CN109516977A - A kind of aniline pyrimidine/quinoline heterocomplex, preparation method and medical usage - Google Patents

A kind of aniline pyrimidine/quinoline heterocomplex, preparation method and medical usage Download PDF

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CN109516977A
CN109516977A CN201910062995.7A CN201910062995A CN109516977A CN 109516977 A CN109516977 A CN 109516977A CN 201910062995 A CN201910062995 A CN 201910062995A CN 109516977 A CN109516977 A CN 109516977A
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methoxyl group
added
carboxylic acid
ethyl ester
tfa
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CN109516977B (en
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韩春
吴林韬
苏峰
李梦瑶
胡晓琴
武曦
王晓霞
孙龙
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Changzhi University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Abstract

The invention discloses a kind of aniline pyrimidine/quinoline heterocomplex, preparation method and medical usages.Compound provided by the invention has different degrees of inhibited proliferation to non-small cell lung cancer cell A549, H1975, HCC827, human colon cancer cell HCT116, human liver cancer cell HepG2, people epidermis cancer cell A431, and part of compounds is better than positive drug Gefitinib to the inhibited proliferation of Partial tumors cell.Moreover, majority of compounds provided by the invention is weaker to the inhibited proliferation of normal cell HBE, higher to the selectivity of tumour cell, safety is significantly better than positive drug Gefitinib.

Description

A kind of aniline pyrimidine/quinoline heterocomplex, preparation method and medical usage
Technical field
The invention belongs to field of medicinal chemistry, and in particular to a kind of aniline pyrimidine/quinoline heterocomplex, preparation method and medicine Purposes.
Background technique
Cancer has become the bad dream of contemporary mankind, therefore to be then that scientific circles are all-out grind the discovery about anticancer drug Study carefully field.
Cancer cell is often counted as invading the enemy of body, is intended to except it is then fast, therefore researcher's treating cancer is basic Thinking is to develop and chemicals of the clinical application with cancer cell toxicity, this strategy are referred to as chemotherapy.Design synthesis is not Isostructural compound simultaneously tests the important means that its anti-tumor activity is current searching cancer chemotherapeutic drug.
Summary of the invention
The present invention is intended to provide a kind of aniline pyrimidine/quinoline heterocomplex, preparation method and medical usage.
Above-mentioned purpose of the present invention is achieved through the following technical solutions:
A kind of aniline pyrimidine/quinoline heterocomplex, chemical structural formula are as follows:
A method of preparing above compound 1, include the following steps: by suitable 2- methyl -6- methoxyl group -7- (2, 5- dichloro pyrimidine -4- oxygroup) quinoline-3-carboxylic acid ethyl ester, 2- methoxyl group -4- (4- methyl piperidine -1- base) aniline, trifluoracetic acid TFA is added in sec-butyl alcohol, reacts for 24 hours, is concentrated under reduced pressure, column chromatographic purifying at a temperature of 105 DEG C.
A method of above compound 2 is prepared, includes the following steps: 2- methoxyl group -4- morpholinyl phenylamine is taken to be dissolved in secondary In butanol, be added suitable 7- (2- ((2,5- dichloro pyrimidine -4- base) oxygen) -6- methoxyl group -2- methylquinoline -3- carboxylic acid, ethyl ester, It is added with stirring TFA, reacts for 24 hours, is concentrated under reduced pressure, column chromatographic purifying at a temperature of 105 DEG C.
A method of above compound 3 is prepared, includes the following steps: that appropriate 7- (2- ((2,5- is added in sec-butyl alcohol Dichloro pyrimidine -4- base) oxygen) -6- methoxyl group -2- methylquinoline -3- carboxylic acid, ethyl ester, 1- (4- amino -3- methoxyphenyl) piperidines - 4- alcohol, TFA are reacted for 24 hours at 105 DEG C, are concentrated under reduced pressure, column chromatographic purifying.
A method of above compound 4 is prepared, includes the following steps: that (((2,5- dichloros are phonetic by 2- to 7- under stirring condition Pyridine -4- base) oxygen) suitable sec-butyl alcohol, 2- methoxyl group -4- (4- alkene is added in -6- methoxyl group -2- methylquinoline -3- carboxylic acid, ethyl ester Propiono piperazinyl) aniline, TFA, react for 24 hours at a temperature of 105 DEG C, are concentrated under reduced pressure, column chromatographic purifying.
