstner in 2004 etc. also report that 4-hydroxyl-2-pyridinone natural alkaloid has significant anti-tumor activity in succession. (Fuerstner, Alois; Feyen, Fabian; Prinz, Heino; Waldmann, Herbert.SynthesisandevaluationoftheantitumoragentTMC-69-6Handafocusedlibraryofanalogs.Tetrahedron, 2004,60 (43): 9543-9558.Ding, Feiqing; Leow, MinLi; Ma, Jimei; William, Ronny; Liao, Hongze; Liu, Xue-Wei.Collectivesynthesisof4-hydroxy-2-pyridonealkaloi dsandtheirantiproliferationactivities.Chemistry-AnAsianJ ournal, 2014,9 (9): 2548-2554.)
The present invention has synthesized 3-cyano group-4-hydroxyl-2-pyridine compounds, external inhibited to HeLa Cells and liver cancer SMMC7721 etc. to discovery, shows stronger anti-tumor activity.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of 3-cyano group-4-hydroxyl-2-pyridine compounds and Synthesis and applications thereof, compound prepared by the present invention has good anti-tumor activity, preparation method is simple, can be used for the medicine preparing the disease such as prevention or treatment tumour.
A kind of 3-cyano group-4-hydroxyl-2-pyridine compounds of the present invention, the structural formula of described compound is:
wherein R
1for the phenmethyl that methyl or 4-replace; R
2for hydrogen, chlorine or bromine.Substituting group in the phenmethyl that described 4-position replaces is hydrogen, chlorine, bromine, methoxyl group or nitro.
Described 3-cyano group-4-hydroxyl-2-pyridine compounds is specially 1-to methoxy-benzyl-3-cyano group-4-hydroxyl-2-pyridone.
The preparation method of a kind of 3-cyano group-4-hydroxyl-2-pyridine compounds of the present invention, comprising:
3-cyano group-4-methoxyl group-2-pyridine compounds, alkali are dissolved in solvent, in 90 ~ 100 DEG C of stirring reaction 1 ~ 48h, after reaction terminates, add water, dripping acid to pH is 4 ~ 5, stir 5 ~ 20min, separating-purifying, obtains 3-cyano group-4-hydroxyl-2-pyridine compounds.
Described alkali is one or more in triethylamine, pyridine, DMAP, triethylene diamine (DABCO).
Described solvent is one or more in DMF, N,N-dimethylacetamide, hexylmethylphosphoramide.
The mol ratio of described 3-cyano group-4-methoxyl group-2-pyridine compounds and alkali is 1:1 ~ 5.
Described separating-purifying is: adjust pH to 3-4 with acid, separate out white solid, suction filtration, washing, use ethyl alcohol recrystallization.
Described acid adjusts acid in pH to 4 ~ 5 to be mineral acid or organic acid; Wherein mineral acid is the one in hydrochloric acid, sulfuric acid, phosphoric acid; Organic acid is formic acid or acetic acid.
The application of a kind of 3-cyano group-4-hydroxyl-2-pyridine compounds of the present invention, described compound prevents in preparation or treats the application in the medicine of tumour.
The application of a kind of 3-cyano group-4-hydroxyl-2-pyridine compounds of the present invention, the application of described compound in the medicine preparing prevention and therapy cervical cancer and liver cancer.
Chemical compound 3-cyano-4-hydroxyl-2-pyridine compounds the research that the present invention obtains finds, this compound has anti-tumor activity to Cervical Cancer HeLa Cells and liver cancer SMMC7721 cell etc. in vitro.
The principal synthetic routes of compound is as follows: chemical compound 3-cyano-4-methoxyl group-2-pyridone (1) and methyl iodide carry out methylating, bromo then generates compound N-methy-3-cyano group-4-hydroxyl-5-bromo-2-pyridyl ketone (4) under DABCO effect, or the bromobenzyl reacting generating compound (6) of 3-cyano group-4-methoxyl group-2-pyridone (1) and para-orientation, finally under DABCO effect, generate compound N-4-substituted benzyl-3-cyano group-4-hydroxyl-2-pyridone (6), total recovery reaches more than 40%.
beneficial effect
(1) preparation method of compound of the present invention is simple, and yield is high, is produced on a large scale;
(2) the 3-cyano group-4-hydroxyl-2-pyridine compounds that prepared by the present invention can be applicable to preparation prevention or tumor.
