CN105017162A - 4-P-propenylphenylaminoquinazoline derivative and application thereof in preparation of antitumor drugs - Google Patents

4-P-propenylphenylaminoquinazoline derivative and application thereof in preparation of antitumor drugs Download PDF

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CN105017162A
CN105017162A CN201510364043.2A CN201510364043A CN105017162A CN 105017162 A CN105017162 A CN 105017162A CN 201510364043 A CN201510364043 A CN 201510364043A CN 105017162 A CN105017162 A CN 105017162A
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propenylbenzene
quinazoline
amino
base
groups
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CN105017162B (en
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李宝林
王维佳
刘娟
张娅玲
刘敏
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Shaanxi Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

The invention discloses a 4-p-propenylphenylaminoquinazoline derivative and an application thereof in the preparation of antitumor drugs. The structural formula of the derivative is shown in the specification; and in the formula, R<1> and R<2> respectively independently represent anyone of hydrogen, iodine, methyoxy groups, 2-methoxyethoxy groups, 3-(morpholinyl-4-yl)propoxy groups, 2-(morpholinyl-4-yl)ethoxy groups, 5-((2-mesylethylamino)methyl)furan-2-yl groups, 3-chloropropoxy groups, 2-chloroethoxy groups and 5-formylfuran-2-yl groups. The derivative is obtained through Dimroth rearrangement and other reactions of formamidine as a raw material. The above compound has an obvious inhibition effect on propagation of human colorectal carcinoma cells, human lung gland cancer cells and human skin squamous carcinoma cells, and can be used for preparing the antitumor drugs.

Description

4-is to propenylbenzene amido quinazoline derivatives and preparing the application in antitumor drug
Technical field
The present invention relates to the novel 4-of a class to propenylbenzene amino-quinazoline compound, and their preparation method is preparing the purposes in antitumor drug with them.
Background technology
Cancer is that human health one of threatens, mostly traditional anticarcinogen is cytotoxic drug, this kind of medicine is while having lethal effect to cancer cells, great destruction and toxic side effect is had to normal human tissue cell, in order to improve the selectivity to cancer cells effect, the drug treatment that it is therapy target that people have started to pay close attention to for key gene, regulatory molecule and specific cells acceptor is studied.
Research shows, when protein tyrosine kinase overexpression, cell normal growth controls is out of hand, and death is obstructed, and is in vegetative state all the time, finally becomes malignant tumour.As can be seen here, Tyrosylprotein kinase is an important target spot, and the overexpression of Tyrosylprotein kinase will cause malignant tumour.Therefore, suppress tyrosine kinase activity, the intracellular signaling path blocking its activation becomes the new way for the treatment of tumour.
EGF-R ELISA (EGFR) tyrosine kinase inhibitor has played important effect in the treatment of tumour, its mechanism is by being combined with receptor tyrosine kinase competitively with ATP, the phosphorylation of the catalytic activity of Tyrosylprotein kinase and Tyrosylprotein kinase self tyrosine residues is suppressed, thus block downstream signal transduction path, and then inhibition tumor cell propagation, accelerate apoptosis of tumor cells, Tumor suppression invasion and m etastasis.
Some the small molecule epidermal growth factor (EGFR) tyrosine kinase inhibitors are it has been found that, as compounds such as flavones, osajin, quinazoline ditosylate salt, quinoline, miazines, indoles and indazole classes.Wherein, activity is higher, the good small molecule tyrosine kinase inhibitor of selectivity is 4-phenylamino quinazoline compounds, as the antineoplastic compound lapatinibditosylate (lapatinib), the erlotinib (Erlotinib that have gone on the market, Tarceva), Gefitinib (Gefitinib, Iressa) and EKB-2569 etc.These medicines have played good effect in the treatment of tumour, but can produce obvious drug tolerance after life-time service, bring difficulty to the anaphase of tumour.Therefore, find that new antineoplastic compound still has great importance with the resistance overcoming tumour cell with the toxic side effect reducing medicine.
Summary of the invention
Technical problem to be solved by this invention is that the 4-with anti-tumor activity providing a class new is to propenylbenzene amido quinazoline derivatives, and these compounds are preparing the purposes in antitumor drug.
Solving the problems of the technologies described above adopted technical scheme is: the structural formula of this kind of 4-to propenylbenzene amido quinazoline derivatives is as follows:
R in formula 1, R 2represent hydrogen, iodine, methoxyl group, 2-methoxy ethoxy, 3-(morpholine-4-base) propoxy-, 2-(morpholine-4-base) oxyethyl group, 5-((2-methylsulfonylethyl amino) methyl independently of one another) furans-2-base, 3-chlorine propoxy-, 2-chloroethoxy, any one in 5-formylfuran-2-base.
Above-mentioned 4-is to any one in propenylbenzene amido quinazoline derivatives preferred following compounds A ~ H:
A:4-[4-(E)-propenylbenzene is amino]-7-methoxyl group-6-[3-(morpholine-4-base) propoxy-] quinazoline
B:4-[4-(E)-propenylbenzene is amino]-7-methoxyl group-6-[2-(morpholine-4-base) oxyethyl group] quinazoline
C:4-[4-(E)-propenylbenzene is amino]-6-[3-(morpholine-4-base) propoxy-] quinazoline
D:4-[4-(E)-propenylbenzene is amino]-6-[2-(morpholine-4-base) oxyethyl group] quinazoline
E:4-[4-(E)-propenylbenzene is amino]-6-methoxyl group-7-[3-(morpholine-4-base) propoxy-] quinazoline
F:4-[4-(E)-propenylbenzene is amino]-6-methoxyl group-7-[2-(morpholine-4-base) oxyethyl group] quinazoline
G:4-[4-(E)-propenylbenzene is amino]-6,7-bis-(2-methoxy ethoxy) quinazoline
H:4-[4-(E)-propenylbenzene is amino]-6-[5-((2-methylsulfonylethyl is amino) methyl) furans-2-base] quinazoline
The synthetic route of above-claimed cpd A ~ F is as follows:
R in formula 3for any one in 3-chlorine propoxy-, 2-chloroethoxy, methoxyl group; R 4for any one in 3-chlorine propoxy-, 2-chloroethoxy, methoxyl group, hydrogen; Its synthetic method take acetic acid as solvent, narrow with p-aminophenyl propylene as raw material obtains the quinazoline compounds shown in formula 3 through Dimroth rearrangement reaction with the first shown in formula 2, then by quinazoline compounds shown in formula 3 under the existence of KI, be obtained by reacting the 4-shown in formula 1 to propenylbenzene amido quinazoline derivatives with morpholine.