A method of above compound 5 is prepared, includes the following steps: that ((2,5- dichloros are phonetic by 2- to 7- under stirring condition Pyridine -4- oxygen) ethyoxyl) suitable sec-butyl alcohol, 2- methoxyl group -4- is added in -6- methoxyl group -2- methylquinoline -3- carboxylic acid, ethyl ester (4- methyl piperidine -1- base) aniline, TFA, reacts 30h at a temperature of 105 DEG C, is concentrated under reduced pressure, column chromatographic purifying.
A method of above compound 6 is prepared, includes the following steps: that suitable 7- (2- (2,5- is added into sec-butyl alcohol Dichloro pyrimidine -4- oxygen) ethyoxyl) -6- methoxyl group -2- methylquinoline -3- carboxylic acid, ethyl ester, 2- methoxyl group -4- morpholinyl phenylamine, TFA reacts 30h, column chromatographic purifying at 105 DEG C under agitation.
A method of above compound 7 is prepared, includes the following steps: to be added under stirring condition into sec-butyl alcohol suitable TFA, 7- (2- (2,5- dichloro pyrimidine -4- oxygen) ethyoxyl) -6- methoxyl group -2- methylquinoline -3- carboxylic acid, ethyl ester, 1- (4- amino - 3- methoxyphenyl) piperidines -4- alcohol, 72h is reacted at 105 DEG C, filters rear pillar chromatographic purifying.
A method of above compound 8 is prepared, includes the following steps: that suitable TFA, 7- (2- is added into sec-butyl alcohol (2,5- dichloro pyrimidine -4- oxygen) ethyoxyl) -6- methoxyl group -2- methylquinoline -3- carboxylic acid, ethyl ester, 2- methoxyl group -4- (4- allyl Acyl piperazine base) aniline, reacts 72h, column chromatographic purifying at 105 DEG C.
Above compound application in preparation of anti-tumor drugs.
The utility model has the advantages that
Compound provided by the invention is to non-small cell lung cancer cell A549, H1975, HCC827, human colon cancer cell HCT116, human liver cancer cell HepG2, people epidermis cancer cell A431 have different degrees of inhibited proliferation, part of compounds Positive drug Gefitinib is better than to the inhibited proliferation of Partial tumors cell.Moreover, majority of compounds provided by the invention Weaker to the inhibited proliferation of normal cell HBE, higher to the selectivity of tumour cell, safety is significantly better than positive drug Ji It is non-to replace Buddhist nun.
Specific embodiment
Essentiality content of the present invention is specifically introduced below with reference to embodiment, but does not limit protection model of the invention with this It encloses.
Embodiment 1: the preparation of compound and structural identification
The synthesis (intermediate) of 2- methyl -6- methoxyl group -7- benyloxyquinoline -3- carboxylic acid, ethyl ester
2- amino -5- methoxyl group -4- benzoxybenzaldehyde (3.00g, 11.66mmol) is added in 250mL round-bottomed flask, Dehydrated alcohol (75mL), ethyl acetoacetate (1.78mL, 14.00mmol), piperidines (2.88mL, 0.29mol), under magnetic agitation Heat 90 DEG C of back flow reaction 30h.Stop reaction, it is cooling, it stands.There is yellow solid precipitation, filters, with ethyl alcohol, water elutes filter cake, Dry, weigh to obtain 2.00g, and 137.5-139.4 DEG C of fusing point, yield 49%.1H NMR(400MHz,d6-DMSO)δ1.37(t, 3H,COOCH2CH 3, J=7.08Hz), 2.80 (s, 3H, ArCH 3),3.91(s,3H,OCH3),4.35(q,2H,COOCH 2CH3,J =7.08Hz), 5.30 (s, 2H, PhCH 2),7.45–7.36(m,4H,4×PhH),7.49(s,2H,2×PhH,),7.52(s, 1H,PhH,),8.67(s,1H,ArH).
The synthesis (intermediate) of 2- methyl -6- methoxyl group -7- oxyquinoline -3- carboxylic acid, ethyl ester
In 75mL methanol be added 2- methyl -6- methoxyl group -7- benyloxyquinoline -3- carboxylic acid, ethyl ester (0.15g, 0.43mmol), then the palladium carbon of catalytic amount is passed through hydrogen into reaction unit, after reacting 12h, stop reaction, filtrate is concentrated It is dried to obtain Off-white solid 0.11g, 129.0-129.2 DEG C of fusing point, yield 98%.1H NMR(400MHz,d6-DMSO)δ1.37 (t,3H,COOCH2CH 3, J=7.08Hz), 2.79 (s, 3H, ArCH 3),3.92(s,3H,OCH3),4.34(q,2H, COOCH 2CH3, J=7.08Hz), 7.22 (s, 1H, PhH), 7.46 (s, 1H, PhH), 8.64 (s, 1H, ArH), 10.44 (s, 1H, OH).
