CN102875558A - 2-chloro-4-substituted-8-nitrobenzofuran [3,2-d] miazines compound, preparation method of compound and application of compound - Google Patents
2-chloro-4-substituted-8-nitrobenzofuran [3,2-d] miazines compound, preparation method of compound and application of compound Download PDFInfo
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Abstract
The invention relates to 2-chloro-4-substituted-8-nitrobenzofuran [3,2-d] miazines compound, a preparation method of the compound and application of the compound. A structure of the compound is shown in the specification, a substituent group R in the formula can be halogen atoms, nitro, amino or amido substituent group. 2-chloro-4-substituted-8-nitrobenzofuran [3,2-d] miazines compound uses 5-nitrososalicylaldehyde, acetic anhydride, hydroxylamine hydrochloride, ethyl bromoacetate and the like as raw materials and is synthesized by six steps, and more than tens of compounds are synthesized and can be used for preparing for antineoplastic medicines.
Description
Technical field
The present invention relates to 2-chloro-4-replacement-8-nitrobenzofuran [3,2-d] pyrimidines that has antitumour activity and preparation method thereof.
Background technology
Cumarone [3,2-d] pyrimidines structure and quinazoline, pyrrolopyrimidine, Thienopyrimidine, pyrido-pyrimidines are similar, have the biological activity of wide spectrum, such as anticancer, anti-inflammatory, antibiotic isoreactivity.
The people such as Bridges (Bridges A. J., et al.. WO1995019970,1995-07-27.) study and find that cumarone [3,2-d] pyrimidines has the effect that suppresses epidermal growth factor recipient tyrosine kinase, to the IC of human epidermal cancer cells A431
50Value is 740nmol/L.2005, the people such as Hurley (Hurley L. H., et al.. US20050239794,2005-10-27.) reported a series of cumarones [3,2-d] Preparation method and use of pyrimidines, the some of them compound belongs to the kinase inhibitor of many target spots, and GIST882 JEG-3 and pancreas cancer cell strain MIAPaCa and PANC-1 are had good restraining effect.
2006, the people such as Harris (Harris N., et al.. WO20060050965A1,2006-5-18.) study and find that cumarone [3,2-d] pyrimidines can be used for treating rheumatoid disease sacroiliitis, ulcerative colitis, allergic rhinitis and other diseases associated with inflammation as the histamine conditioning agent.2009, Ramsden (Ramsden N.. EP2020412A1,2009-02-04) research is found, cumarone [3,2-d] pyrimidines has the histamine h 4 receptor of adjusting, prevention and the treatment receptor-mediated panimmunity disease of histamine H4 and inflammatory reaction.
The people such as Kamble (Kamble D. G., et al.. Indian J. Heter. Chem., 1999,9:23-26) with gentamicin medicament in contrast, tested cumarone [3,2-d] pyrimidines is active to streptococcus aureus and colibacillary inhibition, finds that it has inhibition to intestinal bacteria.2003, the people such as Bodke (Bodke Y., et al.. Indian Chem. Soc, 2003,80:187-189) research finds that some cumarones [3,2-d] pyrimidines has anti-Staphylococcus aureus and anticolibacillary activity.
Summary of the invention
Take cumarone miazines compound with antitumour activity as lead compound, 2-chloro-4-replacement-8-nitrobenzofuran [3, the 2-d] pyrimidines of the synthetic a series of novel structures of design carries out the research of antitumour activity.Its general structure is as follows:
In the formula: substituent R can be halogen atom, nitro, amino or amido substituting group, and wherein, the amido substituting group refers to aliphatic amide substituting group, aromatic amine substituting group or amide substituents.
The present invention is take 5-nitrosalicylaldehyde, oxammonium hydrochloride, acetic anhydride, ethyl bromoacetate, sodium ethylate, urea, phosphorus oxychloride as raw material, and take glacial acetic acid, acetone, ethanol, methylene dichloride, Virahol as reaction solvent, synthetic through six steps, synthetic route is as follows:
The first step: 2-hydroxyl-5-nitrobenzonitrile synthetic
The 5-nitrosalicylaldehyde is joined in the glacial acetic acid, add oxammonium hydrochloride, steam glacial acetic acid behind the reflux 1-5h, add acetic anhydride, behind the reflux 1-6h, underpressure distillation goes out acetic anhydride, add sodium hydroxide solution after the cooling and regulate pH to 5-6, get yellow solid, the suction filtration after washing, the filter cake oven dry gets 2-hydroxyl-5-nitrobenzonitrile.
5-nitrosalicylaldehyde: oxammonium hydrochloride=1:1-1.5 (mol ratio)
Temperature of reaction: 25-135 ℃
Reaction times: 2-11h
Second step: 2-cyano group-4-nitrophenoxy ethyl acetate synthetic
2-hydroxyl-5-nitrobenzonitrile is joined in the acetone, add salt of wormwood and ethyl bromoacetate after the dissolving, reflux 8-12h, after finishing, reaction is chilled to room temperature, filter out solid, solid merges acetone solution with acetone solution washing three times, get solid after concentrated, the solid recrystallization gets product 2-cyano group-4-nitrophenoxy ethyl acetate.
