CN100522965C - 8-arylamine-3H-imidazole [4,5-g] quinazoline derivatives and its solid phase synthesis method - Google Patents
8-arylamine-3H-imidazole [4,5-g] quinazoline derivatives and its solid phase synthesis method Download PDFInfo
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- CN100522965C CN100522965C CNB2006100538950A CN200610053895A CN100522965C CN 100522965 C CN100522965 C CN 100522965C CN B2006100538950 A CNB2006100538950 A CN B2006100538950A CN 200610053895 A CN200610053895 A CN 200610053895A CN 100522965 C CN100522965 C CN 100522965C
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Abstract
The present invention belongs to the field of compound synthesis technology, in the concrete, it relates to a 8-arylamino-3H-imidazole [4,5-g] quinazoline derivative and its solid-phase synthesis method. It is characterized by that on the benzene ring in the quinazoline mother ring an imidazole ring is parallelly-connected, so that three rings in the improved new structure are formed into a linear arrangement. Besides, said invention also provides the concrete steps of its synthesis method. Said compound can be used for preparing anticancer medicine.
Description
Technical field
It is synthetic to the invention belongs to compound, relates generally to a kind of 8-aryl amine-3H-imidazoles [4,5-g] quinazoline derivative and solid phase synthesis process thereof.
Background technology
In recent years, the inhibitor of research epithelial cell growth factor receptor 2 body (epiderma1 growth factor receptor is called for short EGFR) has become the new direction of research and development PTS.EGFR is a Tyrosylprotein kinase, is regulating and control intracellular a series of signal conduction.Aspect the differentiation of tumour cell, growth, growth, the anti-ageing and migration important role is being arranged.The inhibitor of EGFR is to develop from molecule mechanism.Therefore, compare, the attack of cancer cells is had better choice with conventional medicament.It is little to have side effect, good effectiveness.
Studies show that in a large number 4-aryl amine quinazoline compounds is a kind of EGFR inhibitor of efficient highly selective.For example: the new drug Iressa and the Tarceva of two non-minicell lung cancer of treatment of just having gone on the market at present; Lead compound 4-(3-bromine) anilino-6,7-dimethoxyquinazoline (PD153035) are a kind of extraordinary EGFR inhibitor, its IC
50Value reach 0.025nM (J.Med.Chem.1996,39,918-28).Further studies show that: being similar to 8-aryl amine-3H-imidazoles [4,5-g] quinazoline compounds, to have the activity of compound of linear array tricyclic structure also all well and good, 8-(3-bromophenyl)-3H-imidazoles [4,5-g] quinazoline for example, its IC
50Value can reach 0.008nM.Research is recently reported: this class formation all has restraining effect (US2005187231) for the growth of cancer cells HepG2, U251, Caki-1, UMRC2, Hs578T, MCF-7 and Lox IMVI.RESEARCH ON CELL-BIOLOGY is found: the quinazoline compound of this type of tricyclic structure can enter cell fast, by the ATP end binding site of highly selective competition EGFR, the signal conduction that produces thereby cut-out is excited by EGF-.So a large amount of compound libraries that synthesize 8-aryl amine-3H-imidazoles [4,5-g] the quinazoline ditosylate salt structure with molecular diversity are for the lead compound of screening and find anti-kidney, lung cancer, mammary cancer and the cancer of the brain, and are significant.
Summary of the invention
The objective of the invention is the structure of existing 4-aryl amine quinazoline compounds is transformed, and provide a kind of 8-aryl amine 3H-imidazoles [4,5-g] quinazoline derivative and solid phase synthesis process thereof, imidazole ring in the parallel connection again on the phenyl ring in the female ring of quinazoline, and make three linear arranging of ring in the improved new texture.Simultaneously, we use the method for combinatorial chemistry, make in the improved structure 2 and 3 s' substituting group and the substituting group on 8 aryl that multiple variation can be arranged, help synthesizing fast and in large quantities 8-aryl amine-3H-imidazoles [4,5-g] quinazoline compounds library of molecules with molecular diversity.
The technical solution adopted for the present invention to solve the technical problems.This 8-aryl amine provided by the invention-3H-imidazoles [4,5-g] quinazoline derivant has following general structure:
R wherein
1Be alkoxyl group, alkane sulfydryl, hydrogen, alkyl, C
3-C
7Cycloalkyl, C
1-C
10The alkyl that is connected with other substituted radical, fluorine, chlorine, bromine, iodine, cyano group, can be on phenyl ring the position of substitution arbitrarily, can be multiple replacement.
R
2Be hydrogen, C
1-C
10Alkyl, C
1-C
10The alkyl that is connected with other substituted radical, C
3-C
10Aralkyl, C
1-C
10Be connected with aralkyl, the C of other substituted radical
3-C
7Cycloalkyl, C
3-C
7Be connected with the cycloalkyl of other substituted radical.
R
3Be hydrogen, C
1-C
10Alkyl, C
1-C
10The alkyl that is connected with other substituted radical, C
3-C
10Aralkyl, C
1-C
10Be connected with aralkyl, the C of other substituted radical
3-C
7Cycloalkyl, C
3-C
7Be connected with the cycloalkyl of other substituted radical.