The synthesis (intermediate) of 2- methyl -6- methoxyl group -7- (2,5- dichloro pyrimidine -4- oxygroup) quinoline-3-carboxylic acid ethyl ester
By 2- methyl -6- methoxyl group -7- oxyquinoline -3- carboxylic acid, ethyl ester (600mg, 2.30mmol), potassium carbonate (630mg, 3.44mmol), 2,4,5- trichloropyrimidines (0.345mL, 3.01mmol) are added in 37.5mLDMF, are reacted at room temperature, by reaction solution Pouring into cold water has solid precipitation, filters, dry, weighs, and obtains Off-white solid 750mg, and fusing point is 174.3-176.1 DEG C, Yield 80%.1H NMR(400MHz,d6-DMSO)δ1.40(t,3H,COOCH2CH 3, J=7.12Hz), 2.84 (s, 3H, ArCH3),3.88(s,3H,OCH3),4.39(q,2H,COOCH 2CH3, J=7.12Hz), 7.96 (s, 2H, 2 × PhH), 8.83 (s,1H,ArH),8.92(s,1H,ArH).
2- methyl-6- methoxyl group-7- (2- (2- methoxyl group-4- (4- methyl-1-piperazinyl) anilino-)-5- chlorine pyrimidine-4- Oxygroup) quinoline-3-carboxylic acid ethyl ester synthesis (compound 1)
By 2- methyl -6- methoxyl group -7- (2,5- dichloro pyrimidine -4- oxygroup) quinoline-3-carboxylic acid ethyl ester (16mg, 0.04mmol), 2- methoxyl group -4- (4- methyl piperidine -1- base) aniline (9mg, 0.04mmol), TFA (6.00mL, 94.9mmol) It is added in 22.5mL sec-butyl alcohol, reacts for 24 hours, be concentrated under reduced pressure at a temperature of 105 DEG C, column chromatographs (methylene chloride: methanol=25:1) 7mg yellow solid is obtained, fusing point is 88.1-89.0 DEG C, yield 31%.1H NMR(400MHz,d6-DMSO):δ1.38(t,3H, COOCH2CH 3, J=7.12Hz), 2.17 (s, 3H, NCH3),2.33(br s,4H,2×NCH 2CH2N),2.80(s,7H,2× NCH 2CH2N,ArCH3),3.63(s,3H,OCH3),3.81(s,3H,OCH3),4.37(q,2H,COOCH 2CH3, J=7.12Hz), 5.54 (br s, 1H, PhH), 6.31 (s, 1H, PhH), 6.82 (d, 1H, PhH, J=8.68Hz), 7.74 (s, 1H, PhH), 7.75 (s,1H,PhH),8.05(s,1H,ArNH),8.33(s,1H,ArH),8.82(s,1H,ArH).
7- ((5- chloro- 2 (2- methoxyl group -4- morpholinyl phenylamino) pyrimidine-4-yl) oxygen) -6- methoxyl group -2- methylquinoline - The synthesis (compound 2) of 3- carboxylic acid, ethyl ester
2- methoxyl group -4- morpholinyl phenylamine (169mg, 0.81mmol) is taken to be dissolved in 25ml sec-butyl alcohol, addition 7- (2- ((2, 5- dichloro pyrimidine -4- base) oxygen) -6- methoxyl group -2- methylquinoline -3- carboxylic acid, ethyl ester (300mg, 0.74mmol), it is added with stirring Trifluoracetic acid TFA (109 μ l, 1.47mmol).It reacts for 24 hours, is concentrated under reduced pressure, column chromatographic purifying at a temperature of 105 DEG C.Obtain sterling 186mg, yield 39%, mp 190.9-192.7 DEG C.1H NMR(400MHz,d6-DMSO):δ1.41(t,3H,COOCH2CH 3, ), J=7.08Hz 2.82 (br s, 2H, NCH2),2.84(s,3H,ArCH3),2.92(t,2H,NCH2, J=4.04Hz), 3.65 (br s,2H,OCH2),3.67(s,3H,OCH3),3.71(t,2H,OCH2, J=4.36Hz), 3.86 (s, 3H, OCH3),4.41 (q,2H,COOCH 2CH3, J=7.00Hz), 5.52 (br s, 1H, PhH), 6.37 (s, 1H, PhH), 6.88 (br s, 1H, PhH), 7.78(s,1H,PhH),7.79(s,1H,PhH),8.17(s,1H,ArNH),8.38(s,1H,ArH),8.86(s,1H,ArH).
