CN101899011B - Dithiocarbamates compound, preparation method and application thereof - Google Patents
Dithiocarbamates compound, preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a dithiocarbamates compound with a structure shown as the general formula (I) as well as a medical salt, a preparation method and application thereof in the preparation of antitumor drugs, wherein definitions of all groups are specified in the specification. The compound of the invention is a new kind of tyrosine kinase inhibitors, and is used as an antitumor drug, preferably as a drug for treating breast cancer, non-small cell lung cancer, gastric cancer or pancreatic cancer.
Description
Technical field
The present invention relates to a kind of dithiocarbamates compound, its preparation method and application, the compounds of this invention is the new tyrosine kinase inhibitor of a class, can be used as antitumor drug.
Background technology
EGF-R ELISA (ErbB) family belongs to I receptor family tyrosine kinase, and there are four member: ErbB-1 (EGFR) in this family, ErbB-2 (HER-2), ErbB-3 and ErbB-4.Studies show that, in the tumour cells such as bladder cancer, mammary cancer, colorectal carcinoma, lung cancer, EGFR and HER-2 all have high expression level, between solid tumor and their high expression level very strong dependency are arranged.Therefore, carrying out anti-tumor drugs targeting research with EGFR and HER-2 as target spot is in recent years paid much attention to.
At present, the major structural types of the EGFR that has found and HER-2 inhibitor has following 5 kinds, be 4-amino-quinazoline (4-Aminoquinazolines, A), 4-Amino 3 cyano quinoline (4-Aminoquinoline-3-carbonitriles, B), α-tolylene propane dinitrile class (Benzylidenemalononitriles, C), salicylamide (Salicylanilides, D) and pyrrolotriazine class (Pyrrolotrazines, E).Most study is 4-amino-quinazoline (A) and 4-Amino 3 cyano quinoline (B) class in these 5 kinds of structures, for example the open WO2008/0033748 of Chinese patent application CN200610023526.7 and international application and the disclosed compound of WO2008/0033749.And found the good compound of some anti-tumor activities, some has entered clinical.
Dithiocarbamates compound is the compound that an other class has anti-tumor activity, the people such as Li Runtao disclose this compounds in Chinese invention patent application CN01118399.3 and CN200410054686.9, wherein disclosed compound 990208 (Hyd) and 990227 is preferably two kinds of compounds of activity.
Based on prior art to the result of study of dithiocarbamates compound and the progress of epidermal growth factor receptor inhibitor (EGFR inhibitor), the inventor has found the epidermal growth factor receptor inhibitor that a class formation is brand-new, active by force, selectivity is high, toxicity is low through great many of experiments.
Summary of the invention
The purpose of this invention is to provide a class has the compound or pharmaceutically acceptable salt thereof of following general formula (I) structure:
Wherein:
A be nitrogen-atoms or-CCN;
D is-(CH
2)
m-,-(CH
2)
m-O-,-(CH
2)
m-NH-or-CH
2CH
2CONH-, wherein m independently is the integer of 1-3 separately;
E is sulphur atom or NR
3, R wherein
3H, methyl, ethyl or phenyl;
R is R
4R
5N-or R
6S-, wherein R
4And R
5H, alkyl or aryl independently of one another, or R
4And R
5Represent to replace or unsubstituted, the other saturated heterocyclic that also contains 1 nitrogen-atoms, Sauerstoffatom or sulphur atom with the nitrogen-atoms that connects, wherein said substituting group is C
1-4Alkyl, described C
1-4Alkyl can be replaced by phenyl or halogenophenyl one or polysubstituted; Or R wherein
6The expression following radicals:
R wherein
7And R
8Hydrogen, methyl, ethyl, phenyl or benzyl independently of one another; Q is the integer of 1-3;
R
1Be selected from following radicals: halogen, phenyl, phenoxy group, benzyl, benzyloxy, pyridylmethyl or pyridyl methoxyl group wherein can have 1-3 substituting group that is selected from following radicals: halogen, hydroxyl, amino, C on described phenyl, benzyl or pyridyl
1-4Alkyl or C
1-4Alkoxyl group;
N is the integer of 1-3; With
R
2H, C
1-4The C that alkyl, halogen replace
1-4Alkyl, C
1-4The C that alkoxy or halogen replaces
1-4Alkoxyl group.
The pharmaceutical salts of general formula of the present invention (I) compound refers to the acid salt of the compounds of this invention, comprise inorganic acid addition salt or organic acid addition salt, described mineral acid is such as being sulfuric acid, hydrochloric acid, sulfurous acid, boric acid, phosphoric acid, sulfonic acid, Hydrogen bromide or hydrofluoric acid etc.; Described organic acid is such as being acetic acid, valeric acid, acetic acid, toxilic acid, fumaric acid, oxalic acid, oleic acid, lactic acid, palmitinic acid, lauric acid, stearic acid, citric acid, succsinic acid, tartrate, phenylformic acid, methylsulfonic acid, toluenesulphonic acids, gluconic acid, lactobionic acid or lauryl sulfonic acid etc.; Among described salt, can also also have basic metal or alkaline earth metal cation, positively charged ion such as lithium, sodium, potassium, calcium, magnesium etc., and various organic ammonium positively charged ions, the ammonium salt positively charged ion of formation such as tetramethyl-amine, tetraethyl-amine, methylamine, dimethylamine, ethamine.
Above-claimed cpd of the present invention is epidermal growth factor receptor inhibitor (EGFR inhibitor), can be used for treating tumour, be specially adapted to treat the disease by the protein tyrosine kinase mediation, such as mammary cancer, nonsmall-cell lung cancer, cancer of the stomach, carcinoma of the pancreas etc.
Preferably, the group D in general formula of the present invention (I) compound is-CH
2-,-(CH
2)
3-,-(CH
2)
3-O-,-(CH
2)
3-NH-or-CH
2CH
2CONH-; Group E wherein be sulphur atom or-NH-; More preferably wherein said-E-D-group is :-NH-CH
2-,-NH-(CH
2)
3-,-S-(CH
2)
3-O-or-S-CH
2CH
2CONH-.
R group in general formula is R
4R
5N-, and R wherein
4And R
5With the nitrogen-atoms that connects represent to replace or unsubstituted, when in addition also containing the saturated heterocyclic of 1 nitrogen-atoms, Sauerstoffatom or sulphur atom, wherein said saturated heterocyclic is saturated hexa-atomic or seven membered heterocyclic.Preferably, wherein said saturated hexa-atomic or seven membered heterocyclic is:
Preferred saturated heterocyclic is for replacing or unsubstituted piperazine or morpholine ring.When described saturated hexa-atomic or seven membered heterocyclic had substituting group, preferred described substituting group was methyl, halogenophenyl methyl or two (difluorophenyl) methyl.4-methylpiperazine base most preferably.
When the R described in the general formula is R
6During S-, R wherein
6Preferred expression following radicals:
Preferred R
1Group is selected from: halogen, benzyloxy or have the benzyloxy of 1-3 halogenic substituent, and the group that more preferably is connected on quinoline ring or the quinazoline ring 4-bit amino is:
Preferred R
2Group is H, C
1-4The C that alkoxy or halogen replaces
1-4Alkoxyl group; More preferably H or methoxyl group.
In the above-mentioned definition of the compounds of this invention, wherein used term " alkyl " refers to saturated alkyl, the alkyl that preferably has the straight or branched of 1-6 carbon atom more preferably has the alkyl of the straight or branched of 1-3 carbon atom, such as methyl, ethyl, propyl group, sec.-propyl etc.
Term used herein " aryl " refers to that phenyl, naphthyl etc. have the aromatic group of 6-10 carbon atom, preferred phenyl or naphthyl.
Term used in the present invention " halogen " refers to fluorine, chlorine, bromine and iodine atom, is preferably fluorine, chlorine or bromine atom.
The compounds of this invention defines in the used term " replacement or unsubstituted ", and wherein said " replacement " refers to be replaced or polysubstituted group by described substituting group list on commutable optional position.
The preferred compound of the present invention is:
4-methylpiperazine-1-dithio formic acid-[3-[4-(the 3-bromobenzene is amino) quinazoline-6-oxygen]] propyl ester (compound 1);
4-methylpiperazine-1-dithio formic acid-[3-[4-(3-chloro-4-fluoroanilino) quinazoline-6-oxygen]] propyl ester (compound 2);
4-methylpiperazine-1-dithio formic acid-[3-[4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino] quinazoline-6-oxygen] propyl ester (compound 3);
4-methylpiperazine-1-dithio formic acid-and 3-[4-(the 3-bromobenzene is amino)-7-methoxyl group quinazoline-6-oxygen] } propyl ester (compound 4);
4-methylpiperazine-1-dithio formic acid-and 3-[4-(3-chloro-4-fluoroanilino)-7-methoxyl group quinazoline-6-oxygen] } propyl ester (compound 5);
4-methylpiperazine-1-dithio formic acid-[3-[4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino]-7-methoxyl group quinazoline-6-oxygen]] propyl ester (compound 6);
Piperazine-4-dithio formic acid-[3-[4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino]-7-methoxyl group quinazoline-6-oxygen]] propyl ester (compound 7);
Homopiperazine-4-dithio formic acid-[3-[4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino]-7-methoxyl group quinazoline-6-oxygen]] propyl ester (compound 8);
Morpholine-4-dithio formic acid-[3-[4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino]-7-methoxyl group quinazoline-6-oxygen]] propyl ester (compound 9);
Thiomorpholine-4-dithio formic acid-[3-[4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino]-7-methoxyl group quinazoline-6-oxygen]] propyl ester (compound 10);
4-[two (4-fluorophenyl) methyl] piperazine-1-dithio formic acid-[3-[4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino]-7-methoxyl group quinazoline-6-oxygen]] propyl ester (compound 11);
4-methylpiperazine-1-dithio formic acid-[2-[4-(3-chloro-4-fluoroanilino) quinazoline-6-carbamyl]] ethyl ester (compound 12);
4-methylpiperazine-1-dithio formic acid-[2-[4-(3-chloro-4-fluoroanilino)-7-methoxyl group quinazoline-6-carboxamide]] ethyl ester (compound 13);
4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino] quinazolyl }-6-methylamino dithiocarbamate formic acid-2-[2-(1,3-dioxy cyclopentyl)] ethyl ester (compound 14);
[4-(3-chloro-4-fluoroanilino) quinazolyl]-6-methylamino dithiocarbamate formic acid-2-[2-(1,3-dioxy cyclopentyl)] ethyl ester (compound 15);
[4-(the 3-bromobenzene is amino) quinazolyl]-6-methylamino dithiocarbamate formic acid-2-[2-(1,3-dioxy cyclopentyl)] ethyl ester (compound 16);
4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino] quinazolyl }-6-methylamino dithiocarbamate formic acid-2-cyano group ethyl ester (compound 17);
4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino] quinazolyl }-6-methylamino dithiocarbamate formic acid-2-methoxycarbonyl base ethyl ester (compound 18);
4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino] quinazolyl }-6-methylamino dithiocarbamate formic acid-2-benzyl sulfuryl ethyl ester (compound 19);
4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino]-3-cyano group-7-methoxy quinoline base }-6-methylamino dithiocarbamate formic acid-2-[2-(1,3-dioxy cyclopentyl)] ethyl ester (compound 20)
[4-(3-chloro-4-fluoroanilino)-3-cyano group-7-methoxy quinoline base]-6-methylamino dithiocarbamate formic acid-2-[2-(1,3-dioxy cyclopentyl)] ethyl ester (compound 21);
[4-(the 3-bromobenzene is amino)-3-cyano group-7-methoxy quinoline base]-6-methylamino dithiocarbamate formic acid-2-[2-(1,3-dioxy cyclopentyl)] ethyl ester (compound 22); With
[4-(the 3-bromobenzene is amino) quinazolyl]-6-methylamino dithiocarbamate formic acid-2-benzyl sulfuryl ethyl ester (compound 23).