2-hydroxyl-5-nitrobenzonitrile: ethyl bromoacetate: salt of wormwood=1:1-1.5:1-1.5 (mol ratio)
Temperature of reaction: 25-56 ℃
Reaction times: 8-12h
The 3rd step: 3-amino-5-nitro-2-benzofurancarboxylic acid ethyl ester synthetic
2-cyano group-4-nitrophenoxy ethyl acetate is joined in the ethanol, add sodium ethylate after the dissolving, reflux 1-4h concentrates to get solid after reaction is finished, and solid washes post-drying with water and gets product 3-amino-5-nitro-2-benzofurancarboxylic acid ethyl ester.
2-cyano group-4-nitrophenoxy ethyl acetate: sodium ethylate=1:1-1.5 (mol ratio)
Temperature of reaction: 25-78 ℃
Reaction times: 1-4h
The 4th step: 1,3-dihydro-8-nitro-cumarone [3,2-d] pyrimidine-2,4-diketone synthetic
Add excessive urea and 3-amino-5-nitro-2-benzofurancarboxylic acid ethyl ester mixing post-heating reaction 2-5h, solid washs successively with water-ethanol mixing solutions, the hot water of heat after the cooling, and recrystallization gets product 1,3-dihydro-8-nitro-cumarone [3 after the oven dry, 2-d] pyrimidine-2, the 4-diketone.
3-amino-5-nitro-2-benzofurancarboxylic acid ethyl ester: urea=1:1-10 (mol ratio)
Temperature of reaction: 150-220 ℃
Reaction times: 2-5h
The 5th step: the synthesizing of 2-chloro-4-replacements-8-nitrobenzofuran [3,2-d] pyrimidines
With 1,3-dihydro-8-nitro-cumarone [3,2-d] pyrimidine-2, the 4-diketone joins in the excessive phosphorus oxychloride, the DMF that adds catalytic amount, reflux 5-15h is cooled to room temperature after reaction is finished, to stir in the reaction solution impouring trash ice and constantly, produce a large amount of solids, the suction filtration after washing, recrystallization gets 2 after the filter cake oven dry, 4-two chloro-8-nitrobenzofuran [3,2-d] pyrimidines.Compound 2,4 of 4-two chloro-8-nitrobenzofuran [3,2-d] pyrimidines substitution reaction occur can obtain a series of cumarones [3,2-d] pyrimidine derivatives.
According to the present invention synthetic compound R be the chlorine atom ,-N-cyclohexyl-amino ,-N-antipyrine-4-is amino ,-N-ethanol based-amino ,-N-neighbour aminophenyl amino ,-N-o-methyl-phenyl--amino ,-N-phenyl-amino ,-N-between bromophenyl-amino ,-N-phenylethylamine base ,-N-m-nitro base-amino ,-N-n-dodecane amido ,-the N-n-butylamine-based ,-N, N-diethyl-amino ,-N, N-diethyl alcohol radical-amino ,-N-1-naphthyl-amino ,-N-2-naphthyl-amino ,-the N-morpholine.Above compound was all done nuclear magnetic resonance hydrogen spectruming determining and mass spectroscopy.
In synthesis step five, select aromatic amine or aliphatic amide and 4 upper chlorine atom generation substitution reactions of 2,4-, two chloro-8-nitrobenzofuran [3,2-d] pyrimidines of different structure, just can obtain above-mentioned different R
3Substituent cumarone [3,2-d] pyrimidine derivatives.
The target compound title synthetic with the inventive method is as follows, respectively with a, b ... p, q numbering, and all made nuclear magnetic resonance hydrogen spectruming determining and mass spectroscopy:
A.2,4-two chloro-8-nitrobenzofuran [3,2-d] pyrimidines
B.2-chloro-4-(N-cyclohexyl-amino)-8-nitrobenzofuran [3,2-d] pyrimidine
C.2-chloro-4-(N-antipyrine-4-amino)-8-nitrobenzofuran [3,2-d] pyrimidine
D.2-chloro-4-(N-ethanol based-amino)-8-nitrobenzofuran [3,2-d] pyrimidine
E.2-chloro-4-(N-adjacent aminophenyl amino)-8-nitrobenzofuran [3,2-d] pyrimidine
F.2-chloro-4-(N-o-methyl-phenyl--amino)-8-nitrobenzofuran [3,2-d] pyrimidine
G.2-chloro-4-(N-phenyl-amino)-8-nitrobenzofuran [3,2-d] pyrimidine
H.2-chloro-4-(bromophenyl-amino between N-)-8-nitrobenzofuran [3,2-d] pyrimidine
I.2-chloro-4-(N-phenylethylamine base)-8-nitrobenzofuran [3,2-d] pyrimidine
J.2-chloro-4-(N-m-nitro base-amino)-8-nitrobenzofuran [3,2-d] pyrimidine
K.2-chloro-4-(N-n-dodecane amido)-8-nitrobenzofuran [3,2-d] pyrimidine
L.2-chloro-4-(N-n-butylamine-based)-8-nitrobenzofuran [3,2-d] pyrimidine
M.2-chloro-4-(N, N-diethyl-amino)-8-nitrobenzofuran [3,2-d] pyrimidine
N.2-chloro-4-(N, N-diethyl alcohol radical-amino)-8-nitrobenzofuran [3,2-d] pyrimidine
O.2-chloro-4-(N-1-naphthyl-amino)-8-nitrobenzofuran [3,2-d] pyrimidine
P.2-chloro-4-(N-2-naphthyl-amino)-8-nitrobenzofuran [3,2-d] pyrimidine
Q.2-chloro-4-(N-morpholine)-8-nitrobenzofuran [3,2-d] pyrimidine
Theoretically, the compound that can synthesize with the inventive method should comprise that R is halogen atom, nitro, amino, amido substituting group amide substituents in the general structure, and the amido substituting group refers to aliphatic amide substituting group or amide substituents.