6- methoxyl group -7- (2- (2- methoxyl group -4- (4- hydroxyl -1- piperidyl) anilino-) -5- chlorine pyrimidine -4- oxygroup) - The synthesis (compound 3) of 2- methylquinoline -3- carboxylic acid, ethyl ester
7- (2- ((2,5- dichloro pyrimidine -4- base) oxygen) -6- methoxyl group -2- methylquinoline -3- is added in 15mL sec-butyl alcohol Carboxylic acid, ethyl ester (9mg, 0.02mmol), 1- (4- amino -3- methoxyphenyl) piperidines -4- alcohol (5mg, 0.02mmol), TFA (3.20mL, 43.10mmol) is reacted for 24 hours at 105 DEG C, is concentrated under reduced pressure after stopping reaction, and column chromatographs (methylene chloride: first Alcohol=25:1) after obtain 4.00mg yellow solid, fusing point is 187.8-189.3 DEG C, yield 31%.1H NMR(400MHz,d6- DMSO):δ1.32(m,2H,CHCH 2),1.38(t,3H,COOCH2CH 3, J=7.12Hz), 1.68 (m, 2H, CHCH 2),2.51 (m,2H,NCH2),2.80(s,3H,ArCH3),3.17(m,2H,NCH2),3.49(m,1H,CHCH2),3.62(s,3H,OCH3), 3.81(s,3H,OCH3),4.37(q,2H,COOCH 2CH3, J=7.12Hz), 4.60 (d, 1H,HOCH, J=3.00Hz), 5.51 (br s,1H,PhH),6.31(s,1H,PhH),6.79(br s,1H,PhH),7.74(s,1H,PhH),7.75(s,1H,PhH), 8.05(s,1H,ArNH),8.33(s,1H,ArH),8.82(s,1H,ArH).
7- ((2- ((4- (4- acryloyl-piperazine -1- base) -2- anisyl) amino) -5- Chloropyrimide -4- base) oxygen) - The synthesis (compound 4) of 6- methoxyl group -2- methylquinoline -3- carboxylic acid, ethyl ester
Under magnetic stirring to 7- (2- ((2,5- dichloro pyrimidine -4- base) oxygen) -6- methoxyl group -2- methylquinoline -3- carboxylic acid Sec-butyl alcohol (15mL), 2- methoxyl group -4- (4- allyl acyl group piperazinyl) aniline are added in ethyl ester (110mg, 0.27mmol) (60mg, 0.27mmol), TFA (4.00mL, 0.05mmol) is reacted for 24 hours at a temperature of 105 DEG C, is concentrated under reduced pressure, column chromatography (two Chloromethanes: methanol=25:1) obtain 50mg yellow solid, yield 31%.93.1-94.7 DEG C of fusing point.1HNMR(400MHz,d6- DMSO):δ1.37(t,3H,COOCH2CH 3, J=7.16Hz), 2.80 (s, 3H, ArCH3),2.83(br s,4H,2× NCH 2CH2N),3.57(br s,4H,2×NCH 2CH2N),3.63(s,3H,OCH3),3.81(s,3H,OCH3),4.37(q,2H, COOCH 2CH3, J=7.12Hz), 5.61 (br s, 1H, PhH), 5.68 (dd, 1H, 1/2 × CH 2=CHCO, J=2.00, 10.32Hz),6.11(dd,1H,1/2×CH 2=CHCO, J=2.12,16.56Hz), 6.38 (s, 1H, PhH), 6.78 ((dd, 1H,CH2=CHCO, J=10.40,16.68Hz), 6.87 (br s, 1H, PhH), 7.74 (s, 1H, PhH), 7.75 (s, 1H, PhH),8.10(s,1H,ArNH),8.34(s,1H,ArH),8.82(s,1H,ArH).