Another object of the present invention has provided the preparation method of above-mentioned general formula (I) compound or pharmaceutically acceptable salt thereof, the method comprises at first synthetic method synthesis of quinoline ring or the quinazoline ring according to routine, then successively introduces in any order required amino substituting group in its 4-position and introduces required group in its 6-position according to ordinary method.
For example, when general formula (I) compound be quinazoline derivant, be connected in the 6-position be Sauerstoffatom the time, synthetic quinazoline ring and introduce the substituent method of required amino in its 4-position and can carry out with reference to the disclosed reaction scheme 1 of WO2008/0033749,2,6 or 15; Can obtain quinazoline ring 6-position according to above various synthetic methods is the midbody compound of hydroxyl or protected hydroxyl:
Then, making its deprotection, is midbody compound and general formula (III) compound of hydroxyl with quinazoline ring 6-position: X (CH
2)
mBr reacts, and obtains general formula (IV) compound:
Wherein said m defines as mentioned, and X is halogen;
With above-claimed cpd (IV) and dithiocarbonic anhydride and R
4R
5NH reacts under the reaction conditions of routine, and can obtain the R group is R
4R
5The purpose compound of N-.
When general formula (I) compound be quinazoline derivant, be connected in the 6-position be nitrogen-atoms the time, synthetic quinazoline ring and introduce the substituent method of required amino in its 4-position and can carry out with reference to the disclosed reaction scheme 3 of WO2008/0033749; The 6-position that can obtain the quinazoline ring according to above various synthetic methods is amino midbody compound, and then, making quinazoline ring 6-position is amino midbody compound and R
6X and CS
2React under the reaction conditions of routine, can obtain the R group is R
6The purpose compound of S-.
When general formula (I) compound is quinazoline derivant, and that be connected in quinazoline ring 6-position is C
1-3During the alkylamino dithiocarbamates, the preparation method of described purpose compound comprises the protected intermediate of alkylamino that at first prepares quinazoline ring 6-position, and wherein said blocking group is take phthaloyl as example:
Then make resulting midbody compound deprotection, and with this midbody compound and R
6X and CS
2Under the reaction conditions of routine, react, can obtain quinazoline-6-C
1-3The purpose compound of alkylamino dithio formate class.
When described general formula (I) compound is quinoline, that namely be connected in quinoline ring 6-position is C
1-3During the dithiocarbamates compound of alkylamino, quinoline is raw material accordingly, according to preparing corresponding purpose compound with the similar method of above-mentioned reaction process.
When wherein the protected intermediate of quinoline ring 6-bit amino was the aminomethyl intermediate, it was that the method for amino protected aminomethylation intermediate for example can be that another kind obtains quinoline ring 6-position:
Then, make above-mentioned midbody compound deprotection, with R
6X and CS
2Under the reaction conditions of routine, react, can obtain quinoline-6-methylamino dithiocarbamate formate ester purpose compound.
In this reaction process, be methyl corresponding to above-mentioned midbody compound 6-bit position in the starting material compound raw material, be understandable that, according to the desired carbon atom number of purpose compound, described methyl can be C
1-3Alkyl group.
The preparation of the pharmaceutical salts of general formula of the present invention (I) compound can be finished in the process of this compound of preparation, also can after preparing this compound, according to the ordinary method of preparation additive salt, make this compound and corresponding acid react acquisition.
Various raw materials used in the aforesaid method all can have been bought in market, or adopt the currently known methods preparation.
Another object of the present invention has provided a kind of pharmaceutical composition, this pharmaceutical composition is a kind of tyrosine kinase inhibitor, can be used for treating the disease by the protein tyrosine kinase mediation, for example can be used for treating tumour, be specially adapted to treat mammary cancer, nonsmall-cell lung cancer, cancer of the stomach, carcinoma of the pancreas etc.Said composition wherein can also at random contain pharmaceutical carrier take general formula of the present invention (I) compound or pharmaceutically acceptable salt thereof as activeconstituents.
Concrete, said composition contains general formula of the present invention (I) compound or pharmaceutically acceptable salt thereof for the treatment of significant quantity, and one or more pharmaceutically acceptable carriers.Preferably, the content of activeconstituents is 0.5%-99% in the present composition, and the content of pharmaceutical carrier is 1%-99.5%.
Composition of the present invention can be made the pharmaceutical dosage form of various routines, for example makes form oral, administered parenterally, and the form of described administered parenterally for example is the form of various drug administration by injection, topical, inhalation, rectal administration or drug delivery implant.
Be suitable for medicinal oral Preparation such as being that tablet, capsule, granule or other are suitable for the preparation of medicinal liquid form such as solution, emulsion, suspension agent etc.Preferred oral preparations is tablet, and described tablet can be made dressing, enteric, slowly-releasing or the quantitative form that discharges.
In order to prepare applicable formulation, can in activeconstituents, add as required one or more pharmaceutical carriers, described pharmaceutical carrier comprises the medicinal adjuvant of various routines, such as vehicle, weighting agent, thinner, disintegrating agent, tensio-active agent, wetting agent, sanitas, sweeting agent, pigment etc.
According to the type of disease, serious degree and patient's situation, such as sex, age, body weight etc. selected suitable formulation and application dosage, and the application dosage of usually being grown up is preferably between the 1-50mg/kg body weight/day in the 1-200mg/kg body weight/day.
The various preparations of medicinal compositions of the present invention and said composition can be according to the known ordinary method preparation of pharmacy field.
Another object of the present invention has provided the pharmaceutical usage of general formula (I) compound or its acceptable salt, the invention discloses above-mentioned general formula (I) compound or its acceptable salt, and the application of pharmaceutical composition in the preparation tyrosine kinase inhibitor, the particularly application in the preparation antitumor drug that contain above-claimed cpd.Described antitumor drug is specially adapted to treat the tumours such as mammary cancer, nonsmall-cell lung cancer, cancer of the stomach, carcinoma of the pancreas.
Screen by the activity to the compounds of this invention, comprise that the result who carries out protein tyrosine kinase inhibition screening active ingredients test and anti tumor activity in vitro test can find out, the compound or pharmaceutically acceptable salt thereof of general formula of the present invention (I) has excellent albumen butyric acid kinase inhibiting activity and antitumour activity, is expected to develop the anti-cancer agent that becomes a class new texture type.
Another object of the present invention has provided a kind of method for the treatment of tumour, and the method comprises that general formula (I) compound or pharmaceutically acceptable salt thereof with the treatment significant quantity is applied to the patient of this treatment of needs.
Embodiment
Below by concrete embodiment technical scheme of the present invention is further described, the embodiment that wherein exemplifies is to explanation of the present invention, and limits never in any form its protection domain.
Preparation Example 1 6-hydroxyl-3H-quinazoline-4-one
2-amino-5-hydroxy-benzoic acid (1.53g, 10mmol) is added in the 10mL methane amide, 150 ℃ of lower reaction 0.5h, reaction solution is cooled to room temperature, in reaction solution, add 30mL water, separate out a large amount of solids, suction filtration, oven dry, 1.44g brown solid product, yield is 88%, m.p.＞300 ℃.
1H NMR(300MHz，DMSO-d
6)：δ＝7.25(s，1H)，7.40(s，1H)，7.52(s，1H)，7.90(s，1H)，10.07(s，1H)，12.03(s，1H)。
Preparation Example 2 6-acetoxy-3 H-quinazoline-4-ones
With 6-hydroxyl-3H-quinazoline-4-one (0.81g, 5mmol) add in the 8mL diacetyl oxide, add the 1mL pyridine, backflow 2h, reaction solution is cooled to room temperature, in reaction solution, add the 30mL frozen water, separate out a large amount of solids, suction filtration, oven dry, 0.66g pale solid product, yield 64%, m.p.＞300 ℃.
1H NMR(300MHz，DMSO-d
6)：δ＝2.32(s，3H)，7.60(dd，J＝2.7，8.7Hz，1H)，7.73(d，J＝2.7Hz，1H)，7.83(d，J＝2.4Hz，1H)，8.11(s，1H)，12.35(s，1H)。
Preparation Example 3 4-(the 3-bromobenzene is amino)-6-acetoxyl group quinazoline
With 6-acetoxy-3 H-quinazoline-4-one (1.03g, 5mmol) join in the 10mL thionyl chloride, splash into DMF (DMF) (0.5mL), back flow reaction 6h, remove excessive thionyl chloride under reduced pressure, get intermediate 4-chloro-6-acetoxyl group quinazoline, not purified, directly be dissolved in the 15mL Virahol, add m-bromoaniline (0.86g, 5mmol), the 1mL triethylamine, back flow reaction 4h, reaction solution is cooled to room temperature, and suction filtration, filter cake are used Virahol successively, water, the ether washing, oven dry, get 1.24g faint yellow solid product, yield 69%, m.p.238-239 ℃.
1H NMR(300MHz，DMSO-d
6)：δ＝2.40(s，3H)，7.44-7.54(m，2H)，7.78(d，J＝7.5Hz，1H)，7.93-8.09(m，3H)，8.67(s，1H)，8.99(s，1H)，11.39(s，1H)。
Preparation Example 4 4-(3-chloro-4-fluoroanilino)-6-acetoxyl group quinazoline
According to Preparation Example 3 described methods, just change m-bromoaniline into 3-chloro-4-fluoroaniline, yield 74%, m.p.＞300 ℃.
Preparation Example 5 4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino]-6-acetoxyl group quinazoline
By Preparation Example 3 described methods, just change m-bromoaniline into 3-chloro-4-(3-fluorine benzyloxy) aniline, yield 73%, m.p.290-292 ℃.
Preparation Example 6 4-(the 3-bromobenzene is amino)-6-hydroxyl quinazoline
4-(the 3-bromobenzene is amino)-6-acetoxyl group quinazoline (0.72g, 2mmol) is dissolved in the 15mL methyl alcohol, adds 4mL ammoniacal liquor, react 3h under the room temperature, suction filtration, oven dry gets the 0.31g pale solid, filtrate is concentrated by silicagel column separation and purification (eluent, sherwood oil: ethyl acetate=1: 2, v: v), get 0.28g pale solid 0.59g, yield 93%, m.p.＞300 ℃.
1H NMR(300MHz，DMSO-d
6)：δ＝7.28-7.37(m，1H)，7.46(d，J＝9.0Hz，1H)，7.71(d，J＝9.0Hz，1H)，7.80(s，1H)，8.27(s，1H)，8.52(s，1H)，9.60(s，1H)，10.11(s，1H)。
Preparation Example 7 4-(3-chloro-4-fluoroanilino)-6-hydroxyl quinazoline
According to Preparation Example 6 described methods, just change 4-(the 3-bromobenzene is amino)-6-acetoxyl group quinazoline into 4-(3-chloro-4-fluoroanilino)-6-acetoxyl group quinazoline, yield 91%, m.p.＞300 ℃.
1H NMR(300MHz，DMSO-d
6)：δ＝7.56(t，J＝9.0Hz，1H)，7.72-7.74(m，2H)，7.92(d，J＝8.7Hz，1H)，8.04-8.07(m，2H)，8.87(s，1H)，10.98(s，1H)，11.38(s，1H)。
Preparation Example 8 4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino]-6-hydroxyl quinazoline
According to Preparation Example 6 described methods, just change 4-(the 3-bromobenzene is amino)-6-acetoxyl group quinazoline into 4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino]-6-acetoxyl group quinazoline, yield 94%, m.p.＞300 ℃.