Embodiment
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.In addition should be understood that those skilled in the art can make various changes or modifications the present invention, and these equivalent form of values fall within the application's appended claims limited range equally after the content of having read the present invention's instruction.
Embodiment 1
The preparation of the bromo-3-cyano group of 5--4-methoxyl group-2-pyridone
3-cyano group-4-methoxyl group-2-pyridone 0.30g (2.0mmol) is added successively in 25mL round-bottomed flask, 0.39g (2.2mmol) N-bromo-succinimide (NBS), 42 μ L trifluoroacetic acids and 5mL acetonitrile, stir 6 hours at normal temperatures, TLC monitors reaction, on a rotary evaporator solvent is spin-dried for after having reacted, adds 10mL water, stir, filter, dried by filter cake, obtain white solid 0.36g, productive rate is 79.3%.Directly carry out next step reaction, m.p.:212 ~ 214 DEG C .IR (KBr) ν cm
-1: 3439,2921,2855,2221,1642,1470,1229,977,872,774;
1hNMR (400MHz, DMSO-d
6): δ 4.32 (s, 3H, OCH
3), 8.04 (s, 1H, Ar-H), 12.42 (s, 1H, Ar-H).
13cNMR (400MHz, DMSO-d
6): δ 61.28,88.83,92.87,115.30,141.55,162.12,169.18.
Embodiment 2
The preparation of 3-cyano group-4-methoxyl group-2-pyridone
Get 3-cyano group-4-methoxyl group-2-pyridone 0.40g (2.7mmol) and 30mLTHF and be placed in 100mL round-bottomed flask, add 0.12g (3.0mmol) 60%NaH under ice bath in batches, magnetic agitation is after 20 minutes, add 1.14g (8.03mmol) methyl iodide, room temperature reaction 2 hours.TLC monitors reaction, after reacting completely, is spin-dried for by solvent on a rotary evaporator, and add water 10mL, and filtering drying obtains white solid 0.42g, yield 95.4%, m.p.:198 ~ 200 DEG C; IR (KBr) ν cm
-1: 3420,2921,2857,2219,1653,1604,1535,1496,1457,1358,1314,1256,1136,1046,776;
1hNMR (400MHz, DMSO-d
6): δ 3.42 (s, 3H, NCH
3), 3.97 (s, 3H, OCH
3), 6.42 (d, 1H, Ar-H), 8.10 (d, 1H, Ar-H).;
13cNMR (400MHz, DMSO-d
6): δ 37.15,58.07,86.16,94.14,115.10,146.54,161.30,173.06.
Embodiment 3
The preparation of N-methyl-5-bromine 3-cyano group-4-methoxyl group-2-pyridone
Get 0.30g (1.83mmol) compound 1-methyl-3-cyano group-4-methoxyl group-2-pyridone, 0.36g (2.01mmol) NBS, 42 μ L trifluoroacetic acids and 5mL acetonitrile add in 25mL round-bottomed flask successively, stir 10 hours under normal temperature.TLC monitors reaction, on a rotary evaporator solvent is spin-dried for after having reacted, adds 20mL methylene dichloride and dissolve, and rinse with 20mL S-WAT and the 20mL1mol/LNaOH aqueous solution respectively, water layer methylene dichloride (2 × 20mL) extracts, merge organic layer, add anhydrous sodium sulfate drying, placement of spending the night, be spin-dried for, obtain product as white needles 0.36g, yield is 81.1%, m.p.:242 ~ 244 DEG C.IR(KBr)νcm
-1:3427,3048,2921,2855,2215,1637,1596,1524,1452,1406,1093,1038,986,831,762；
1HNMR(400MHz,DMSO-d
6):δ3.41(s,3H,NCH
3),4.31(s,3H,OCH
3),8.43(s,1H,Ar-H)；
13CNMR(400MHz,DMSO-d
6):δ37.22,61.33,88.20,92.20,115.28,145.36,161.32,168.45；MS(EI)m/e:242[M]
+,227,199,160,133,42.