The synthesis (intermediate) of 7- (2- ethoxy) -6- methoxyl group -2- methylquinoline -3- carboxylic acid, ethyl ester
2- methyl -6- methoxyl group -7- oxyquinoline -3- carboxylic acid, ethyl ester is sequentially added in the synthesis of 250mL round-bottomed flask (1.00g, 3.83mmol), Anhydrous potassium carbonate (2.64g, 19.15mmol) are then added 30mLDMF dissolution, are eventually adding 2- bromine Ethyl alcohol (1.087mL, 15.32mmol), 90 DEG C of back flow reactions are heated under magnetic agitation, and 6h stops reaction, reaction solution is poured into ice It in water, filters, is extracted with ethyl acetate (3 × 20mL), merge organic layer, wash (3 × 20mL), it is dry, it is concentrated to get milky white Color solid 0.50g, 138.5-139.0 DEG C of fusing point, yield 43%.1H NMR(400MHz,CDCl3)δ1.45(t,3H, COOCH2CH 3, J=7.12Hz), 2.88 (s, 1H, OH), 2.95 (s, 3H, ArCH3),3.95(s,3H,OCH3),4.08–4.18 (t,2H,OCH2CH 2OH, J=4.28Hz), 4.26-4.36 (t, 2H, OCH 2CH2OH, J=4.36Hz), 4.42 (q, 2H, COOCH 2CH3, J=7.12Hz), 7.03 (s, 1H, PhH), 7.35 (s, 1H, PhH), 8.57 (s, 1H, ArH)
The synthesis of 7- (2- (2,5- dichloro pyrimidine -4- oxygen) ethyoxyl) -6- methoxyl group -2- methylquinoline -3- carboxylic acid, ethyl ester (intermediate)
Compound 7- (2- ethoxy) -6- methoxyl group -2- methylquinoline -3- carboxylic acid, ethyl ester is added into the DMF of 30mL (1.17g, 3.83mmol), sodium hydride (0.18g, 7.66mmol), 2,4,5- trichloropyrimidines (0.48mL, 4.21mmol), in room Temperature is lower to carry out magnetic agitation reaction, and reaction solution is poured into cold water until there is solid precipitation, filter, dry, weigh, obtain it is milky white The solid 1.38g of color, 143.6-145.0 DEG C of fusing point, yield 80%.1HNMR(400MHz,d6-DMSO)δ1.37(t,3H, COOCH2CH 3, J=7.12Hz), 2.83 (s, 3H, ArCH3),3.88(s,3H,OCH3),4.36(q,2H,COOCH 2CH3, J= 7.12Hz),4.56–4.62(m,2H,OCH2CH 2OH),4.83–4.91(m,2H,OCH 2CH2OH),7.47(s,1H,PhH), 7.52(s,1H,PhH),8.68(s,1H,ArH),8.71(s,1H,ArH).
7- (2- ((the chloro- 2- of 5- ((2- methoxyl group -4- methyl piperazine base phenyl) amino) -4- pyrimidine radicals) oxygroup) ethoxy Base) -6- methoxyl group -2- methylquinoline -3- carboxyethyl synthesis (compound 5)
Under magnetic stirring to compound 7- (2- (2,5- dichloro pyrimidine -4- oxygen) ethyoxyl) -6- methoxyl group -2- methyl quinoline Sec-butyl alcohol (25mL), 2- methoxyl group -4- (4- methyl piperidine -1- base) are added in quinoline -3- carboxylic acid, ethyl ester (0.66g, 1.46mmol) Aniline (0.30g, 1.46mmol), TFA (0.45mL, 5.97mmol), react 30h at a temperature of 105 DEG C.It is concentrated under reduced pressure, column layer Analysis (methylene chloride: methanol=25:1) obtains 102mg yellow solid, and fusing point is 247.0-248.0 DEG C, yield 11%.1HNMR (400MHz,CDCl3):δ1.48(t,3H,COOCH2CH 3, J=7.12Hz), 2.41 (s, 3H, NCH3),2.65(t,4H,2× NCH 2CH2N, J=4.72Hz), 2.95 (s, 3H, ArCH3),3.21(t,4H,2×NCH 2CH2N, J=4.70Hz), 3.90 (s, 3H,OCH3),4.01(s,3H,OCH3),4.46(q,2H,COOCH 2CH3, J=7.12Hz), 4.65 (t, 2H, OCH2, J= 5.04Hz),4.94(t,2H,OCH2, J=4.80Hz), 6.56 (m, 2H, 2 × PhH), 7.12 (t, 1H, PhH, J=4.56H), 7.49(s,1H,PhH),7.57(s,1H,PhH),8.10(s,1H,ArNH),8.16(s,1H,ArH),8.63(s,1H,ArH).