1H NMR(300MHz，DMSO-d
6)：δ＝5.25(s，1H)，7.16-7.34(m，4H)，7.40-7.51(m，2H)，7.67(d，J＝8.7Hz，1H)，7.74-7.78(m，2H)，8.07(d，J＝2.7Hz，1H)，8.44(s，1H)，9.50(s，1H)，10.09(s，1H)。
Preparation Example 9 4-(the 3-bromobenzene is amino)-6-(3-chlorine propoxy-) quinazoline
With 4-(the 3-bromobenzene is amino)-6-hydroxyl quinazoline (0.32g, 1mmol) be dissolved in the 20mL acetonitrile, the Tetrabutyl amonium bromide that adds salt of wormwood (0.56g, 4mmol) and catalytic amount, reflux 20min, add 1,3-bromo-chloropropane (0.32g, 2mmol), back flow reaction 2h, reaction solution is cooled to room temperature, filter, filter cake washs with acetonitrile, and filtrate is concentrated, silicagel column separation and purification (eluent, sherwood oil: ethyl acetate=2: 1, v: v), get the 0.27g pale solid, yield 68%, m.p.175-176 ℃.
1H NMR(300MHz，DMSO-d
6)：δ＝2.29(t，J＝6.0Hz，2H)，3.88(t，J＝6.0Hz，2H)，4.30(t，J＝6.0Hz，2H)，7.30-7.41(m，2H)，7.54-7.57(m，2H)，7.77(d，J＝9.0Hz，1H)，7.90-7.96(m，2H)，8.19(s，1H)，8.57(s，1H)，9.70(s，1H)。
Preparation Example 10 4-(3-chloro-4-fluoroanilino)-6-(3-chlorine propoxy-) quinazoline
According to Preparation Example 9 described methods, just change 4-(the 3-bromobenzene is amino)-6-hydroxyl quinazoline into 4-(3-chloro-4-fluoroanilino)-6-hydroxyl quinazoline, yield 60%, m.p.140-141 ℃.
1H NMR(300MHz，DMSO-d
6)：δ＝2.29(t，J＝6.3Hz，2H)，3.88(t，J＝5.7Hz，2H)，4.30(t，J＝6.0Hz，2H)，7.44-7.57(m，2H)，7.75-7.82(m，2H)，7.93(s，1H)，8.16-8.18(m，1H)，8.55(s，1H)，9.74(s，1H)。
Preparation Example 11 4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino]-6-(3-chlorine propoxy-) quinazoline
According to Preparation Example 9 described methods, just change 4-(the 3-bromobenzene is amino)-6-hydroxyl quinazoline into 4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino]-6-hydroxyl quinazoline, yield 67%, m.p.144-146 ℃.
1H NMR(300MHz，DMSO-d
6)：δ＝2.28(t，J＝6.6Hz，2H)，3.87(t，J＝6.0Hz，2H)，4.28(t，J＝5.7Hz，2H)，5.26(s，2H)，7.19(m，1H)，7.27-7.35(m，3H)，7.47-7.54(m，2H)，7.72-7.75(m，2H)，7.91(m，1H)，7.99(d，J＝2.4Hz，1H)，8.49(s，1H)，9.61(s，1H)。
Embodiment 1 4-methylpiperazine-1-dithio formic acid-[3-[4-(the 3-bromobenzene is amino) quinazoline-6-oxygen]] propyl ester
With N methyl piperazine (0.10g, 1mmol) be dissolved among the 15mL DMF, add anhydrous phosphoric acid potassium (0.43g, 2mmol), splash into dithiocarbonic anhydride (0.19g under the stirring at room, 2.5mmol), behind the reaction 30min, add 4-(the 3-bromobenzene is amino)-6-(3-chlorine propoxy-) quinazoline (0.40g, 1mmol), continue stirring at room, TLC detects, until reaction finishes.In reaction system, add 15mL water, with ethyl acetate extraction (15mL * 3), merge organic layer, washing (15mL * 2), anhydrous sodium sulfate drying, concentrated, residuum acetonitrile recrystallization obtains the 0.38g solid, yield 71%, m.p.152-153 ℃.
1H NMR(300MHz，DMSO-d
6)：δ＝2.20-2.24(m，5H)，2.38(t，J＝5.1H z，4H)，3.47(t，J＝7.2H z，2H)，3.91(m，2H)，4.24(t，J＝5.4H z，4H)，7.30-7.40(m，2H)，7.54(dd，J＝2.7，9.3Hz，1H)，7.76(d，J＝9.0Hz，1H)，7.91-7.93(m，2H)，8.19-8.20(m，1H)，8.57(s，1H)，9.67(s，1H)。Ultimate analysis C
23H
26BrN
5OS
2: theoretical value: C, 51.88; H, 4.92; N, 13.15. measured value: C, 51.81; H, 4.92; N, 13.03.
Embodiment 2 4-methylpiperazine-1-dithio formic acid-[3-[4-(3-chloro-4-fluoroanilino) quinazoline-6-oxygen]] propyl ester
According to embodiment 1 described method, just change raw material 4-(the 3-bromobenzene is amino)-6-(3-chlorine propoxy-) quinazoline into 4-(3-chloro-4-fluoroanilino)-6-(3-chlorine propoxy-) quinazoline, yield 63%, m.p.154-155 ℃.
1H NMR(300MHz，DMSO-d
6)：δ＝2.20-2.24(m，5H)，2.39(t，J＝5.1H z，4H)，3.46(t，J＝7.2H z，2H)，3.92(m，2H)，4.25(t，J＝5.7H z，4H)，7.47(t，J＝9.0H z，1H)，7.54(dd，J＝2.4，9.0Hz，1H)，7.76(d，J＝9.0Hz，1H)，7.81-7.87(m，1H)，7.91(d，J＝2.1Hz，1H)，8.17(dd，J＝2.7，6.9Hz，1H)，8.55(s，1H)，9.70(s，1H)。Ultimate analysis C
23H
25ClFN
5OS
2: theoretical value: C, 54.59; H, 4.98; N, 13.84. measured value: C, 54.65; H, 5.00; N, 13.75.
Embodiment 3 4-methylpiperazine-1-dithio formic acid-[3-[4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino] quinazoline-6-oxygen] propyl ester
According to embodiment 1 described method, just change raw material 4-(the 3-bromobenzene is amino)-6-(3-chlorine propoxy-) quinazoline into 4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino]-6-(3-chlorine propoxy-) quinazoline, yield 57%, m.p.128-130 ℃.
1H NMR(300MHz，DMSO-d
6)：δ＝2.19(m，5H)，2.39(t，J＝4.8Hz，4H)，3.46(t，J＝6.6H z，2H)，3.92(m，2H)，4.24(s，4H)，5.26(s，2H)，7.19(t，J＝8.7H z，1H)，7.27-7.35(m，3H)，7.44-7.53(m，2H)，7.71-7.74(m，2H)，7.90(s，1H)，7.99(d，J＝2.4Hz，1H)，8.49(s，1H)，9.59(s，1H)。HRMS:C
30H
31ClFN
5O
2S
2+ H, theoretical value 612.16700; Measured value (ESI-FTMS, (M+H)
+ 1), 612.16556.
Preparation Example 12 3-hydroxyl-4-methoxyl methyl benzoate
3-hydroxyl-4-methoxybenzoic acid (1.68g, 10mmol) is dissolved in the 15mL methyl alcohol, slowly drips thionyl chloride (1.1mL) under the ice bath, drip and finish, react 24h under the room temperature, steam except excessive methyl alcohol, add 15mL water, with ethyl acetate extraction (15mL * 3), merge organic layer, anhydrous sodium sulfate drying, concentrated, the silicagel column separation and purification, eluent (sherwood oil: ethyl acetate=5: 1, v: v), get the 1.56g white solid product, yield 85%, m.p.61-63 ℃.
1H NMR(300MHz，CDCl
3)：δ＝3.88(s，1H)，3.95(s，1H)，5,67(s，1H)，6.87(d，J＝8.1Hz，1H)，7.60(s，1H)，7.63(d，J＝1.5Hz，1H)。
Preparation Example 13 3-(3-chlorine propoxy-)-4-methoxyl methyl benzoate
Preparation Example 12 products (1.82g, 10mmol) are dissolved in the 20mL acetonitrile, add salt of wormwood (2.76g, 20mmol) and the Tetrabutyl amonium bromide of catalytic amount, reflux 20min adds 1,3-bromo-chloropropane (0.32g, 2mmol), back flow reaction 4h, reaction solution is cooled to room temperature, steam except acetonitrile, in reaction system, add 15mL water, with ethyl acetate extraction (15mL * 3), merge organic layer, anhydrous sodium sulfate drying, concentrated, silicagel column separation and purification (eluent, sherwood oil: ethyl acetate=5: 1, v: v), get the 2.41g white solid, yield 93%, m.p.51-52 ℃.
1H NMR(300MHz，DMSO-d
6)：δ＝2.14-2.23(m，2H)，3.77-3.85(m，8H)，4.12(t，J＝6.0Hz，2H)，7.09(d，J＝8.7Hz，1H)，7.47(d，J＝1.8Hz，1H)，7.60(dd，J＝1.8，8.4Hz，1H)。
Preparation Example 14 2-nitro-4-methoxyl group-5-(3-chlorine propoxy-) methyl benzoate
With Preparation Example 13 product (6.46g, 25mmol) be dissolved in the 50mL chloroform, 10 ℃ of lower nitration mixture that are made into by concentrated nitric acid (4.5mL) and the vitriol oil (5mL) that drip, drip and finish, 20 ℃ of lower reaction 4h add 50mL frozen water dilute reaction solution, branch vibration layer, chloroform layer washs with the 20mL saturated sodium bicarbonate aqueous solution, be washed to neutrality, anhydrous sodium sulfate drying, steaming desolventizes, silicagel column separation and purification (eluent, sherwood oil: ethyl acetate=5: 1, v: v), get the 6.84g yellow solid, yield 90%, m.p.68-70 ℃.
1H NMR(300MHz，DMSO-d
6)：δ＝2.21(t，J＝6.0Hz，2H)，3.78(t，J＝6.3Hz，2H)，3.82(s，3H)，3.92(s，3H)，4.25(t，J＝6.0Hz，2H)，7.37(s，1H)，7.65(s，1H)。
Preparation Example 15 2-amino-4-methoxyl-5-(3-chlorine propoxy-) methyl benzoate
With Preparation Example 14 product (1.83g, 6mmol), ammonium chloride (1.61g, 30mmol), reduced iron powder (1.11g, 19.8mmol) adds in 30mL methyl alcohol and the 15mL water, back flow reaction 2h, reaction solution is cooled to room temperature, with saturated sodium bicarbonate aqueous solution reaction solution is transferred to neutrality, suction filtration, elimination insolubles, filtrate extracts with methylene dichloride (15mL * 3), merge organic layer, anhydrous sodium sulfate drying, steaming desolventizes, silicagel column separation and purification (eluent, sherwood oil: ethyl acetate=4: 1, v: v), get the 6.84g white solid, yield 65%, m.p.97-99 ℃.