Embodiment 4
The preparation of N-methyl-3-cyano group-4-hydroxyl-2-pyridone
Compound 1-methyl-3-cyano group-4-methoxyl group-2-pyridone 0.20g (1.22mmol) is added successively in 25mL round-bottomed flask, triethylene diamine (DABCO) 0.28g (2.50mmol) and 4mLDMF, be placed in 90 DEG C of oil baths to react, TLC monitors reaction, reacts completely after 5 hours.Cooling, adds 10mL water in reaction solution, more dropwise dropping 2NHCl to pH is 4 ~ 5, and adularescent solid is separated out, and suction filtration is dried, and ethyl alcohol recrystallization obtains product 0.16g, and productive rate is 87.4%, m.p.:284 ~ 286 DEG C.IR(KBr)νcm
-1:3434,2923,2855,2358,2211,1633,1569,1507,1421,1121,1014,806,564；
1HNMR(400MHz,DMSO-d
6):δ3.36(s,3H,NCH
3),6.02(d,1H,Ar-H),7.82(d,1H,Ar-H),12.64(s,1H,OH)；
13CNMR(400MHz,DMSO-d
6):δ36.84,85.55,98.26,115.61,144.96,161.96,172.57.；MS(EI)m/e:150[M]
+,121,84,67,42.HRMS(EI):calcd.150.0429forC
7H
6N
2O
2[M
+]found150.0432.
Embodiment 5
The preparation of the bromo-3-cyano group of 5--4-hydroxyl-2-pyridone
The bromo-3-cyano group of compound 5--4-methoxyl group-2-pyridone 0.30g (1.31mmol) is added successively in 25mL round-bottomed flask, DABCO0.19g (1.31mmol) and 4mLDMF, be placed in 90 DEG C of oil baths to react, TLC monitors reaction, reacts completely after 5 hours.Cooling, adds 10mL water in reaction solution, then to drip 2N hydrochloric acid to pH be 4 ~ 5, and adularescent solid is separated out, and suction filtration is dried, and ethyl alcohol recrystallization obtains white product 0.20g, productive rate 72.1%, m.p.248 ~ 250 DEG C.IR(KBr)νcm
-1:3423,2924,2855,2378,2208,1611,1569,1502,1422,1262,1088,1046,872,768,588；
1HNMR(400MHz,DMSO-d
6):δ7.32(s,1H,Ar-H),8.64(s,1H,OH)；10.02(s,1H,NH)；
13CNMR(400MHz,DMSO-d
6):δ83.21,102.85,121.04,135.25,165.31,174.24；MS(EI)m/e:214[M]
+,148,136,80,44.HRMS(EI):calcd.213.9378forC
6H
3N
2O
2Br[M
+]found213.9380.
Embodiment 6
The preparation of N-methyl-5-bromine 3-cyano group-4-hydroxyl-2-pyridone
The bromo-3-cyano group of compound 5--4-methoxyl group-2-pyridone 0.30g (1.23mmol) is added successively in 25mL round-bottomed flask, DABCO0.14g (1.23mmol) and DMF4mL, be placed in 90 DEG C of oil baths to react, TLC monitors reaction, reacts completely after 5 hours.Cooling, adds 10mL water in reaction solution, then to drip 2N hydrochloric acid pH be 4 ~ 5, and adularescent solid is separated out, and suction filtration dries to obtain product 0.25g, and productive rate is 88.7%, m.p.246 ~ 248 DEG C.IR(KBr)νcm
-1:3426,3063,2924,2849,2218,1723,1646,1534,1467,1356,1262,1226,1197,1116,1042,758,668,493；
1HNMR(400MHz,DMSO-d
6):δ3.36(s,1H,NHCH
3),8.31(s,1H,Ar-H),9.69(s,1H,OH)；
13CNMR(400MHz,DMSO-d
6):δ36.79,86.86,92.33,115.73,144.99,161.37,168.86；HRMS(EI):calcd.227.9534forC
6H
3N
2O
2Br[M
+]found227.9529.