Nitro on 8 of the compounds of this invention can be reduced amino, N-substituted amido or amide substituents and replace, and the amido substituting group refers to aliphatic amide substituting group or aromatic amine substituting group.
2 upper Cl atoms of the compounds of this invention can be substituted by amido substituting group or amide substituents, and wherein, the amido substituting group is the aliphatic amide substituting group, comprises chain aliphatic amide substituting group and ring-shaped fat amine substituting group or aromatic amine substituting group.
With the synthetic above-claimed cpd of the inventive method, have the effect that suppresses preferably lung carcinoma cell and leukemia cell, have preferably anti-tumor activity, so the purposes of the compounds of this invention is for the preparation of anti-tumor drug.
With restraining effect test method and the result of the compounds of this invention to the Leukemia K562 cell strain:
Exist the desaturase relevant with NADP in the plastosome of viable cell, the MTT of yellow can be reduced to insoluble hepatic Formanzan, and the desaturase relevant with NADP of dead cell disappeared, MTT can not be reduced.This shaker test comes test sample to the effect situation of Leukemia K562 cell strain according to the reducing degree of MTT.
Testing method is for being mixed with each concentration, each concentration triplicate with medicine with the DMSO dissolving.With the human leukaemia K562 cell of logarithmic growth with tryptic digestion after, be resuspended among the RPMI 1640 or DMDM substratum that contains 10% FBS, with 2 * 10
4The final concentration of individual/mL is inoculated in 96 well culture plates, every hole 100 μ L, and the rightmost side one is classified the blank group as, adds acellular serum RPMI 1640 substratum that have.Place 37 ℃, 5% CO
2The saturated humidity incubator in cultivate 24 h and make cell attachment.Sop up substratum, add the blood serum medium that has that contains different pharmaceutical concentration, every hole 200 μ L notice that the DMSO final concentration can not surpass 0.1% in the substratum, and the every hole of blank group adds 200 μ L perfect mediums.Remove supernatant, add the MTT that 100 μ L contain concentration 0.5 mg/mL, add again 100 μ L behind cultivation 4 h under the similarity condition and contain 10% SDS.37 ℃ of lower 10 h that keep make crystallisate fully dissolve rear taking-up, and 5 min are swung in microseism, place 30 min under the room temperature, survey the OD value under the 595nm wavelength, and calculate inhibiting rate.
The anti-human leukemia cell line K562 of table 1 target product cell screening result
Annotate: each concentration replicate(determination) of each sample of this screening experiment 3 times, repeated experiments 2 times, the result represents with M ± SD.
With restraining effect test method and the result of the compounds of this invention to human lung cancer cell A549's strain:
Sulforhodamine B (SRB) is a kind of protein binding dyestuff, can be combined by the basic aminoacids in biomacromolecule, and its OD value in particular range of wavelengths and cell quantity are good linear relationship.This shaker test model comes test sample to the restraining effect situation of human lung carcinoma cell line A549 cell according to the OD value of SRB binding substances.
Testing method is for being mixed with each concentration, each concentration triplicate with medicine with the DMSO dissolving; Get the A549 cell (cell concn is 20000/mL, 100 μ L/ holes) in 96 orifice plates that is in Exponential growth stage, cultivate 24h and make cell attachment, remove supernatant, add 200 μ L/ pore area medicine fresh cultures.Compound is dissolved in the DMSO in advance, when test, is diluted to desired concn with perfect medium, notices that the DMSO total concn can not surpass 0.1%.Each concentration is established 6 multiple holes, and establishes blank hole and positive control, establishes equally 6 multiple holes.Continue to be cultured to the test design time, stop to cultivate, remove supernatant, every hole adds 10%TCA 200 μ L, and 4 ℃ of conditions are 1h fixedly.With redistilled water flushing 5 times, naturally dry rear every hole and add 4mg/mL SRB solution, the 15min that dyes under the room temperature discards supernatant liquor, with 5 times dyestuffs with the removal non-specific binding of 1% acetic acid flushing.Every hole adds 100 μ L 10mmol/L Tris solution, surveys the OD value under the 490nm wavelength, and calculates inhibiting rate.
The anti-human lung cancer cell line A549 of table 2 target product cell screening result
Annotate: each concentration replicate(determination) of each sample of this screening experiment 3 times, repeated experiments 2 times, the result represents with M ± SD.