1H NMR(400MHz，CDCl
3)：δ＝2.20-2.26(m，2H)，3.76(t，J＝4.8Hz，2H)，3.84(s，3H)，3.84(s，3H)，4.08(t，J＝4.5Hz，2H)，5.51(s，2H)，6.15(s，1H)，7.36(s，1H)。
Preparation Example 16 4-hydroxyl-6-(3-chlorine propoxy-)-7-methoxyl group quinazoline
Preparation Example 15 products (0.55g, 2mmol) are added in the 5mL methane amide oil bath heating, stirring makes solid entirely molten, slowly drips the 1mL phosphorus oxychloride, and the control temperature is between 85-95 ℃, dropwise, under this temperature, react 2h, after question response is complete, in the sorrel dope of gained, add an amount of frozen water, stir under the room temperature, regulate pH 6～7 with the aqueous sodium hydroxide solution of 1N, get the orange dirty solution, suction filtration gets puce solid 0.35g, yield 65%, m.p.213-215 ℃.
1H NMR(300MHz，DMSO-d
6)：δ＝2.23(t，J＝6.3Hz，2H)，3.81(t，J＝6.3Hz，2H)，3.92(s，3H)，4.19(t，J＝6.3Hz，2H)，7.15(s，1H)，7.47(s，1H)，7.99(s，1H)，12.09(s，1H)。
Preparation Example 17 4-(the 3-bromobenzene is amino)-6-(3-chlorine propoxy-)-7-methoxyl group quinazoline
With Preparation Example 16 product (1.08g, 4mmol) add in the 10mL thionyl chloride, splash into 0.5mL DMF, back flow reaction 3h removes excessive thionyl chloride under reduced pressure, get intermediate 4-chloro-6-(3-chlorine propoxy-)-7-methoxyl group quinazoline, do not separate, intermediate is dissolved in the 15mL Virahol, add m-bromoaniline (0.69g, 4mmol), the 1mL triethylamine, back flow reaction 3h is cooled to room temperature with reaction solution, suction filtration, the cold isopropanol washing, drying gets faint yellow solid 1.52g, yield 89%, m.p.198-200 ℃.
1H NMR(400MHz，DMSO-d
6)：δ＝2.27-2.34(m，2H)，3.86(t，J＝4.8Hz，2H)，3.96(s，3H)，4.29(t，J＝4.5Hz，2H)，7.23(s，1H)，7.27-7.30(m，1H)，7.36(t，J＝6.0Hz，1H)，7.84-7.89(m，1H)，7.96(s，1H)，8.15(t，J＝1.5Hz，1H)，8.53(s，1H)，9.53(s，1H)。
Preparation Example 18 4-(3-chloro-4-fluoroanilino)-6-(3-chlorine propoxy-)-7-methoxyl group quinazoline
According to Preparation Example 17 described methods, just change the stock yard bromaniline into 3-chloro-4-fluoroaniline, yield 82%, m.p.224-226 ℃.
1H NMR(300MHz，DMSO-d
6)：δ＝2.29(t，J＝6.0Hz，2H)，3.85(t，J＝5.4Hz，2H)，4.02(s，3H)，4.34(t，J＝5.7Hz，2H)，7.31(s，1H)，7.57(t，J＝8.7Hz，1H)，7.70(s，1H)，8.01(d，J＝7.2Hz，1H)，8.23(s，1H)，8.87(s，1H)，11.21(s，1H)。
Preparation Example 19 4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino]-6-(3-chlorine propoxy-)-7-methoxyl group quinazoline
According to Preparation Example 17 described methods, just change the stock yard bromaniline into 3-chloro-4-(3-fluorine benzyloxy) aniline, yield 72%, m.p.194-196 ℃.
1H NMR(300MHz，DMSO-d
6)：δ＝2.31(t，J＝4.8Hz，2H)，3.85(t，J＝4.8Hz，2H)，4.01(s，3H)，4.34(t，J＝4.5Hz，2H)，5.31(s，2H)，7.17-7.22(m，1H)，7.32-7.36(m，4H)，7.46-7.51(m，1H)，7.61(dd，J＝1.8，6.6Hz，1H)，7.85(d，J＝1.8Hz，1H)，8.26(s，1H)，8.84(s，1H)，11.25(s，1H)。
Embodiment 4 4-methylpiperazine-1-dithio formic acid-and 3-[4-(the 3-bromobenzene is amino)-7-methoxyl group quinazoline-6-oxygen] } propyl ester
With N methyl piperazine (0.10g, 1mmol) be dissolved in 15mL DMF, add anhydrous phosphoric acid potassium (0.43g, 2mmol), splash into dithiocarbonic anhydride (0.19g under the stirring at room, 2.5mmol), behind the reaction 30min, add 4-(the 3-bromobenzene is amino)-6-(3-chlorine propoxy-)-7-methoxyl group quinazoline (0.43g, 1mmol), continue stirring at room, detected by TLC, until reaction finishes.In reaction system, add 15mL water, with ethyl acetate extraction (15mL * 3), merge organic layer, washing (15mL * 2), anhydrous sodium sulfate drying, concentrated, residuum acetonitrile recrystallization obtains the 0.42g solid, yield 74%, m.p.166-168 ℃.
1H NMR(300MHz，DMSO-d
6)：δ＝2.20-2.25(m，5H)，2.39(t，J＝4.5Hz，4H)，3.44(t，J＝6.6Hz，2H)，3.95(s，5H)，4.25(t，J＝5.7Hz，4H)，7.23(s，1H)，7.27-7.39(m，2H)，7.86-7.90(m，2H)，8.15(s，1H)，8.53(s，1H)，9.52(s，1H)。Ultimate analysis C
24H
28BrN
5O
2S
2: theoretical value: C, 51.24; H, 5.02; N, 12.45. measured value: C, 51.29; H, 5.06; N, 12.61.
Embodiment 5 4-methylpiperazine-1-dithio formic acid-and 3-[4-(3-chloro-4-fluoroanilino)-7-methoxyl group quinazoline-6-oxygen] } propyl ester
According to embodiment 4 described methods, just change raw material 4-(the 3-bromobenzene is amino)-6-(3-chlorine propoxy-)-7-methoxyl group quinazoline into 4-(3-chloro-4-fluoroanilino)-6-(3-chlorine propoxy-)-7-methoxyl group quinazoline, yield 69%, m.p.86-87 ℃.
1H NMR(300MHz，DMSO-d
6)：δ＝2.20-2.25(m，5H)，2.38(t，J＝5.1Hz，4H)，3.44(t，J＝7.2Hz，2H)，3.95(s，5H)，4.22(t，J＝5.7Hz，4H)，7.22(s，1H)，7.46(t，J＝9.0Hz，4H)，7.79-7.84(m，2H)，8.12(dd，J＝2.4，6.9Hz，1H)，8.51(s，1H)，9.55(s，1H)。Ultimate analysis C
24H
27ClFN
5O
2S
2: theoretical value: C, 53.77; H, 5.08; N, 13.06. measures: C, 53.69; H, 5.06; N, 12.97.
Embodiment 6 4-methylpiperazine-1-dithio formic acid-[3-[4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino]-7-methoxyl group quinazoline-6-oxygen]] propyl ester
According to embodiment 4 described methods, just change raw material 4-(the 3-bromobenzene is amino)-6-(3-chlorine propoxy-)-7-methoxyl group quinazoline into 4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino]-6-(3-chlorine propoxy-)-7-methoxyl group quinazoline, yield 62%, m.p.84-85 ℃.
1H NMR(300MHz，DMSO-d
6)：δ＝2.19-2.23(m，5H)，2.37(t，J＝4.5Hz，4H)，3.42(t，J＝7.2Hz，2H)，3.92(s，5H)，4.21(s，4H)，5.24(s，2H)，7.15-7.33(m，6H)，7.42-7.50(m，1H)，7.69(dd，J＝2.4，8.7Hz，1H)，7.81(s，1H)，7.94(d，J＝2.4Hz，1H)，8.44(s，1H)。Ultimate analysis C
31H
33ClFN
5O
3S
2.CH
3CN: theoretical value: C, 58.01; H, 5.31; N, 12.30. measured value: C, 57.90; H, 5.42; N, 12.23.
Embodiment 7 piperazines-4-dithio formic acid-[3-[4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino]-7-methoxyl group quinazoline-6-oxygen]] propyl ester
Piperazine mono-hydrochloric salts (0.1mmol) is dissolved among the 10mL DMF, slowly splash into dithiocarbonic anhydride (0.1mmol), behind the stirring at room 0.5h, add anhydrous phosphoric acid potassium (0.2mmol) and 4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino]-6-(3-chlorine propoxy-)-7-methoxyl group quinazoline (0.1mmol), continue the stirring at room reaction, the TLC monitoring reaction is to reacting completely.In reaction system, add 15mL water, with ethyl acetate extraction (15mL * 3), merge organic layer, washing (15mL * 2), anhydrous sodium sulfate drying, concentrated, residuum acetonitrile recrystallization obtains the 35mg solid, yield 55%, m.p.124-126 ℃.HRMS:C
30H
31ClFN
5O
3S
2+ H, theoretical value 628.16191; Measured value (ESI-FTMS, (M+H)
+ 1), 628.16196.
Embodiment 8 homopiperazines-4-dithio formic acid-[3-[4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino]-7-methoxyl group quinazoline-6-oxygen]] propyl ester
According to embodiment 7 described methods, just change raw material piperazine mono-hydrochloric salts into the homopiperazine mono-hydrochloric salts, yield 47%, m.p.179-180 ℃.
1H NMR(400MHz，DMSO-d
6)：δ＝1.21(s，1H)，2.03-2.20(m，5H)，3.92-4.55(m，14H)，5.24(s，2H)，7.15-7.20(m，2H)，7.24-7.34(m，3H)，7.44-7.49(m，1H)，7.69(dd，J＝1.8，6.9Hz，1H)，7.81(s，1H)，7.94(d，J＝1.5Hz，1H)，8.45(s，1H)，9.42(s，1H)。
Embodiment 9 morpholines-4-dithio formic acid-[3-[4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino]-7-methoxyl group quinazoline-6-oxygen]] propyl ester
According to embodiment 6 described methods, just change the raw material N methyl piperazine into morpholine, yield 66%, m.p.80-82 ℃.
1H NMR(400MHz，DMSO-d
6)：δ＝2.20-2.27(m，2H)，3.46(t，J＝5.4Hz，2H)，3.66((t，J＝3.3Hz，4H)，3.94(s，5H)，4.23(t，J＝4.5Hz，4H)，5.25(s，2H)，7.16-2.21(m，2H)，7.26-7.35(m，3H)，7.45-7.50(m，1H)，7.69(dd，J＝1.8，6.6Hz，1H)，7.83(s，1H)，7.95(d，J＝1.8Hz，1H)，8.46(s，1H)，9.42(s，1H)。Ultimate analysis C
30H
30ClFN
4O
4S
2: theoretical value: C, 57.27; H, 4.81; N, 8.90. measured value: C, 57.69; H, 4.91; N, 8.70.
Embodiment 10 thiomorpholines-4-dithio formic acid-[3-[4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino]-7-methoxyl group quinazoline-6-oxygen]] propyl ester
According to embodiment 6 described methods, just change the raw material N methyl piperazine into thiomorpholine, yield 80%, m.p.176-177 ℃.
1HNMR(400MHz，DMSO-d
6)：δ＝2.20-2.27(m，2H)，2.71-2.74(m，4H)，3.46(t，J＝5.4Hz，2H)，3.94(s，3H)，4.22-4.52(m，6H)，5.25(s，2H)，7.16-7.21(m，2H)，7.26-7.35(m，3H)，7.45-7.50(m，1H)，7.69(dd，J＝2.1，6.9Hz，1H)，7.82(s，1H)，7.95(d，J＝1.8Hz，1H)，8.46(s，1H)，9.42(s，1H)。Ultimate analysis C
30H
30ClFN
4O
3S
3: theoretical value: C, 55.84; H, 4.69; N, 8.68. measured value: C, 55.86; H, 4.91; N, 8.67.