The synthetic route of above-claimed cpd G is as follows:
Its synthetic method is: with the N'-of formula 4 [2-cyano group-4,5-(2-methoxy ethoxy) phenyl]-N, N-dimethyl carbonamidine and p-aminophenyl propylene for raw material, be obtain compound G through Dimroth rearrangement reaction under the condition of solvent at acetic acid.
The synthetic route of above-claimed cpd H is as follows:
Its synthetic method is: with N'-(2-cyano group-4-iodophenyl)-N, the N-dimethyl carbonamidine shown in formula 5 and p-aminophenyl propylene for raw material obtains compound shown in formula 6 through Dimroth rearrangement reaction; Then, under the existence of Pd/C, there is Suzuki coupling and obtain compound shown in formula 7 in compound 6 and 5-formylfuran-2-ylboronic acid; Again under sodium cyanoborohydride exists, compound shown in formula 7 and 2-(methylsulfonyl) ethylamine hydrochloride react and obtain compound H.
4-of the present invention is preparing the purposes in antitumor drug to propenylbenzene amido quinazoline derivatives, and it is medicinal preparations routinely, makes with the conventional fabrication process of pharmaceutically acceptable carrier according to various preparation, can be tablet, granule, capsule.
4-provided by the invention is simple to propenylbenzene amido quinazoline derivatives synthetic method, has good restraining effect, can be used for preparing antitumor drug to the propagation of tumour cell, both can medication alone, also can with other medicines conbined usage; Wherein compd A, C, E propagation to human lung carcinoma cell line A549 have obvious restraining effect, and its successful is better than the antitumor drug Gefitinib of Clinical practice.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail, but protection scope of the present invention is not limited only to these embodiments.
Synthesized reference document [the Chinese invention patent 201410842598.9 of (E)-4-propenyl aniline and part material in the embodiment of the present invention; Chemical research and application, 2013,25 (8): 1180-1184; Shaanxi Normal University's journal (natural science edition), 2013, (6): 42-45] method carries out.Other agents useful for same is analytical pure.Compound structure determine nuclear magnetic resonance data used by Bruker Avance300,400,600 NMR spectrometer with superconducting magnet measure, TMS is as interior mark; Ir data adopts Nicolet 170SXFT-IR determination of infrared spectroscopy; Fusing point adopts X-6 micro melting point apparatus (Tyke, Beijing Instrument Ltd.) to measure (temperature corrects); Mass-spectrometric data Bruker Esquire3000plus mass spectrograph measures.
Embodiment 1: synthetic compound A
1,4-[4-(E)-propenylbenzene is amino]-7-methoxyl group-6-(3-chlorine propoxy-) quinazoline is prepared
By 0.89g (3.0mmol) N'-[2-cyano group-4-(3-chlorine propoxy-)-5-p-methoxy-phenyl]-N, N-dimethyl carbonamidine, 0.44g (3.3mmol) 4-(E)-propenyl aniline, 2.8mL acetic acid add in 50mL there-necked flask, react 20 minutes at 130 DEG C.Steam acetic acid, add 5.0mL distilled water, with the pH to 9 of strong aqua regulation system, then continue stirring 30 minutes, suction filtration, dry, gained solid is carried out silica gel column chromatography separation (ethyl acetate: sherwood oil=1:1, V/V), obtain faint yellow solid 4-[4-(E)-propenylbenzene is amino]-7-methoxyl group-6-(3-chlorine propoxy-) quinazoline 0.92g, its productive rate is 80%, and structural characterization data are as follows:
1H NMR(600MHz，DMSO-d 6)δ(ppm)：9.49(s，1H)，8.48(s，1H)，7.89(s，1H)，7.77(d，J＝6.6Hz，2H)，7.39(d，J＝6.6Hz，2H)，7.21(s，1H)，6.39(d，J＝15.6Hz，1H)，6.25-6.24(m，1H)，4.29(brs，2H)，3.95(s，3H)，3.87(brs，2H)，2.31(m，2H)，1.86(d，J＝6.5Hz，3H)。
13C NMR(151MHz，DMSO-d 6)δ(ppm)：156.2，154.2，152.9，147.9，147.0，138.2，132.6，130.5，125.7，124.0，122.3，108.9，107.3，103.0，65.6，55.8，42.0，31.7，18.2。
2, compd A is prepared
The 4-that step 1 obtained [4-(E)-propenylbenzene is amino]-7-methoxyl group-6-(3-propoxy-) quinazoline and 60mg potassiumiodide join in 50mL single port bottle, then add 2.8mL morpholine, 120 DEG C of reflux 1.5 hours.Be cooled to room temperature, steam morpholine, residue is separated (methylene dichloride: ethyl acetate: methyl alcohol=8:1:0.5 through silica gel column chromatography, V/V) crude product is obtained, crude product obtains faint yellow solid compound A-40 .79g through re-crystallizing in ethyl acetate, its productive rate is 76%, m.p.:186.9-187.4 DEG C, and structural characterization data are as follows:
1H NMR(400MHz，DMSO-d 6)δ(ppm)：9.47(s，1H，NH)，8.46(s，1H)，7.84(s，1H)，7.74(d，J＝8.0Hz，2H)，7.39(d，J＝8.0Hz，2H)，7.18(s，1H)，6.37(d，J＝16.0Hz，1H，-CH＝CH-)，6.27-6.18(m，1H)，4.18(t，J＝5.9Hz，2H)，3.93(s，3H)，3.58(brs，4H)，2.47(t，J＝7.0Hz，2H)，2.38(brs，4H)，2.00-1.97(m，2H)，1.85(d，J＝6.4Hz，3H)。
13C NMR(101MHz，DMSO-d 6)δ(ppm)：156.2，154.3，152.8，148.2，146.9，138.2，132.5，130.5，125.7，124.0，122.2，108.9，107.2，102.7，67.1，66.1，55.8，54.9，53.4，25.9，18.2。
IRv max(KBr)cm -1：3418，3022，2953，2870，1622，1512，1427，1240，1113，955，858。
ESI-MS:C 25h 30n 4o 3[M+H] +calculated value 435.2396, measured value 435.2395.