This 8-aryl amine-3 of the present invention
HThe solid phase synthesis process of-imidazoles [4,5-g] quinazoline compounds, key step is as follows:
(2.1), 2-amino-4-fluorobenzoic acid and acetic acid methyl ether react generation 7-fluquinconazole quinoline-4 (3H)-ketone;
(2.2), 7-fluquinconazole quinoline-4 (3H)-ketone is nitrated, obtains 6-nitro-7-fluquinconazole quinoline-4 (3H)-ketone;
(2.3), 6-nitro-7-fluquinconazole quinoline-4 (3H)-ketone sulfur oxychloride chlorination, obtain 4-chloro-7-fluoro-6-nitro-quinazoline;
(2.4), formaldehyde-based resin and contain R
1Substituent arylamine reaction obtains resin-carried arylamine;
(2.5), above-mentioned resin-carried arylamine and preparation according to the method described above the reaction of 4-chloro-7-fluoro-6-nitro-quinazoline, obtain resin-carried 4-aryl amine-6-nitro-7-fluquinconazole quinoline;
(2.6), above-mentioned resin-carried 4-aryl amine-6-nitro-7-fluquinconazole quinoline with contain R
2Substituent primary amine reaction obtains resin-carried 4-aryl amine-6-nitro-7-fat amido quinazoline;
(2.7), above-mentioned resin-carried 4-aryl amine-6-nitro-7-fat amido quinazoline is at DMF, tin protochloride, R
3Under the substituent aldehyde acting in conjunction, generate resin-carried 8-aryl amine-3H-imidazoles [4,5-g] quinazoline;
(2.8), after the mixed solvent that is made into trifluoroacetic acid and methylene dichloride of above-mentioned resin-carried 8-aryl amine-3H-imidazoles [4,5-g] quinazoline handles, obtain target product 8-aryl amine-3H-imidazoles [4, the 5-g] quinazoline that disintegrates down from resin.
The further concrete step of this solid phase synthesis process is as follows:
(3.1), 1 equivalent 2-amino-4-fluorobenzoic acid (I) and 1 equivalent acetic acid methyl ether (II) be solvent with the ethylene glycol monomethyl ether, reflux obtained 0.9 equivalent 7-fluquinconazole quinoline-4 (3H)-ketone (III) after 18 hours;
(3.2), 7-fluquinconazole quinoline-4 (3H)-ketone (III) 47.4g of getting according to the method described above preparation with the nitrosonitric acid of the vitriol oil of 100ml and 100ml 100 degrees centigrade nitrated, obtain 33.7g 6-nitro-7-fluquinconazole quinoline-4 (3H)-ketone (IV);
(3.3), 10 normal 6-nitro-7-fluquinconazole quinolines-4 (3H)-ketone (IV) are with the chlorination of 40ml sulfur oxychloride, back flow reaction 3 hours obtains 9 normal 4-chloro-7-fluoro-6-nitro-quinazolines (V);
(3.4), 1 equivalent formaldehyde-based resin (VI) and 10 equivalents contain corresponding substituent arylamine at N, react in dinethylformamide (DMF) solution, and, obtain the resin-carried arylamine of 1 equivalent (VII) with the sodium cyanoborohydride reduction;
(3.5), this resin-carried arylamine (VII) and 10 equivalents prepare according to the method described above 4-chloro-7-fluoro-6-nitro-quinazoline (V) room temperature reaction 24 hours in tetrahydrofuran (THF), obtain the resin-carried 4-aryl amine of 1 equivalent-6-nitro-7-fluquinconazole quinoline (VIII);
(3.6), this resin-carried 4-aryl amine-6-nitro-7-fluquinconazole quinoline (VIII) room temperature reaction 24 hours in the dichloromethane solution of the primary amine of corresponding 1mol/L, obtain the resin-carried 4-aryl amine of 1 equivalent-6-nitro-7-fat amido quinazoline (IX);
(3.7), this resin-carried 4-aryl amine-6-nitro-7-fat amido quinazoline (IX) is under the effect of the DMF of 2mol/L tin protochloride solution, the corresponding alkanoic of 10 equivalents, reacted 1 hour down at 50 degrees centigrade, one step formed the 3rd imidazole ring, generate resin-carried 8-aryl amine-3H-imidazoles [4, the 5-g] quinazolines (X) of 0.9 equivalent;
(3.8), through after trifluoroacetic acid/dichloromethane=1:1 solvent treatment, target product 8-aryl amine-3H-imidazoles [4,5-g] quinazoline (XI) cuts down from resin, obtains the crude product of compound (XI), through obtaining pure compound (XI) after the conventional organic process.
General structure of the present invention can make by above-mentioned steps, following reaction formula is preparation-aryl amine-3H-imidazoles [4,5-g] reaction expression of quinazoline derivant (compound XI), reaction intermediate 4-chloro-7-fluoro-6-nitro-quinazoline (V) is according to document (J.Med.Chem.1996,39,918-28) synthetic.
The effect that the present invention is useful is: the synthesis condition gentleness of 8-aryl amine provided by the invention-3H-imidazoles [4,5-g] quinazoline derivant, and raw material is easy to get, and purity and productive rate are all higher.And can synthesize 8-aryl amine-3H-imidazoles [4,5-g] quinazoline derivant library of molecules in a large number with molecular diversity, help high flux screening and find the cancer therapy drug lead compound.
Embodiment:
Below in conjunction with embodiment the present invention is further described, embodiment will help to understand the present invention better, but the present invention is not limited only to following embodiment.
Embodiment 1: this 8-aryl amine provided by the invention-3H-imidazoles [4,5-g] quinazoline derivant has following general structure:
R wherein
1Be alkoxyl group, alkane sulfydryl, hydrogen, alkyl, C
3-C
7Cycloalkyl, C
1-C
10The alkyl that is connected with other substituted radical, fluorine, chlorine, bromine, iodine, cyano group, can be on phenyl ring the position of substitution arbitrarily, can be multiple replacement.
R
2Be hydrogen, C
1-C
10Alkyl, C
1-C
10The alkyl that is connected with other substituted radical, C
3-C
10Aralkyl, C
1-C
10Be connected with aralkyl, the C of other substituted radical
3-C
7Cycloalkyl, C
3-C
7Be connected with the cycloalkyl of other substituted radical.
R
3Be hydrogen, C
1-C
10Alkyl, C
1-C
10The alkyl that is connected with other substituted radical, C
3-C
10Aralkyl, C
1-C
10Be connected with aralkyl, the C of other substituted radical
3-C
7Cycloalkyl, C
3-C
7Be connected with the cycloalkyl of other substituted radical.