Embodiment 11 4-[two (4-fluorophenyl) methyl] piperazine-1-dithio formic acid-[3-[4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino]-7-methoxyl group quinazoline-6-oxygen]] propyl ester
According to embodiment 6 described methods, just change the raw material N methyl piperazine into 1-[two (4-fluorophenyl) methyl] piperazine, yield 45%, m.p.151-153 ℃.
1H NMR(400MHz，DMSO-d
6)：δ＝2.09(s，1H)，2.21(t，J＝5.1Hz，2H)，2.36(t，J＝3.3Hz，4H)，3.42(t，J＝5.4Hz，2H)，3.93(s，4H)，4.21(t，J＝4.5Hz，4H)，4.46(s，1H)，5.26(s，2H)，7.12-7.21(m，6H)，7.26-7.35(m，3H)，7.42-7.50(m，5H)，7.70(dd，J＝1.8，6.6Hz，1H)，7.81(s，1H)，7.94(d，J＝1.8Hz，1H)，8.46(s，1H)，9.41(s，1H)。Ultimate analysis C
43H
39ClF
3N
5O
3S
2: theoretical value: C, 62.20; H, 4.73; N, 8.43. measured value: C, 62.41; H, 4.97; N, 8.29.
Preparation Example 20 5-nitro isatin
Isatin (5.88g, 40mmol) is dissolved in the 25.2mL vitriol oil, stirs under the ice bath, slowly drip the 1.88mL nitrosonitric acid, 0 ℃ of lower reaction 45min reacts complete, reaction solution is poured in the trash ice, separate out the orange solid, suction filtration washes with water to neutrality, oven dry, get 6.3g orange solid, yield 81%, m.p.253-254 ℃.
Preparation Example 21 2-amino-5-nitrobenzoic acid
5-nitro isatin (1.92g, 10mmol) is dissolved in the 50mL 1N aqueous sodium hydroxide solution, drips the 3.2mL hydrogen peroxide, drip and finish, 10～15 ℃ of lower reaction 30min react complete, with the reaction solution suction filtration, the elimination insolubles, filtrate transfers to pH=5～6 with the 3N hydrochloric acid soln, separate out a large amount of yellow solids, suction filtration, oven dry gets the 1.24g yellow solid, yield 68%, m.p.275-276 ℃.
1H NMR(300MHz，DMSO-d
6)：δ＝6.87(d，J＝9.3Hz，1H)，7.88(s，2H)，8.08(dd，J＝3.0，9.3Hz，1H)，8.59(d，J＝2.7Hz，1H)，13.29(br s，1H)。
Preparation Example 22 4-hydroxyl-6-nitro-quinazoline
2-amino-5-nitrobenzoic acid (0.91g, 5mmol) is added in the 5mL methane amide 150 ℃ of lower reaction 6h, reaction solution is chilled to room temperature, in reaction flask, adds the 30mL ethyl acetate, suction filtration, remove insolubles, filtrate merges organic layer with ethyl acetate-water mixed system extraction, anhydrous sodium sulfate drying, concentrated, residuum methanol-water recrystallization gets the 0.60g yellow solid, yield 62%, m.p.284-286 ℃.
1H NMR(300MHz，DMSO-d
6)：δ＝7.87(d，J＝9.0Hz，1H)，8.32(s，1H)，8.56(dd，J＝2.7，9.0Hz，1H)，8.81(d，J＝2.7Hz，1H)，12.77(s，1H)。
Preparation Example 23 4-(3-chloro-4-fluoroanilino)-6-nitro-quinazoline
With 4-hydroxyl-6-nitro-quinazoline (0.96g, 5mmol) add in the 10mL thionyl chloride, splash into 0.5mL DMF, back flow reaction 6h removes excessive thionyl chloride under reduced pressure, get intermediate 4-chloro-6-nitro-quinazoline, do not separate, intermediate is dissolved in the 15mL Virahol, add 3-chloro-4-fluoroaniline (0.73g, 5mmol), the 1mL triethylamine, back flow reaction 4h, reaction solution is cooled to room temperature, suction filtration, with Virahol, water, ether washing, oven dry gets the 1.24g light yellow solid to filter cake successively, two step total recoverys 87%, m.p.244-246 ℃.
Preparation Example 24 4-(3-chloro-4-fluoroanilino)-6-amido quinazoline
With 4-(3-chloro-4-fluoroanilino)-6-nitro-quinazoline (0.64g, 2mmol) be dissolved in the 30mL dehydrated alcohol, add glass putty (1.19g, 10mmol), stir under the room temperature, add the 10mL concentrated hydrochloric acid, continue to react 12h under the room temperature, in reaction solution, add 50ml ethyl acetate and 50mL water, vigorous stirring, with the 1N aqueous sodium hydroxide solution pH of mixed solution is transferred to 8～9, suction filtration is removed insolubles, separatory, water layer extracts with ethyl acetate (15mL * 2), merge organic layer, anhydrous sodium sulfate drying, concentrated, silica gel column chromatography separates (eluent, sherwood oil: ethyl acetate=1: 2, v: v), get the 0.38g yellow solid, yield 65%, m.p.260-262 ℃.
Preparation Example 25 4-(3-chloro-4-fluoroanilino)-6-(3-bromine propionamido-) quinazoline
With 4-(3-chloro-4-fluoroanilino)-6-amido quinazoline (0.58g, 2mmol) be dissolved in the 20mL tetrahydrofuran (THF), add the 1mL triethylamine, drip 3-bromo propionyl chloro (0.69g under the ice bath, 4mmol), drip to finish room temperature reaction 2h, in reaction system, add 15mL water, with ethyl acetate extraction (15mL * 3), merge organic layer, anhydrous sodium sulfate drying, concentrated, silica gel column chromatography separates (eluent, sherwood oil: ethyl acetate=1: 1, v: v), get the 0.45g yellow solid, yield 53%.
Embodiment 12 4-methylpiperazine-1-dithio formic acid-[2-[4-(3-chloro-4-fluoroanilino) quinazoline-6-formamyl]] ethyl ester
With N methyl piperazine (0.10g, 1mmol) be dissolved among the 15mL DMF, add anhydrous phosphoric acid potassium (0.43g, 2mmol), splash into dithiocarbonic anhydride (0.19g under the stirring at room, 2.5mmol), behind the reaction 30min, add 4-(3-chloro-4-fluoroanilino)-6-(3-bromine propionamido-) quinazoline (0.43g, 1mmol), continue stirring at room, TLC detects until reaction finishes.In reaction system, add 15mL water, with ethyl acetate extraction (15mL * 3), merge organic layer, washing (15mL * 2), anhydrous sodium sulfate drying, concentrated, silica gel column chromatography separates (eluent, ethyl acetate: methyl alcohol=15: 1, v: v), obtain the 0.25g solid, yield 48%, m.p.236-237 ℃.
1H NMR(300MHz，DMSO-d
6)：δ＝2.19(s，3H)，2.37(s，4H)，2.87(t，J＝6.0Hz，2H)，3.57(t，J＝5.4Hz，2H)，3.88(s，2H)，4.23(s，2H)，7.39-7.46(m，1H)，7.78-7.79(m，3H)，8.12(d，J＝6.9Hz，1H)，8.54(d，J＝1.8Hz，1H)，8.74(s，1H)，9.93(s，1H)，10.36(s，1H)。Ultimate analysis C
23H
24ClFN
6OS
2: theoretical value: C, 53.22; H, 4.66; N, 16.19. measured value: C, 53.20; H, 4.68; N, 16.16.
Preparation Example 26 4-hydroxyl-7-chloro-quinazoline
4-chloro-2-benzaminic acid (1.72g, 10mmol) is added in the 10mL methane amide, 150 ℃ of lower reaction 5h, reaction solution is cooled to room temperature, separate out a large amount of solids, in reaction solution, add 10mL water, suction filtration, oven dry, get the 1.65g pale solid, yield 91%, m.p.248-250 ℃.
1H NMR(300MHz，DMSO-d
6)：δ＝7.56(d，J＝7.8Hz，1H)，7.73(s，1H)，8.10-8.15(m，2H)，12.40(s，1H)。
Preparation Example 27 4-hydroxyl-6-nitro-7-chloro-quinazoline
4-hydroxyl-7-chloro-quinazoline (1.60g, 8.86mmol) is slowly joined under ice bath in the vitriol oil (4mL) and nitrosonitric acid (4mL) the composition nitration mixture, finish, be warming up to 90 ℃ of reaction 3h, react complete, be cooled to room temperature, reaction solution is poured in the 100mL frozen water, separate out a large amount of faint yellow solids, suction filtration, oven dry gets the 1.80g faint yellow solid, yield 90%, m.p.＞300 ℃.
1H NMR(300MHz，DMSO-d
6)：δ＝8.05(s，1H)，8.33(s，1H)，8.69(s，1H)，12.80(s，1H)。
Preparation Example 28 4-hydroxyl-6-nitro-7-methoxyl group quinazoline
Under condition of ice bath, with sodium Metal 99.5 (0.41g, 17.64mmol) join in the 20mL anhydrous methanol, stir until sodium dissolves fully, with 4-(3-chloro-4-fluoroanilino)-6-nitro-quinazoline (1.26g, 5, DMF 58ml) (20ml) solution joins in the reaction system, adds 0.98g (5.58mmol) potassiumiodide again, and reaction solution is at 90 ℃ of lower reaction 24h, react complete, with acetic acid reaction solution pH is transferred to about 7,20mL water is joined in the reaction solution, stir, a large amount of yellow mercury oxides appear, suction filtration, oven dry gets the 0.91g yellow solid, yield 73%, m.p.240-242 ℃.
Preparation Example 29 4-(3-chloro-4-fluoroanilino)-6-nitro-7-methoxyl group quinazoline
According to Preparation Example 23 described methods, change raw material 4-hydroxyl-6-nitro-quinazoline into 4-hydroxyl-6-nitro-7-methoxyl group quinazoline, yield 45%, m.p.234-236 ℃.
1H NMR(300MHz，DMSO-d
6)：δ＝4.11(s，1H)，7.53-7.59(m，1H)，7.62-7.64(m，1H)，7.75-7.76(m，1H)，8.06-8.08(m，1H)，8.95(s，1H)，9.58-9.63(m，1H)，11.71(s，1H)。
Preparation Example 30 4-(3-chloro-4-fluoroanilino)-6-amino-7-methoxyl group quinazoline
According to Preparation Example 24 described methods, just change raw material 4-(3-chloro-4-fluoroanilino)-6-nitro-quinazoline into 4-(3-chloro-4-fluoroanilino)-6-nitro-7-methoxyl group quinazoline, yield 61%, m.p.260-262 ℃.
Preparation Example 31 4-(3-chloro-4-fluoroanilino)-6-(3-bromine propionamido-)-7-methoxyl group quinazoline
According to Preparation Example 25 described methods, just change raw material 4-(3-chloro-4-fluoroanilino)-6-amido quinazoline into 4-(3-chloro-4-fluoroanilino)-6-amino-7-methoxyl group quinazoline, yield 47%.
Embodiment 13 4-methylpiperazine-1-dithio formic acid-[2-[4-(3-chloro-4-fluoroanilino)-7-methoxyl group quinazoline-6-carboxamide]] ethyl ester
According to embodiment 12 described methods, just change raw material 4-(3-chloro-4-fluoroanilino)-6-(3-bromine propionamido-) quinazoline into 4-(3-chloro-4-fluoroanilino)-6-(3-bromine propionamido-)-7-methoxyl group quinazoline, yield 43%, m.p.242-244 ℃.