Embodiment 2: synthetic compound B
1,4-[4-(E)-propenylbenzene is amino]-7-methoxyl group-6-(2-chloroethoxy) quinazoline is prepared
By 1.27g (4.5mmol) N'-[2-cyano group-4-(2-chloroethoxy)-5-p-methoxy-phenyl]-N, N-dimethyl carbonamidine, 0.67g (5.0mmol) 4-(E)-propenyl aniline, 3.8mL acetic acid add in 50mL there-necked flask, react 20 minutes at 130 DEG C.Steam acetic acid, add 7.0mL distilled water, with the pH to 9 of strong aqua regulation system, then continue stirring 30 minutes, suction filtration, dry, gained solid is carried out silica gel column chromatography separation (ethyl acetate: sherwood oil=1:1, V/V), obtain faint yellow solid 4-[4-(E)-propenylbenzene is amino]-7-methoxyl group-6-(2-chloroethoxy) quinazoline 1.28g, its productive rate is 77%, and structural characterization data are as follows:
1H NMR(400MHz，DMSO-d 6)δ(ppm)：9.45(s，1H)，8.47(s，1H)，7.87(s，1H)，7.74(d，J＝8.0Hz，2H)，7.40(d，J＝8.0Hz，2H)，7.21(s，1H)，6.37(d，J＝15.6Hz，1H)，6.27-6.19(m，1H)，4.44(t，J＝4.5Hz，2H)，4.08(t，J＝4.5Hz，2H)，3.95(s，3H)，1.84(d，J＝6.0Hz，3H)。
13C NMR(101MHz，DMSO-d 6)δ(ppm)：156.3，154.2，153.1，147.4，147.1，138.1，132.6，130.4，125.7，124.1，122.2，108.8，107.4，103.3，69.1，55.8，42.6，18.2。
2, compd B is prepared
Step 2 gained 4-[4-(E)-propenylbenzene amino]-7-methoxyl group-6-(2-chloroethoxy) quinazoline and 70mg potassiumiodide are joined in 50mL single port bottle, then adds 3.3mL morpholine, 120 DEG C of reflux 1.5 hours.Be cooled to room temperature, steam morpholine, residue is separated (methylene dichloride: ethyl acetate: methyl alcohol=8:1:0.5 through silica gel column chromatography, V/V) crude product is obtained, crude product obtains compound as white solid B 1.05g through re-crystallizing in ethyl acetate, its productive rate is 71%, m.p.:204.9-205.9 DEG C, and structural characterization data are as follows:
1H NMR(400MHz，DMSO-d 6)δ(ppm)：9.43(s，1H)，8.47(s，1H)，7.86(s，1H)，7.75(d，J＝8.4Hz，2H)，7.40(d，J＝8.4Hz，2H)，7.19(s，1H)，6.40(dd，J＝15.7Hz，1H，-CH＝CH-)，6.23(dq，J＝15.7，6.4Hz，1H，-CH＝CH-)，4.26(t，J＝6.0Hz，2H)，3.94(s，3H)，3.60(t，J＝4.6Hz，4H)，2.81(t，J＝6.0Hz，2H)，2.54(t，J＝4.6Hz，4H)，1.85(d，J＝6.4Hz，3H)。
13C NMR(101MHz，DMSO-d 6)δ(ppm)：156.2，154.2，152.9，148.0，146.9，138.2，132.6，130.5，125.7，124.0，122.2，108.9，107.3，102.8，66.6，66.2，56.9，55.8，53.7，18.2。
IRv max(KBr)cm -1：3418，3020，2932，2850，1624，1578，1514，1117，964，847。
ESI-MS:C 24h 28n 4o 3[M+H] +calculated value 421.2239, measured value 421.2243.
Embodiment 3: synthetic compound C
1,2-amino-5-(3-chlorine propoxy-) cyanobenzene is prepared
By 2.89g (12mmol) 2-nitro-5-(3-chlorine propoxy-) cyanobenzene, 10.45g (60mmol) vat powder (Na 2s 2o 4), 36mL distilled water, 18mL dehydrated alcohol add in reaction flask, react 25 minutes at 50 DEG C.Be warming up to 85 DEG C, slowly drip 12.0mL concentrated hydrochloric acid, react 1.5 hours.Be cooled to room temperature, regulate pH to be 9 ~ 10 with the aqueous sodium hydroxide solution that massfraction is 30%, continue stirring 1 hour.Suction filtration, filtrate is extracted with ethyl acetate, organic over anhydrous dried over mgso, boil off ethyl acetate, gained solid is separated (ethyl acetate: sherwood oil=1:5, V/V) through silica gel column chromatography, obtains brown solid 2-amino-5-(3-chlorine propoxy-) cyanobenzene 2.00g, its productive rate is 79%, and structural characterization data are as follows:
1H NMR(600MHz，CDCl 3)δ(ppm)：6.97(dd，J＝9.0、3.0Hz，1H)，6.88(d，J＝3.0Hz，1H)，6.71(d，J＝9.0Hz，1H，)，4.02(t，J＝6.0Hz，2H)，3.72(t，J＝6.3Hz，2H)，2.22-2.17(m，2H)。