7- (2- ((the chloro- 2- of 5- ((2- methoxyl group -4- morpholinyl phenyl) amino) -4- pyrimidine radicals) oxygroup) ethyoxyl) -6- first The synthesis (compound 6) of oxygroup -2- methylquinoline -3- carboxyethyl
7- (2- (2,5- dichloro pyrimidine -4- oxygen) ethyoxyl) -6- methoxyl group -2- methyl quinoline is added to sec-butyl alcohol (25mL) Quinoline -3- carboxylic acid, ethyl ester (0.66g, 1.46mmol), 2- methoxyl group -4- morpholinyl phenylamine (0.30g, 1.46mmol), TFA (0.45mL, 5.97mmol) reacts 30h at being 105 DEG C in magnetic agitation temperature, is concentrated under reduced pressure, column chromatographs (methylene chloride: first Alcohol=25:1) obtain 150mg yellow solid, 90.5-92.2 DEG C of fusing point, yield 16%.1H NMR(400MHz,d6-DMSO):δ 1.34(t,3H,COOCH2CH 3, J=7.24Hz), 2.77 (s, 3H, ArCH3),3.03(br s,4H,2×NCH2),3.69(br s,4H,2×OCH2),3.75(s,3H,OCH3),3.85(s,3H,OCH3),4.31(q,2H,COOCH 2CH3, J=6.88Hz), 4.51(t,2H,OCH2, J=4.24Hz), 4.72 (t, 2H, OCH2, J=4.64Hz), 6.39 (d, 1H, PhH, J=8.92H), 6.59 (s, 1H, PhH), 7.44 (d, 1H, PhH, J=9.24H), 7.55 (s, 2H, PhH), 8.09 (s, 1H, ArNH), 8.16 (s, 1H,ArH),8.63(s,1H,ArH).
7- (2- ((5- chloro -2- ((4- (4- hydroxy piperidine -1- base) -2- anisyl) amino) pyrimidine-4-yl) oxygen) second Oxygroup) -6- methoxyl group -2- methylquinoline -3- carboxylic acid, ethyl ester synthesis (compound 7)
Under magnetic stirring, sec-butyl alcohol makees solvent (25ml), adds TFA (0.217ml, 2.92mmol), 7- (2- (2, 5- dichloro pyrimidine -4- oxygen) ethyoxyl) -6- methoxyl group -2- methylquinoline -3- carboxylic acid, ethyl ester (660mg, 1.46mmol), 1- (4- Amino -3- methoxyphenyl) piperidines -4- alcohol (325mg, 1.46mmol), reacts at 105 DEG C.Stop reaction, mistake after reacting 72h Rear pillar chromatography (petroleum ether: ethyl acetate=1:1) is filtered, obtains yellow solid 200mg, 186.7-187.9 DEG C of fusing point, yield is 22%.1H NMR(400MHz,d6-DMSO):δ1.33(t,3H,COOCH2CH 3, J=7.12Hz), 1.43 (m, 2H, CHCH 2), 1.75(m,2H,CHCH 2),2.71(m,2H,NCH2),2.77(s,3H,ArCH3),3.42(m,2H,NCH2),3.55(m,1H, CHCH2),3.73(s,3H,OCH3),3.84(s,3H,OCH3),4.31(q,2H,COOCH 2CH3, J=7.12Hz), 4.51 (t, 2H,OCH2, J=4.96Hz), 4.60 (d, 1H,HOCH, J=4.20Hz), 4.69 (t, 2H, OCH2, J=4.64Hz), 6.37 (d, 1H, PhH, J=8.76H), 6.56 (s, 1H, PhH), 7.43 (d, 2H, 2 × PhH, J=8.04H), 7.46 (s, 1H, PhH), 8.12(s,1H,ArNH),8.15(s,1H,ArH),8.64(s,1H,ArH).