Embodiment 7
N-is to the preparation of nitrobenzyl-3-cyano group-4-methoxyl group-2-pyridone
3-cyano group-4-methoxyl group-2-pyridone 0.5g (3.33mmol), 0.57g (3.33mmol) p-nitrobenzyl chloride and 0.92g (6.67mmol) K is added successively in 25mL round-bottomed flask
2cO
3, add 15mL acetonitrile, be heated to backflow under magnetic stirring, TCL monitors reaction, reacts completely after 5 hours.By reacting liquid filtering, removing inorganic salt impurities, use acetonitrile flush cake, filtrate be spin-dried for, obtain white solid 0.75g after oven dry, productive rate is 91.5%, m.p.150 ~ 152 DEG C; IR (KBr) ν cm
-1: 3422,3102,2921,2222,1664,1598,1535,1493,1424,1347,1276,1108,934,852,788,735,692,558,
1hNMR (400MHz, DMSO-d
6): δ 4.02 (s, 3H, OCH
3), 5.25 (s, 2H, CH
2), 6.58 (s, 1H, Ar-H), 7.52 (d, 2H, Ar-H), 8.22 (s, 2H, Ar-H), 8.31 (s, 1H, Ar-H).
13cNMR (400MHz, DMSO-d
6): δ 51.54,58.33,86.82,114.32,124.22,129.15,144.62,146.04,147.42,160.89,173.52.MS (EI) m/e:285 [M]
+, 238,136,106,89,78,63.
Embodiment 8
N-is to the preparation of nitrobenzyl-3-cyano group-4 hydroxyl-2-pyridone
In 25mL round-bottomed flask, add 0.30g (1.22mmol) compound N-to nitrobenzyl-3-cyano group-4-methoxyl group-2-pyridone and 0.13g (1.22mmol) DABCO and 5mLDMF successively, oil bath is heated to 90 DEG C of reactions.TCL monitors reaction, reacts completely after 5 hours.Cooling, add 10mL water, being neutralized to PH with 2N hydrochloric acid is 4 ~ 5.Have yellow mercury oxide to separate out, filtration drying obtains light yellow product 0.22g, and yield is 77.7%, m.p.252 ~ 254 DEG C; IR (KBr) ν cm
-1: 3429,3075,2925,2858,2218,1645,1519,1482,1388,1345,1201,1109,860,798,694.
1hNMR (400MHz, DMSO-d
6): δ 5.20 (s, 2H, CH
2), 6.14 (s, 1H, Ar-H), 7.50 (d, 2H, Ar-H), 8.01 (s, 1H, Ar-H), 8.23 (d, 2H, Ar-H), 12.91 (s, 1H, OH).
13cNMR (400MHz, DMSO-d
6): δ 51.18,86.04,99.46,115.37,124.21,129.02,144.44,145.01,147.36,161.59,173.07; MS (EI) m/e:271 [M]
+, 136,120,106,89,78,63.HRMS (EI): calcd.271.0593forC
13h
9n
3o
4[M
+] found271.0592.
Embodiment 9
N-is to the preparation of methoxy-benzyl-3-cyano group-4-methoxyl group-2-pyridone
0.50g (3.33mmol) 4-methoxyl group-3-itrile group-2-pyridone is added successively in 25mL round-bottomed flask, 0.52g is to methyl benzyl chlorine and 0.92g (6.67mmol) salt of wormwood, add 15mL acetonitrile again, be heated to backflow under magnetic stirring.TLC monitors reaction, reacts completely after 4 hours.Filtered by reaction mixture, rinsed by filter residue sherwood oil, dry, obtain white product 0.66g, yield is 85.8%, m.p.206 ~ 208 DEG C; IR (KBr) ν cm
-1: 3434,2923,2212,1743,1629,1516,1383,1246,1032,805;
1hNMR (400MHz, DMSO-d
6): δ 3.73 (s, 3H, OCH
3), 3.98 (s, 3H, OCH
3), 5.03 (s, 2H, CH
2), 6.47 (s, 2H, Ar-H), 6.90 (d, 2H, Ar-H), 7.27 (d, 2H, Ar-H), 8.23 (d, 1H, Ar-H).
13cNMR (400MHz, DMSO-d
6): δ 51.18,55.58,58.16,86.64,94.93,114.48,115.00,128.97,129.96,145.67,159.39,160.89,173.12; MS (EI) m/e:270 [M]
+, 228,121,103,91,78,65,52.