13C NMR(151MHz，CDCl 3)δ(ppm)：145.4，139.2，117.9，112.3，111.8，110.6，90.9，60.0，36.2，26.9。
2, N'-[2-cyano group-4-(3-chlorine propoxy-)-5-p-methoxy-phenyl]-N, N-dimethylamidine is prepared
By 2.15g (10mmol) 2-amino-5-(3-chlorine propoxy-) cyanobenzene, 6.6mL (50mmol) N, dinethylformamide dimethylacetal (DMF-DMA) and 200 μ L acetic acid add in 50mL single port bottle, react at 40 DEG C, TLC tracks to and reacts completely, boil off excessive DMF-DMA, gained residue is through column chromatography for separation (ethyl acetate: sherwood oil=1:2, V/V), obtain faint yellow solid N'-[2-cyano group-4-(3-chlorine propoxy-)-5-p-methoxy-phenyl]-N, N-dimethylamidine 1.83g, its productive rate is 69%, structural characterization data are as follows:
1H NMR(600MHz，CDCl 3)δ(ppm)：7.55(s，1H)，7.03-7.01(m，2H)，6.90(d，J＝9.0Hz，1H)，4.07(t，J＝5.7Hz，2H)，3.74(t，J＝6.3Hz，2H)，3.06(d，J＝7.8Hz，6H)，2.25-2.21(m，2H)。
13CNMR(151MHz，CDCl 3)δ(ppm)：153.6，153.5，149.3，121.4，121.1，118.5，117.3，106.6，65.0，41.4，40.3，34.6，32.1。
3,4-[4-(E)-propenylbenzene is amino]-6-(3-chlorine propoxy-) quinazoline is prepared
By 0.72g (2.7mmol) N'-[2-cyano group-4-(3-chlorine propoxy-)-5-p-methoxy-phenyl]-N, N-dimethylamidine, 0.40g (3.0mmol) 4-(E)-propenyl aniline, 2.7mL acetic acid add in 50mL there-necked flask, react 15 minutes at 130 DEG C.Steam acetic acid, add 4.5mL distilled water, with the pH to 9 of strong aqua regulation system, then continue stirring 30 minutes.Suction filtration, dry, gained solid is carried out silica gel column chromatography separation (ethyl acetate: sherwood oil=1:2, V/V), obtain yellow solid 4-[4-(E)-propenylbenzene is amino]-6-(3-chlorine propoxy-) quinazoline 0.70g, its productive rate is 73%, and structural characterization data are as follows:
1H NMR(600MHz，DMSO-d 6)δ(ppm)：9.64(s，1H)，8.51(s，1H)，7.96(d，J＝3.0Hz，1H)，7.79(d，J＝8.4Hz，2H)，7.73(d，J＝9.0Hz，1H)，7.51(dd，J＝9.0、3.0Hz，1H)，7.42(d，J＝8.4Hz，2H)，6.41(d，J＝15.9Hz，1H)，6.25(dq，J＝15.9、6.6Hz，1H)，4.29(t，J＝6.0Hz，2H)，3.88(t，J＝6.6Hz，2H)，2.31-2.27(m，2H)，1.86(d，J＝6.6Hz，3H)。
13C NMR(151MHz，DMSO-d 6)δ(ppm)：156.8，156.4，152.4，145.0，137.9，132.9，130.4，129.4，125.7，124.2，124.2，122.4，115.7，103.0，65.1，42.0，31.7，18.2。
4, Compound C is prepared
4-[4-(E)-propenylbenzene is amino]-6-(3-chlorine propoxy-) quinazoline step 3 obtained and 57mg potassiumiodide join in 50mL single port bottle, add 2.5mL morpholine again, 120 DEG C of reflux 1.5 hours, be cooled to room temperature, steam morpholine, residue is separated (methylene dichloride: ethyl acetate: methyl alcohol=8:1:0.5 through silica gel column chromatography, V/V) crude product is obtained, crude product obtains compound as white solid C 0.53g after re-crystallizing in ethyl acetate, its productive rate is 66%, m.p.:190.5-191.7 DEG C, structural characterization data are as follows:
1H NMR(600MHz，DMSO-d 6)δ(ppm)：9.63(s，1H)，8.49(s，1H)，7.93(s，1H)，7.79(d，J＝8.4Hz，2H)，7.71(d，J＝9.0Hz，1H)，7.49(d，J＝9.0Hz，1H)，7.41(d，J＝8.4Hz，2H)，6.40(d，J＝15.6Hz，1H)，6.28-6.23(m，1H)，4.19(t，J＝6.0Hz，2H)，3.58(brs，4H)，2.48(t，J＝7.2Hz，2H)，2.39(brs，4H)，1.99-1.97(m，2H)，1.86(d，J＝6.6Hz，3H)。
13C NMR(151MHz，DMSO-d 6)δ(ppm)：156.8，156.7，152.3，145.0，138.0，132.8，130.4，129.4，125.7，124.2，124.1，122.4，115.7，103.0，66.6，66.2，54.9，53.4，25.9，18.3。
IRv max(KBr)cm -1：3456，3024，2957，2851，1630，1599，1514，1423，1229，1117，964，839，781。
ESI-MS:C 24h 28n 4o 2[M+H] +calculated value 405.2290, measured value 405.2275.