1H NMR(300MHz，DMSO-d
6)：δ＝2.21(s，3H)，2.40(s，4H)，2.93(s，2H)，3.56(t，J＝7.2Hz，2H)，3.90-4.00(m，5H)，4.24(s，2H)，7.28(s 1H)，7.42(t，J＝8.7Hz，1H)，7.78-7.79(m，1H)，8.12(d，J＝5.1Hz，1H)，8.53(s，1H)，8.53(s，1H)，9.63(s，1H)，9.82(s，1H)。HRMS:C
24H
26ClFN
6O
2S
2+ H, theoretical value 549.13095; Measured value (ESI-FTMS, (M+H)
+ 1), 549.12920.
Preparation Example 32 4-hydroxyl-6-methyl quinazoline
2-amino-5-tolyl acid (7.20g, 48mmol) and methane amide (7.6mL, 192mmol) are mixed, be heated to 130-135 ℃, back flow reaction 4h.Splash into the reaction of 1mL water destruct after reaction finishes, add again 20mL water when temperature is down to 60 ℃, be cooled to room temperature, continue to stir 30min.Suction filtration, washing gets pale solid.Recrystallizing methanol obtains white cotton-shaped solid 5.50g, yield 77%, m.p.266-267 ℃.
1H NMR(300MHz，DMSO-d
6)：δ2.44(s，3H)，7.57(d，J＝8.4Hz，1H)，7.64(dd，J＝8.25Hz，1.2Hz，1H)，7.92(d，J＝0.9Hz，1H)，8.03(s，1H)，12.17(br，1H)。
Preparation Example 33 4-chloro-6-methyl quinazolines
4-hydroxyl-6-methyl quinazoline (3.12g, 21mmol) is added in the thionyl chloride (52mL), splash into the DMF (1mL) of catalytic amount, heating reflux reaction 3h.Reaction removes thionyl chloride under reduced pressure, the separation and purification of residue utilization silicagel column (eluent, sherwood oil: ethyl acetate=3: 1, v: v), get yellow solid compound 1.36g, yield 36%, m.p.107-108 ℃ after finishing.
1H NMR(300MHz，CDCl
3)：δ2.62(s，3H)，7.81(dd，J＝8.5Hz，1.5Hz，1H)，7.98(d，J＝8.7Hz，1H)，8.04(s，1H)，8.99(s，1H)。
Preparation Example 34 6-brooethyl-4-chloro-quinazoline
4-chloro-6-methyl quinazoline (0.89g, 5mmol) and N-bromosuccinimide (NBS) (0.89g, 5mmol) are dissolved in CCl
4(10mL), add the benzoyl peroxide of catalytic amount, reflux 0.5h.The TLC detection reaction is cooled to room temperature after finishing, and filters, and removes solvent under reduced pressure, and crude product is through silicagel column separation and purification (eluent, sherwood oil: ethyl acetate=15: 1, v: v), get white solid 0.60g, yield 45%, m.p.118-120 ℃.
1H NMR(300MHz，CDCl
3)：δ4.69(s，2H)，8.01(d，J＝8.7Hz，2.1Hz，1H)，8.09(d，J＝8.4Hz，1H)，8.26(d，J＝1.5Hz，1H)，9.07(s，1H)。
Preparation Example 35 4-chloro-6-(phthalimide methyl) quinazolines
The sylvite (0.74g, 4mmol) of phthalic imidine is dissolved in the acetone (10mL), is heated to backflow, splash into the acetone soln of 6-brooethyl-4-chloro-quinazoline (1.03g, 4mmol), continue backflow 1h.TLC detects raw material and disappears, and stopped reaction is cooled to room temperature, filters, filter cake is target compound, utilizes silicagel column separation and purification (eluent, sherwood oil: ethyl acetate=1: 1, v: v) after filtrate is concentrated, get white solid 1.20g, yield 92%, m.p.212-214 ℃.
1H NMR(300MHz，CDCl
3)：δ5.09(s，2H)，7.74-7.77(m，2H)，7.88-7.91(m，2H)，8.06(s，2H)，8.34(s，1H)，9.04(s，1H)。EI-MS:[M+]=323.1. (molecular formula: C
17H
10ClN
3O
2, molecular weight: 323.733)
Preparation Example 36 4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino]-6-(phthalimide methyl) quinazoline
Preparation Example 35 products (1mmol) and 3-chloro-4-(3-fluorine benzyloxy) aniline (1mmol) are mixed in the adding Virahol (2mL), be heated to backflow, there is solid to separate out, stopped reaction, cooling is filtered, dry, get yellow solid product, yield 77%, m.p.259-262 ℃.
1H NMR(300MHz，DMSO-d
6)：δ5.01(s，2H)，5.30(s，2H)，7.17-7.22(m，1H)，7.30-7.35(m，3H)，7.44-7.57(m，2H)，7.82(d，J＝5.7Hz，1H)，7.87-7.97(m，5H)，8.07-8.10(d，J＝8.7Hz，1H)，8.64(s，1H)，8.90(s，1H)，11.49(br，1H)。
Preparation Example 37 2-[4-(3-chloro-4-fluoroanilino)-6-(phthalimide methyl) quinazoline
According to Preparation Example 36 described methods, just change raw material 3-chloro-4-(3-fluorine benzyloxy) aniline into 3-chloro-4-fluoroaniline, yield 81%, m.p.267-268 ℃.
1H NMR(300MHz，DMSO-d
6)：δ4.98(s，2H)，7.45(t，J＝9.0Hz，1H)，7.74-7.95(m，7H)，8.13(d，J＝6.0Hz，1H)，8.44(s，1H)，8.61(s，1H)，9.98(br，1H)。
Preparation Example 38 2-[4-(the 3-bromobenzene is amino) 6-(phthalimide methyl) quinazoline
According to Preparation Example 36 described methods, just change raw material 3-chloro-4-(3-fluorine benzyloxy) aniline into m-bromoaniline, yield 92%, m.p.236-237 ℃.
1H NMR(300MHz，DMSO-d
6)：δ5.02(s，2H)，7.43-7.56(m，2H)，7.68(d，J＝8.1Hz，1H)，7.87-7.98(m，6H)，8.10(d，J＝8.7Hz，1H)，8.70(s，1H)，8.96(s，1H)，11.57(br，1H)。
Embodiment 14 4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino] quinazolyl }-6-methylamino dithiocarbamate formic acid-2-[2-(1,3-dioxy cyclopentyl)] ethyl ester
The product (0.20g) of Preparation Example 36 is dissolved in the methyl alcohol (2mL), splashes into methylamine alcohol solution (10mL) after stirring, stir 10min, add methyl alcohol to reaction solution and clarify stirred overnight at room temperature.Reaction removes solvent under reduced pressure after finishing, residuum 3N hydrochloric acid (5mL) solution acidifying, there is solid to separate out, add water to solid entirely molten, ethyl acetate extraction (20mL * 2), water alkalizes to pH 7-8 with the 1N sodium hydroxide solution, ethyl acetate extraction (20mL * 3), merge the rear ethyl acetate layer of alkalization, saturated common salt washing (30mL), anhydrous sodium sulfate drying, filter, evaporated under reduced pressure gets solid.Solid (1mmol) is dissolved among the DMF (2mL), splashes into Et
3N (2mmol) behind the stirring 10min, splashes into CS
2(4mmol), behind the stirring 15min, splash into 2-(2-bromotrifluoromethane)-DOX (1.2mmol), stirred overnight at room temperature.After reaction finishes, add excessive water (50mL), with ethyl acetate extraction (30mL * 3), merge organic phase, saturated common salt washing (30mL), anhydrous sodium sulfate drying filters, utilize silicagel column separation and purification (eluent after filtrate is concentrated, sherwood oil: ethyl acetate=1: 1.5, v: v), get title product, yield 35%, m.p.158-160 ℃.
1H NMR(300MHz，DMSO-d
6)：δ1.95-2.04(m，2H)，3.31(t，J＝7.5Hz，2H)，3.80-3.97(m，4H)，4.92(t，J＝7.5Hz，1H)，5.05(d，J＝5.1Hz，2H)，5.31(s，2H)，7.20-7.39(m，4H)，7.48-7.56(m，1H)，7.77-7.82(m，3H)，8.07(d，J＝2.1Hz，1H)，8.50(s，1H)，8.63(s，1H)，9.88(br，1H)，10.57(br，1H)。Ultimate analysis C
28H
26ClFN
4O
3S
2: theoretical value: C, 57.48; H, 4.48; N, 9.58. measured value: C, 57.32; H, 4.75; N, 9.43.
Embodiment 15 [4-(3-chloro-4-fluoroanilino) quinazolyl]-6-methylamino dithiocarbamate formic acid-2-[2-(1,3-dioxy cyclopentyl)] ethyl ester
According to embodiment 14 described methods, just the product of raw material Preparation Example 36 is changed into the product of Preparation Example 37, yield 40%, m.p.162-163 ℃.
1H NMR(300MHz，DMSO-d
6)：δ1.90-1.97(m，2H)，3.26(t，J＝7.5Hz，2H)，3.75-3.92(m，4H)，4.88(t，J＝7.5Hz，1H)，5.01(d，J＝5.4Hz，2H)，7.47(t，J＝9.0Hz，1H)，7.80(s，3H)，8.19-8.21(m，1H)，8.47(s，1H)，8.64(s，1H)，9.96(br，1H)，10.54(br，1H)。Ultimate analysis C
21H
20ClFN
4O
2S
2: theoretical value: C, 52.66; H, 7.21; N, 11.70. measured value: C, 52.51; H, 4.233; N, 11.36.
Embodiment 16 [4-(the 3-bromobenzene is amino) quinazolyl]-6-methylamino dithiocarbamate formic acid-2-[2-(1,3-dioxy cyclopentyl)] ethyl ester
According to embodiment 14 described methods, just the product of raw material Preparation Example 36 is changed into the product of Preparation Example 38, yield 36%, m.p.90-92 ℃.
1H NMR(300MHz，DMSO-d
6)：δ1.90-1.99(m，2H)，3.26(t，J＝7.5Hz，2H)，3.75-3.92(m，4H)，4.88(t，J＝7.5Hz，1H)，5.02(d，J＝5.4Hz，2H)，7.30-7.40(m，2H)，7.80(s，2H)，7.93(t，J＝6.9Hz，1H)，8.23(s，1H)，8.51(s，1H)，8.67(s，1H)，9.92(br，1H)，10.54(br，1H)。HRMS:C
21H
21BrN
4O
2S
2+ H, theoretical value 505.03621; Measured value (ESI-FTMS, (M+H)
+ 1), 505.03601.
Embodiment 17 4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino] quinazolyl }-6-methylamino dithiocarbamate formic acid-2-cyano group ethyl ester
According to embodiment 14 described methods, just change raw material 2-(2-bromotrifluoromethane)-DOX into β-bromine the third cyanogen, yield 45%, m.p.173-177 ℃.
1H NMR(300MHz，DMSO-d
6)：δ2.93(t，J＝6.3Hz，2H)，3.50(t，J＝6.9Hz，2H)，5.02(s，2H)，5.27(s，2H)，7.17-7.49(m，5H)，7.72-7.79(m，3H)，8.03(s，1H)，8.47(s，1H)，8.59(s，1H)，9.84(br，1H)，10.75(br，1H)。HRMS:C
26H
21ClFN
5OS
2+ H, theoretical value 538.09328; Measured value (ESI-FTMS, (M+H)
+ 1), 538.09230.