Embodiment 10
N-is to the preparation of methoxy-benzyl-3-cyano group-4 hydroxyl-2-pyridone
In the round-bottomed flask of 25mL, add compound N-to methoxy-benzyl-3-cyano group-4-methoxyl group-2-pyridone 0.30g (1.10mmol), 0.15g (1.3mmol) DABCO and 5mLDMF successively, oil bath is heated to 90 DEG C of reactions.TLC monitors reaction, reacts completely after 5 hours.Cooling reaction solution, add 10mL water, being neutralized to pH with 2N hydrochloric acid is 4 ~ 5.Adularescent Precipitation, filtration drying obtains white product 0.22g, and yield is 78%, m.p.238 ~ 240 DEG C; IR (KBr) ν cm
-1: 3437,2922,2843,2210,1629,1587,1508,1440,1394,1345,1109,1019,742,560;
1hNMR (400MHz, DMSO-d
6): δ 3.73 (s, 3H, OCH
3), 4.97 (s, 2H, CH
2), 6.07 (d, 1H, Ar-H), 6.90 (d, 2H, Ar-H), 7.24 (d, 2H, Ar-H), 7.93 (d, 1H, Ar-H), 12.74 (s, 1H, OH).
13cNMR (400MHz, DMSO-d
6): δ 50.79,55.58,85.89,98.91,114.47,115.48,129.24,129.84,144.14,159.31,161.55,172.57.MS (EI) m/e:256 [M]
+, 228,121,91,77,76,63,51.HRMS (EI): calcd.256.0848forC
14h
12n
2o
3[M
+] found256.0850
Embodiment 11
N-is to the preparation of methoxy-benzyl-3-cyano group-4 hydroxyl-2-pyridone
In the round-bottomed flask of 25mL, add compound N-to methoxy-benzyl-3-cyano group-4-methoxyl group-2-pyridone 0.54g (2.0mmol), 0.37g (3.0mmol) DMAP and 15mLDMF successively, oil bath is heated to 90 DEG C of reactions.TLC monitors reaction, reacts completely after 8 hours.Cooling reaction solution, add 40mL water, being neutralized to pH with 2N sulfuric acid is 4 ~ 5, adularescent Precipitation, and filtration drying obtains white product 0.31g, and yield is 61%, m.p.236 ~ 238 DEG C.
Embodiment 12
N-is to the preparation of methoxy-benzyl-3-cyano group-4 hydroxyl-2-pyridone
In the round-bottomed flask of 25mL, add compound N-to methoxy-benzyl-3-cyano group-4-methoxyl group-2-pyridone 5.4g (0.02mmol), 3.03g (0.03mmol) triethylamine and 20mL N,N-DIMETHYLACETAMIDE successively, oil bath is heated to 90 DEG C of reactions 36 hours.Cooling reaction solution, add 40mL water, being neutralized to pH with glacial acetic acid is 4 ~ 5, adularescent Precipitation, and filtration drying obtains white product 1.64g, and yield is 32%, m.p.235 ~ 237 DEG C.
Embodiment 13
N-is to the preparation of methoxy-benzyl-3-cyano group-4 hydroxyl-2-pyridone
In the round-bottomed flask of 25mL, add compound N-to methoxy-benzyl-3-cyano group-4-methoxyl group-2-pyridone 1.35g (5.0mmol), 2.8g (25.0mmol) DABCO and 20mL hexylmethylphosphoramide successively, oil bath is heated to 90 DEG C of reactions.TLC monitors reaction, reacts completely after 12 hours.Cooling reaction solution, add 40mL water, being neutralized to pH with glacial acetic acid is 4 ~ 5, adularescent Precipitation, and filtration drying obtains white product 0.65g, and yield is 52%, m.p.236 ~ 238 DEG C.
Embodiment 14
Antitumor activity screening is tested
Detect the restraining effect of 3-cyano group-4 hydroxyl-2-pyridine compounds to vitro culture human cervical carcinoma Hela cell and liver cancer SMMC7721 with mtt assay, measuring method and condition as follows:
Screening method: mtt assay
Cell strain: human cervical carcinoma Hela cell's strain and liver cancer SMMC7721 cell strain
Operation steps:
Get and be in good one bottle, the cell of growth conditions exponential phase of growth, add 0.25% tryptic digestion, attached cell is come off, make every milliliter containing 2 × 10
4~ 4 × 10
4the suspension of cell, is inoculated in 96 orifice plates, and every hole 150 μ L, puts 5%CO
272h is cultivated in 37 DEG C in incubator, every hole adds 5mg/mLMTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-dibromobenzene bromination tetrazole] solution 100 μ LDMSO Rong Xie Jia Za (formazan) crystallization, after micro oscillator mixing, be absorbing wavelength by microplate reader in 492nm, 630nm is that reference wavelength measures optical density(OD), and computerized compound is to the inhibiting rate of growth of tumour cell.