Embodiment 4: synthetic compound D
1,2-amino-5-(2-chloroethoxy) cyanobenzene is prepared
By 2.72g (12mmol) 2-nitro-5-(2-chloroethoxy) cyanobenzene, 10.45g (60mmol) vat powder (Na 2s 2o 4), 36mL water, 18mL ethanol adds in reaction flask, react 25 minutes at 50 DEG C.Be warming up to 85 DEG C, slowly drip 12.0mL concentrated hydrochloric acid, react 1.5 hours.Be cooled to room temperature, regulate pH to be 9 ~ 10 with the aqueous sodium hydroxide solution that massfraction is 30%, continue stirring 1 hour.Suction filtration, filtrate is extracted with ethyl acetate, anhydrous magnesium sulfate drying, boil off ethyl acetate, gained solid is separated (ethyl acetate: sherwood oil=1:5 through silica gel column chromatography, V/V) obtain brown solid 2-amino-5-(2-chloroethoxy) cyanobenzene 1.82g, its productive rate is 77%, and structural characterization data are as follows:
1H NMR(300MHz，CDCl 3)δ(ppm)：7.01(dd，J＝9.0，2.7Hz，1H)，6.90(d，J＝2.7Hz，1H)，6.72(d，J＝9.0Hz，1H)，4.14(t，J＝5.7Hz，2H)，3.77(t，J＝5.7Hz，2H)。
13C NMR(75MHz，CDCl 3)δ(ppm)：150.1，144.9，123.6，117.3，117.1，116.5，96.2，69.2，41.9。
2, N'-[2-cyano group-4-(2-chloroethoxy) phenyl]-N, N-dimethylamidine is prepared
By 1.97g (10mmol) 2-amino-5-(2-chloroethoxy) cyanobenzene, 6.6mL (50mmol) N, dinethylformamide dimethylacetal (DMF-DMA) and 200 μ L acetic acid join in 50mL single port bottle, react at 40 DEG C, TLC tracks to and reacts completely.Boil off excessive DMF-DMA, gained residue is through column chromatography for separation (ethyl acetate: sherwood oil=1:2, V/V) faint yellow solid N'-[2-cyano group-4-(2-chloroethoxy) phenyl]-N is obtained, N-dimethylamidine 1.54g, its productive rate is 61%, and structural characterization data are as follows:
1H NMR(300MHz，CDCl 3)δ(ppm)：7.55(s，1H)，7.06-7.02(m，2H)，6.92-6.88(m，1H)，4.18(t，J＝5.7Hz，2H)，3.80(t，J＝5.7Hz，2H)，3.06(s，6H)。
13C NMR(75MHz，CDCl 3)δ(ppm)：153.6，153.1，149.7，121.7，121.1，118.4，117.6，106.6，68.8，41.9，40.3，34.6。
3,4-[4-(E)-propenylbenzene is amino]-6-(2-chloroethoxy) quinazoline is prepared
By 0.96g (3.8mmol) N'-[2-cyano group-4-(2-chloroethoxy) phenyl]-N, N-dimethylamidine, 0.56g (4.2mmol) 4-(E)-propenyl aniline, 3.5mL acetic acid join in 50mL there-necked flask, react 15 minutes at 130 DEG C.Steam acetic acid, add 6.4mL water, with the pH to 9 of strong aqua regulation system, then continue stirring 30 minutes.Suction filtration, dry, gained solid is carried out silica gel column chromatography separation (ethyl acetate: sherwood oil=1:2, V/V) yellow solid 4-[4-(E)-propenylbenzene is amino]-6-(2-chloroethoxy) quinazoline 0.81g is obtained, its productive rate is 63%, and structural characterization data are as follows:
1H NMR(600MHz，DMSO-d 6)δ(ppm)：9.64(s，1H)，8.55(s，1H)，8.01(d，J＝2.4Hz，1H)，7.82(d，J＝8.4Hz，2H)，7.77(d，J＝9.0Hz，1H)，7.57(dd，J＝9.0、2.4Hz，1H)，7.45(d，J＝8.4Hz，2H)，6.43(d，J＝16.2Hz，1H)，6.32-6.26(m，1H)，4.49(t，J＝5.1Hz，2H)，4.11(t，J＝5.1Hz，2H)，1.89(d，J＝6.0Hz，3H)。
13C NMR(151MHz，DMSO-d 6)δ(ppm)：156.8，155.9，152.5，145.2，137.9，132.9，130.4，129.5，125.7，124.2，123.9，122.3，115.7，103.5，68.6，42.8，18.2。
4, Compound D is prepared
The 4-that step 3 obtained [4-(E)-propenylbenzene is amino]-6-(2-chloroethoxy) quinazoline and 80mg potassiumiodide join in 50mL single port bottle, then add 3.5mL morpholine, 120 DEG C of reflux 1.5 hours.Be cooled to room temperature, steam morpholine, residue is separated (methylene dichloride: ethyl acetate: methyl alcohol=8:1:0.5 through silica gel column chromatography, V/V) crude product is obtained, crude product obtains compound as white solid D 0.66g after re-crystallizing in ethyl acetate, its productive rate is 71%, m.p.:191.7-192.1 DEG C, and structural characterization data are as follows:
1H NMR(300MHz，DMSO-d 6)δ(ppm)：9.60(s，1H)，8.51(s，1H)，7.96(s，1H)，7.80(d，J＝8.4Hz，2H)，7.71(d，J＝9.0Hz，1H)，7.52-7.49(m，1H)，7.42(d，J＝8.4Hz，2H)，6.38(d，J＝15.9Hz，1H)，6.30-6.19(m，1H)，4.26(t，J＝5.3Hz，2H)，3.61(brs，4H)，2.79(t，J＝5.3Hz，2H)，2.52(brs，4H)，1.87(d，J＝6.0Hz，3H)。
13CNMR(75MHz，DMSO-d 6)δ(ppm)：156.8，156.5，152.3，145.0，138.0，132.8，130.4，129.4，125.7，124.2，124.1，122.3，115.7，103.0，66.2，65.9，57.0，53.7，18.4。
IRv max(KBr)cm -1：3271，3022，2957，2932，2854，1603，1512，1423，1225，1117，966，843。
ESI-MS:C 23h 26n 4o 2[M+H] +calculated value: 391.2134, measured value: 391.2120.