The solid phase synthesis process of this 8-aryl amine of the present invention-3H-imidazoles [4,5-g] quinazoline compounds, key step is as follows:
1.1), the preparation of 7-fluquinconazole quinoline-4 (3H)-ketone III
6.3g (41mmol) 2-amino-4-fluorobenzoic acid I and 8.5g (82mmol) acetic acid second are narrowed II and are joined in the 100ml three-necked bottle, add ethylene glycol monomethyl ether 40ml then, after system refluxed 18 hours, normal pressure is with solvent evaporate to dryness as far as possible, obtain residue, with the ammonia scrubbing of 0.01M, finally can obtain 6.0g7-fluquinconazole quinoline-4 (3H)-ketone III.Productive rate 90%.m.p.238℃
1.2), the preparation of 6-nitro-7-fluquinconazole quinoline-4 (3H)-ketone IV
Get the three-necked bottle that adds 250ml by example 1 synthetic 7-fluquinconazole quinoline-4 (3H)-ketone III47.4g (0.29mol), add concentrated nitric acid 100ml, concentrated hydrochloric acid 100ml, and be warmed up to 100 ℃.React after 1 hour, reaction solution is poured in the frozen water of 1.5L, obtain yellow solid.Collect solid and, can obtain the pure product 33.7g of 6-nitro-7-fluquinconazole quinoline-4 (3H)-ketone IV with behind the Glacial acetic acid recrystallization.Productive rate 56%m.p.282-284 ℃
1.3), the preparation of 4-chloro-6-nitro-7-quinazoline (V)
Get by example 2 synthetic 6-nitros-7-fluquinconazole quinoline-4 (3H)-ketone IV10.45g (50mmol), add the 250ml three-necked bottle, add 200ml SOCl again
2, three DMF.Then solution was refluxed 3 hours evaporated under reduced pressure SOCl
2Obtain the crude product 10.24g of 4-chloro-6-nitro-7-quinazoline V.Productive rate 90%.
1.4), the preparation of 2-propyl group-3-sec.-propyl-8-(4-methyl) anilino-3H-imidazoles [4,5-g] quinazoline
With 100mg (0.1mmol, volume containing the sample 1mmol/g) formaldehyde-based resin (available from Nova Biochem production code member; NO:01-64-0331, degree of crosslinking 1%) enclose resin pocket, to monomethylaniline 0.107g (1mmol), N, dinethylformamide 10ml, Glacial acetic acid 0.1ml, sodium cyanoborohydride 0.063g (1mmol), add in the reaction flask of 15ml, put shaking table after the sealing, the room temperature vibration was rocked 24 hours, the liquid of falling the dereaction then, resin pocket is used N successively, and dinethylformamide, methylene dichloride, ethanol respectively wash three times, dry in air.Obtain being similar to the structure (R of VII this moment
1=CH
3).
Get 4-chloro-6-nitro-7-quinazoline V1.14g (5mmol) according to example 3 described preparations, tetrahydrofuran (THF) 5ml, air dried resin pocket after the last step reaction (100mg, 0.1mmol), triethylamine 0.5ml adds the 15ml reaction flask, put shaking table after the sealing, the room temperature vibration was rocked 24 hours, and the liquid of falling the dereaction is used N successively with resin pocket then, dinethylformamide, methylene dichloride, ethanol respectively wash three times, dry in air.Obtain being similar to the structure (R of VIII this moment
1=CH
3).
Get step reaction back air dried resin pocket (100mg, 0.1mmol), 0.86ml (10mmol) Isopropylamine, methylene dichloride 10ml adds in the reaction flask of 15ml, put shaking table after the sealing, the room temperature vibration was rocked 24 hours, and the liquid of falling the dereaction is used N successively with resin pocket then, dinethylformamide, methylene dichloride, ethanol respectively wash three times, dry in air.Obtain being similar to the structure (R of IX this moment
1=CH
3, R
2=sec.-propyl).
Get step reaction back air dried resin pocket (100mg, 0.1mmol), SnCl
22H
2O4.5g (20mmol), N, dinethylformamide 10ml, butyraldehyde-n 0.88ml (10mmol) adds the 15ml reaction tubes, and system is heated to 50 ℃, and constantly stir, reacted 1 hour, the liquid of falling the dereaction is used N successively with resin pocket then, dinethylformamide, methylene dichloride, ethanol respectively wash three times, dry in air.Obtain being similar to the structure (R of X this moment
1=CH
3, R
2=sec.-propyl, R
3=n-propyl).
(100mg 0.1mmol), puts into the test tube of 8ml to the air dried resin pocket after getting the step reaction, add trifluoroacetic acid and methylene chloride volume again than being the mixing solutions 5ml of 1:1, test tube sealed, 1 as a child the back take out resin pocket, behind the solution normal pressure evaporate to dryness in the test tube, obtain yellow solid.This solid washs with saturated sodium bicarbonate, and with ethyl acetate extraction 3 times.Collected organic layer is also used anhydrous sodium sulfate drying, filters then.The ethyl acetate solution that obtains is concentrated, and product obtains yellow solid 24.05mg after column chromatography.Productive rate 66.9%, purity (HPLC) 91.3%.
1HNMR(500MHz，CDCl
3)δ：8.65(1H，s)，8.30-8.58(1H，brs)，8.39(1H，s)，8.05(1H，s)，7.57-7.59(2H，m)，7.18-7.20(2H，m)，4.69-4.73(1H，q，J＝6.9Hz)，2.86-2.89(2H，t，J＝7.6Hz)，2.34(3H，s)，1.85-1.90(2H，m)，1.67-1.68(6H，d，J＝6.9Hz)，1.03-1.06(3H，t，J＝7.3Hz)
13CNMR(500MHz，CDCl
3)δ：160.1，158.6，152.6，143.0，138.3，135.6，134.7，129.6，122.6，110.6，110.0，107.3，48.3，30.4，20.998，20.944，14.0
The preparation of embodiment 2:2-isobutyl--3-propyl group-8-(4-methyl) anilino-3H-imidazoles [4,5-g] quinazoline
Operating process is with the step 1.4 of embodiment 1), just replace Isopropylamine with Tri N-Propyl Amine, isovaleric aldehyde replaces butyraldehyde-n, obtains white solid 25.62mg.Productive rate 68.6%, purity (HPLC) 94.6%.