Pharmacological experiments shows, 1 × 10
-5under mol/L concentration, selected objective target compound N-have certain inhibit activities to Cervical Cancer HeLa Cells and liver cancer SMMC7721 cell to methoxy-benzyl-3-cyano group-4 hydroxyl-2-pyridone, inhibiting rate is respectively 61.3% and 58.2%, the bromo-3-cyano group of compound 5--4-hydroxyl-2-pyridone and the inhibiting rate of N-methyl-3-cyano group-4-hydroxyl-2-pyridone to s are respectively 39.6% and 42.3%, are respectively 35.7% and 40.2% to the inhibiting rate of liver cancer SMMC7721 cell.The inhibiting rate of positive control drug 4-hydroxyl-3-cyano group-2-pyridone to Cervical Cancer HeLa Cells and liver cancer SMMC7721 cell is respectively 38.1% and 31.5%.
Claims (10)
1. a 3-cyano group-4-hydroxyl-2-pyridine compounds, is characterized in that: the structural formula of described compound is:
wherein R
1for the phenmethyl that methyl or 4-replace; R
2for hydrogen, chlorine or bromine.
2. a kind of 3-cyano group-4-hydroxyl-2-pyridine compounds according to claim 1, is characterized in that: the substituting group in the phenmethyl that described 4-position replaces is hydrogen, chlorine, bromine, methoxyl group or nitro.
3. a kind of 3-cyano group-4-hydroxyl-2-pyridine compounds according to claim 1, is characterized in that: described 3-cyano group-4-hydroxyl-2-pyridine compounds is that 1-is to methoxy-benzyl-3-cyano group-4-hydroxyl-2-pyridone.
4. a preparation method for the 3-cyano group-4-hydroxyl-2-pyridine compounds as described in as arbitrary in claim 1-3, comprising:
3-cyano group-4-methoxyl group-2-pyridine compounds, alkali are dissolved in solvent, in 90 ~ 100 DEG C of stirring reaction 1 ~ 48h, after reaction terminates, add water, dripping acid to pH is 4 ~ 5, stir 5 ~ 20min, suction filtration, obtains 3-cyano group-4-hydroxyl-2-pyridine compounds.
5. the preparation method of a kind of 3-cyano group-4-hydroxyl-2-pyridine compounds according to claim 4, is characterized in that: described alkali is one or more in triethylamine, pyridine, DMAP, triethylene diamine DABCO; Solvent is one or more in DMF, N,N-dimethylacetamide, hexylmethylphosphoramide.
6. the preparation method of a kind of 3-cyano group-4-hydroxyl-2-pyridine compounds according to claim 4, is characterized in that: the mol ratio of described 3-cyano group-4-methoxyl group-2-pyridine compounds and alkali is 1:1 ~ 5.
7. the preparation method of a kind of 3-cyano group-4-hydroxyl-2-pyridine compounds according to claim 4, is characterized in that: described separating-purifying is: adjust pH to 3-4 with acid, separate out white solid, suction filtration, washing, use ethyl alcohol recrystallization.
8. the preparation method of a kind of 3-cyano group-4-hydroxyl-2-pyridine compounds according to claim 7, is characterized in that: described acid adjusts acid in pH to 4 ~ 5 to be mineral acid or organic acid; Wherein mineral acid is the one in hydrochloric acid, sulfuric acid, phosphoric acid; Organic acid is formic acid or acetic acid.
9. an application for 3-cyano group-4-hydroxyl-2-pyridine compounds as claimed in claim 1, is characterized in that: described compound prevents in preparation or treats the application in the medicine of tumour.
10. an application for 3-cyano group-4-hydroxyl-2-pyridine compounds as claimed in claim 1, is characterized in that: the application of described compound in the medicine preparing prevention and therapy cervical cancer and liver cancer.
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| WO2022126388A1 (en) * | 2020-12-15 | 2022-06-23 | 深圳市华先医药科技有限公司 | Method for synthesizing 5-bromo-1h-3-amino-1,2,4-triazole |
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