Embodiment 5: synthetic compound E
1,4-[4-(E)-propenylbenzene is amino]-6-methoxyl group-7-(3-chlorine propoxy-) quinazoline is prepared
In the step 1 of embodiment 1, N ' used-[2-cyano group-4-(3-chlorine propoxy-)-5-p-methoxy-phenyl]-N, N-dimethyl carbonamidine equimolar N'-[2-cyano group-5-(3-chlorine propoxy-)-4-p-methoxy-phenyl]-N, N-dimethyl carbonamidine is replaced, other step is identical with the step 1 of embodiment 1, obtain yellow solid 4-[4-(E)-propenylbenzene is amino]-6-methoxyl group-7-(3-chlorine propoxy-) quinazoline 0.90g, its productive rate is 78%, and structural characterization data are as follows:
1H NMR(600MHz，DMSO-d 6)δ(ppm)：9.49(s，1H)，8.47(s，1H)，7.86(s，1H)，7.76(d，J＝8.4Hz，2H)，7.40(d，J＝8.4Hz，2H)，7.22(s，1H)，6.39(d，J＝15.6Hz，1H，-CH＝CH-)，6.27-6.21(m，1H)，4.27(t，J＝6.0Hz，2H)，3.98(s，3H)，3.83(t，J＝6.4Hz，2H)，2.29-2.25(m，2H)，1.86(d，J＝6.6Hz，3H)。
13C NMR(151MHz，DMSO-d 6)δ(ppm):156.2，153.2，152.8，148.9，146.8，138.2，132.6，130.5，125.7，124.1，122.2，109.0，107.9，102.1，65.2，56.3，41.8，31.5，18.2。
2, compd E is prepared
In the step 2 of embodiment 1,4-[4-(E)-propenylbenzene is amino]-7-methoxyl group-6-(3-chlorine propoxy-) quinazoline used is replaced with equimolar 4-[4-(E)-propenylbenzene is amino]-6-methoxyl group-7-(3-chlorine propoxy-) quinazoline, other step is identical with the step 2 of embodiment 1, obtain faint yellow solid compd E 0.51g, its yield is 50%, m.p.:170.3-171.9 DEG C, structural characterization data are as follows:
1H NMR(400MHz，CDCl 3)δ(ppm)：8.64(s，1H)，7.64(s，1H)，7.58(d，J＝8.4Hz，2H)，7.34(d，J＝8.4Hz，2H)，7.23(s，1H)，7.13(s，1H)，6.38(d，J＝15.7Hz，1H，-CH＝CH-)，6.23-6.14(m，1H)，4.17(t，J＝6.6Hz，2H)，3.92(s，3H)，3.71(t，J＝4.6Hz，4H)，2.53(t，J＝7.2Hz，2H)，2.46(brs，4H)，2.10-2.03(m，2H)，1.88(d，J＝6.5Hz，3H)。
13C NMR(101MHz，CDCl 3)δ(ppm)：156.4，154.1，153.6，149.6，147.3，137.1，134.3，130.4，126.4，125.1，122.1，109.0，108.4，99.8，67.3，66.9，56.3，55.3，53.7，25.9，18.5。
IRv max(KBr)cm -1：3379，3024，2957，2932，2851，1624，1512，1421，1244，1117，964，862，787。
ESI-MS:C 25h 30n 4o 3[M+H] +calculated value 435.2396, measured value 435.2382.
Embodiment 6: synthetic compound F
1,4-[4-(E)-propenylbenzene is amino]-6-methoxyl group-7-(2-chloroethoxy) quinazoline is prepared
In the step 1 of embodiment 2, N'-[2-cyano group-4-(2-chloroethoxy)-5-p-methoxy-phenyl]-N used, N-dimethyl carbonamidine equimolar N'-[2-cyano group-5-(2-chloroethoxy)-4-p-methoxy-phenyl]-N, N-dimethyl carbonamidine is replaced, other step is identical with the step 1 of embodiment 2, obtain faint yellow solid 4-[4-(E)-propenylbenzene is amino]-6-methoxyl group-7-(2-chloroethoxy) quinazoline 1.25g, its productive rate is 75%, and structural characterization data are as follows:
1H NMR(600MHz，DMSO-d 6)δ(ppm)：9.52(s，1H)，8.47(s，1H)，7.88(s，1H)，7.76(d，J＝8.4Hz，2H)，7.41(d，J＝8.4Hz，2H)，7.23(s，1H)，6.39(d，J＝15.6Hz，1H)，6.28-6.22(m，1H)，4.44(t，J＝4.8Hz，2H)，4.05(t，J＝4.8Hz，2H)，3.99(s，3H)，1.85(d，J＝6.6Hz，3H)。
13C NMR(151MHz，DMSO-d 6)δ(ppm):156.2，152.9，152.8，148.8，146.6，138.1，132.6，130.5，125.7，124.1，122.3，109.2，108.1，102.3，68.7，56.3，42.7，18.2。
2, compound F 17-hydroxy-corticosterone is prepared
In the step 2 of embodiment 2,4-[4-(E)-propenylbenzene is amino]-7-methoxyl group-6-(2-chloroethoxy) quinazoline used is replaced with equimolar 4-[4-(E)-propenylbenzene is amino]-6-methoxyl group-7-(2-chloroethoxy) quinazoline, other step is identical with the step 2 of embodiment 2, obtain faint yellow solid compound F 17-hydroxy-corticosterone 0.78g, its yield is 55%, m.p.:215.1-216.8 DEG C, structural characterization data are as follows:
1H NMR(600MHz，CDCl 3)δ(ppm)：8.64(s，1H)，7.70(s，1H)，7.59(d，J＝8.4Hz，2H)，7.33(d，J＝8.4Hz，2H)，7.21(s，1H)，7.15(s，1H)，6.36(d，J＝15.6Hz，1H，-CH＝CH-)，6.22-6.16(m，1H)，4.23(t，J＝6.0Hz，2H)，3.90(s，3H)，3.71(t，J＝4.5Hz，4H)，2.88(t，J＝6.0Hz，2H)，2.58(brs，4H)，1.89(d，J＝6.0Hz，3H)。
13C NMR(151MHz，CDCl 3)δ(ppm)：156.4，153.9，153.6，149.6，147.1，137.1，134.3，130.4，126.4，125.1，122.1，109.2，108.5，100.0，66.9，66.8，57.0，56.3，54.1，18.5。
IRv max(KBr)cm -1：3418，3026，2947，2856，1622，1512，1420，1240，1105，970，851，787。
ESI-MS:C 24h 28n 4o 3[M+H] +calculated value 421.2239, measured value 421.2227.
Embodiment 7: synthetic compound G
By 0.71g (2.2mmol) N'-[2-cyano group-4,5-bis-(2-methoxy ethoxy) phenyl]-N, N-dimethyl carbonamidine, 0.32g (2.4mmol) 4-(E)-propenyl aniline, 3.6mL acetic acid join in 50mL there-necked flask, react 60 minutes at 130 DEG C.Steam acetic acid, add 7.6mL distilled water, with the pH to 9 of strong aqua regulation system, then continue stirring 30 minutes.Suction filtration, dry, gained solid is carried out pillar layer separation (moving phase is ethyl acetate), obtain faint yellow solid compound G 0.67g, its yield is 74%, m.p.:151.3-152.8 DEG C, and structural characterization data are as follows:
1H NMR(600MHz，CDCl 3)δ(ppm)：8.62(s，1H)，7.69(s，1H)，7.60(d，J＝8.4Hz，2H)，7.33(d，J＝8.4Hz，2H)，7.26(s，1H)，7.16(s，1H)，6.37(d，J＝15.7Hz，1H，-CH＝CH-)，6.18(dq，J＝15.7，6.6Hz，1H，-CH＝CH-)，4.20-4.17(m，4H)，3.79-3.78(m，2H)，3.75(t，J＝4.8Hz，2H)，3.41(s，3H)，3.40(s，3H)，1.88(d，J＝6.6Hz，3H)。
13C NMR(151MHz，CDCl 3)δ(ppm)：156.5，154.5，153.8，148.7，147.4，137.3，134.2，130.4，126.4，125.0，122.0，109.2，108.7，102.9，70.9，70.4，69.2，68.3，59.3，59.2，18.5。
IRv max(KBr)cm -1：3426，3020，2926，2883，1620，1576，1514，1427，1244，1123，966，856。
ESI-MS:C 23h 27n 3o 4[M+H] +calculated value 410.2080, measured value 410.2085.