1HNMR(400MHz，CDCl
3+DMSO)δ：9.19(1H，brs)，8.71(1H，s)，8.61(1H，s)，7.77(1H，s)，7.69-7.71(2H，m)，7.18-7.22(2H，m)，4.16-4.20(2H，t，J＝7.2Hz)，2.81-2.83(2H，d，J＝7.1Hz)，2.35-2.42(4H，m)，1.88-1.93(2H，m)，1.08-1.09(6H，d，J＝6.6Hz)，0.99-1.03(3H，t，J＝7.3Hz).
13CNMR(400MHz，CDCl
3+DMSO)δ：159.0，158.6，152.5，144.1，141.9，139.5，136.0，133.4，128.8，122.4，111.0，110.8，104.8，45.1，36.0，27.2，22.4，22.2，20.5，10.9
The preparation of embodiment 3:2-isobutyl--3-propyl group-8-(the 4-tertiary butyl) anilino-3H-imidazoles [4,5-g] quinazoline
Operating process is with the step 1.4 of embodiment 1), just replace monomethylaniline with p-tert-butyl-aniline, Tri N-Propyl Amine replaces Isopropylamine, and isovaleric aldehyde replaces butyraldehyde-n, obtains yellow solid 26.88mg.Productive rate 64.7%, purity (HPLC) 92.1%.
1HNMR(400MHz，CDCl
3)δ8.65(1H，s)，8.39(1H，s)，8.25(1H，brs)，7.77(1H，s)，7.65-7.67(2H，m)，7.40-7.42(2H，m)，4.04-4.08(2H，t，J＝7.4Hz)，2.74-2.76(2H，d，J＝7.1Hz)，2.31-2.38(1H，m)，1.82-1.87(2H，m)，1.33(9H，s)，1.01-1.02(6H，d，J＝6.0Hz)，0.958-0.995(3H，t，J＝7.4Hz).
13CNMR(400MHz，CDCl
3)δ160.0，158.4，152.8，147.6，144.1，142.4，139.9，135.7，125.9，121.9，111.1，109.7，105.6，45.6，36.6，34.4，31.4，27.8，22.8，22.6，11.3
The preparation of embodiment 4:2-sec.-propyl-3-(3-methoxyl group) propyl group-8-(3, the 4-dimethoxy) anilinos-3H-imidazoles [4,5-g] quinazoline
Operating process is with the step 1.4 of embodiment 1), just to use 3, the 4-dimethoxyaniline replaces monomethylaniline, and 3 methoxypropyl amine replaces Isopropylamine, and isobutyric aldehyde replaces butyraldehyde-n, obtains yellow solid 34.14mg.Productive rate 78.4%, purity (HPLC) 96.2%.
1HNMR(500MHz，CDCl
3)δ：8.67(1H，s)，8.30(1H，s)，7.83(1H，s)，7.67-7.85(1H，brs)，7.47(1H，s)，7.16-7.18(1H，m)，6.90-6.92(1H，m)，4.32-4.35(2H，t，J＝6.9Hz)，3.92(3H，s)，3.90(3H，s)，3.31-3.36(6H，m)，2.09-2.14(2H，m)，1.48-1.49(6H，d，J＝6.6Hz)
13CNMR(500MHz，CDCl
3)δ：165.6，158.4，153.2，149.2，146.4，145.1，142.5，140.0，131.9，114.6，111.6，111.1，109.4，107.4，106.2，68.6，58.8，56.2，56.0，40.7，29.6，26.5，21.6
The preparation of embodiment 5:2-ethyl-3-propyl group-8-(the 4-tertiary butyl) anilino-3H-imidazoles [4,5-g] quinazoline
Operating process is with the step 1.4 of embodiment 1), just replace monomethylaniline with p-tert-butyl-aniline, Tri N-Propyl Amine replaces Isopropylamine, and propionic aldehyde replaces butyraldehyde-n, obtains yellow solid 27.40mg.Productive rate 70.7%, purity (HPLC) 91.1%.
1HNMR(500MHz，DMSO)δ：9.83(1H，brs)，8.87(1H，s)，8.53(1H，s)，7.87(1H，s)，7.79-7.80(2H，m)，7.41-7.42(2H，m)，4.25-4.28(2H，t，J＝7.2Hz)，2.97-3.01(2H，q，J＝7.3Hz)，1.78-1.82(2H，m)，1.39-1.42(3H，t，J＝7.4Hz)，1.31-1.33(9H，s)，0.91-0.94(3H，J＝7.3Hz)
13CNMR(500MHz，CDCl
3)δ：163.1，161.3，158.6，153.1，147.2，141.4，135.9，125.7，121.8，113.6，111.3，106.2，105.8，45.3，34.3，31.3，22.5，21.0，16.7，11.2
The preparation of embodiment 6:2-sec.-propyl-3-normal-butyl-8-(4-fluorine) anilino-3H-imidazoles [4,5-g] quinazoline
Operating process is with the step 1.4 of embodiment 1), just replace monomethylaniline with para-fluoroaniline, n-Butyl Amine 99 replaces Isopropylamine, and isobutyric aldehyde replaces butyraldehyde-n, obtains yellow solid 6.42mg.Productive rate 17.0%, purity (HPLC) 73.5%.
1HNMR(400MHz，CDCl
3)δ：8.70(1H，s)，8.24(1H，s)，7.81(1H，s)，7.71-7.74(2H，m)，7.58(1H，brs)，7.11-7.15(2H，m)，4.20-4.24(2H，t，J＝7.6Hz)，3.25-3.28(1H，m)，1.85-1.91(2H，m)，1.49-1.51(6H，d，J＝6.8Hz)，1.43-1.47(2H，m)，0.98-1.02(3H，J＝7.4Hz)
13CNMR(400MHz，CDCl
3)δ：163.6，151.8，144.4，141.2，138.8，123.09，123.03，123.00，114.0，113.9，110.4，104.6，104.5，42.5，30.6，25.5，20.6，19.0，12.7
The preparation of embodiment 7:2-isobutyl--3-(3-oxyethyl group) propyl group-8-(4-methoxyl group) anilino-3H-imidazoles [4,5-g] quinazoline
Operating process is with the step 1.4 of embodiment 1), just replace monomethylaniline with P-nethoxyaniline, the 3-ethoxycarbonyl propyl replaces Isopropylamine, and isovaleric aldehyde replaces butyraldehyde-n, obtains yellow solid 34.51mg.Productive rate 79.6%, purity (HPLC) 97.8%.