Embodiment 18 4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino] quinazolyl }-6-methylamino dithiocarbamate formic acid-2-methoxycarbonyl base ethyl ester
According to embodiment 14 described methods, just change raw material 2-(2-bromotrifluoromethane)-DOX into methyl acrylate, yield 38%, m.p.169-171 ℃.
1H NMR(300MHz，DMSO-d
6)：δ2.74(t，J＝6.3Hz，2H)，3.50(t，J＝6.9Hz，2H)，3.61(s，3H)，5.00(d，J＝4.5Hz，2H)，5.26(s，2H)，7.16-7.52(m，5H)，7.12-7.78(m，3H)，8.03(s，1H)，8.45(s，1H)，8.58(s，1H)，9.84(br，1H)，10.59(br，1H)。Ultimate analysis C
27H
24ClFN
4O
3S
2: theoretical value: C, 56.78; H, 4.24; N, 9.81. measured value: C, 56.85; H, 4.255; N, 9.757.
Embodiment 19 4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino] quinazolyl }-6-methylamino dithiocarbamate formic acid-2-benzyl sulfuryl ethyl ester
According to embodiment 14 described methods, just change raw material 2-(2-bromotrifluoromethane)-DOX into (2-bromotrifluoromethane sulfuryl) methylbenzene, yield 24%, m.p.168-170 ℃.
1H NMR(400MHz，DMSO-d
6)：δ3.40-3.44(m，2H)，3.57-3.61(t，J＝8.4，2.4Hz，2H)，4.57(s，2H)，5.00-5.01(d，J＝5.2Hz，2H)，5.26(s，2H)，7.16-7.21(m，1H)，7.29-7.35(m，3H)，7.38-7.50(m，6H)，7.73(dd，J＝8.8，2.8Hz，1H)，7.78(s，1H)，8.02(d，J＝2.8Hz，1H)，8.46(s，1H)，8.59(s，1H)，9.85(br，1H)，10.70(br，1H)。Ultimate analysis C
32H
28ClFN
4O
3S
3: theoretical value: C, 57.60; H, 4.23; N, 8.40. measured value: C, 57.15; H, 4.23; N, 8.38.
Preparation Example 39 2-cyano group-3-(3-methoxyl group-4-methylbenzene is amino) ethyl propenoate
With 3-methoxyl group-4-monomethylaniline (10.96g, 80mmol) be dissolved in the toluene (32mL) reflux 5h with 2-cyano group-3-ethoxy ethyl acrylate (13.54g, 80mmol), leave standstill cooling, separate out a large amount of yellow solids, filter, the ether washing, dry, get yellow solid 18.6g, yield 94%, m.p.152-156 ℃.
1H NMR(300MHz，CDCl
3)：δ1.37(t，J＝7.2Hz，3H)，2.19(s，3H)，3.85(s，3H)，4.26-4.33(m，1H)，6.51(d，J＝1.8Hz，1H)，6.60(dd，J＝7.8，2.1Hz，1H)，7.12(d，J＝8.1Hz，1H)，7.83(d，J＝13.5Hz，1H)，10.72(br，1H)。
Preparation Example 40 3-cyano group-4-hydroxyl-6-methyl-7-methoxy quinoline
Preparation Example 39 products (5.00g, 19mmol) are dissolved in phenyl ether and the biphenyl mixed solution (200mL, v: v, 3: 1), be heated to 258 ℃ of backflow 24h, cooling is poured in the 100mL hexanaphthene, filters, black solid compound 2.14g, yield 53%, m.p.＞300 ℃.
1H NMR(300MHz，DMSO-d
6)：δ2.25(s，3H)，3.91(s，3H)，6.99(s，1H)，7.88(s，1H)，8.63(s，1H)，12.58(br，1H)。
Preparation Example 41 3-cyano group-4-chloro-6-methyl-7-methoxy quinoline
Preparation Example 40 products (0.39g, 2mmol) are added in the phosphorus oxychloride (2mL), splash into catalytic amount DMF (3), 110 ℃ of reflux 2h.Cooling splashes into reaction solution in the frozen water, adds 10N sodium hydroxide to pH value of solution=7, filters, filter cake is through silicagel column separation and purification (eluent, sherwood oil: ethyl acetate=1: 1, v: v), get faint yellow solid compound 0.37g, yield 84%, m.p.196-197 ℃.
1H NMR(300MHz，DMSO-d
6)：δ2.42(s，3H)，4.04(s，3H)，7.53(s，1H)，8.08(s，1H)，9.06(s，1H)。
Preparation Example 42 3-cyano group-4-chloro-6-brooethyl-7-methoxy quinoline
Preparation Example 41 products (0.37g, 1.7mmol) and N-bromosuccinimide (NBS) (0.36g, 2mmol) are dissolved in CCl
4(5mL), add the benzoyl peroxide of catalytic amount, reflux 0.5h.After the TLC detection reaction finished, stopped heating was chilled to room temperature, filtered, and filtrate is concentrated, and crude product is through silicagel column separation and purification (eluent, sherwood oil: ethyl acetate=4: 1, v: v), get white solid 0.43g, yield 85%, m.p.178-182 ℃.
1H NMR(300MHz，DMSO-d
6)：δ4.10(s，3H)，4.14(s，3H)，4.90(s，2H)，7.58(s，1H)，7.63(s，1H)，7.69(s，1H)，8.45(s，1H)，8.60(s，1H)，9.13(s，1H)，9.17(s，1H)。
Preparation Example 43 3-cyanogen-4-chloro-6-phthalimide methyl-7-methoxy quinoline
The sylvite (0.55g, 3mmol) of phthalic imidine is dissolved in the acetone (20mL), is heated to backflow, splash into the acetone soln of Preparation Example 42 products (0.43g, 1.5mmol), continue backflow 1h.TLC detects raw material and disappears, and stopped reaction is cooled to room temperature, filters, filter cake is compound c-7, utilizes silicagel column separation and purification (eluent, sherwood oil: ethyl acetate=2: 1, v: v) after filtrate is concentrated, get white solid compound 0.23g, yield 45%, m.p.240-244 ℃.
1H NMR(300MHz，DMSO-d
6)：δ4.06(s，3H)，4.96(s，2H)，7.63(s，1H)，7.88-7.97(m，5H)，9.11(s，1H)。
Preparation Example 44 3-cyano group-4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino]-6-phthalimide methyl-7-methoxy quinoline
Preparation Example 43 compounds (1mmol) and 3-chloro-4-(3-fluorine benzyloxy) aniline (1mmol) are mixed in the adding Virahol (2mL), be heated to backflow, have solid to separate out, stopped reaction, cooling is filtered, drying, yield 80%, m.p.278-282 ℃.
1H NMR(300MHz，DMSO-d
6)：δ4.01(s，3H)，4.84(s，3H)，5.24(s，2H)，7.15-7.46(m，8H)，7.83-7.94(m，4H)，8.05(s，1H)，8.50(s，1H)，9.61(br，1H)。
Preparation Example 45 3-cyano group-4-(3-chloro-4-fluoroanilino)-6-phthalimide methyl-7-methoxy quinoline
According to Preparation Example 44 described methods, just change raw material 3-chloro-4-(3-fluorine benzyloxy) aniline into 3-chloro-4-fluoroaniline, yield 83%, m.p.310-313 ℃.
1H NMR (300MHz，DMSO-d
6)：δ4.05(s，3H)，4.85(s，2H)，7.37-7.47(m，3H)，7.64(d，J＝1.8Hz，1H)，7.90(d，J＝8.4Hz，4H)，8.15(s，1H)，8.83(s，1H)，10.44(br，1H)。
Preparation Example 46 3-cyano group-4-(the 3-bromobenzene is amino)-6-phthalimide methyl-7-methoxy quinoline
According to Preparation Example 44 described methods, just change raw material 3-chloro-4-(3-fluorine benzyloxy) aniline into the 3-bromaniline, yield 99%, m.p.310-312 ℃.
1H NMR(300MHz，DMSO-d
6)：δ4.05(s，3H)，4.85(s，2H)，7.31-7.60(m，5H)，7.86-7.94(m，5H)，8.25(s，1H)，8.95(s，1H)，10.91(br，1H)。
Embodiment 20 4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino]-3-cyano group-7-methoxy quinoline base }-6-methylamino dithiocarbamate formic acid-2-[2-(1,3-dioxy cyclopentyl)] ethyl ester
The product (0.20g) of Preparation Example 44 is dissolved in the methyl alcohol (2mL), splashes into methylamine alcohol solution (10mL) after stirring, stir 10min, add methyl alcohol to reaction solution and clarify stirred overnight at room temperature.Reaction removes solvent under reduced pressure after finishing, residuum 3N hydrochloric acid soln (5mL) acidifying, there is solid to separate out, add water to solid entirely molten, ethyl acetate extraction (20mL * 2), water alkalizes to pH 7-8 with the 1N sodium hydroxide solution, ethyl acetate extraction (20mL * 3), merge the rear ethyl acetate layer of alkalization, saturated common salt washing (30mL), anhydrous sodium sulfate drying, filter, evaporated under reduced pressure gets solid chemical compound.Above-claimed cpd (1mmol) is dissolved among the DMF (2mL), splashes into Et
3N (2mmol) behind the stirring 10min, splashes into CS
2(4mmol), behind the stirring 15min, splash into 2-(2-bromotrifluoromethane)-DOX, stirred overnight at room temperature.After reaction finishes, add excessive water (50mL), with ethyl acetate extraction (30mL * 3), merge organic phase, saturated common salt washing (30mL), anhydrous sodium sulfate drying filters, utilize silicagel column separation and purification (eluent after filtrate is concentrated, sherwood oil: ethyl acetate=1: 1.5, v: v), get target compound, yield 24%, m.p.174-177 ℃.
1H NMR(300MHz，DMSO-d
6)：δ1.86-1.93(m，2H)，3.20(t，J＝7.5Hz，2H)，3.72-3.89(m，4H)，3.97(s，3H)，4.83(t，J＝4.5Hz，3H)，5.25(s，2H)，7.17-7.47(m，8H)，8.27(s，1H)，8.51(s，1H)。HRMS:C
31H
28ClFN
4O
4S
2+ H, theoretical value 639.12973; Measured value (ESI-FTMS, (M+H)
+ 1), 639.12921.
Embodiment 21 [4-(3-chloro-4-fluoroanilino)-3-cyano group-7-methoxy quinoline base]-6-methylamino dithiocarbamate formic acid-2-[2-(1,3-dioxy cyclopentyl)] ethyl ester
According to embodiment 20 described methods, be the product that changes Preparation Example 45 into raw material Preparation Example 44 products, yield 53%, m.p.190-192 ℃.
1H NMR(300MHz，DMSO-d
6)：δ1.88-1.90(m，2H)，3.21(t，J＝7.5Hz，2H)，3.77-3.99(m，9H)，4.86(s，3H)，7.25-7.47(m，4H)，8.21(s，1H)，8.61(s，1H)，9.78(br，1H)，10.19(br，1H)。HRMS:C
24H
22ClFN
4O
3S
2+ H, theoretical value 533.08786; Measured value (ESI-FTMS, (M+H)
+ 1), 533.08724.
Embodiment 22 [4-(the 3-bromobenzene is amino)-3-cyano group-7-methoxy quinoline base]-6-methylamino dithiocarbamate formic acid-2-[2-(1,3-dioxy cyclopentyl)] ethyl ester
According to embodiment 20 described methods, just the product of Preparation Example 44 is changed into the product of Preparation Example 46, yield 41%, m.p.155-157 ℃.