Embodiment 8: synthetic compound H
1,4-[4-(E)-propenylbenzene is amino]-6-iodine quinazoline is prepared
By 2.24g (7.5mmol) N'-(2-cyano group-4-iodophenyl)-N, N-dimethyl carbonamidine, 1.10g (8.3mmol) 4-(E)-propenyl aniline, 4.5mL acetic acid join in 50mL single port bottle, react 15 minutes at 130 DEG C.Steam acetic acid, add 7mL distilled water, with the pH to 9 of strong aqua regulation system, then continue stirring 30 minutes.Suction filtration, drying, carries out silica gel column chromatography separation (ethyl acetate: sherwood oil=1:4, V/V) and obtains off-white color solid 4-[4-(E)-propenylbenzene is amino]-6-iodine quinazoline 2.64g by gained solid, its yield is 91%, and structural characterization data are as follows:
1H NMR(300MHz，DMSO-d 6)δ(ppm)：9.88(s，1H)，9.01(s，1H)，8.62(s，1H)，8.10(d，J＝8.1Hz，1H)，7.81(d，J＝7.8Hz，2H)，7.58(d，J＝8.1Hz，1H)，7.41(d，J＝7.8Hz，2H)，6.38(d，J＝15.9Hz，1H)，6.29-6.22(m，1H)，1.87(d，J＝5.4Hz，3H)。
13C NMR(75MHz，DMSO-d 6)δ(ppm)：156.3，154.8，148.7，141.3，137.6，133.1，131.4，130.4，129.7，125.7，124.4，122.2，116.9，91.4，18.3。
2,4-[4-(E)-propenylbenzene is amino]-6-(5-formylfuran-2-base) quinazoline is prepared
By 2.32g (6.0mmol) 4-[4-(E)-propenylbenzene is amino]-6-iodine quinazoline, 1.26g (9.0mmol) 5-formylfuran-2-boric acid, 0.56g 5%Pd/C, 60mL 1; 2-glycol dimethyl ether, 30mL methyl alcohol and 2.42g (24mmol) triethylamine join in reaction flask, and 50 DEG C are stirred 4 hours.By diatomite suction filtration while hot, rotary evaporation filtrate, adds 240mL ethyl acetate, 110mL tetrahydrofuran (THF), 40mL water and 40mL saturated sodium bicarbonate aqueous solution in gained residue, to stir after 15 minutes point to get organic layer.Solvent is boiled off, vacuum-drying after the washing of organic layer saturated sodium-chloride water solution, anhydrous sodium sulfate drying.Gained solid is carried out silica gel column chromatography separation (ethyl acetate: chloroform=1:10; V/V) safran solid 4-[4-(E)-propenylbenzene is amino]-6-(5-formylfuran-2-base) quinazoline 1.22g is obtained; its productive rate is 57%, and structural characterization data are as follows:
1H NMR(300MHz，DMSO-d 6)δ(ppm)：10.05(s，1H)，9.64(s，1H)，8.94(s，1H)，8.56(s，1H)，8.21(d，J＝8.7Hz，1H)，7.82-7.69(m，4H)，7.36(d，J＝8.7Hz，3H)，6.36(d，J＝15.9Hz，1H)，6.28-6.17(m，1H)，1.84(d，J＝6.0Hz，3H)。
3, compound H is prepared
Under condition of ice bath, join in 50mL single port bottle by 0.19g (1.16mmol) 2-(methylsulfonyl) ethylamine hydrochloride, 5.0mL methyl alcohol, 0.5mL triethylamine, stirring after 20 minutes, is 5 ~ 6 with first acid for adjusting pH.Add 0.44g (3.08mmol) anhydrous sodium sulphate, 0.10g (1.54mmol) sodium cyanoborohydride.Again the mixture of 0.27g (0.77mmol) 4-[4-(E)-propenylbenzene is amino]-6-(5-formylfuran-2-base) quinazoline and 5mL DMF is joined in reaction system under stirring.Add 0.10g (1.54mmol) sodium cyanoborohydride after 30 minutes, TLC follows the tracks of reaction to completely, about needs 3 hours.Adjust pH to 9 ~ 10 with aqueous sodium hydroxide solution, suction filtration, filtrate is revolved and is steamed to dry.Carry out silica gel column chromatography separation (methyl alcohol: chloroform=1:15, V/V) to residue, obtain light yellow solid Compound H 0.30g, its yield is 83%, m.p.:215.3-215.9 DEG C, and structural characterization data are as follows:
1H NMR(300MHz，DMSO-d 6)δ(ppm)：9.92(s，1H)，8.78(s，1H)，8.57(s，1H)，8.13(d，J＝8.7Hz，1H)，7.83-7.80(m，3H)，7.42(d，J＝8.1Hz，2H)，7.06(d，J＝2.7Hz，1H)，6.50(d，J＝2.7Hz，1H)，6.38(d，J＝15.9Hz，1H，-CH＝CH-)，6.30-6.21(m，1H)，3.85(s，2H)，3.31(t，J＝6.2Hz，2H)，3.05-3.00(m，5H)，1.86(d，J＝5.7Hz，3H)。
13C NMR(75MHz，DMSO-d 6)δ(ppm)：157.5，154.7，154.2，151.5，148.9，137.8，133.1，130.4，128.5，128.4，128.3，125.7，124.4，122.5，116.5，115.5，109.5，107.8，53.6，45.2，42.1，41.5，18.2。
IRv max(KBr)cm -1：3381，3018，2920，1568，1514，1420，1286，1128，1020，964，841，785。
ESI-MS:C 25h 26n 4o 3s [M+H] +calculated value 463.1804, measured value 463.1789.