7- (2- ((2- ((4- (4- acryloyl-piperazine -1- base) -2- anisyl) amino) -5- Chloropyrimide -4- base) Oxygen) ethyoxyl) -6- methoxyl group -2- methylquinoline -3- carboxylic acid, ethyl ester synthesis (compound 8)
TFA (0.48mL, 7.84mmol) is added in sec-butyl alcohol (25ml), 7- (2- (2,5- dichloro pyrimidine -4- oxygen) ethoxy Base) -6- methoxyl group -2- methylquinoline -3- carboxylic acid, ethyl ester (660mg, 1.46mmol), 2- methoxyl group -4- (4- allyl acyl piperazine Base) aniline (304mg, 1.17mmol), reacts at 105 DEG C, stops reaction after reacting 72h, column chromatography obtains yellow-white product 200mg.Yield is 20%.Fusing point: 131.4-133.2 DEG C.1H NMR(400MHz,d6-DMSO):δ1.33(t,3H, COOCH2CH 3, J=7.12Hz), 2.76 (s, 3H, ArCH3),3.06(t,4H,2×NCH 2CH2N, J=4.56Hz), 3.64 (br s,4H,2×NCH 2CH2N),3.75(s,3H,OCH3),3.84(s,3H,OCH3),4.30(q,2H,COOCH 2CH3, J= 7.08Hz),4.50(t,2H,OCH2, J=4.24Hz), 4.70 (t, 2H, OCH2, J=4.64Hz), 5.67 (dd, 1H, 1/2 × CH 2=CHCO, J=2.36,10.40Hz), 6.10 (dd, 1H, 1/2 × CH 2=CHCO, J=2.36,16.68Hz), 6.40 (dd, 1H, PhH, J=2.40,8.80Hz), 6.62 (d, 1H, PhH, J=2.48Hz), 6.80 (dd, 1H, CH2=CHCO, J= ), 10.40,16.64Hz 7.42 (s, 1H, PhH), 7.45 (s, 1H, PhH), 7.52 (d, 1H, PhH, J=8.76Hz), 8.16 (s, 2H,ArNH andArH),8.64(s,1H,ArH).
Embodiment 2:MTT method measures the inhibited proliferation of 1~8 pair of compound different tumor cell lines
1, cell strain
During non-small cell lung cancer cell A549 and H1975, human colon cancer cell HCT116, human liver cancer cell HepG2 are purchased from The academy of sciences, state Shanghai Institute of Cell Biology, non-small cell lung cancer cell HCC827, people epidermis cancer cell A431 and people are normal Bronchial epithelial cell HBE is purchased from Shanghai Fu Heng Biotechnology Co., Ltd, cultivates data according to it and saves in this laboratory And secondary culture.Each cell routine is inoculated in 50mL Tissue Culture Flask, with the DMEM/RPI-1640 for containing 10% fetal calf serum Culture solution is in 37 DEG C, 5%CO2, cultivate under 100% humidity, change liquid daily.It is mixed with pancreatin EDTA when it grows to 80-90% Close liquid digestion, 1:3 passage.
2, experimental method
Cell in vitro proliferation activity Inhibition test investigates target compound to the shadow of each cell viability using mtt assay It rings.It with each cell of pancreatin digestion logarithmic growth phase, blows even with liquid-transfering gun after collection and counts, be 1 × 10 by density4A/mL Cell 96 orifice plates are inoculated in every 100 μ l of hole, in 37 DEG C, 5%CO2, under 100% humidity condition of culture overnight after, discard original Culture solution is given and is free of serum blank cultures culture 48h (n=3) containing different final concentration target compounds (0-40 μM).Afterwards 10 hole μ l/ of 5mg/mL MTT solution is added, continues every hole after being incubated for 4h and 100 μ l, tri- liquid is added, stayed overnight in incubator.Use microplate reader The survival rate of five kinds of cells after 570nm wavelength measures its absorbance and calculates administration, and calculate IC50Value.
3, experimental result
The IC of compound 1~8 and positive drug to different cells (tumour cell and normal cell) inhibited proliferation50Value is such as Table 1.
The IC that 1 compound 1~8 of table and positive drug act on different cell inhibitory effects50Value
It is above-mentioned the experimental results showed that, 1~8 couple of non-small cell lung cancer cell A549, H1975 of compound, HCC827, people's colon Cancer cell HCT116, human liver cancer cell HepG2, people epidermis cancer cell A431 have different degrees of inhibited proliferation, part Compound is better than positive drug Gefitinib to the inhibited proliferation of Partial tumors cell.Moreover, 2~8 pairs of compound normal thin The inhibited proliferation of born of the same parents HBE is weaker, higher to the selectivity of tumour cell, is significantly better than positive drug Gefitinib.