1H NMR(300MHz，DMSO-d
6)：δ1.88-1.99(m，2H)，3.21(t，J＝7.5Hz，2H)，3.74-4.05(m，7H)，4.85(t，J＝4.5Hz，3H)，7.16-7.41(m，5H)，8.22(s，1H)，8.66(s，1H)，9.80(br，1H)，10.19(br，1H)。Ultimate analysis C
24H
23BrN
4O
3S
2: theoretical value: C, 51.52; H, 4.14; N, 10.01. measured value: C, 51.26; H, 4.15; N, 9.94.
Embodiment 23 [4-(the 3-bromobenzene is amino) quinazolyl]-6-methylamino dithiocarbamate formic acid-2-benzyl sulfuryl ethyl ester
According to embodiment 14 described methods, just the product of raw material Preparation Example 36 is changed into the product of Preparation Example 38, change raw material 2-(2-bromotrifluoromethane)-DOX into (2-bromotrifluoromethane sulfuryl) methylbenzene, yield 39%, m.p.180-182 ℃.
1H NMR (300MHz, DMSO-d
6): δ 3.38-3.43 (m, 2H), 3.55-3.60 (m, 2H), (4.57 s, 2H), 4.55 (s, 2H), (4.50 s, 2H), 7.29-7.39 (m, 8H), (7.80 s, 2H), 7.91 (d, J=8.1Hz, 1H), 8.22 (s, 1H), 8.50 (s, 1H), 8.65 (s, 1H) .HRMS:C
25H
23BrN
4O
2S
3+ H, theoretical value 587.02393; Measured value (ESI-FTMS, (M+H)
+ 1), 587.02408.
The evaluated biological activity of test example 1 compound-protein tyrosine kinase suppresses screening active ingredients
Screening method: enzyme-linked immunosorbent assay (ELISA)
The present embodiment adopts the pharmaceutical field protein tyrosine kinase to suppress the ordinary method that screening active ingredients is tested, for example the open described method of CN1944398A of Chinese patent.Test-results sees the following form 1.
The inhibiting rate of table 1 tyrosine kinase activity (%)
| Compound number | The average inhibiting rate of EGFR (%) | Activity rating |
| Embodiment 2 | 88.4 | Effectively |
| Embodiment 3 | 92.1 | Effectively |
| Embodiment 4 | 95.6 | Effectively |
| Embodiment 6 | 98.6 | Effectively |
| Embodiment 14 | 98.2 | Effectively |
| Embodiment 15 | 88.2 | Effectively |
| Embodiment 20 | 88.1 | Effectively |
| Embodiment 22 | 77.8 | Effectively |
| Embodiment 23 | 100 | Effectively |
| Lapatinibditosylate | 98.3 | Effectively |
Lapatinibditosylate wherein (Lapatinib) is known antitumor drug, is a kind of new EGFR target therapeutic agent mammary cancer new drug in late period, in above-mentioned test as positive control drug.
In above-mentioned test, Tyrosylprotein kinase (EGFR) concentration: 10 μ M; Action time: 1h; Result evaluation: invalid: 10 μ M＜50%; Effectively: 10 μ M 〉=50%.
The evaluated biological activity of test example 2 compounds-anti tumor activity in vitro test
The test method that the present embodiment adopts is the anti-tumor activity test method of pharmaceutical field routine, for example can be referring to following document: (J.Immunol Method, 1983,65,55).Test is with the representative example of compound 23 as the compounds of this invention, and with the positive control drug of known drug Gefitinib, test-results sees the following form 2.
The cytoactive test-results of table 2 embodiment compound 23
* screening method and test model: A:MTT method (HL-60 human leukemia); B:SRB method (BGC-823 people's cancer of the stomach); C:SRB method (Bel-7402 people's liver cancer); D:SRB method (KB human nasopharyngeal carcinoma).
Can clearly be seen that from above-mentioned test-results, the present invention requires the compound of the general formula (I) of patented protection to have excellent albumen butyric acid kinase inhibiting activity and antitumour activity.Be expected to develop the anti-cancer agent that becomes a class new texture type.
Embodiment of the present invention have been described now in detail, clearly can do a lot of improvement and variation for a person skilled in the art and can not deviate from essence spirit of the present invention, all these changes and improvements are being within the scope of the present invention all, and its feature is determined by above-mentioned specification sheets.
Claims (17)
1. dithiocarbamates compound or its pharmaceutical salts with general formula (I) structure:
Wherein:
A is nitrogen-atoms or carbon atom, and described carbon atom quilt-CN replaces;
D is-(CH
2)
m-,-(CH
2)
m-O-,-(CH
2)
m-NH-or-CH
2CH
2CONH-, wherein m is the integer of 1-3 independently of one another;
E is sulphur atom or NR
3, R wherein
3H, methyl, ethyl or phenyl;
R is R
4R
5N-or R
6S-is when the R group is R
4R
5During N-, R wherein
4And R
5Represent to replace or unsubstituted, the other saturated hexa-atomic or seven membered heterocyclic that also contains 1 nitrogen-atoms, Sauerstoffatom or sulphur atom with the nitrogen-atoms that connects, substituting group wherein is methyl, halogenophenyl methyl or two (difluorophenyl) methyl; Or when described R be R
6During S-, R wherein
6The expression following radicals:
R wherein
7And R
8Hydrogen, methyl or phenmethyl independently of one another; Q is the integer of 1-3;
R
1Be selected from following radicals: halogen or benzyloxy wherein can have 1-3 halogen on benzyl;
N is the integer of 1-3; With
R
2H, C
1-4The C that alkyl, halogen replace
1-4Alkyl, C
1-4The C that alkoxy or halogen replaces
1-4Alkoxyl group.
2. compound according to claim 1, wherein said group D is-CH
2-,-(CH
2)
3-,-(CH
2)
3-O-,-(CH
2)
3-NH-or-CH
2CH
2CONH-.
3. compound according to claim 1, wherein said group E be sulphur atom or-NH-.
4. according to claim 2 or 3 described compounds, wherein said-E-D-group is :-NH-CH
2-,-NH-(CH
2)
3-,-S-(CH
2)
3-O-or-S-CH
2CH
2CONH-.
5. compound according to claim 1, wherein said saturated hexa-atomic or seven membered heterocyclic is:
6. compound according to claim 1 is when described R group is R
6During S-, R wherein
6The expression following radicals:
7. compound according to claim 1, the group that wherein is connected on quinoline ring or the quinazoline ring 4-bit amino is:
8. compound according to claim 1, wherein said R
2Group is H or methoxyl group.
9. compound according to claim 1, wherein said compound is:
4-methylpiperazine-1-dithio formic acid-[3-[4-(the 3-bromobenzene is amino) quinazoline-6-oxygen]] propyl ester;
4-methylpiperazine-1-dithio formic acid-[3-[4-(3-chloro-4-fluoroanilino) quinazoline-6-oxygen]] propyl ester;
4-methylpiperazine-1-dithio formic acid-[3-[4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino] quinazoline-6-oxygen] propyl ester;
4-methylpiperazine-1-dithio formic acid-and 3-[4-(the 3-bromobenzene is amino)-7-methoxyl group quinazoline-6-oxygen] } propyl ester;
4-methylpiperazine-1-dithio formic acid-and 3-[4-(3-chloro-4-fluoroanilino)-7-methoxyl group quinazoline-6-oxygen] } propyl ester;
4-methylpiperazine-1-dithio formic acid-[3-[4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino]-7-methoxyl group quinazoline-6-oxygen]] propyl ester;
Piperazine-4-dithio formic acid-[3-[4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino]-7-methoxyl group quinazoline-6-oxygen]] propyl ester;
Homopiperazine-4-dithio formic acid-[3-[4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino]-7-methoxyl group quinazoline-6-oxygen]] propyl ester;
Morpholine-4-dithio formic acid-[3-[4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino]-7-methoxyl group quinazoline-6-oxygen]] propyl ester;
Thiomorpholine-4-dithio formic acid-[3-[4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino]-7-methoxyl group quinazoline-6-oxygen]] propyl ester;
4-[two (4-fluorophenyl) methyl] piperazine-1-dithio formic acid-[3-[4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino]-7-methoxyl group quinazoline-6-oxygen]] propyl ester;
4-methylpiperazine-1-dithio formic acid-[2-[4-(3-chloro-4-fluoroanilino) quinazoline-6-carbamyl]] ethyl ester;
4-methylpiperazine-1-dithio formic acid-[2-[4-(3-chloro-4-fluoroanilino)-7-methoxyl group quinazoline-6-carboxamide]] ethyl ester;
4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino] quinazolyl }-6-methylamino dithiocarbamate formic acid-2-[2-(1,3-dioxy cyclopentyl)] ethyl ester;
[4-(3-chloro-4-fluoroanilino) quinazolyl]-6-methylamino dithiocarbamate formic acid-2-[2-(1,3-dioxy cyclopentyl)] ethyl ester;
[4-(the 3-bromobenzene is amino) quinazolyl]-6-methylamino dithiocarbamate formic acid-2-[2-(1,3-dioxy cyclopentyl)] ethyl ester;
4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino] quinazolyl }-6-methylamino dithiocarbamate formic acid-2-cyano group ethyl ester;
4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino] quinazolyl }-6-methylamino dithiocarbamate formic acid-2-methoxycarbonyl base ethyl ester;
4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino] quinazolyl }-6-methylamino dithiocarbamate formic acid-2-benzyl sulfuryl ethyl ester;
4-[3-chloro-4-(3-fluorine benzyloxy) phenylamino]-3-cyano group-7-methoxy quinoline base }-6-methylamino dithiocarbamate formic acid-2-[2-(1,3-dioxy cyclopentyl)] ethyl ester;
[4-(3-chloro-4-fluoroanilino)-3-cyano group-7-methoxy quinoline base]-6-methylamino dithiocarbamate formic acid-2-[2-(1,3-dioxy cyclopentyl)] ethyl ester;
[4-(the 3-bromobenzene is amino)-3-cyano group-7-methoxy quinoline base]-6-methylamino dithiocarbamate formic acid-2-[2-(1,3-dioxy cyclopentyl)] ethyl ester; With
[4-(the 3-bromobenzene is amino) quinazolyl]-6-methylamino dithiocarbamate formic acid-2-benzyl sulfuryl ethyl ester.
10. pharmaceutical composition, wherein containing the described general formula of claim 1-9 any one (I) compound or pharmaceutically acceptable salt thereof for the treatment of significant quantity is activeconstituents, and optional one or more pharmaceutical carriers that contains.
11. pharmaceutical composition according to claim 10, wherein the content of activeconstituents is 0.5%-99%, and the content of pharmaceutical carrier is 1%-99.5%.
12. pharmaceutical composition according to claim 11, wherein said composition is made into the form of oral or administered parenterally, and the form of described administered parenterally comprises the form of drug administration by injection, topical, inhalation, rectal administration or drug delivery implant.
13. pharmaceutical composition according to claim 12, wherein the formulation of oral administration is tablet, capsule, granule or the preparation that is suitable for medicinal liquid form.
14. pharmaceutical composition according to claim 13, wherein said tablet are dressing, enteric, slowly-releasing or the quantitative form that discharges.
15. the described compound of claim 1-9 any one or the described pharmaceutical composition of the claim 10-14 any one application in the preparation tyrosine kinase inhibitor.
16. application according to claim 15, wherein said tyrosine kinase inhibitor is antitumor drug.
17. application according to claim 16, wherein said antitumor drug are the medicines that is used for the treatment of mammary cancer, nonsmall-cell lung cancer, cancer of the stomach or carcinoma of the pancreas.
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