1HNMR(500MHz，CDCl
3)δ：8.66(1H，s)，8.32(1H，s)，7.93(1H，brs)，7.78(1H，s)，7.59-7.60(2H，m)，6.93-6.95(2H，m)，4.30-4.33(2H，t，J＝6.8Hz)，3.81(3H，s)，3.44-3.48(2H，q，J＝7.0Hz)，3.34-3.37(2H，t，J＝5.5Hz)，2.81-2.82(2H，d，J＝7.2Hz)，2.36(1H，m)，2.07-2.11(2H，m)，1.23-1.26(3H，t，J＝7.0Hz)，1.02-1.03(6H，d，J＝6.2Hz).
13CNMR(500MHz，CDCl
3)δ：160.0，158.6，156.8，153.5，145.5，142.4，139.7，131.5，124.4，114.3，111.3，109.4，106.4，66.4，66.3，55.5，40.8，36.2，29.4，27.8，22.6，15.2
The preparation of embodiment 8:2-sec.-propyl-3-(3-methoxyl group) propyl group-8-(the 4-tertiary butyl) anilino-3H-imidazoles [4,5-g] quinazoline
Operating process is with the step 1.4 of embodiment 1), just replace monomethylaniline with p-tert-butyl-aniline, the 3-methoxy-propyl replaces Isopropylamine, and isobutyric aldehyde replaces butyraldehyde-n, obtains yellow solid.(28.66mg productive rate 66.4% purity (HPLC): 90.5%)
1HNMR(500MHz，CDCl
3)δ8.70(1H，s)，8.28(1H，s)，7.82(1H，s)，7.67-7.69(3H，m)，7.44-7.46(2H，m)，4.34-4.36(2H，t，J＝7.0Hz)，3.31-3.37(6H，m)，2.10-2.15(2H，m)，1.48-1.50(6H，d，J＝6.8Hz)，1.35(9H，s).
13CNMR(500MHz，CDCl
3)δ165.5，158.2，153.4，147.4，145.6，142.4，139.9，135.9，126.0，121.7，111.4，109.2，106.5，68.6，58.8，40.7，34.4，31.4，29.6，26.5，21.6
The preparation of embodiment 9:2-sec-butyl-3-(3-oxyethyl group) propyl group-8-(4-methoxyl group) anilino-3H-imidazoles [4,5-g] quinazoline
Operating process is with the step 1.4 of embodiment 1), just replace monomethylaniline with P-nethoxyaniline, the 3-ethoxycarbonyl propyl replaces Isopropylamine, and 2 methyl butyraldehyde replaces butyraldehyde-n, obtains yellow solid.(31.35mg productive rate 72.3% purity (HPLC): 94.3%)
1HNMR(500MHz，CDCl
3)δ8.67(1H，s)，8.25(1H，s)，7.82(1H，s)，7.61-7.63(2H，m)，7.59(1H，brs)，6.96-6.98(2H，m)，4.34-4.38(2H，t，J＝7.1Hz)，3.83(3H，s)，3.45-3.49(2H，q，J＝7.0Hz)，3.38-3.42(2H，m)，3.09-3.14(1H，m)，2.10-2.15(2H，m)，1.98-2.02(IH，m)，1.80-1.84(1H，m)，1.46-1.47(3H，d，J＝6.8Hz)，1.23-1.26(3H，t，J＝7.0Hz)，0.96-0.99(3H，t，J＝7.4Hz)
13CNMR(500MHz，CDCl
3)δ164.9，158.5，156.8，153.4，145.5，142.5，139.8，131.5，124.1，114.4，111.2，109.1，106.5，66.5，66.4，55.5，40.8，33.3，29.8，29.1，19.4，15.2，12.0
The preparation of embodiment 10:2-propyl group-3-cyclohexyl-8-anilino-3H-imidazoles [4,5-g] quinazoline
Operating process is with the step 1.4 of embodiment 1), just replace monomethylaniline with aniline, hexahydroaniline replaces Isopropylamine, obtains yellow solid.(23.98mg productive rate 62.2% purity (HPLC): 89.4%)
1HNMR(400MHz，CDCl
3)δ8.72(1H，s)，8.23(1H，s)，8.06(1H，s)，7.79-7.81(2H，m)，7.65(1H，brs)，7.42-7.46(2H，m)，7.16-7.20(1H，m)，4.22-4.26(1H，m)，2.93-2.97(2H，t，J＝7.8Hz)，2.40-2.44(2H，m)，1.95-2.05(4H，m)，1.77-1.93(4H，m)，1.40-1.51(2H，m)，1.10-1.13(3H，t，J＝7.6Hz)
13CNMR(400MHz，CDCl
3)δ?160.1，158.0，153.2，145.0，143.2，138.6，133.4，129.1，124.3，121.7，110.9，109.1，107.0，56.7，30.9，30.6，26.1，25.2，21.1，14.0
The preparation of embodiment 11:2-sec.-propyl-3-cyclohexyl-8-(4-methoxyl group) anilino-3H-imidazoles [4,5-g] quinazoline
Operating process is with the step 1.4 of embodiment 1), just replace monomethylaniline with P-nethoxyaniline, hexahydroaniline replaces Isopropylamine, and isobutyric aldehyde replaces butyraldehyde-n to obtain yellow solid 29.67mg.Productive rate 71.4%, purity (HPLC) 96.3%.