The effect of above-described embodiment is specifically to introduce essentiality content of the invention, but those skilled in the art should know Protection scope of the present invention should not be confined to the specific embodiment by road.

Claims (10)

1. a kind of aniline pyrimidine/quinoline heterocomplex, which is characterized in that chemical structural formula is as follows:
2. a kind of method for preparing compound 1 in claim 1, which comprises the steps of: by suitable 2- first Base -6- methoxyl group -7- (2,5- dichloro pyrimidine -4- oxygroup) quinoline-3-carboxylic acid ethyl ester, 2- methoxyl group -4- (4- methyl piperidine -1- Base) aniline, trifluoracetic acid TFA be added sec-butyl alcohol in, reacted at a temperature of 105 DEG C for 24 hours, be concentrated under reduced pressure, column chromatographic purifying.
3. a kind of method for preparing compound 2 in claim 1, which comprises the steps of: take 2- methoxyl group -4- Morpholinyl phenylamine is dissolved in sec-butyl alcohol, and suitable 7- (2- ((2,5- dichloro pyrimidine -4- base) oxygen) -6- methoxyl group -2- methyl is added Quinoline-3-carboxylic acid ethyl ester, is added with stirring TFA, reacts for 24 hours, is concentrated under reduced pressure, column chromatographic purifying at a temperature of 105 DEG C.
4. a kind of method for preparing compound 3 in claim 1, which comprises the steps of: be added in sec-butyl alcohol Appropriate 7- (2- ((2,5- dichloro pyrimidine -4- base) oxygen) -6- methoxyl group -2- methylquinoline -3- carboxylic acid, ethyl ester, 1- (4- amino -3- Methoxyphenyl) piperidines -4- alcohol, TFA, react for 24 hours at 105 DEG C, are concentrated under reduced pressure, column chromatographic purifying.
5. a kind of method for preparing compound 4 in claim 1, which comprises the steps of: to 7- under stirring condition (be added in 2- ((2,5- dichloro pyrimidine -4- base) oxygen) -6- methoxyl group -2- methylquinoline -3- carboxylic acid, ethyl ester suitable sec-butyl alcohol, 2- methoxyl group -4- (4- allyl acyl group piperazinyl) aniline, TFA is reacted for 24 hours at a temperature of 105 DEG C, is concentrated under reduced pressure, and column chromatography is pure Change.
6. a kind of method for preparing compound 5 in claim 1, which comprises the steps of: to 7- under stirring condition Suitable Zhong Ding is added in (2- (2,5- dichloro pyrimidine -4- oxygen) ethyoxyl) -6- methoxyl group -2- methylquinoline -3- carboxylic acid, ethyl ester Alcohol, 2- methoxyl group -4- (4- methyl piperidine -1- base) aniline, TFA, react 30h at a temperature of 105 DEG C, are concentrated under reduced pressure, column chromatography Purifying.
7. a kind of method for preparing compound 6 in claim 1, which comprises the steps of: be added into sec-butyl alcohol Suitable 7- (2- (2,5- dichloro pyrimidine -4- oxygen) ethyoxyl) -6- methoxyl group -2- methylquinoline -3- carboxylic acid, ethyl ester, 2- methoxy Base -4- morpholinyl phenylamine, TFA react 30h, column chromatographic purifying at 105 DEG C under agitation.
8. a kind of method for preparing compound 7 in claim 1, which comprises the steps of: to secondary under stirring condition Suitable TFA, 7- (2- (2,5- dichloro pyrimidine -4- oxygen) ethyoxyl) -6- methoxyl group -2- methylquinoline -3- carboxylic is added in butanol Acetoacetic ester, 1- (4- amino -3- methoxyphenyl) piperidines -4- alcohol react 72h at 105 DEG C, filter rear pillar chromatographic purifying.
9. a kind of method for preparing compound 8 in claim 1, which comprises the steps of: be added into sec-butyl alcohol Suitable TFA, 7- (2- (2,5- dichloro pyrimidine -4- oxygen) ethyoxyl) -6- methoxyl group -2- methylquinoline -3- carboxylic acid, ethyl ester, 2- first Oxygroup -4- (4- allyl acyl group piperazinyl) aniline reacts 72h, column chromatographic purifying at 105 DEG C.
10. compound application in preparation of anti-tumor drugs described in claim 1.
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