Embodiment 9: compd A ~ H is to the Cell suppression test of tumour cell
1, cell strain
Human skin epidermoid carcinoma cell strain A431 (purchased from Chinese Academy of Sciences's Shanghai cell bank); Human lung carcinoma cell line A549 (purchased from Chinese Academy of Sciences's Shanghai cell bank); Human colon cancer cell strain SW480 (purchased from Chinese Academy of Sciences's Shanghai cell bank).
2, reagent and material
MTT (MPBIO), 96 porocyte culture plates (CorningCostar), foetal calf serum (Gibco), substratum (Gibco), microplate reader (ThermoMULTISKANMK3).
3, experimental procedure
The growth inhibitory activity of compd A ~ H to tumour cell utilizes mtt assay to measure.Human tumor cells SW480, A549, A431 of taking the logarithm respectively vegetative period, with the tryptic digestive juice digestion of 0.25%, centrifugal, resuspended rear counting, prepare cell suspension, and adjustment concentration of cell suspension is 2.5 × 10 4~ 5 × 10 4individual/mL.Obtained cell suspension is inoculated in (100 μ L/ hole) in 96 well culture plates, puts saturated humidity, 37 DEG C and 5%CO 224h is cultivated in incubator.With substratum dilution test-compound to desired concn, add in the 96 orifice plates cultivations inoculating human tumor cells (100 μ L/ hole), DMSO final concentration is 0.5%, is placed in incubator and cultivates 72h.MTT is added (20 μ L/ hole) in 96 orifice plates, in incubator, react 4h.Liquid in hole is abandoned in suction, and add DMSO (150 μ L/ hole), shaking table shakes 10min, and Shi formazan is dissolved completely.Then measure the absorbancy (OD value) at 570nm wavelength place by microplate reader, the absorbancy at 630nm wavelength place, as reference, with coordinative solvent in contrast, calculates inhibitory rate of cell growth.
The account form of test-compound to growth of tumour cell inhibiting rate is as follows:
Growth of tumour cell inhibiting rate %=[1-(ODs-OD nC)/(OD pC-OD nC)] × 100%
Wherein: OD srepresent the absorbance (cell+testing compound+MTT) of sample well; OD pCrepresent the absorbance (cell+DMSO+MTT) of control wells; OD nCrepresent the absorbance (substratum+DMSO+MTT) in zeroing hole; ODs=OD 570s-OD 630s; OD pC=OD 570 contrasts-OD 630 contrasts; OD nC=OD 570 zeroings-OD 630 zeroings.
Test-compound suppresses matching and the IC of curve to growth of tumour cell 50calculating:
Adopt GraphpadPrism5 matching test-compound to the suppression curve of growth of tumour cell, and draw IC 50value.Often group arranges 3 multiple holes, at least repeats 3 times.
4, experimental result
With the antitumor drug Gefitinib of Clinical practice for positive control, experimental result is as shown in table 1.
The IC of table 1 test-compound inhibition tumor cell propagation 50(μm ol/L)
From experimental data in table 1, test-compound all has restraining effect in various degree to the propagation of 3 kinds of tumor cell lines, wherein compd A, C, E propagation to human lung carcinoma cell line A549 have obvious restraining effect, and its successful is better than Gefitinib.

Claims (4)

1. 4-is to a propenylbenzene amido quinazoline derivatives, it is characterized in that the structural formula of this derivative is as follows:
R in formula 1, R 2represent hydrogen, iodine, methoxyl group, 2-methoxy ethoxy, 3-(morpholine-4-base) propoxy-, 2-(morpholine-4-base) oxyethyl group, 5-((2-methylsulfonylethyl amino) methyl independently of one another) furans-2-base, 3-chlorine propoxy-, 2-chloroethoxy, any one in 5-formylfuran-2-base.
2. 4-according to claim 1 is to propenylbenzene amido quinazoline derivatives, it is characterized in that this derivative is any one in following compounds A ~ H:
A:4-[4-(E)-propenylbenzene is amino]-7-methoxyl group-6-[3-(morpholine-4-base) propoxy-] quinazoline
B:4-[4-(E)-propenylbenzene is amino]-7-methoxyl group-6-[2-(morpholine-4-base) oxyethyl group] quinazoline
C:4-[4-(E)-propenylbenzene is amino]-6-[3-(morpholine-4-base) propoxy-] quinazoline
D:4-[4-(E)-propenylbenzene is amino]-6-[2-(morpholine-4-base) oxyethyl group] quinazoline
E:4-[4-(E)-propenylbenzene is amino]-6-methoxyl group-7-[3-(morpholine-4-base) propoxy-] quinazoline
F:4-[4-(E)-propenylbenzene is amino]-6-methoxyl group-7-[2-(morpholine-4-base) oxyethyl group] quinazoline
G:4-[4-(E)-propenylbenzene is amino]-6,7-bis-(2-methoxy ethoxy) quinazoline
H:4-[4-(E)-propenylbenzene is amino]-6-[5-((2-methylsulfonylethyl is amino) methyl) furans-2-base] quinazoline
3. 4-according to claim 1 is preparing the purposes in antitumor drug to propenylbenzene amido quinazoline derivatives.
4. 4-according to claim 3 is preparing the purposes in antitumor drug to propenylbenzene amido quinazoline derivatives, it is characterized in that: described tumour behaviour lung cancer.
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CN107200715A (en) * 2017-06-22 2017-09-26 陕西师范大学 Quinazoline derivant and its application in antineoplastic is prepared
CN107200715B (en) * 2017-06-22 2020-05-29 陕西师范大学 Quinazoline derivative and application thereof in preparation of antitumor drugs
CN107827877A (en) * 2017-11-21 2018-03-23 陕西师范大学 Dialkyl amido quinazoline compounds and its application in antineoplastic is prepared

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