Embodiment
Synthetic (compound number is b) of embodiment one, 2-chloro-4-(N-cyclohexyl-amino)-8-nitrobenzofuran [3,2-d] pyrimidine:
(1) 2-hydroxyl-5-nitrobenzonitrile is synthetic:
Add 10mmol 5-nitrosalicylaldehyde in the there-necked flask, add the 15mL glacial acetic acid, after heating for dissolving is complete, add the 12mmol oxammonium hydrochloride, behind the reflux 2h, steam glacial acetic acid, add the 15mL diacetyl oxide, be warming up to 135 ℃ of reaction 2h, steam diacetyl oxide, add sodium hydroxide solution after the cooling and regulate pH to 5-6, obtain a large amount of yellow solids, filter cake is dried to get product 1.36g, product yield: 86%, mp:152 ℃-153 ℃ after the suction filtration washing.IR:?3566?(O-H),?2232?(C≡N),?1636,?1487,?1437,?1348(NO
2)cm
-1。
(2) 2-cyano group-4-nitrophenoxy ethyl acetate is synthetic:
Add 13mmol 2-hydroxyl-5-nitrobenzonitrile and 35mL acetone in the there-necked flask, after heating for dissolving is complete, add 15mmol salt of wormwood, drip the 1.6mL ethyl bromoacetate, reflux is behind the reaction 10h, stopped reaction is cooled to room temperature, filters out solid, solids washed with acetone three times, merge acetone solution, namely get crude product after concentrating, the crude product recrystallization gets 2-cyano group-4-nitrophenoxy ethyl acetate 3.0g, yield 92%, mp:138 ℃ ~ 140 ℃; IR:3445,2237 (C ≡ N), 1749 (C=O), 1616,1587,1491,1352,1217 cm
-1;
1H NMR (500MHz, (CD
3)
2CO): δ ppm 1.27 (t, 3H,
J=7.2Hz, CH
2-C
H 3), 4.24 (q, 2H,
J=7.3Hz ,-C
H 2CH
3), 5.19 (s, 2H, OC
H 2CO), 7.45 (d, 1H,
J=9.7Hz, Ar-
H-6), 8.50 (dd, 1H,
J=2.9,9.7Hz, Ar-
H-5), 8.65 (d, 1H,
J=2.9Hz, Ar-
H-3).
(3) 3-amino-5-nitro-2-benzofurancarboxylic acid ethyl ester is synthetic:
Add 1.75g 2-cyano group-4-nitrophenoxy ethyl acetate and 20mL dehydrated alcohol in the there-necked flask, after the heating for dissolving, add 0.52g sodium ethylate and 10mL dehydrated alcohol, after continuing back flow reaction 2h, the ethanol that evaporate to dryness is unnecessary adds entry after the cooling, separate out a large amount of yellow solids, suction filtration also washes to get product 1.6g with water, yield 91%, mp:172 ℃ ~ 176 ℃; IR 3449,3347 (NH
2), 1674 (C=O), 1638,1524,1335,1294 cm
-1;
1H NMR (500MHz, DMSO-
d 6 ): δ ppm 1.33 (t, 3H,
J=7.2Hz, CH
2-C
H 3), 4.32 (q, 2H,
J=7.3Hz ,-C
H 2-CH
3), 6.66 (s, 2H ,-N
H 2), 7.74 (d, 1H,
J=9.2Hz, Ar-
H-7), 8.35 (dd, 1H,
J=2.3,9.2Hz, Ar-
H-6), 9.09 (d, 1H,
J=2.3Hz, Ar-
H-4).
(4) 1,3-dihydro-8-nitro-cumarone [3,2-d] pyrimidine-2,4-diketone synthetic:
In the there-necked flask, add 20g 3-amino-5-nitro-2-benzofurancarboxylic acid ethyl ester and 28.8g urea, urea melts fully when being heated to 180 ℃, after continuing to be warming up to 220 ℃ of reaction 1.5h, reaction is finished, be cooled to room temperature after, add 150mL 50% ethanol-water solution reflux 0.5h, suction filtration while hot, filter cake must crude product with hot wash 5-6 time (200mL/ time).Crude product with the DMSO heating for dissolving after the activated carbon decolorizing recrystallization get pure products 15.4g, yield 78%, mp: 350 ℃; EI-MS (m/z): 247[M
+], 204,156,148,102,75;
1H NMR (500MHz, DMSO-
d 6 ): δ ppm 12.03 (s, 1H, N-
H), 11.57 (s, 1H, N-
H), 8.92 (s, 1H, Ar-
H-9), 8.42 (d, 1H,
J=8.0Hz, Ar-
H-7), 7.96 (d, 1H,
J=8.0Hz, Ar-
H-6);
13C NMR (125MHz, DMSO-
d 6 ): δ ppm 158.4 (C-4), 155.2 (C-11), 151.5 (C-2), 144.5 (C-8), 134.0 (C-13), 133.6 (C-10), 125.3 (C-12), 119.1 (C-7), 118.8 (C-9), 114.7 (C-6).
Synthesizing of (5) 2,4-two chloro-8-nitrobenzofuran [3,2-d] pyrimidines
Add 4.94g 1,3-dihydro-8-nitro-cumarone [3,2-d] pyrimidine-2,4-diketone and 30mL POCl in the there-necked flask
3Add 5 ~ 6 DMF, heating reflux reaction 10h, the TLC detection reaction is finished, and is cooled to after the room temperature reaction solution slowly joined in the beaker that trash ice is housed and constantly to stir, and produces a large amount of yellow solids, suction filtration and wash with water after crude product, crude product gets pure products 3.5g with chloroform-Virahol recrystallization, productive rate 62%, mp:214 ℃ ~ 217 ℃; EI-MS (m/z): 283[M
+], 253,237,225,148,112,87,69,57;
1H NMR (500MHz, CDCl
3): δ ppm 9.18 (d, 1H,
J=2.3Hz, Ar-
H-9), 8.71 (dd, 1H,
J=2.3,9.2Hz, Ar-
H-7), 7.92 (d, 1H,
J=9.2Hz, Ar-
H-6);
13C NMR (125MHz, CDCl
3): δ ppm 160.9 (C-2), 154.9 (C-4), 152.7 (C-11), 145.4 (C-8), 145.3 (C-12), 144.9 (C-10), 128.3 (C-7), 121.6 (C-9), 119.9 (C-6), 114.4 (C-13).