1HNMR(400MHz，CDCl
3)δ：8.68(1H，s)，8.29(1H，s)，7.89(1H，brs)，7.80(1H，s)，7.60-7.62(2H，m)，6.94-6.97(2H，m)，4.24-4.30(1H，m)，3.25-3.30(1H，m)，1.93-2.07(4H，m)，1.73-1.89(4H，m)，1.46-1.48(6H，d，J＝6.8Hz)，1.26-1.42(m，2H)
13CNMR(400MHz，CDCl
3)δ：165.0，158.7，157.1，143.1，138.8，131.0，124.3，121.9，114.4，114.2，110.4，109.7，108.3，56.5，55.6，30.8，27.4，26.2，25.0，21.4
The preparation of embodiment 12:2-sec.-propyl-3-cyclohexyl-8-anilino-3H-imidazoles [4,5-g] quinazoline
Operating process is with the step 1.4 of embodiment 1), just replace monomethylaniline with aniline, hexahydroaniline replaces Isopropylamine, and isobutyric aldehyde replaces butyraldehyde-n to obtain yellow solid 27.14mg.Productive rate 70.4%, purity (HPLC) 91.8%.
1HNMR(400MHz，CDCl
3)δ：8.72(1H，s)，8.28(1H，s)，8.07(1H，s)，7.79-7.81(2H，m)，7.66(1H，brs)，7.41-7.45(2H，m)，7.15-7.19(1H，m)，4.29-4.31(1H，m)，3.28-3.31(1H，m)，1.93-2.04(4H，m)，1.64-1.87(4H，m)，1.49-1.50(6H，d，J＝6.8Hz)，1.34-1.46(2H，m).
13CNMR(400MHz，CDCl
3)δ：164.8，157.9，153.2，144.9，143.1，138.70，138.65，129.1，124.3，121.6，110.8，109.23，109.18，56.3，30.8，27.3，26.1，25.6，21.5
The preparation of embodiment 13:2-sec.-propyl-3-sec.-propyl-8-anilino-3H-imidazoles [4,5-g] quinazoline
Operating process is with the step 1.4 of embodiment 1), just replace monomethylaniline with aniline, isobutyric aldehyde replaces butyraldehyde-n to obtain yellow solid 23.77mg.Productive rate 68.8%, purity (HPLC) 90.2%.
HNMR(400MHz，CDCl
3)δ：8.75(1H，s)，8.25(1H，s)，8.04(1H，s)，7.80-7.82(2H，m)，7.64(1H，brs)，7.42-7.46(2H，m)，7.16-7.20(1H，m)，4.80-4.84(1H，q，J＝6.9Hz)，3.26-331(1H，q，J＝6.8Hz)，1.75-1.76(6H，d，J＝6.9Hz)，1.50-1.52(6H，d，J＝6.8Hz)
13CNMR(400MHz，CDCl
3)δ：163.6，156.0，153.3，145.7，146.5，138.7，138.3，128.9，125.3，121.5，110.3，108.8，108.3，47.9，29.7，22.7，21.2
The preparation of embodiment 14:2-sec.-propyl-3-normal-butyl-8-(4-methoxyl group) anilino-3H-imidazoles [4,5-g] quinazoline
Operating process is with the step 1.4 of embodiment 1), just replace monomethylaniline with P-nethoxyaniline, n-Butyl Amine 99 replaces Isopropylamine, and isobutyric aldehyde replaces butyraldehyde-n to obtain yellow solid 28.16mg.Productive rate 72.3%, purity (HPLC) 94.3%.
1HNMR(500MHz，CDCl
3+DMSO)δ：8.91(1H，brs)，8.66(1H，s)，8.59(1H，s)，7.70-7.73(3H，m)，6.95-6.96(2H，m)，4.20-4.23(2H，t，J＝7.6Hz)，3.84(3H，s)，3.25-3.28(1H，m)，1.85-1.88(2H，m)，1.48-1.50(6H，d，J＝6.8Hz)，1.43-1.46(2H，m)，0.98-1.01(3H，d，J＝7.4Hz)
13CNMR(500MHz，CDCl
3+DMSO)δ：164.2，157.8，156.4，153.0，145.8，141.8，139.4，132.8，124.1，113.7，110.6，108.7，105.3，55.1，43.3，31.3，26.3，21.2，19.8，13.3
The preparation of embodiment 15:2-propyl group-3-(3-methoxyl group) propyl group-8-(the 4-tertiary butyl) anilino-3H-imidazoles [4,5-g] quinazoline
Operating process is with the step 1.4 of embodiment 1), just replace monomethylaniline with p-tert-butyl-aniline, 3 methoxypropyl amine replaces Isopropylamine 28.44mg.Productive rate 65.9%, purity (HPLC) 94.3%.
1HNMR(500MHz，DMSO)δ：9.65(1H，brs)，8.85(1H，s)，8.49(1H，s)，7.80-7.83(3H，m)，7.39-7.40(2H，m)，4.32-4.35(2H，t，J＝6.9Hz)，3.30-3.33(2H，t，J＝7.2Hz)，3.24(3H，s)，2.91-2.94(2H，t，J＝7.4Hz)，1.99-2.03(2H，m)，1.88-1.93(2H，m)，1.31(9H，s)，1.04-1.06(3H，t，J＝7.4Hz)
13CNMR(500MHz，DMSO)δ：160.6，158.4，153.4，148.2，145.4，141.5，139.6，136.1，125.7，121.7，111.4，108.9，106.4，68.3，58.6，45.6，34.3，31.3，29.2，26.2，20.2，13.9
The preparation of embodiment 16:2-cyclohexyl-3-sec.-propyl-8-(4-methyl) anilino-3H-imidazoles [4,5-g] quinazoline
Operating process is with the step 1.4 of embodiment 1), just replace butyraldehyde-n 27.05mg with hexamethylene aldehyde.Productive rate 67.7%, purity (HPLC): 92.1%.
1HNMR(400MHz，CDCl
3)δ：8.70(1H，s)，8.22(1H，s)，8.03(1H，s)，7.63-7.65(2H，m)，7.42-7.46(1H，brs)，7.23-7.25(2H，m)，4.76-4.83(1H，m)，2.88-2.96(1H，m)，2.38(3H，s)，1.95-2.06(4H，m)，1.81-1.90(4H，m)，1.74-1.75(6H，d，J＝6.9Hz)，1.45-1.51(2H，m).