(6) 2-chloro-4-(N-cyclohexyl-amino)-8-nitrobenzofuran [3,2-d] pyrimidine is synthetic
Add 142mg2 in the round-bottomed flask, 4-two chloro-8-nitrobenzofurans [3,2-d] pyrimidine and 5mL methylene dichloride, then add 0.6mmol compound hexahydroaniline and 0.7mmol triethylamine, after normal-temperature reaction 24h became, concentrated, solid successively water, washed with isopropyl alcohol got pure products, product yield 98%, 250 ℃-252 ℃ of m.p.; EI-MS (m/z): 346[M
+], 311,289,264,243,218,55,41;
1H NMR (400MHz, DMSO-
d 6 ): δ ppm 8.81 (d, 1H,
J=2.0Hz, Ar-
H-9), 8.52 (dd, 1H,
J=2.4,9.2Hz, Ar-
H-7), 8.01 (d, 1H,
J=9.2Hz, Ar-
H-6), 4.02 (s, 1H, N-
H), 1.12-1.93 (m, 11H ,-C
H 2-);
13C NMR (125MHz, DMSO-
d 6 ): δ ppm 159.2 (C-2), 154.9 (C-4), 150.0 (C-11), 146.1 (C-8), 144.8 (C-12), 126.2 (C-10), 122.7 (C-7), 120.2 (C-9), 118.2 (C-6), 114.6 (C-13), 60.3 (C-1'), 50.0 (C-2'), 32.5 (C-6'), 25.6 (C-3'), 25.3 (C-5'), 14.6 (C-4').
Synthetic (compound number is e) of embodiment two, 2-chloro-4-(the adjacent aminophenyl of N-is amino)-8-nitrobenzofuran [3,2-d] pyrimidine:
Synthetic such as embodiment one method and condition, only in the end a step is changed to O-Phenylene Diamine with the reaction raw materials hexahydroaniline, ultrasonic (power 200W) reacts 3h, after reaction is finished, concentrated, get crude product, crude product successively after water, the washed with isopropyl alcohol recrystallization get 2-chloro-4-(the adjacent aminophenyl of N-is amino)-8-nitrobenzofuran [3,2-d] pyrimidine, yield 68%, 253 ℃-255 ℃ of m.p.; EI-MS (m/z): 355[M
+], 320,274,118,65;
1H NMR (400MHz, DMSO-
d 6 ): δ ppm 9.99 (s, 1H, N-
H), 8.89 (d, 1H,
J=1.6Hz, Ar-
H-9), 8.55 (d, 1H,
J=8.8Hz, Ar-
H-7), 8.04 (d, 1H,
J=8.4Hz, Ar-
H-6), 7.12 (d, 1H,
J=7.6Hz, Ar-
H-3'), 7.05 (t, 1H,
J=7.6Hz, Ar-
H-4'), 6.78 (d, 1H,
J=8.0Hz, Ar-
H-6'), 6.60 (t, 1H,
J=7.4Hz, Ar-
H-5'), 5.10 (s, 2H, N
H 2);
13C NMR (125MHz, DMSO-
d 6 ): δ ppm 159.2 (C-2), 154.7 (C-4), 150.3 (C-11), 145.2 (C-8), 144.9 (C-12), 137.2 (C-10), 128.4 (C-1'), 128.3 (C-2'), 126.2 (C-5'), 122.7 (C-6'), 121.8 (C-7), 118.2 (C-9, C-4'), 116.3 (C-3'), 116.1 (C-6), 114.6 (C-13).
Synthetic (compound number is d) of embodiment three, 2-chloro-4-(N-ethanol based-amino)-8-nitrobenzofuran [3,2-d] pyrimidine:
Synthetic such as embodiment one method and condition, only in the end single step reaction raw material hexahydroaniline is changed to thanomin, ultrasonic reaction 3h, after reaction is finished, concentrated, get crude product, crude product successively after water, the washed with isopropyl alcohol recrystallization get 2-chloro-4-(N-ethanol based-amino)-8-nitrobenzofuran [3,2-d] pyrimidine, yield 96%, 213 ℃-214 ℃ of m.p.; EI-MS (m/z): 308[M
+], 277,264,231,195,167,139,30;
1H NMR (400MHz, DMSO-
d 6 ): δ ppm 8.82 (d, 1H,
J=2.4Hz, Ar-
H-9), 8.52 (dd, 1H,
J=2.4,8.8Hz, Ar-
H-7), 8.04 (d, 1H,
J=9.2Hz, Ar-
H-6), 7.84 (brs, 1H ,-O
H), 4.85 (s, 1H, N-
H), 3.59 (q, 4H,
J=7.5Hz ,-C
H 2-C
H 2-);
13C NMR (125MHz, DMSO-
d 6 ): δ ppm 159.0 (C-2), 154.9 (C-4), 150.7 (C-11), 145.8 (C-8), 144.7 (C-12), 136.7 (C-10), 125.9 (C-7), 122.6 (C-9), 117.8 (C-6), 114.5 (C-13), 59.5 (C-2'), 58.0 (C-1').