13CNMR(400MHz，CDCl
3)δ：160.2，157.4，154.8，146.2，141.8，138.6，135.4，132.7，128.9，123.1，111.2，109.6，106.6，47.8，37.1，31.8，26.3，21.1，21.0，14.1
The preparation of embodiment 17:2-propyl group-3-(3-methoxyl group) propyl group-8-(3, the 4-dimethoxy) anilinos-3H-imidazoles [4,5-g] quinazoline
Operating process is with the step 1.4 of embodiment 1), just with 3, the 4-dimethoxyaniline replaces monomethylaniline, and 3 methoxypropyl amine replaces Isopropylamine 32.58mg.Productive rate 74.8%, purity (HPLC) 94.3%.
1HNMR(500MHz，DMSO)δ：9.78(1H，brs)，8.84(1H，s)，8.52(1H，s)，7.80(1H，s)，7.48-7.51(2H，m)，6.97-6.99(1H，m)，4.32-4.35(2H，t，J＝6.8Hz)，3.79(3H，s)，3.77(3H，s)，3.30-3.32(2H，t，J＝5.7Hz)，3.24(3H，s)，2.91-2.94(2H，t，J＝7.4Hz)，1.99-2.03(2H，m)，1.88-1.92(2H，m)，1.03-1.06(3H，t，J＝7.3Hz)
13CNMR(500MHz，DMSO)δ：164.4，157.7，152.5，147.2，145.7，149.9，143.0，141.2，131.6，113.8，112.1，111.8，109.4，108.6，105.5，68.3，58.4，56.0，54.9，40.6，29.1，29.0，19.4，13.8
The preparation of embodiment 18:2-sec.-propyl-3-butyl-8-(3, the 4-dimethoxy) anilinos-3H-imidazoles [4,5-g] quinazoline
Operating process is with the step 1.4 of embodiment 1), just with 3, the 4-dimethoxyaniline replaces monomethylaniline, and n-Butyl Amine 99 replaces Isopropylamine, and isobutyric aldehyde replaces butyraldehyde-n 30.58mg.Productive rate 72.9%, purity (HPLC) 92.3%.
1HNMR(500MHz，CDCl
3)δ：8.69(1H，s)，8.25(1H，s)，7.80(1H，s)，7.52(1H，brs)，7.48(1H，s)，7.14-7.15(1H，m)，6.91-6.92(1H，m)，4.19-4.22(2H，t，J＝7.1Hz)，3.93(3H，s)，3.90(3H，s)，3.80-3.88(1H，m)，2.28-2.31(2H，m)，1.85-1.88(2H，m)，1.49-1.51(6H，d，J＝6.7Hz)，0.99-1.02(3H，d，J＝7.4Hz)
13CNMR(500MHz，CDCl
3)δ：165.2，158.4，153.4，149.3，146.4，145.4，142.5，140.0，131.9，114.5，111.6，111.2，109.2，107.4，106.4，56.2，56.0，43.8，31.9，26.8，21.6，20.3，13.7
The preparation of embodiment 19:2-sec.-propyl-3-allyl group-8-(4-methoxyl group) anilino-3H-imidazoles [4,5-g] quinazoline
Operating process is with the step 1.4 of embodiment 1), just replace monomethylaniline with P-nethoxyaniline, allylamine replaces Isopropylamine, and isobutyric aldehyde replaces butyraldehyde-n 28.68mg.Productive rate 76.8%, purity (HPLC) 92.5%.
1HNMR(500MHz，DMSO)δ：9.58(1H，brs)，8.83(1H，s)，8.43(1H，s)，7.74-7.79(3H，m)，6.94-6.96(2H，m)，6.02-6.07(1H，m)，5.19-5.21(1H，d，J＝10.3Hz)，4.98-5.01(2H，m)，4.92-4.96(1H，d，J＝17.3Hz)，3.77，(3H，s)，3.29-3.32(1H，m)，1.38-1.39(6H，d，J＝6.7Hz)
13CNMR(500MHz，DMSO)δ：161.3，157.8，155.6，152.7，145.5，142.1，139.4，135.6，130.3，123.4，114.5，115.1，110.3，108.7，107.2，55.5，46.1，29.3，26.9
The preparation of embodiment 20:2-ethyl-3-propyl group-8-(4-methoxyl group) anilino-3H-imidazoles [4,5-g] quinazoline
Operating process is with the step 1.4 of embodiment 1), just replace Isopropylamine with propylamine, propionic aldehyde replaces butyraldehyde-n 21.97mg.Productive rate 63.6%, purity (HPLC) 90.4%.
1HNMR(400MHz，CDCl
3+DMSO)δ：10.00(1H，brs)，8.87(1H，s)，8.64(1H，s)，7.96(1H，s)，7.65-7.67(2H，m)，7.23-7.25(2H，m)，4.18-4.21(2H，t，J＝7.3Hz)，2.96-3.01(2H，q，J＝7.5Hz)，2.38(3H，s)，1.88-1.94(2H，m)，1.50-1.54(3H，t，J＝7.5Hz)，0.99-1.03(3H，t，J＝7.4Hz).
13CNMR(400MHz，CDCl
3+DMSO)δ：161.3，159.2，150.8，142.3，140.1，139.7，135.0，134.6，128.8，123.1，111.8，109.8，102.2，45.0，30.6，22.2，20.5，10.9，10.8
The preparation of embodiment 21:2-sec.-propyl-3-propyl group-8-(4-methoxyl group) anilino-3H-imidazoles [4,5-g] quinazoline
Operating process is with the step 1.4 of embodiment 1), just replace aniline with P-nethoxyaniline, propylamine replaces Isopropylamine, and isobutyric aldehyde replaces butyraldehyde-n 27.93mg.Productive rate 74.4%, purity (HPLC) 94.7%.