Synthetic (compound number is i) of embodiment four, 2-chloro-4-(N-phenylethylamine base)-8-nitrobenzofuran [3,2-d] pyrimidine:
Synthetic such as embodiment one method and condition, only in the end single step reaction raw material hexahydroaniline is changed to phenylethylamine, ultrasonic (power 200W) reacts 1.5h, after reaction is finished, concentrated, get crude product, crude product successively after water, the washed with isopropyl alcohol recrystallization get 2-chloro-4-(N-phenylethylamine base)-8-nitrobenzofuran [3,2-d] pyrimidine, yield 96%, 249 ℃-250 ℃ of m.p.; EI-MS (m/z): 368[M
+], 277,264,231,139,104,91;
1H NMR (400MHz, DMSO-
d 6 ): δ ppm 8.82 (d, 1H,
J=2.0Hz, Ar-
H-9), 8.52 (dd, 1H,
J=2.4,9.2Hz, Ar-
H-7), 8.04 (d, 1H,
J=9.2Hz, Ar-
H-6), 7.90 (s, 1H, N-
H), 7.21-7.36 (m, 5H, Ar-
H-4', 5', 6', 7', 8'), 2.85-3.05 (m, 4H ,-C
H 2-C
H 2-);
13C NMR (125MHz, DMSO-
d 6 ): δ ppm 159.1 (C-2), 154.9 (C-4), 150.6 (C-11), 146.1 (C-8), 144.8 (C-12), 139.6 (C-3'), 129.2 (C-5', C-7'), 127.3 (C-4', C-8'), 126.8 (C-10), 126.0 (C-6'), 122.8 (C-7), 121.6 (C-9), 118.1 (C-6), 114.6 (C-13), 42.4 (C-1'), 33.5 (C-2').
Synthetic (compound number is h) of embodiment five, 2-chloro-4-(bromophenyl-amino between N-)-8-nitrobenzofuran [3,2-d] pyrimidine:
Synthetic such as embodiment one method and condition, only in the end single step reaction raw material hexahydroaniline is changed to m-bromoaniline, ultrasonic (power 200W) reacts 6h, after reaction is finished, concentrated, get crude product, crude product successively after water, the washed with isopropyl alcohol recrystallization get 2-chloro-4-(bromophenyl-amino between N-)-8-nitrobenzofuran [3,2-d] pyrimidine, yield 62%, 191 ℃-193 ℃ of m.p.; EI-MS (m/z): 420[M
+], 383,373,339,293,155,116,102,75;
1H NMR (400MHz, DMSO-
d 6 ): δ ppm 10.91 (s, 1H, N-
H), 8.94 (d, 1H,
J=2.4Hz, Ar-
H-9), 8.60 (dd, 1H,
J=2.4,9.2Hz, Ar-
H-7), 8.11-8.16 (m, 2H, Ar-
H-4', 6'), 7.85 (d, 1H,
J=7.6Hz, Ar-
H-6), 7.35-7.42 (m, 2H, Ar-
H-2', 5');
13C NMR (125MHz, DMSO-
d 6 ): δ ppm 159.1 (C-2), 154.9 (C-4), 150.5 (C-11), 145.9 (C-8), 145.1 (C-12), 144.8 (C-1'), 137.1 (C-5'), 128.6 (C-3'), 128.2 (C-4'), 126.5 (C-10), 122.7 (C-7), 121.8 (C-9), 118.2 (C-6'), 116.7 (C-2'), 116.2 (C-6), 114.6 (C-13).
Synthetic (compound number is c) of embodiment six, 2-chloro-4-(N-antipyrine-4-is amino)-8-nitrobenzofuran [3,2-d] pyrimidine:
Synthetic such as embodiment one method and condition, only in the end single step reaction raw material hexahydroaniline is changed to the amino antipyrine of 4-, ultrasonic (power 200W) reacts 9h, after reaction is finished, concentrated, get crude product, crude product successively after water, the washed with isopropyl alcohol recrystallization get 2-chloro-4-(N-antipyrine-4-is amino)-8-nitrobenzofuran [3,2-d] pyrimidine, yield 81%, 260 ℃-263 ℃ of m.p.; EI-MS (m/z): 450[M
+], 340,83,56,42;
1H NMR (400MHz, CDCl
3): δ ppm 10.59 (s, 1H, N-
H), 8.91 (d, 1H,
J=2.0Hz, Ar-
H-9), 8.48 (dd, 1H,
J=2.4,8.8Hz, Ar-
H-7), 7.54-7.59 (m, 4H, Ar-
H), 7.40-7.45 (m, 2H, Ar-
H), 3.28 (s, 3H, N-C
H 3), 2.20 (s, 3H, C-C
H 3);
13C NMR (125MHz, CDCl
3): δ ppm 162.8 (C-3'), 159.1 (C-2), 154.9 (C-4), 152.0 (C-11), 148.9 (C-8), 146.7 (C-12), 144.7 (C-1''), 135.6 (C-5'), 134.3 (C-4'), (129.7 C-3'', C-5''), 127.9 (C-4''), 125.6 (C-10), (125.1 C-2'', C-6''), 121.8 (C-7), 118.5 (C-9), 113.3 (C-6), 107.4 (C-13), 35.8 (N-CH
3), 12.3 (CH
3).
Synthetic (compound number is m) of embodiment seven, 2-chloro-4-(N, N-diethyl-amino)-8-nitrobenzofuran [3,2-d] pyrimidine:
Synthetic such as embodiment one method and condition, only in the end single step reaction raw material hexahydroaniline is changed to diethylamine, ultrasonic (power 200W) reacts 3h, and be after reaction is finished, concentrated, get crude product, crude product successively after water, the washed with isopropyl alcohol recrystallization get 2-chloro-4-(N, N-diethyl-amino)-8-nitrobenzofuran [3,2-d] pyrimidine, yield 84%, 194 ℃-196 ℃ of m.p.; EI-MS (m/z): 320[M
+], 305,291,277,245,231,168,139,72,44;
1H NMR (500MHz, CDCl
3): δ ppm 9.01 (d, 1H,
J=2.5Hz, Ar-
H-9), 8.47 (dd, 1H,
J=2.8,9.2Hz, Ar-
H-7), 7.71 (d, 1H,
J=9.2Hz, Ar-
H-6), 3.81-3.95 (m, 4H, N-C
H 2-), 1.34-1.41 (m, 6H ,-C
H 3);
13C NMR (125MHz, CDCl
3): δ ppm 158.9 (C-2), 154.8 (C-4), 150.7 (C-11), 145.7 (C-8), 144.7 (C-12), 136.6 (C-10), 125.9 (C-7), 122.5 (C-9), 117.8 (C-6), 114.5 (C-13), 58.3 (C-1', C-1''), 12.3 (C-2', C-2'').
Synthetic (compound number is g) of embodiment eight, 2-chloro-4-(N-phenyl-amino)-8-nitrobenzofuran [3,2-d] pyrimidine:
Synthetic such as embodiment one method, in the end single step reaction is changed to Virahol with reaction solvent, the reaction raw materials hexahydroaniline is changed to aniline, and microwave reaction 0.5h is after reaction is finished, be cooled to room temperature, add elutriation and go out solid, water, washing with alcohol get 2-chloro-4-(N-phenyl-amino)-8-nitrobenzofuran [3,2-d] pyrimidine successively behind the solid filtering, yield 52%, 293 ℃-294 ℃ of m.p.; EI-MS (m/z): 340[M
+], 305,293,259,77,43;
1H NMR (400MHz, DMSO-
d 6 ): δ ppm 10.78 (s, 1H, N-
H), 8.91 (d, 1H,
J=2.4Hz, Ar-
H-9), 8.57 (dd, 1H,
J=2.0,9.2Hz, Ar-
H-7), 8.09 (d, 1H,
J=9.2Hz, Ar-
H-6), 7.82 (d, 2H,
J=8.0Hz, Ar-
H-2', 6'), 7.42 (t, 2H,
J=8.0Hz, Ar-
H-3', 5'), 7.17 (t, 1H,
J=7.2Hz, Ar-
H-4');
13C NMR (125MHz, DMSO-
d 6 ): 159.2 (C-2), 155.4 (C-4), 148.6 (C-11), 148.1 (C-8), 144.9 (C-12), 135.8 (C-1'), 134.7 (C-10), 129.2 (C-3', C-5'), 126.8 (C-4'), 125.9 (C-7), 124.1 (C-2', C-6'), 122.6 (C-9), 118.7 (C-6), 114.2 (C-13).
The compound proton nmr spectra data of partial synthesis of the present invention are as shown in table 3, and the carbon-13 nmr spectra data are as shown in table 4, and mass-spectrometric data is as shown in table 5.
The proton nmr spectra data of table 3 compound
The embodiment of the invention is aided with explanation technical scheme of the present invention, is not the whole of synthetic compound.
Claims (6)
1. one kind is used for antineoplastic 2-chloro-4-replacement-8-nitrobenzofuran [3,2-d] pyrimidines and preparation method thereof, and its structure is shown in following general formula;
Substituent R can be halogen atom, nitro, amino or amido substituting group, and wherein, the amido substituting group refers to aliphatic amide substituting group, aromatic amine substituting group or amide substituents.
2. described a kind of for antineoplastic 2-chloro-4-replacement-8-nitrobenzofuran [3,2-d] pyrimidines compound according to right 1, it is characterized in that the compound of partial synthesis is as follows:
A.2,4-two chloro-8-nitrobenzofuran [3,2-d] pyrimidines
B.2-chloro-4-(N-cyclohexyl-amino)-8-nitrobenzofuran [3,2-d] pyrimidine
C.2-chloro-4-(N-antipyrine-4-amino)-8-nitrobenzofuran [3,2-d] pyrimidine
D.2-chloro-4-(N-ethanol based-amino)-8-nitrobenzofuran [3,2-d] pyrimidine
E.2-chloro-4-(N-adjacent aminophenyl amino)-8-nitrobenzofuran [3,2-d] pyrimidine
F.2-chloro-4-(N-o-methyl-phenyl--amino)-8-nitrobenzofuran [3,2-d] pyrimidine
G.2-chloro-4-(N-phenyl-amino)-8-nitrobenzofuran [3,2-d] pyrimidine
H.2-chloro-4-(bromophenyl-amino between N-)-8-nitrobenzofuran [3,2-d] pyrimidine
I.2-chloro-4-(N-phenylethylamine base)-8-nitrobenzofuran [3,2-d] pyrimidine
J.2-chloro-4-(N-m-nitro base-amino)-8-nitrobenzofuran [3,2-d] pyrimidine
K.2-chloro-4-(N-n-dodecane amido)-8-nitrobenzofuran [3,2-d] pyrimidine
L.2-chloro-4-(N-n-butylamine-based)-8-nitrobenzofuran [3,2-d] pyrimidine
M.2-chloro-4-(N, N-diethyl-amino)-8-nitrobenzofuran [3,2-d] pyrimidine
N.2-chloro-4-(N, N-diethyl alcohol radical-amino)-8-nitrobenzofuran [3,2-d] pyrimidine
O.2-chloro-4-(N-1-naphthyl-amino)-8-nitrobenzofuran [3,2-d] pyrimidine
P.2-chloro-4-(N-2-naphthyl-amino)-8-nitrobenzofuran [3,2-d] pyrimidine
Q.2-chloro-4-(N-morpholine)-8-nitrobenzofuran [3,2-d] pyrimidine
3. the described compound of any one is for the preparation of anti-tumor drug according to claim 1-2.