1HNMR(400MHz，DMSO)δ：11.24(1H，brs)，9.01(1H，s)，8.85(1H，s)，7.98(1H，s)，7.63-7.65(2H，m)，7.05-7.07(2H，m)，4.32-4.35(2H，t，J＝7.2Hz)，3.81(s，3H)，3.28-3.30(1H，m)，1.78-1.84(2H，m)，1.38-1.40(6H，d，J＝6.8Hz)，0.91-0.95(3H，t，J＝7.4Hz)
13CNMR(400MHz，DMSO)δ：163.2，157.4，156.3，152.9，146.0，142.1，139.2，132.9，123.7，113.4，110.4，109.1，105.2，55.4，42.8，29.8，26.7，20.7，19.9。
Claims (2)
1, the solid phase synthesis process of a kind of 8-aryl amine-3H-imidazoles [4,5-g] quinazoline compounds, it is characterized in that: key step is as follows:
(1.1), 2-amino-4-fluorobenzoic acid and acetic acid methyl ether react generation 7-fluquinconazole quinoline-4 (3H)-ketone;
(1.2), 7-fluquinconazole quinoline-4 (3H)-ketone is nitrated, obtains 6-nitro-7-fluquinconazole quinoline-4 (3H)-ketone;
(1.3), 6-nitro-7-fluquinconazole quinoline-4 (3H)-ketone sulfur oxychloride chlorination, obtain 4-chloro-7-fluoro-6-nitro-quinazoline;
(1.4), formaldehyde-based resin and contain R
1Substituent arylamine reaction obtains resin-carried arylamine;
(1.5), the 4-chloro-7-fluoro-6-nitro-quinazoline reaction of above-mentioned resin-carried arylamine and preparation according to the method described above, obtain resin-carried 4-aryl amine-6-nitro-7-fluquinconazole quinoline;
(1.6), above-mentioned resin-carried 4-aryl amine-6-nitro-7-fluquinconazole quinoline with contain R
2Substituent primary amine reaction obtains resin-carried 4-aryl amine-6-nitro-7-fat amido quinazoline;
(1.7), above-mentioned resin-carried 4-aryl amine-6-nitro-7-fat amido quinazoline at DMF, tin protochloride, contain R
3Under the substituent aldehyde acting in conjunction, generate resin-carried 8-aryl amine-3H-imidazoles [4,5-g] quinazoline;
(1.8), after the mixed solvent that is made into trifluoroacetic acid and methylene dichloride of above-mentioned resin-carried 8-aryl amine-3H-imidazoles [4,5-g] quinazoline handles, obtain target product 8-aryl amine-3H-imidazoles [4, the 5-g] quinazoline that disintegrates down from resin;
8-aryl amine-3H-imidazoles [4,5-g] quinazoline compounds general structure is:
R wherein
1Be alkoxyl group, alkane sulfydryl, hydrogen, alkyl, C
3-C
7Cycloalkyl, fluorine, chlorine, bromine, iodine, cyano group;
R
2Be hydrogen, C
1-C
10Alkyl, C
3-C
10Aralkyl, C
3-C
7Cycloalkyl;
R
3Be hydrogen, C
1-C
10Alkyl, C
3-C
10Aralkyl, C
3-C
7Cycloalkyl.
2, the solid phase synthesis process of 8-aryl amine according to claim 1-3H-imidazoles [4,5-g] quinazoline compounds, it is characterized in that: key step is as follows:
(2.1), 1 equivalent 2-amino-4-fluorobenzoic acid and 1 equivalent acetic acid methyl ether be solvent with the ethylene glycol monomethyl ether, reflux obtained 0.9 equivalent 7-fluquinconazole quinoline-4 (3H)-ketone after 18 hours;
(2.2), 7-fluquinconazole quinoline-4 (3H)-ketone 47.4g of getting according to the method described above preparation with the nitrosonitric acid of the vitriol oil of 100ml and 100ml 100 degrees centigrade nitrated, obtain 33.7g6-nitro-7-fluquinconazole quinoline-4 (3H)-ketone;
(2.3), 10 normal 6-nitro-7-fluquinconazole quinolines-4 (3H)-ketone are with the chlorination of 40ml sulfur oxychloride, back flow reaction 3 hours obtains 9 normal 4-chloro-7-fluoro-6-nitro-quinazolines;
(2.4), 1 equivalent formaldehyde-based resin and 10 equivalents contain R
1Substituent arylamine reacts in the dinethylformamide solution at N, and with the sodium cyanoborohydride reduction, obtains the resin-carried arylamine of 1 equivalent;
(2.5), the 4-chloro-7-fluoro-6-nitro-quinazoline for preparing according to the method described above of this resin-carried arylamine and 10 equivalents room temperature reaction 24 hours in tetrahydrofuran (THF), obtain the resin-carried 4-aryl amine of 1 equivalent-6-nitro-7-fluquinconazole quinoline;
(2.6), this resin-carried 4-aryl amine-6-nitro-7-fluquinconazole quinoline is at the R that contains of 1mol/L
2Room temperature reaction is 24 hours in the dichloromethane solution of substituent primary amine, obtains the resin-carried 4-aryl amine of 1 equivalent-6-nitro-7-fat amido quinazoline;
(2.7), this resin-carried 4-aryl amine-6-nitro-7-fat amido quinazoline contains R at the DMF of 2mol/L tin protochloride solution, 10 equivalents
3Under the effect of substituent alkanoic, reacted 1 hour down, generate the resin-carried 8-aryl amine-3H-imidazoles of 0.9 equivalent [4,5-g] quinazoline at 50 degrees centigrade;
(2.8), through after trifluoroacetic acid/dichloromethane=1:1 solvent treatment, target product 8-aryl amine-3H-imidazoles [4,5-g] quinazoline cuts down from resin, through obtaining pure compound after conventional organic aftertreatment.
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| Evaluation of Novel Epidermal Growth Factor ReceptorTyrosine Kinase Inhibitors. Rae, James M. et al.Breast Cancer Research and Treatment,Vol.83 No.2. 2004 |
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