4. according to claim 1 a kind of for antineoplastic 2-chloro-4-replacement-8-nitrobenzofuran [3,2-d] preparation method of pyrimidines, it is characterized in that take 5-nitrosalicylaldehyde, oxammonium hydrochloride, acetic anhydride, ethyl bromoacetate, sodium ethylate, urea, phosphorus oxychloride as raw material, take glacial acetic acid, acetone, ethanol, methylene dichloride, Virahol as reaction solvent, go on foot synthetic forming through following five:
The first step: 2-hydroxyl-5-nitrobenzonitrile synthetic
The 5-nitrosalicylaldehyde is joined in the glacial acetic acid, add oxammonium hydrochloride, steam glacial acetic acid behind the reflux 1-5h, add acetic anhydride, behind the reflux 1-6h, underpressure distillation goes out acetic anhydride, add sodium hydroxide solution after the cooling and regulate pH to 5-6, get yellow solid, the suction filtration after washing, the filter cake oven dry gets 2-hydroxyl-5-nitrobenzonitrile;
5-nitrosalicylaldehyde: oxammonium hydrochloride=1:1-1.5 (mol ratio)
Temperature of reaction: 25-135 ℃
Reaction times: 2-11h
Second step: 2-cyano group-4-nitrophenoxy ethyl acetate synthetic
2-hydroxyl-5-nitrobenzonitrile is joined in the acetone, add salt of wormwood and ethyl bromoacetate after the dissolving, reflux 8-12h, after finishing, reaction is chilled to room temperature, filter out solid, solid merges acetone solution with acetone solution washing three times, get solid after concentrated, the solid recrystallization gets product 2-cyano group-4-nitrophenoxy ethyl acetate;
2-hydroxyl-5-nitrobenzonitrile: ethyl bromoacetate: salt of wormwood=1:1-1.5:1-1.5 (mol ratio)
Temperature of reaction: 25-56 ℃
Reaction times: 8-12h
The 3rd step: 3-amino-5-nitro-2-benzofurancarboxylic acid ethyl ester synthetic
2-cyano group-4-nitrophenoxy ethyl acetate is joined in the ethanol, add sodium ethylate after the dissolving, reflux 1-4h concentrates to get solid after reaction is finished, and solid washes post-drying with water and gets product 3-amino-5-nitro-2-benzofurancarboxylic acid ethyl ester;
2-cyano group-4-nitrophenoxy ethyl acetate: sodium ethylate=1:1-1.5 (mol ratio)
Temperature of reaction: 25-78 ℃
Reaction times: 1-4h
The 4th step: 1,3-dihydro-8-nitro-cumarone [3,2-d] pyrimidine-2,4-diketone synthetic
Add excessive urea and 3-amino-5-nitro-2-benzofurancarboxylic acid ethyl ester mixing post-heating reaction 2-5h, solid washs successively with water-ethanol mixing solutions, the hot water of heat after the cooling, and recrystallization gets product 1,3-dihydro-8-nitro-cumarone [3 after the oven dry, 2-d] pyrimidine-2, the 4-diketone;
3-amino-5-nitro-2-benzofurancarboxylic acid ethyl ester: urea=1:1-10 (mol ratio)
Temperature of reaction: 150-220 ℃
Reaction times: 2-5h
The 5th step: the synthesizing of 2-chloro-4-replacements-8-nitrobenzofuran [3,2-d] pyrimidines
With 1,3-dihydro-8-nitro-cumarone [3,2-d] pyrimidine-2, the 4-diketone joins in the excessive phosphorus oxychloride, the DMF that adds catalytic amount, reflux 5-15h is cooled to room temperature after reaction is finished, to stir in the reaction solution impouring trash ice and constantly, produce a large amount of solids, the suction filtration after washing, recrystallization gets 2 after the filter cake oven dry, 4-two chloro-8-nitrobenzofurans [3,2-d] pyrimidine, compound 2,4-two chloro-8-nitrobenzofurans [3,2-d] 4 of pyrimidine substitution reactions occur can obtain a series of 2-chloro-4-replacement-8-nitrobenzofurans [3,2-d] pyrimidines.
5. described a kind of for antineoplastic 2-chloro-4-replacement-8-nitrobenzofuran [3 according to right 1,2-d] pyrimidines, it is characterized in that the nitro on 8 can be reduced amino, N-substituted amido or amide substituents replacement, the amido substituting group refers to aliphatic amide substituting group or aromatic amine substituting group.
6. described a kind of for antineoplastic 2-chloro-4-replacement-8-nitrobenzofuran [3 according to right 1,2-d] pyrimidines, it is characterized in that 2 upper Cl atoms can be substituted by amido substituting group or amide substituents, wherein, the amido substituting group is the aliphatic amide substituting group, comprises chain aliphatic amide substituting group and ring-shaped fat amine substituting group or aromatic amine substituting group.
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